Cancer Research Clinical Oncology HIJ 30th German Cancer Congress

Transcription

Volume 138 • Supplement 1 • February 2012
JOUR NAL OF
AND
Cancer Research
Clinical Oncology
30th German Cancer Congress
22.–25. February 2012
ICC and Messe Berlin
Congress President: Univ.-Prof. Dr. P. Albers
30. Deutscher Krebskongress
22.-25. Februar 2012
Messe und ICC Berlin
Kongresspräsident: Univ.-Prof. Dr. P. Albers
HIJ
Inhaltsverzeichnis
Inhaltsverzeichnis
Best of Poster
Best of Poster – GI-Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Best of Poster – Hauttumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Best of Poster – Lungentumoren . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Best of Poster – Lymphome/Leukämien/kindliche Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Best of Poster – Mammakarzinom/gynäkologische Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . 10
Best of Poster – Molekulare Onkologie. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Best of Poster – Palliativmedizin/Supportivtherapie. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Best of Poster – Seltene Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Best of Poster – Versorgungsstrukturen/Qualitätssicherung. . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Best of Poster – Urologische Tumoren . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Discussed Poster
Discussed Poster – GI-Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Discussed Poster – Mammakarzinom/gynäkologische Tumoren. . . . . . . . . . . . . . . . . . . . . . . 23
Discussed Poster – Molekulare Onkologie. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Discussed Poster – Seltene Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Discussed Poster – Supportivtherapie/Palliativmedizin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Discussed Poster – Versorgungsstrukturen/Qualitätssicherung. . . . . . . . . . . . . . . . . . . . . . . . 33
General Poster
GI-Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Hauttumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Lungentumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Lymphome/Leukämien/pädiatrische Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Mammakarzinom/gynäkologische Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Molekulare Onkologie. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .90
Seltene Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Supportivmedizin/Palliativtherapie . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Urologische Tumoren. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Versorgungsstrukturen/Qualitätssicherung. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
KOK
KOK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
This supplement was not sponsored
by outside commercial interests. It was
funded entirely by the publisher.
Autorenverzeichnis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Journal of Cancer Research and Clinical Oncology Suppl 1 · 2011 | 1
Abstracts
J Cancer Res Clin Oncol (2012)
[Suppl 1] · 138:2–162
10.1007/s00432-011-1144-4
© Springer-Verlag 2012
30. Deutscher Krebskongress
22.–25. Februar 2012
Messe und ICC Berlin
Kongresspräsident
Univ.-Prof. Dr. P. Albers
Programmkomitee DKK 2012
Steering Comitee
Adam G (Hamburg), Albers P (Düsseldorf),
Bartsch HH (Freiburg), Beckmann MW (Erlangen), Bokemeyer C (Hamburg), Brümmendorf T (Aachen), Bruns J (Berlin), Creutzig U (Hannover), Domagk K (Hamburg),
Ehninger G (Dresden), Engers R (Düsseldorf), Enghofer E (Leverkusen), Feyer P (Berlin), Gabbert HE (Düsseldorf), Graeven U
(Mönchengladbach), Gschwend J (München),
Hallek M (Köln), Hauschild A (Kiel), Hegewisch-Becker (Hamburg), Helbig U (Berlin),
Helou A (Bonn), Hofstädter F (Regensburg),
Hohenberger W (Erlangen), Hölscher A
(Köln), Hübner J (Frankfurt/M), Iro H (Erlangen), Kastenholz H (Bonn), Kerschgens C
(Berlin), Kleeberg U (Hamburg), Klingebiel
T (Frankfurt), Klinkhammer-Schalke M
(Regensburg), Kohlhuber F (Bonn), Kortmann R-D (Leipzig), Kotzerke J (Dresden),
Lang H (Mainz), Meier K (Soltau), Nettekoven G (Bonn), Ortmann, O (Regensburg),
Paradies K (Hamburg), Propping P (Bonn),
Riemann JF (Ludwigshafen), Schadendorf
D (Essen), Schirren J (Wiesbaden), Schmidberger H (Mainz), Schmiegel W (Bochum),
Schmutzler R (Köln), Singer S (Leipzig),
Stummer W (Münster), Thomas M (Heidelberg), Wallwiener D (Tübingen), Weis J (Freiburg), Wesselmann S (Berlin), Wiedenmann
B (Berlin), Wiegel T (Ulm), Wiestler O (Heidelberg), Wittekind C (Leipzig), Wolff K-D
(München), Wylegalla C (Freiburg), Zeeb H
(Bremen)
Albers P (Düsseldorf), Beckmann MW (Erlangen), Bokemeyer C (Hamburg), Brümmendorf T (Aachen), Bruns J (Berlin), Graeven U (Mönchengladbach), Hallek M (Köln),
Hauschild A (Kiel), Ortmann, O (Regensburg), Schmiegel W (Bochum), Zeeb H (Bremen)
2 | Gutachter 2012
Al-Batran S (Frankfurt/M.), Albers P (Düsseldorf), Alberti W (Wuppertal), Bamberg
M (Tübingen), Barth J (Gießen), Bartsch H
(Freiburg), Beckmann M (Erlangen), Belka
C (München), Berdel W (Münster), Berking
C (München), Biersack H (Bonn), Bokemeyer C (Hamburg), Bosslet K (Penzberg),
Branscheid D (Bielefeld), Britzen-Laurent
N (Erlangen), Brossart P (Bonn), Budach
W (Düsseldorf), Büttner R (Köln), Dartsch
D (Hamburg), Debatin K (Ulm), Dunst J
(Lübeck), Ebert M (Mannheim), Einsele H
(Würzburg), Emons G (Göttingen), Engenhart-Cabillic R (Marburg), Engers R (Neuss),
Engert A (Köln), Fehm T (Tübingen), Feyer
P (Berlin), Folprecht G (Dresden), Freidank
A (Fulda), Friedel G (Gerlingen), Gabbert H
(Düsseldorf), Ganser A (Hannover), Geißler
M (Esslingen a.N.), Glimm H (Heidelberg),
Graeven U (Mönchengladbach), Gutzmer R
(Hannover), Hallek M (Köln), Hartenstein
R (München), Hartmann J (Kiel), Heike M
(Dortmund), Henne-Bruns D (Ulm), Hense
H (Münster), Hertenstein B (Bremen), Hillemanns P (Hannover), Hochhaus A (Jena),
Hofheinz R (Mannheim), Hohenberger W
Journal of Cancer Research and Clinical Oncology Suppl 1 · 2011
(Erlangen), Hölscher A (Köln), Howaldt H
(Gießen), Hübner J (Frankfurt/M.), Jaehde U
(Bonn), Jocham D (Lübeck), Jonat W (Kiel),
Jordan K (Halle/S.), Kaaks R (Heidelberg),
Keller M (Heidelberg), Kiechle M (München),
Kimmig R (Essen), Klug S (Dresden), Knüchel-Clarke R (Aachen), Koch U (Hamburg),
Köhne C (Oldenburg), Kortmann R (Leipzig),
Kreienberg R (Ulm), Krug B (Köln), Kubicka
S (Reutlingen), Lang H (Mainz), Lehnert T
(Bremen), Lipp M (Berlin), Loquai C (Mainz),
Lordick F (Braunschweig), Lorenzen S (München), Lutz M (Saarbrücken), Mackensen A
(Erlangen), Marmé D (Freiburg), Meier K
(Soltau), Meyer H (Solingen), Meyer T (Ansbach), Miller K (Berlin), Möhler M (Mainz),
Molls M (München), Müller R (Köln), Neuhaus P (Berlin), Niederle N (Leverkusen),
Oettle H (Friedrichshafen), Ortmann O
(Regensburg), Paradies K (Hamburg), Petersen C (Hamburg), Possinger K (Berlin),
Propping P (Bonn), Reinacher-Schick A (Bochum), Riemann J (Ludwigshafen), Rödel C
(Frankfurt/M.), Schäfer R (Berlin), Schirren
J (Wiesbaden), Schlag P (Berlin), Schlegel U
(Bochum), Schmidt E (Bremen), SchmidtWolf I (Bonn), Schmieder K (Mannheim),
Schmiegel W (Bochum), Schöning T (Heidelberg), Schuler M (Essen), Schütte W Halle/S.,
Schwarz M (Tübingen), Seufferlein T Halle/S.,
Singer S (Leipzig), Stahl M (Essen), Stenzl A
(Tübingen), Stuschke M (Essen), Tannapfel
A (Bochum), Thomas M (Heidelberg), Trarbach T (Essen), Trefzer U (Berlin), Trepel M
(Hamburg), Trümper L (Göttingen), Ukena
D (Bremen), Unger C (Freiburg), Vanhoefer
U (Hamburg), Wecht D (Marburg), Wiegel
T (Ulm), Wirth M (Dresden), Wittekind C
(Leipzig), Wylegalla C (Freiburg)
GI-Tumoren
Best of Poster – GI-Tumoren
B2 – 0174
MiR-30a-5p suppresses tumor growth in colon carcinoma by
targeting DTL
B1 – 0077
Protein profiling identifies HDAC2 and TXNL1 as aneuploidy-associated markers in colorectal cancer
*A. Baraniskin1,2, K. Birkenkamp-Demtroder3, A. Maghnouj1, H. Zöllner1,
A. Reinacher-Schick2,4, W. Schmiegel2,4, S. Hahn1
1
Ruhr-University, Center of Clinical Research, Bochum, Deutschland,
2
Knappschaftskrankenhaus, Ruhr-University of Bochum, Department of
Internal Medicine, Bochum, Deutschland, 3Aarhus University Hospital,
Dept. of Molecular Medicine, Aarhus, Dänemark, 4Ruhr-University, Center
for Clinical Studies in Oncology, Bochum, Deutschland
*T. Gemoll1,2,3, U. Roblick1,2,3, S. Szymczak4, T. Braunschweig5, S. Becker3,
B.-W. Igl4, H.-P. Bruch1, A. Ziegler4, U. Hellman6, M. Difilippantonio7, T. Ried7,
H. Jörnvall2, G. Auer3, J. Habermann1,2,3,7
1
University of Lübeck, Department of Surgery, Lübeck, Deutschland,
2
Karolinska Institut, Stockholm, Schweden, 3Karolinska Biomic Center,
Stockholm, Schweden, 4University of Lübeck, Institute for Medical Biometry and Statistics, Lübeck, Deutschland, 5University Clinic RWTH Aachen,
Institute of Pathology, Aachen, Deutschland, 6Ludwig Institute for Cancer
Research, Uppsala, Schweden, 7NCI/NIH, Genetics Department, Bethesda,
Deutschland
Background. DNA aneuploidy has been identified as prognostic factor
for epithelial malignancies. Further understanding of the translation of
DNA aneuploidy into protein expression will help to define therapies,
prognosis and prevention. We therefore aimed at identifying aneuploidy-associated protein expression.
Methods. DNA ploidy assessment by image cytometry identified three
diploid and four aneuploid colorectal cancer cell lines. All cell lines were
subjected to protein expression profiling by two-dimensional gel electrophoresis. Proteins were identified by mass spectrometry, subjected to
Ingenuity Pathway Analysis (IPA), and target proteins were validated by
Western Blot. Validated proteins were clinically evaluated by immunohistochemistry using a tissue microarray (TMA). The TMA comprised
47 aneuploid and 31 diploid primary colorectal carcinomas, as well as 19
adjacent normal mucosa specimens.
Results. Two independent statistical analyses revealed 64 proteins that
were significantly differentially expressed between the diploid and
aneuploid cell lines. Of these, 26 proteins could be identified by mass
spectrometry and were subjected to IPA. The majority of these proteins
interacted in two overlapping high-ranked IPA networks maintaining
Cellular Assembly and Organization, Cellular Function and Maintenance, Infection Mechanism, Cell Cycle, and Cellular Growth and
Proliferation. Network proteins showed cancer-associated functions of
Cellular Assembly and Organization, Cell-To-Cell Signalling, and Cell
Death (p<0.00001 to p=0.0481). While CAPZA1, TXNL1 and HDAC2
were significantly validated by Western blotting, the latter two showed
expression differences also in clinical samples discerning aneuploid
from diploid carcinomas (p<0.05).
Conclusion. Distinct protein expression patterns discern aneuploid
from diploid colorectal carcinomas. TXNL1 and HDAC2 expression alterations characterize aneuploid subtypes of colorectal cancers that are
known to present poor prognosis.
MicroRNAs (miRNA) are evolutionarily conserved, on average 22 nucleotides long non-coding RNAs that are involved in different biological
processes by suppressing target gene expression. Altered expression
of miR-30a-5p has been reported in colon carcinoma. To elucidate its
potential biological role in colon cancer miR-30a-5p was overexpressed
via a lentiviral vector system in two different colon cancer cell lines:
HCT116 and SW480. This induced in both lines miR-30a-5p mediated
growth inhibition, attributable to a cell cycle arrest at the G1 phase
and an induction of apoptosis. Furthermore, making use of a so called „sponge“ against antisense-miR-30a-5p we were able to rule out a
possible „off-target“ effect by the antisense-miR-30a-5p and thus confirmed that the observed effect on cell growth is primarily mediated by
the sense miRNA miR-30a-5p. Combining global gene expression analyses of miR-30a-5p transgenic line HCT116 with in-silico miRNA target prediction we identified the denticleless homolog (DTL) as potential
miRNA-30a-5p target. In addition, CDKN1A expression was increased
in miR-30a-5p overexpressing HCT116 cells, suggesting that CDKN1A
is mediating the observed G1 arrest. Subsequent reporter gene assays
confirmed the predicted miR-30a-5p binding site in the 3’UTR region
of DTL. Importantly, overexpression of DTL in HCT116 cells rescued
these cells from miR-30a-5p mediated growth suppression. Finally, 379
colorectal cancer tissues were screened for DTL expression and DTL
was found to be overexpressed in 95.8% of human colorectal cancers
compared to normal colon mucosa. In conclusion, our data provide
evidence that miR-30a-5p, which is frequently downregulated in colon
carcinoma, supports the multi-step process of colorectal cancer development via modulating DTL expression which in turn alters CDKN1A
expression and thus influences cell cycle progression. Therefore, both
miR-30a-5p and DTL can be regarded as potential targets for colon cancer therapy by either re-expressing miR-30a-5p and/or interfering with
DTL function.
B3 – 0481
Selective PI3K inhibition in wild type and PIK3CA mutated human gastrointestinal cancer
*A. Müller1, E. Bachmann1, M. Linnig1, K. Khillimberger1, P.R. Galle1,
M. Moehler1
1
Universitätsmedizin Mainz, I. Med. Klinik, Mainz, Deutschland
New targeted agents such as antibodies or small tyrosine kinase inhibitors clearly expanded the standard treatment options not only in gastrointestinal cancer patients. However, tumor resistance is still a challenge.
As 20% and 10% of all patients with human colorectal and gastric cancer
carry PI3K mutations, respectively, they do not respond to the current
receptor inhibitors. Thus, selective tyrosine kinase inhibitors have been
generated which directly target the PI3K signalling pathways. So far,
* Erstautor
Abstracts
their therapeutical role for human gastrointestinal cancers has not yet
been clarified.
To define the inhibitory and pro-apoptotic effects of two PI3K inhibitors BEZ235 and BKM120, three human colon cancer (HT-29, HCT-116,
DLD-1) and three gastric cancer cell lines (NCIn87, AGS, MKN-45) with
different PIK3CA mutation status were analysed. First, viability, apoptosis and caspase assays were performed during incubation with these
inhibitors alone or combined with classical cytotoxic agents. Second,
molecular consequences for cell cycle and the signalling pathways were
analysed by defining the protein levels by FACS and Western blot.
Both, BKM120 and the dual PI3K/mTOR inhibitor BEZ235 induced a
significant concentration-dependent reduction in cell viability and an
increase of apoptotic cell death, while mutated cells reacted more sensitive to treatment. Here, BKM120 was more effective than BEZ235. It caused a G1 arrest in tumor cells. In contrast, BKM120 induced a G2 shift
in all gastrointestinal cancer cell lines. BKM120 clearly down-regulated
the AKT pathway and BEZ235 additionally inhibited the mTOR (via
p70S6K) pathway. In colon cancer cells, BEZ235 caused a synergistic
induction of apoptosis combined with irinotecan. Combinations with
5-fluoruracil and both substances induced additive apoptotic effects.
Human gastric cancer cells were less sensitive to BEZ235 and BKM120.
In sum, BEZ235 and BKM120 had high pro-apoptotic effects in all human cell lines and in special cases a better response in the PIK3CA mutated cells. Our in vitro data further support the clinical development of
these PI3K inhibitors BEZ235 and BKM120 as potential targeting agents
for patients with different wild type or mutated gastrointestinal cancer
cells.
B4 – 0499
STAT3 is a potential molecular target to sensitize colorectal
cancer cells to chemoradiotherapy
*M. Grade1, M. Spitzner1, G. Emons1, E. Kendziorra1, M. Rave-Fränk2, J. Gaedcke1, H. Becker1, T. Beißbarth3, M. Ghadimi1
1
Universitätsmedizin Göttingen, Klinik für Allgemein- und Viszeralchirurgie, Göttingen, Deutschland, 2Universitätsmedizin Göttingen, Klinik für
Strahlentherapie und Radioonkologie, Göttingen, Deutschland, 3Universitätsmedizin Göttingen, Medizinische Statistik, Göttingen, Deutschland
Background. Resistance to preoperative chemoradiotherapy represents
a major clinical problem in the treatment of patients with locally advanced rectal cancer. Therefore, the identification of molecular biomarkers
that differentiate responsive and resistant tumors is exceedingly important, because this may lead to the identification of novel molecular
targets whose modification could be harnessed to sensitize a priori resistant tumors to multimodal treatment.
Materials and methods. We recently established an in vitro model for
5-FU based chemoradiotherapy, and correlated differences in treatment
sensitivity of 12 colorectal cancer cell lines with pretherapeutic gene expression profiles. One gene the expression of which correlated positively with treatment resistance was the signal transducer and activator of
transcription 3, STAT3. To test the functional relevance of this observation, we first determined STAT3 mRNA and protein expression levels in
all cell lines. Next, we established doxycycline-inducible stable shRNA
single-cell clone (SCC) populations. Successful silencing of STAT3 was
detected by Western blot analysis. The induced SCCs were treated with
3 µM 5-FU, and subsequently exposed to 0, 1, 2, 4, 6, and 8 Gy of Xrays. In addition, STAT3 was inhibited using two different siRNAs, and
a small-molecular inhibitor (STATTIC).
Results. STAT3 was significantly overexpressed in resistant cells. In
SW480 and SW837 cells, both shRNA- and siRNA-mediated silencing
as well as STATTIC-induced inhibition of STAT3-phosphorylation re-
4 | Journal of Cancer Research and Clinical Oncology Suppl 1 · 2011
sulted in a significantly increased chemoradiosensitivity, with dose-reduction factors of 1.8 to 2.
Conclusion. These results highlight the potential relevance of STAT3 as a
novel molecular target to sensitize a priori resistant tumor cells to chemoradiotherapy.
Hauttumoren
Best of Poster – Hauttumoren
B5 – 0178
Efficient induction of apoptosis in melanoma cells and reduced
melanoma growth in nude mice by a gene therapy approach
based on oncolytic adenoviral vectors with inducible expression
of TRAIL
*L.F. Fecker1, H. Fechner2, J. Eberle1
1
Charité – Universitätsmedizin Berlin Klinik für Dermatologie, Venerologie
und Allergologie, Hauttumorzentrum, AG Apoptoseregulation in Hauttumoren, Berlin, Deutschland, 2Technische Universität, Institut für Biotechnologie, Berlin, Deutschland
Background. High mortality and therapy resistance of melanoma demands the development of new strategies, and overcoming of apoptosis
deficiency appears as particularly promising. TNF-related apoptosis inducing ligand (TRAIL) has been shown previously as highly effective
for apoptosis induction in melanoma cells and may apply for gene therapy due to its selective impact on tumor cells.
Experimental procedures. Established adenoviral vectors AdV-TRAIL
and AdV-CD95L encode for the death ligands TRAIL and CD95L, respectively. They are characterized by a variant adenoviral E1A protein
and by deletion of E1B aiming at the restriction of viral replication to
tumor cells. For melanoma selectivity, the viral replication gene E1A is
controlled by a tyrosinase promoter. The tetracycline-responsive transactivator rtTA and the death ligand are further controlled by a bidirectional tetracycline-inducible promoter. Apoptosis was monitored by a
DNA fragmentation ELISA and cell killing by crystal violet staining.
For proliferation, real time cell analysis (RTCA) was used. Growth of
tumors established in nude mice was monitored after intratumoral injections of AdV-TRAIL.
Results. AdV-TRAIL mediated strong expression of E1A and doxycycline
-dependent induction of TRAIL selectively in melanoma cells, which
resulted in melanoma cell lysis and induction of apoptosis. In contrast,
non-melanoma cells and normal human melanocytes appeared as protected. Comparison of AdV-TRAIL with AdV-CD95L revealed largely
similar efficacies of both death ligands in melanoma cells. In melanoma
xenotransplantation models, AdV-TRAIL demonstrated its efficacy by
significant growth reduction of established melanomas after intratumoral application. Melanoma cell killing by AdV-TRAIL could be further improved in vitro by combinations with chemotherapeutics.
Conclusions. We demonstrate that melanoma cells can be efficiently targeted by death ligand-based gene therapy. Possible resistance may be
overcome by combined chemotherapy.
The study was supported by the German Cancer Aid (Deutsche Krebshilfe,
grants 107398 and 108008).
B6 – 0275
Cytotoxicity of new Duplex Drugs linking 3’-C-Ethynylcytidine
and 5-Fluor-2’-deoxyuridine against human Melanoma cells
*S. Schott1, H. Niessner2, T. Sinnberg2, S. Venturelli3, A. Berger3, F. Meier2,
C. Garbe2, C. Busch2
1
Universitätsklinikum Heidelberg, Universitätsfrauenklinik, Nationales
Centrum für Tumorerkrankungen, Heidelberg, Deutschland, 2University of
Tübingen, Section of Dermato-Oncology, Department of Dermatology and
Allergology, Tübingen, Deutschland, 3University of Tübingen, Department
of Internal Medicine I, Tübingen, Deutschland
Introduction. Melanoma is an increasingly common and potentially fatal malignancy of the skin and some mucous membranes. Since no cure
exists for metastatic disease (stage IV), there is an urgent need for novel
drugs to overcome melanoma therapy resistance. 2’-Deoxy-5-fluorouridylyl-(3’-5’)-3’-C-ethynylcytidine [5-FdU(3’-5’)ECyd] and 3’-C-ethynylcytidinylyl-(5’->1-O)-2-O-octadecyl-sn-glycerylyl-(3-Oà5')-2'-deoxy5-fluorouridine [ECyd-lipid-5-FdU] represent cytostatic active duplex
drugs, which can be metabolized into various active antimetabolites.
Methods. The cytotoxicity of these heterodinucleoside phosphate analogues, their corresponding monomers ECyd and 5-FdU and combinations thereof were evaluated on five metastatic melanoma cell lines and
six ex-vivo patient-derived melanoma cells in comparison to current
standard cytostatic agents and the BRAF V600E inhibitor Vemurafenib. Further, in vitro studies were performed for cell proliferation and
cell-cycle analysis. Embyrotoxicity was assessed with the chicken embryo assay. In vivo efficacious in the LOX IMVI solid tumor xenograft
mouse model was tested in the Developmental Therapeutic Program
(DTP) of the National Cancer Institute (NCI, US).
Results. In vitro (real-time) proliferation assays demonstrated that
5-FdU(3’-5’)ECyd and ECyd-lipid-5-FdU had a high cytotoxic efficacy
causing 75% melanoma cell death at concentrations in the nano- and
micromolar range. Cytotoxicity was conducted by induction of DNA
cleavage/apoptosis. Chicken embryotoxicity demonstrated that the duplex drugs were less toxic than their parental monomers. In vivo the
duplex drug 5-FdU(3’-5’)ECyd was efficacious in the murine LOX IMVI
solid tumor xenograph model upon administration of 11.2 mg/kg/injection every fourth day.
Conclusion. Both duplex drugs are promising novel cytostatic agents for
the treatment of malignant melanoma meriting clinical evaluation.
B7 – 0332
Inhibition of the PI3K-AKT signalling pathway to overcome therapy resistance in melanoma-derived brain metastasis
*H. Niessner1, A. Adam2, A. Bornemann3, J. Honegger4, L. Quintanilla-Fend2,
C. Busch1, J. Bauer1, L. Just5, K. Hoek6, C. Garbe1, F. Meier1
1
Universität Tübingen, Dermatologische Onkologie, Tübingen, Deutschland, 2Universität Tübingen, Pathologie, Tübingen, Deutschland,
3
Universität Tübingen, Hirnforschung, Tübingen, Deutschland, 4Universität
Tübingen, Neurochirurgie, Tübingen, Deutschland, 5Universität Tübingen,
Anatomie, Tübingen, Deutschland, 6Universität Zürich, Dermatologie,
Zürich, Schweiz
Introduction. Brain metastases occur in over 70% of patients with metastatic melanoma and are the most common cause of death. Current
therapy options are neurosurgery, radiosurgery, whole brain radiation,
chemotherapy and supportive care. The median survival time for mela-
noma patients with brain metastasis ranges from 0.7 to 5 months depending on age and performance status. Therefore, new therapy strategies
are mandatory.
Methods. In melanoma, activation of the RAF-MEK-ERK and PI3KAKT-mTOR signal transduction pathways makes a decisive contribution to tumor progression and treatment resistance. Ongoing clinical
studies suggest a transient effect of BRAF inhibitors in melanoma brain
metastases. We posed the question as to whether blockade of the RAFMEK-ERK or/and PI3K-AKT-mTOR signalling pathways would be a
promising strategy for the treatment of melanoma brain metastases. We
blocked RAF-MEK-ERK or/and PI3K-AKT-mTOR signalling pathways
at different levels using classical and new pharmacological inhibitors
and investigated the effects on viability/proliferation and survival/
apoptosis of >10 newly isolated cell lines derived from melanoma brain
metastases. Furthermore, immunohistochemical analyses of brain metastases from >10 melanoma patients including matched extracerebral
metastases from lung and liver in the same patients for p-ERK, ERK,
AKT, p-AKT and PTEN were performed.
Results. Growth inhibition was most pronounced with PI3K inhibitors
achieving growth inhibition rates of up to 80%. Moreover, PI3K inhibition potently induced apoptosis in cerebral metastatic melanoma cells.
Histochemical analysis showed that both cerebral and extracerebral
metastases were highly positive for ERK and AKT. p-ERK was seen
exclusively at the tumor periphery of both cerebral and extracerebral
metastases. Interestingly, most melanoma brain metastases were highly
positive for activated AKT, whereas matched extracerebral metastases
from lung and liver in the same patients were weakly positive or negative for activated AKT. Moreover, PTEN appeared to be downregulated
in brain metastases.
Conclusion. Together, these findings suggest that activation of AKT is
relevant for the survival and growth of melanoma cells in the brain parenchyma and that inhibition of PI3K-AKT signalling may be a suitable
strategy to enhance and/or prolong the antitumor effect of BRAF inhibitors in melanoma brain metastases.
B8 – 0489
Validation of a fresh-tissue based prognostic gene signature in
formalin-fixed, paraffin-embedded melanomas
*G. Brunner1, L. Suter1, H.-J. Schulze2, C. Berking3, A. Heinecke4, J. Atzpodien5
1
Hauttumorzentrum Hornheide-Münster, Tumorforschung, Münster,
Deutschland, 2Hauttumorzentrum Hornheide-Münster, Dermatologie,
Münster, Deutschland, 3LMU München, Dermatologie und Allergologie,
München, Deutschland, 4WWU Münster, Medizinische Informatik und Bioinformatik, Münster, Deutschland, 5Hauttumorzentrum Hornheide-Münster, Onkologie, Münster, Deutschland
Melanoma incidence is rapidly increasing – with a doubling rate of 10–
20 years. Precision and reliability of conventional histopathological and
clinical staging, however, remain limited in predicting clinical outcome. On the other hand, complementary molecular prognostic markers
are not yet available.
We have recently identified, for the first time, a prognostic gene signature expressed in fresh-frozen primary melanomas (n=135), which is
associated with overall survival (multivariate Cox regression analysis:
p=0.0004, hazard ratio 3.83). The clinical value of a signature-based risk
score is its ability to identify patients at low risk, not identified by conventional AJCC staging, and to define risk patients in need of adjuvant
therapies. The purpose of this study was to establish analysis of the signature genes in formalin-fixed, paraffin-embedded (FFPE) melanoma
tissue and to validate prognostic significance.
Abstracts
We developed a sensitive and robust methodology to analyze and normalize gene expression in FFPE tissue samples (some of them more
than 20 years old): Total RNA was prepared from FFPE sections matching the above fresh-frozen primary melanomas (131 out of 135), quality-controlled, and transcribed into cDNA. Human reference RNA was
included as an internal standard. Following pre-amplification of the
cDNA, expression of the nine signature genes (KRT9, KBTBD10, DCD,
ECG2/SPINK7, PIP, SCGB1D2, SCGB2A2, COL6A6, HES6) and of four
house-keeping genes (18S rRNA, GAPDH, GUSB, BPNT1) was quantified by real-time PCR using TaqMan assays specific for short amplicons.
Gene expression data were normalized, in two steps, to correct for interassay technical variability (based on the reference RNA data) as well as
for inter-sample variability of RNA quality (based on the data for the
house-keeping genes). Significance of correlation of FFPE gene expression data (CT values or estimated mRNA copy numbers) with data from
matched fresh-frozen tissue samples (two-sided t-test) or with patient
overall survival (univariate Cox regression analysis; clinical follow-up
data up to 273 months) was evaluated.
The majority of FFPE primary melanomas (125 out of 131) yielded
mRNA of sufficient quality. In matched pairs of FFPE and fresh-frozen tissue samples, there was significant correlation of expression of all
nine signature genes. Significance of correlation was higher with CT
values (r=0.19–0.58; p=0.001–0.05) than with estimated copy numbers.
Expression of 7 out of the 9 genes in FFPE melanomas (CT values or
estimated copy numbers) was significantly associated with overall survival (p=0.0001–0.07).
Thus, our prognostic melanoma gene signature was successfully transferred from fresh-frozen onto FFPE tissue samples. This greatly increases clinical applicability of a gene-signature based prognostic risk score
and, in addition, allows the retrospective prognostic analysis of primary
melanomas.
Lungentumoren
Best of Poster – Lungentumoren
B9 – 0198
Hypofractionated image-guided breath-hold radiotherapy of
pulmonary tumors and metastases – clinical results
A. Frauenfeld1, *J. Boda-Heggemann1, C. Weiss2, U. Attenberger3,
K. Siebenlist1, F. Schneider1, F. Wenz1, F. Lohr1
1
University Medical Center Mannheim, University of Heidelberg, Department of Radiation Oncology, Mannheim, Deutschland, 2University Medical
Center Mannheim, University of Heidelberg, Abteilung für Medizinische
Statistik, Biomathematik und Informationsverarbeitung, Mannheim,
Deutschland, 3University Medical Center Mannheim, University of Heidelberg, Institute of Clinical Radiology and Nuclear Medicine, Mannheim,
Deutschland
Purpose. Stereotactic Ablative RadioTherapy (SABR) of stage I–II tumors has been shown to be a highly effective treatment modality with
low toxicity. It is also a non-invasive therapy option for lung metastases.
Outcome and toxicity were retrospectively evaluated in a single-institution patient cohort who had undergone hypofractionated image-guided
breath-hold lung SBRT.
Patients and methods. 50 lesions of 43 patients with NSCLC (n=27, St. I–
IV including patients with controlled brain metastases or local relapse)
and lung metastases of various primary tumors (n=16) were consecutively treated with image-guided breath-hold SBRT. After an initial dose
finding phase, patients were irradiated with a regimen of 5×12 Gy. Dose
calculation was performed with collapsed cone algorithm in 60% of
the lesions. Breath hold was performed with Active Breathing Control
(ABC®, Elekta), daily imaging with EPIDs and repeat breath hold cone-beam CT. The data were evaluated retrospectively regarding overall
survival (OS), progression-free-survival (PFS), progression pattern and
local control (LC). Radiation parameters and follow-up CT images were
analysed.
Results. BED2 (Biologically Effective Dose) was 87±20 Gy (median
83 Gy). 30 lesions were treated with a BED2 of <90 Gy, and 20 lesions
with a BED2 of >90 Gy. Median follow-up was 15 months. Median OS
was 20 months, without significant difference in patients with primary
lung tumor or metastases. Actuarial 1-year OS-rate was 67%; 2-years OS
rate 43%, respectively. 27% of the patients died on non-disease related
reason (cardiovascular events or infections). Actuarial 1-year PFS-rate
was 42%, 2-years PFS rate 28% without significant difference in patients
with primary lung tumor or metastases. Site of progression pattern was
predominantly distant (60% distant metastases and 32% mediastinal
lymph nodes). Actuarial 1-year LC-rate was 90%, 2-years local control
rate 85%. 95% of the lesions treated with a BED2 >90 Gy was controlled
locally after one year. Local progression was observed in only 5 cases,
mainly in the initial dose finding phase, in one patient with an extremely large PTV and in one patient with an only retrospectively recognised
pleural invasion of the irradiated lesion. Clinically apparent pneumonitis (requiring treatment) was present in 23% of the cases. No patient
experienced fatal toxicity.
Conclusions. Despite the unfavorable patient selection, high local control rates could be achieved. If a reasonably high BED2 can be applied,
image-guided breath-hold SBRT is an effective non-invasive treatment
modality with a high local control rate and relatively low toxicity in
patients with inoperable lung tumors and lung metastases. As disease
progression was mainly outside the treated area, systemic therapy has
to be improved.
B10 – 0290
First screening round results from the German component LUSI
of the European trial on the efficacy of multislice CT for the early
detection of lung cancer, and the perspective of the European
trial in view of the results of the US NLST trial
*N. Becker1, E. Motsch1, M.-L. Groß1, C.P. Heussel2, H. Dienemann3, P. Schnabel4, M. Eichinger5, D.-E. Optazaite5, M. Puderbach5, J. Tremper5, S. Delorme5
1
Deutsches Krebsforschungszentrum, Epidemiologie von Krebserkrankungen, Heidelberg, Deutschland, 2Thoraxklinik, Radiologie, Heidelberg,
Deutschland, 3Thoraxklinik, Chirurgie, Heidelberg, Deutschland, 4Universität, Medizin/Pathologie, Heidelberg, Deutschland, 5Deutsches Krebsforschungszentrum, Radiologie, Heidelberg, Deutschland
After closure of the recruitment period of the German Lung Cancer
Screening Intervention Trial (LUSI) in 2011 the study comprises 4052
participants, randomised into 2029 subjects in the multislice-CT
(MSCT) screening arm and 2023 into the „usual care“ control arm. The
early recall rate for suspicious nodules requiring further examination
ranges currently around 27%. Nineteen lung cancers have been detected
(detection rate 0.9%). Related to all early recalls, the positive predictive
value was about 3%, and related to the immediate recalls about 35%.
The subsequent screening rounds started in October of the years 2008
(2nd round) to 2011 (5th and final round) having led so far to the identification of eight, two, two and 0 further lung cancers, respectively.
In overall 41 surgical interventions, 15 were benign and 26 malignant.
Among the lung cancers detected in the screening arm 22 were adenocarcinoma, 5 squamous cell carcinoma, two a small-cell carcinoma
and two a carcinoid. One interval cancer has so far been observed (an
adenocarcinoma).
The study contributes to the European multicenter study comprising
studies from the Netherlands and Belgium (NELSON, 15422 participants), Denmark (4104 participants), Italy (DANTE, 2472; ITALUNG,
3206; MILD, 3997) and Germany (LUSI, 4052). The scope is to demonstrate an at least 25% reduction of lung cancer mortality by MSCT. However, in 2011, the National Lung Screening Trial (NLST) conducted in
the USA, provided after an average follow-up of 6 years a significantly
reduced lung cancer mortality by MSCT screening in comparison to
chest X-ray in the control group. Nevertheless, the European studies decided to continue their trials and to conduct a first common evaluation
in 2012 for several reasons, e.g.: (a) an early visible benefit can disappear
after prolonged follow-up due to postponement of cause-specific death
in the screening group, (b) harmful side effects, especially overdiagnosis, cannot be properly assessed in comparison to a control group with
another screening modality (chest X-ray), (c) efficient screening modalities are still undefined such as, risk-related selection of the appropriate target population, appropriate management of suspicious nodules,
screening intervals etc, as to be outlined in the presentation.
B11 – 0436
The role of sleeve resections in advanced nodal disease of NSCLC
*J. Schirren1, M. Eberlein2, A. Fischer3, S. Bölükbas1
1
Dr. Horst Schmidt Klinik, Thoraxchirurgie, Wiesbaden, Deutschland,
2
Carver College of Medicine, Division of Pulmonary, Critical Care and
Occupational Medicine, Iowa City, USA, 3Dr. Horst Schmidt Klinik, Anästhesie und Intensivmedizin, Wiesbaden, Deutschland
Objective. The aim of this study was to contrast the short-term and longterm results of sleeve resections in centrally located non-small cell lung
cancer (NSCLC) depending on limited nodal disease (N0/N1, LND)
and advanced nodal disease (N2/N3, AND).
Methods. All NSCLC-patients undergoing sleeve resections for centrally located NSCLC were reviewed from our prospective database
between January 1999 and December 2008. Patients’ characteristics,
morbidity, mortality, locoregional recurrence, distant recurrence and
survival were analyzed corresponding to LND and AND.
Results. One-hundred seventy sleeve resections out of 213 consecutive
sleeve resections were performed for ventrally located NSCLC (LND:
n=120; AND: n=50). There were no statistically differences between the
both groups for age (LND: 61.8±12.4 vs. 60.8±9.6 years), gender, co-morbidities, type of sleeve resection (bronchial vs. bronchovascular), number of dissected lymph nodes (LND: 40.0±12.4 vs. 36.7±14.0), histology
and completeness of resection (LND: 96.7% vs. 98.0%), respectively.
More patients had induction chemotherapy in AND group (p=0.049).
Similar short-term results were monitored with regard to morbidity
rate (LND: 34.2%, AND: 44.0%), secondary pneumonectomy (LND:
1.7%, AND: 4.0%) and mortality rate (LND: 5.0%, AND: 6.0%), respectively. Better 5-year-survival rate and mean survival were observed in
LND (LND: 80.8 months; AND: 37.7 months; p=0.014; LND: 67%; AND:
42%). In the long-term, more distant metastases were identified in AND
group (26.0% vs. 14.2%, p=0.079) in comparison of identical locoregional recurrence (LND: 1.7%; AND: 0%). Mean time to the development of
distant metastases was similar (LND: 19.1 months; AND: 12.4 months;
p=0.2) in event of metastazing.
Conclusions. Lymph node involvement is a negative prognostic factor
with regard to long-term survival. Sleeve resections in AND are not associated with higher morbidity and mortality. Sleeve resections in AND
are correlated with promising long-term survival and unexpected high
local control of the disease as a result of high complete resection rates.
Further investigation for the systemic control of the disease is warranted because of high rates of distant failure.
B12 – 0475
Prognostic value of estrogen (ESR-1) receptor expression in curatively resected non-small cell lung cancer (NSCLC)
*W. Brückl1, J. Ficker1, A. Hartmann2, R. Wirtz2
1
Klinikum Nürnberg, Medizinische Klinik 3, Nürnberg, Deutschland, 2Universität Erlangen, Institut für Pathologie, Erlangen, Deutschland
Background. Despite undergoing complete resection of NSCLC, 33% and
77% of patients with stage IA and IIIA, respectively, die within 5 years.
The benefit of adjuvant chemotherapy (aCTx) is only modest, whereas
such treatment is associated with adverse effects and predictive factors
are of utmost importance. We recently could show a better outcome in
estrogen (ESR-1) receptor expressing tumors in the palliative treatment
of metastatic NSCLC (Brueckl et al., Proc ASCO 2011). The main objective of this study was to test, whether ESR-1 expression is of prognostic/
predictive value in the curative setting as well.
Methods. Affymetrix microarray data from N=138 non-metastatic
NSCLC patients undergoing curative resection were retrieved from a
data base (Lee et al., Clin Cancer Res 2008) and used as a test set to
hypothesize that ESR-1 expression in the tumor is of prognostic value
in curatively resected NSCLC. Baseline data according to ERS-1 status
were compared with the use of chi-square tests and in a multivariate
logistic model including all variables with p values <0.05. Survival rates
were estimated with the use of the Kaplan-Meier method. Prognostic
data were then tested for robustness in a training set with data from
the JBR.10 trial with same statistics as mentioned above. From this trial
N=90 datasets of Affymetrix microarrays were published and retrieved
from a data base (Zhu et al. JCO 2010). Moreover, in this trial, N=50 of
the patients were treated after curative resection with aCTx while N=40
of those had been in the observation arm. Therefore, it should be as well
possible to create a hypothesis about a predictive value of ESR-1.
Results. Cluster analysis in the curatively resected test cohort identified
several ESR-1 mRNAs expressed on the Affymetrix microarray. N=93
(67%) had a high expression of ESR-1 and those patients had a superior recurrence free survival in contrast to N=41 patients with ESR-1 low
or non expressing tumors (p=0.003). ESR-1 remained an independent
prognostic factor in multivariate analysis. Those data could be confirmed in the obs. arm of the JBR.10 study. Despite the percentage of ESR-1
positive tumors was less in this cohort (30%), N= 12 patients with ESR-1
expressing tumors had a more favorable outcome as those N=28 tumors
with low/no expression (p=0.0338). However, in the aCTx arm (N=50)
there was no statistical difference in survival due to ESR-1 expression,
with survival curves resembling the ESR-1 expressing tumors in the obs.
arm. Therefore, ESR-1 low/non expressing tumors might benefit most of
aCTx in this cohort.
Conclusions. The hypothesis, that ESR-1expression is of positive prognostic value in curatively resected NSCLC, was accepted. Additionally,
in a training cohort this prognostic value was confirmed. Moreover, patients with ESR-1 low/non expressing tumors might benefit most from
aCTx with the hormone receptor status being of predictive value. However, these later data are preliminary and warrant further confirmation.
Work is in progress and further data will be presented at the congress.
Abstracts
Lymphome/Leukämien/kindliche Tumoren
Best of Poster – Lymphome/
Leukämien/kindliche Tumoren
B13 – 0266
Safety and efficacy of Nilotinib therapy in CML patients with
Imatinib failure in routine clinical management – follow-up of
the non-interventional TARGET study
*F. Stegelmann1, J. Dengler2, P. le Coutre3, C. Scheid4, R. Weide5, T. Illmer6,
A. Sauer7, M. Walter8, W. Schneider-Kappus9, M. Kröger10, A. Distelrath11,
G. Stier12, S. Stern13, F. Schlegel14, M. Meincke15, O. Frank15, O.G. Ottmann16
1
Universitätsklinikum Ulm, Klinik für Innere Medizin III, Ulm, Deutschland,
2
Universitätsklinikum Heidelberg, Medizinische Klink, Innere Medizin V,
Heidelberg, Deutschland, 3Charité – Universitätsmedizin Berlin, Campus
Virchow Klinikum (CVK), Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Berlin, Deutschland, 4Uniklinik Köln, Klinik I
für Innere Medizin, Köln, Deutschland, 5Praxisklinik für Hämatologie
und Onkologie Koblenz, Koblenz, Deutschland, 6Gemeinschaftspraxis
Hämatologie – Onkologie, Dresden, Deutschland, 7Medizinisches Versorgungszentrum für Blut- und Krebserkrankungen, Potsdam, Deutschland,
8
Praxis für Innere Medizin, Hämatologie und internistische Onkologie,
Paderborn, Deutschland, 9Hämato-Onkologische Schwerpunkt-Praxis
Ulm, Ulm, Deutschland, 10Gemeinschaftspraxis für Ambulante Onkologie,
Bremerhaven, Deutschland, 11MVZ Osthessen, Fachbereich Innere Medizin,
Fulda, Deutschland, 12Internistisch-Onkologische Praxis, Zella-Mehlis,
Deutschland, 13Praxisklinik für integrative Onkologie, Altötting, Deutschland, 14St.-Antonius-Hospital, Akademisches Lehrkrankenhaus der RWTH
Aachen, Eschweiler, Deutschland, 15Novartis Pharma GmbH, BU Oncology,
Nürnberg, Deutschland, 16Klinikum der J.W. Goethe-Universität Frankfurt,
Med. Klinik II – Hämatologie/Onkologie, Frankfurt, Deutschland
Introduction. Nilotinib is a potent and highly selective BCR-ABL inhibitor with approval for newly diagnosed Ph+ CML patients in CP based
on superior PFS and faster responses vs Imatinib (IM). Nilotinib is also
indicated for CP and AP Ph+ CML pts who failed prior therapy including IM.
Methods. Follow-up analysis of an observational study of nilotinib in
148 pts with Ph+ IM-resistant or -intolerant CML within clinical practice in 71 centres in Germany between Jan 2008 and Nov 2010.
Results. 64.1% of the patients were older than 60 yrs, 7.4% older than 80
yrs (median age 65.8 yrs). 98.6% (1.4%) presented in CP (AP). 95.9% had
a good performance status (ECOG index ≤1). All pts were pretreated
with IM. Further prior drug treatments were chemotherapy (34.5%),
IFN (26.4%), dasatinib (24.3%) and other unspecified drugs (10.8%). Two
patients had received SCT in the past. 64.2% of patients were treated
with nilotinib as 2nd line therapy mostly due to resistance/intolerance against IM (50.0%/48.0%) or dasatinib (16.2%/6.1%). At initial visit, a
dose of 800 mg nilotinib/d was prescribed in 70.3% (400 mg/d in 25%).
Median duration of nilotinib therapy at the data cut-off for this analysis was 235 days. Remission status at study entry was 66.2% in CHR,
41.9% in MCyR (missing data =17.6%), 20.9%/9.5% in MMR/CMR. These
responses improved significantly under nilotinib, reaching cumulative
incidences of CHR, MCyR, MMR and CMR of 89.2%, 33.1%, 41.9% and
31.1%, respectively. Of note, cytogenetic and molecular examinations
were frequently not done (e.g. 81.8% and 26.3% after 6 months, respectively). Overall, the median time to response was 77 days (5–547 days).
Dose reduction or therapy interruption at any time occurred in 18.9%.
In 33.8% nilotinib treatment was stopped prematurely. 73% experienced
at least one AE during the observation period which was considered serious in 14.2%. Hematologic toxicity was observed in 18.9% of pts (12.2%
with thrombocytopenia), non-hematologic toxicities occurred in 43.2%
of pts. The most frequently reported AEs were skin reactions including
pruritus (13.5%) and rash (11.5%), gastrointestinal symptoms such as
nausea (8.8%), diarrhoea (7.4%) and upper abdominal pain (6.1%) as well
as headache (11.5%).
Conclusions. These data from routine clinical management support the
use of nilotinib as an efficacious and safe drug for treatment of a broad
population of CML pts with poor response or intolerance to a prior therapy including IM.
B14 – 0294
Hepatitis B virus infection and risk of lymphoma: results of a
serological analysis within the European case-control study
EPILYMPH
*N. Becker1, P. Schnitzler2, P. Boffetta3,4, P. Brennan3, L. Foretova5, M. Maynadié6, A. Nieters7, A. Staines8, Y. Benavente9, P.L. Cocco10, S. de Sanjosé9
1
Deutsches Krebsforschungszentrum, Epidemiologie von Krebserkrankungen, Heidelberg, Deutschland, 2Universität, Medizin, Heidelberg, Deutschland, 3International Agency for Research on Cancer, Epidemiology, Lyon,
Frankreich, 4International Prevention Research Institute, Epidemiology,
Lyon, Frankreich, 5Masaryk Memorial Cancer Institute, Cancer Epidemiology and Genetics, Brno, Tschechische Republik, 6University, Registre des
Hémopathies Malignes, Dijon, Deutschland, 7Universität, Molecular Epidemiology, Freiburg, Deutschland, 8University, School of Nursing, Dublin,
Irland, 9Unitat d’Infeccions i Càncer – Unit of Infections and Cancer (UNIC),
Institut Català d’Oncologia – Catalan Institute of Oncology, Barcelona,
Spanien, 10University, Occupational Medicine, Cagliari, Italien
Introduction. Epilymph is a European multicentric epidemiologic casecontrol study on the etiology of lymphoma comprising 2362 cases and
2458 controls from 6 countries (Czech Republic, France, Germany, Ireland, Italy, Spain). After having found a significantly elevated lymphoma risk among lymphoma cases with a self-reported medical history of
HBV infection based on questionnaire data, we used the study material
to investigate associations between serological indicators of HBV infection with risk of HL, NHL and specific lymphoma entities.
Methods. We tested HBs-antigen (HBsAg), anti-HBc and anti-HBs to
distinguish between susceptibility, current, past infection and immunity by vaccination. Statistical analysis was carried out with unconditional logistic regression.
Results. We found a statistically significant positive association especially of a past HBV infection with multiple myeloma (MM, OR=1.97,
95%-CL=1.16–3.37). Past HBV infection was also associated with B-CLL
(OR=1.33, 95%-CL=0.82–2.16) and T-NHL (OR=1.59, 95%-CL=0.65–3.90)
which was, however, not statistically significant. Non-significant association occurred also for current HBV infection and NHL (OR=1.49,
95%-CL=0.65–3.41), B-NHL (OR=1.58, 95%-CL=0.69–3.64) and diffuse
large B-cell lymphoma (DLBCL, OR=1.50, 95%-CL=0.47–4.82). Subjects
having HBV infection self-reported were serological positive in 75% of
cases and 80% of controls. For vaccination, the corresponding figures
were 49% and 54%, respectively.
Conclusion. The present results support previous reports of an association between a history of HBV infection with an elevated lymphoma
risk and add multiple myeloma to the list of potentially virus-associated
lymphoma entities. Chronic antigen stimulation and immune response
to a past but not fully cleared HBV infection may be an explanation for
the association.
B15 – 0309
Retrospective analysis of treatment-related toxicities and outcome in high-risk Ewing sarcoma patients receiving Treosulfan or
Busulfan-based high-dose chemotherapy with autologous stem
cell transplantation*
B16 – 0341
First and preliminary results of a functional outcome study in
long-term survivors of Ewing sarcoma*
*H. Jürgens1, U. Dirksen1, S. Jabar1, K. Ehlert1, J. Boos1, P. Bader2, R. Ladenstein3, A. Ranft1
1
University Hospital, Pediatric Hematology and Oncology, Muenster,
Deutschland, 2Johann Wolfgang Goethe University Medical Center,
Frankfurt, Deutschland, 3 3Children‘s Cancer Research Institute (CCRI), Wien,
Österreich
Objective. Busulfan (BU), in combination with melphalan (MEL), highdose chemotherapy (HDC) with autologous stem cell transplantation
is widely used in consolidation treatment of poor-prognosis Ewing sarcoma patients. Treosulfan (TREO) has been newly introduced recently
into the treatment protocols. We analyzed treatment-related toxicities
and outcome in patients treated with BU-MEL or TREO-MEL HDC according to the EURO-E.W.I.N.G.99 (EE99) protocol of the German Society of Pediatric Hematology and Oncology (GPOH) from 1998–2009.
Methods. 157 patients were identified with full records of BU-based
HDC, administrated PO in 113 patients and IV in 44 patients, and 44 patients with IV TREO-based HDC. BU-MEL was given in 31.8% (n=50)
according to high-risk localized disease mainly for poor response to
initial chemotherapy (R2loc), in 25.5% (n=40) for pulmonary metastases (R2pulm), and in 42.7% (n=67) for primary mainly skeletal dissemination (R3). TREO-MEL patients had a more progressed risk profile
(R2loc: 6; 13.6%; R2pulm: 5; 11.4%; R3: 33; 75%; p=0.001). HDC toxicity
was analyzed by descriptive statistics according to modified CTC toxicity grade scales of the EE99 protocol. Outcome was analyzed descriptively by event-free survival (EFS) and overall survival (OS) controlled
for risk factors by multivariate regression analysis.
Results. Grade 3 and 4 ratings occurred in 654 of 2500 toxic episodes
(26.2%) in BU-MEL HDC (PO: 27.3%; IV: 23.5%), and in 163 of 842 toxic
episodes (19.4%) in TREO-MEL HDC (vs. BU-MEL PO+IV: p<0.0001;
IV only: p=0.046). Clinical relevant reductions of severe toxicities
>10% in total in single scales were observed in TREO-MEL compared
to PO+IV BU-MEL and compared to IV BU-MEL: WBC (vs. BU-MEL
PO+IV: p=.001; IV only: p=.016); granulocytes (p=.016; p=.120); platelets (p=.016; p=.114); infection (p=0.020; p=0.075); stomatitis (p<0.001;
p=0.044). 3y-EFS (OS) was 0.51 (0.67; SE=0.08) in IV BU-MEL, 0.45 (0.61;
SE=0.05) in PO BU-MEL, and 0.24 (0.47; SE=0.07–0.08) in TREO-MEL.
Adjusted for risk group (R2loc; R2pulm; R3), primary tumor volume
(cut-off 200 ml) and age (cut-off 15 years), the risk ratio regarding EFS
for TREO-MEL vs. IV BU-MEL was 1.86 (95% CI 1.02–3.39; p=0.044),
and the risk ratio regarding OS was 1.75 (95% CI 0.88–3.47; p=0.110).
Conclusions. Results from this large cohort of high-risk Ewing sarcoma
patients indicate a reduction in toxicity with Treosulfan-based HDC.
The outcome regarding EFS and OS must be carefully monitored.
*supported by Deutsche Krebshilfe.
*C. Hoffmann1, C. Winter2, H. Jürgens1, U. Dirksen1, D. Rosenbaum2, A. Ranft1
1
University Hospital, Pediatric Hematology and Oncology, Muenster,
Deutschland, 2University Hospital, Institute of Experimental Musculoskeletal Medicine (IEMM), Muenster, Deutschland
Objective. Substantial progress has been made in the management of
childhood bone tumors over the last 25 years. The current 10-year survival rate in localized Ewing sarcoma is approximately 70%, however,
long-term impact of multidisciplinary treatment is not well documented. Also no data are available on the effect of multimodal therapy on
the level of physical activity. The aim of this study was to objectively
quantify the level of activity in long-term survivors of Ewing sarcoma
using a continuous measurement device. All patients were treated according the consecutive Ewing sarcoma trials of the German Society of
Pediatric Hematology and Oncology (GPOH).
Methods. Subject of this analysis is a first series of 118 long-term survivors of Ewing sarcoma, initially diagnosed between 1981 and 1998.
The median age at diagnosis was 14 years (range 2–45), median age at
time of assessment was 38 years (range 20–63). Initial local therapy was
surgery alone in 25 patients (21%), surgery and irradiation in 73 patients
(62%), and radiotherapy alone in 20 patients (17%). Degree and intensity
of physical activity were objectively assessed on 14 consecutive days by
using a uniaxial accelerometer, the Step Activity Monitor (SAM). In addition, function was assessed by the TESS (Toronto Extremity Salvage
Score) questionnaire.
Results. Participants averaged 10526 steps per day (SD=3979; median:
9876; range: 1884–25,502) which is acknowledged as an active lifestyle.
Some patients (24%) reached a high level of activity (>12,500 steps/day)
while 5% had to be considered as sedentary (<5000 steps/day). However,
the intensity of activity was rather low. The patients spent 10.8 min/day
on a moderate or high level of activity (i.e., >100 steps/minute), only 8 of
118 (7%) patients reached the time to be spend on this level of activity as
recommended for an active lifestyle (i.e., 30 min/day). The TESS score
(0–100) for tumors located in upper extremity was 90.2 (range 69.6–100;
SD=11.1), and for lower extremity tumors 88.9 (range 40.8–100; SD=12.1)
indicating good function following multimodal tumor treatment was
achieved.
Conclusions. These preliminary data indicate that patients after Ewing
sarcoma treatment can reach step activity levels similar to healthy
adults. However, most patients stay on a rather low intensity of activity.
SAM can be used to capture activity levels in long-term survivors of
Ewing sarcoma. It may be advantageous to consider the use of a combination of outcome measures, including SAM, for objective functional
mobility assessment. Parallel recording of physical activity (SAM) and
TESS provides a better measure reflecting the complex situation of the
patients by combining objective and subjective parameters. The study
is being continued to include all long-term Ewing sarcoma survivors
initially diagnosed between 1980 and 2009.
*supported by Bundesministerium für Bildung und Forschung (BMBF)
01ER0807.
Abstracts
Mammakarzinom/gynäkologische Tumoren
Best-of-Poster – Mammakarzinom/
gynäkologische Tumoren
B17 – 0067
Phase II-study with a targeted cytotoxic LHRH- analog (AEZS108) in patients with LHRH – receptor positive endometrial
cancer: Protocol AGO-Gyn 5, AGO-Study Group
*G. Emons1, S. Tomov2, J. Sehouli3, P. Harter4, P. Wimberger5, L.C. Hanker6,
A. Stähle7, A. Hristamian8, F. Hilpert9, M.W. Beckmann10, P. Dall11, H. Sindermann11, C. Gründker1
1
Georg August Universität, Klinik für Gyn. und Geburtshilfe, Göttingen,
Deutschland, 2University Hospital, Pleven, Bulgarien, 3Charité, Berlin,
Deutschland, 4HSK, Wiesbaden, Deutschland, 5University Hospital, Essen,
Deutschland, 6University Hospital, Frankfurt, Deutschland, 7Karlsruhe,
Germany, Deutschland, 8Plovdiv, Bulgarien, Bulgarien, 9University Hospital,
Kiel, Deutschland, 10University Hospital, Erlangen, Deutschland, 11Aeterna
Zentaris, Frankfurt, Deutschland
Background. Endometrial cancers (EC) commonly express receptors for
luteinizing homone releasing hormone (LHRH ). AEZS-108 is a targeted cytotoxic drug where [ D-Lys(6)]-LHRH is linked to doxorubicin.
We assessed efficacy and toxicity of AEZS-108 in endometrial cancer.
Methods. Patients with LHRH-receptor positive advanced (stages FIGO
III or IV; n=27) or recurrent endometrial cancer (n=16) received AEZS108 (267 mg/m2 3-weekly) for 6 cycles. At least 1 measurable lesion was
required at baseline. Independent radiologic review was performed. Response rate per RECIST was defined as primary endpoint. Secondary
endpoints were sefaty, time-to-progression (TTP) and overall survival
(OS).
Results. 43 patients with median age of 68 years entered the study. Percentages of tumor cells staining for LHRH-R ranged 30–90%. 31 patients showed endometrioid and 8 serous histological subtype. Prior
treatment included surgery (n=42), radiotherapy (n=29), chemotherapy (n=9) and hormonal therapy (n=11). 62.8% received AEZS-108 for
6 courses. One patient was retreated at reduced dose. Possibly drug related adverse events, except for hematologic toxicity grade 3/4 (rapidly
reversible neutropenia: 60%, anemia: 5%), was commonly limited to
CTCAE grade 1/2. There was no evidence of cardiotoxiciy. One patient
stopped therapy because of recurrent anemia. 12 responses were documented (2 CR, 10 PR and 17 SD). After prior chemotherapy, 1 CR, 1 PR
and 2 SDs were assessed. Median TTP was 30 weeks and median OS
62 weeks.
Conclusions. A promising clinical benefit rate of 74% was shown. OS after single agent AEZS-108 is similar to that reported for modern triple
combination chemotherapy, but as achieved with distinctly lower toxicity.
Best of Poster – Mammakarzinom/
B18 – 0117
Pegylated liposomal doxorubicin and carboplatin (C-PLD) versus
paclitaxel and carboplatin (C-P) in platinum-sensitive ovarian
cancer (OC) patients (pts): Treatment at recurrence and overall
survival (OS) final analysis from CALYPSO phase III GCIG trial
*C. Kurzeder1, W. Meier2, C. Jackisch3, A. Staehle4, A. Burges5, J. Pfisterer6,
A. Belau7, G. Emons8, U. Canzler9, W. Schroeder10, J. Sehouli11, A. du Bois1,11,
P. Wimberger12, B. Schmalfeldt13, S. Mahner14, U. Wagner15, E. Pujade-Lauraine16
1
Kliniken Essen Mitte, Evang. Huyssens-Stiftung/Knappschaft GmbH, Gynäkologie & Gynäkologische Onkologie, Essen, Deutschland, 2Evangelisches
Krankenhaus Düsseldorf, Düsseldorf, Deutschland, 3Klinik für Gynäkologie
und Geburtshilfe Offenbach, Offenbach, Deutschland, 4Frauenarztpraxis,
Karlsruhe, Deutschland, 5Klinikum der Universität München, Klinik und
Poliklinik für Frauenheilkunde und Geburtshilfe, München, Deutschland, 6Städt. Klinikum Solingen GmbH, Klinik für Frauenheilkunde und
Geburtshilfe, Solingen, Deutschland, 7Universität Greifswald, Klinik und
Poliklinik für Frauenheilkunde und Geburtshilfe, Greifswald, Deutschland,
8
Universitätsfrauenklinik Göttingen, Göttingen, Deutschland, 9Klinik und
Poliklinik für Frauenheilkunde und Geburtshilfe Universitätsklinikum Carl
Gustav Carus, Dresden, Deutschland, 10Klinikum Bremen Mitte, Frauenklinik, Bremen, Deutschland, 11Charité Campus Virchow-Klinikum, Klinik
für Gynäkologie, Berlin, Deutschland, 12Universitätsklinikum Essen, Klinik
für Frauenheilkunde und Geburtshilfe, Essen, Deutschland, 13Frauenklinik
und Poliklinik der Technischen Universität München, München, Deutschland, 14Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für
Gynäkologie, Hamburg, Deutschland, 15Universitätsklinikum Gießen u.
Marburg GmbH, Standort Marburg, Klinik für Gynäkologie, Gynäkologische
Endokrinologie und Onkologie, Marburg, Deutschland, 16Hopital Hotel-Dieux, Paris, Frankreich
Background. CALYPSO is a large international randomized phase III
trial comparing CPLD and C-P in pts with OC in late relapse. Results
of the progression-free survival (PFS), the primary endpoint, suggest
a benefit in pts treated with C-PLD with a hazard ratio (HR) of 0.82
(p=0.005). Overall severe non-hematologic toxicity (36.8% vs 28.4%;
p<0.01) – including alopecia, neurotoxicity and carboplatin hypersensitivity leading to early discontinuation (15% vs 6%; p<0.001) – occurred
more frequently in the C-P arm.
Methods. From 04/05 to 10/07, 976 eligible pts were randomized to either
C-P (carboplatin AUC 5 iv d1 + paclitaxel [P] 175 mg/m2 3 h iv d1, q3w)
or C-PLD (Carboplatin + PLD 30 mg/m2 iv d1 q4w) for at least 6 cycles.
It was explored whether the treatment effect on PFS recently observed
in CALYPSO was maintained after further treatment. OS of pts was
analysed.
Results. Median follow-up is 40 months (mo). 832 pts (86%) have progressed after CALYPSO treatment (C-PLD or C-P). At time of first progression following CALYPSO, median platinum-free interval (C-PLD:
5.2, C-P: 5.5 mo) and percentage of pts receiving platinum-based treatment (C-PLD: 27%, C-P: 26%) were similar in both arms. Pts initially
treated with C-PLD had significantly less risk of 2nd treatment failure
compared with those initially receiving C-P, with a HR of 0.83 (95% CI:
0.73, 0.96, p=0.01). There was a significant imbalance in the cross-over
rate of PLD and paclitaxel between both arms (from C-PLD to P: 34%,
from C-P to PLD: 57%). Median OS of the global population (n=621
events) was 31.5 mo with a HR of 0.987 (p=0.87) for C-PLD compared
to C-P.
Conclusion. In pts with OC in late relapse, the benefit in disease control
of C-PLD over C-P was maintained at 1st treatment following CALYPSO relapse. OS was similar in both arms while cross-over treatment rate
was superior in the C-P arm.
B19 – 0279
Oncofertility; Xenotransplantation of cryopreserved ovarian
tissue from patients with ovarian tumors into SCID mice – no
evidence of malignant cell contamination
B20 – 0318
Prospective comparison of risk assessment tools in early breast
cancer (Recurrence Score, uPA/PAI-1, central grade, and luminal
subtypes): final correlation analysis from the phase III WSG-Plan
B trial
*A. Müller1, L. Lotz1,2, M. Montag1,2, H. van der Ven2, M. von Wollf2,3, I. Hoffmann1, D. Wachter4, M. Beckmann1, R. Dittrich1
1
Universitätsklinikum Erlangen, Frauenklinik, Erlangen, Deutschland, 2Universitätsklinikum Bonn, Frauenklinik, Bonn, Deutschland, 3Inselspital Bern,
Frauenklinik, Bern, Schweiz, 4Universitätsklinikum Erlangen, Pathologisches Institut, Erlangen, Deutschland
Background. There are still many unanswered questions regarding the
safety of ovarian tissue retransplantation in cancer patients, due to the
potential risk that malignant cells in the frozen tissue may lead to recurrence of the primary disease after transplantation. This study examined
the possible presence of residual malignant cells in ovarian cortex from
patients with ovarian tumors after xenografting of the ovarian tissue
into severe combined immunodeficiency (SCID) mice.
Methods. The ovarian cortex tissue was obtained during surgical laparoscopy or unilateral/bilateral oophorectomy. Before cryopreservation,
the ovarian cortex was examined histologically to ensure that a sufficient quantity of primordial follicles had been obtained and to exclude
involvement of the tissue by malignancy. Freezing of the ovarian tissue
was undertaken in accordance with three similar slow freezing protocols. The ovarian tissue was transplanted into immunodeficient (SCID)
mice in an intramuscular pocket in the neck muscle. Twenty-four weeks
after transplantation, the grafts were recovered and hematoxylin-eosin
stains were performed. In addition, freshly cut sections were stained
with antibodies against pancytokeratin (monoclonal antibody KL1).
Results. All of the patients had a normal follicular distribution relative to their age, and light microscopy showed no evidence of malignant
cells in the ovarian tissues prior to transplantation, even in patients with
bilateral ovarian carcinoma. All of the animals remained in good health
throughout the study and none of the grafts resulted in recurrences.
Nor did any of the mice showed macroscopically metastasis. The serial
sections from human ovarian grafts had a normal histological appearance. No carcinoma cells were seen in any of the H&E-stained slides
examined or in any of the slides with antibodies against cytokeratins.
Conclusion. Ovarian transplantation appears to be a feasible consideration in young female patients with ovarian tumors. The negative
findings do not rule out malignant cell contamination in the ovarian
tissue. A larger number of tissue fragments would increase the validity
of these preliminary results and more sensitive methods may be necessary for assessment of possible micrometastases. In order to increase
the safety of the procedure, ovarian tissue harvesting and re-implantation should take place in the setting of clinical trials with clearly defined
methods, objectives, and end points.
*O. Gluz1, H. Kreipe2, T. Degenhardt1, R. Kates1, C. Liedtke1,3, M. Christgen2,
M. Clemens4, S. Markmann5, C. Uleer6, D. Augustin7, S. Shak8, C. Thomssen9,
U. Nitz1,10, N. Harbeck1,11
1
Westdeutsche Studiengruppe, Mönchengladbach, Deutschland,
2
MHH Hannover, Hannover, Deutschland, 3Uniklinik Münster, Münster,
Deutschland, 4Klinikum Mutterhaus der Borromäerinnen, Trier, Deutschland, 5Uniklinikum Südstadt, Rostock, Deutschland, 6Gynäkologischonkologische Praxis, Hildesheim, Deutschland, 7Klinikum Deggendorf,
Degendorf, Deutschland, 8Genomic Health Inc., Redwood City, Vereinigte
Staaten von Amerika, 9Uniklinikum Halle/Saale, Halle/Saale, Deutschland,
10
EVK Bethesda, Mönchengladbach, Deutschland, 11Uniklinik Köln, Köln,
Deutschland
Background. Both the Recurrence Score® (RS) multi-gene assay and
invasion factors uPA/PAI-1 are recommended by guidelines (ASCO,
AGO) for decision support regarding adjuvant chemotherapy in patients with early breast cancer (BC). Here, we present the final WSGPlan B trial correlation analysis of these risk assessment tools.
Methods. Plan B trial (evaluating anthracyline-free adjuvant chemotherapy, 6×TC, vs. 4×EC-4×DOC in HER2-negative BC; n=2.448 to
be randomized for chemotherapy). RS has been used as the selection
criterion for chemotherapy vs. endocrine therapy alone in HR+ BC (if
RS<11 in pN0 or pN1) since an amendment in August 2009. uPA/PAI-1
(by ELISA) is obtained as an optional risk factor. Evaluation of central
grade and luminal B subtype (using 13.25% or 20% Ki-67 cut-offs) are
performed by the independent trial pathologist in all HR+ tumors.
Results. From April 2009 to June 2011, 3037 patients have been recruited
and 2290 randomized. The study will be completed by August 2011.
Data on RS are available in 2361 patients with HR+ tumors: RS is distributed as follows: 0–11 (18%), 12–25 (61%), >25 (21%). In 257 patients
with 0–3 involved LN, chemotherapy was omitted based on RS results
(12.3% of patients after amendment). By the last interim analysis in February 2011, data on central grade are available in 1509 patients and
Ki-67 in 592 patients. An only moderate positive correlation was observed between Ki-67 and RS (Spearman’s coefficient rs =0.336, p<0.001)
as continuous variables and between RS and central grade (rs=0.498,
p<0.001). High RS is predictive of high grade G3 (66% of RS25 high
risk and 74% of RS30 high risk are G3), but within the RS11 low-risk
group, 33% of tumors were assessed as G3 and within RS18 low-risk,
30% were G3. 14% of G3 tumors were classified as RS11 low-risk and
40% of G3 tumors as RS18 low-risk. When considered as risk categories,
there was only a weak concordance between RS and uPA/PAI-1, using
either standard RS (18; 30) or PlanB cut-offs (low risk <11 RS), with
67% of patients having high uPA/PAI-1 within the low/intermediateRS subgroups. High-risk RS is predictive of high-risk by uPA/PAI-1,
poor grade and luminal B subtype. However, the converse is not true,
since clinically relevant proportions (between 33 and 66%) of patients
identified by uPA/PAI-1 or Ki-67 as being at high-risk had low or intermediate RS. Final correlation analyses in all Plan B patients with HR+
tumors (n>2500) will be presented at the meeting.
Discussion. For the first time, risk groups according to RS, Ki-67 and
uPA/PAI-1 have been prospectively compared within a phase III trial
setting both in N0 and N+ early BC. These data show high-risk status according to RS is predictive of high risk by uPA/PAI-1, high grade
by central pathology and luminal B subtype, but not converse. In the
low and intermediate risk RS groups, there are still patients considered
Abstracts
high-risk according to uPA/PAI-1, Ki-67 or central grade. Further follow-up of the WSG-Plan B trial will clarify the clinical significance of
these findings regarding patient outcomes.
Molekulare Onkologie
Best of Poster – Molekulare Onkologie
B21 – 0208
Transient telomere dysfunction induces chromosomal instability
and carcinogenesis in telomerase-proficient mice
*D. Hartmann1,2, Y. Begus-Nahrmann2, P. Eshraghi2, P. Schirmacher3, H.W. Lee4, A. Lechel2, K.L. Rudolph2
1
Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, München,
Deutschland, 2Institut für Molekulare Medizin und Max-Planck-Forschungsgruppe für Stammzellalterung, Universität Ulm, Ulm, Deutschland, 3Institut
für Pathologie, Universitätsklinikum Heidelberg, Heidelberg, Deutschland,
4
Department of Biochemistry, College of Science, Yonsei University, Seoul,
Korea, Republik
Introduction. A current concept indicates that telomere dysfunction can
increase tumor initiation by induction of chromosomal instability, but
initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven
in vivo since appropriate mouse models were lacking.
Methods. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse
model of inducible telomere dysfunction with wildtype telomerase, (ii)
in telomerase knockout mice with chronic telomere dysfunction (G3
mTerc-/-), and (iii) in wildtype mice with functional telomeres and telomerase.
Results. Transient or chronic telomere dysfunction enhanced the rates
of chromosomal aberrations in developing HCCs, but increases in tumorigenesis compared to wild-type mice occurred only in telomeraseproficient mice. In contrast to mTerc-/- tumors, telomerase-proficient
tumors that experienced transient telomere dysfunction retained the
capacity to minimize DNA damage and exhibited elevated rates of tumor cell proliferation compared to wild-type tumors.
Conclusion. Together, these data provide the first in vivo evidence that
transient telomere dysfunction promotes chromosomal instability and
carcinogenesis in a telomerase-proficient background.
B22 – 0284
Inhibition of Hsp90 impairs hexokinase (HXK-II) activity by disrupting its interactions with voltage dependent anion channels
(VDAC)
*M.E. Mycielska1, C. Moser1, C. Wagner1, E. Scheiffert1, E.K. Geissler1,
H.J. Schlitt1, S.A. Lang1
1
Universitätsklinikum Regensburg, Experimentelle Chirurgie, Regensburg,
Deutschland
Background. Glycolysis is the predominant metabolic pathway in cancer cells (Warburg effect) with hexokinase II (HXK II) as its crucial
enzyme. Due to ATP requirements, this enzyme has to be attached to
VDACs in the mitochondrial membrane. In addition, overexpression of
the molecular chaperone heat-shock protein 90 (Hsp90) in cancer cells
has been described. Interestingly, TOM complex, responsible for import
of proteins (e.g. VDACs) into mitochondria, is an Hsp90 client protein.
Therefore, we hypothesised that targeting Hsp90 would affect localisation of HXK II in cancer cells through changes in VDAC import.
Methods. Human gastric and pancreatic cancer cell lines (TMK1, MiaPaCa2) were used to evaluate the effects of Hsp90 inhibitor 17-DMAG
(17-(dimethylaminoethylamino)-17-demethoxygeldanamycin) on cancer cell metabolism. In vitro, localisation and expression of HXK II and
VDAC protein were determined using Western blotting and immunocytochemistry. Spectrophotometric technique was employed to evaluate enzyme activity. In vivo, murine Panc02 pancreatic adenocarcinoma
cells were used in subcutaneous tumor model.
Results. Overall hexokinase activity in the mitochondrial fraction was
decreased by 25±8.1% and 57±9.7% (n=5; p=0.03–0,04) in cells and tissues when treated with 17-DMAG compared to control conditions, whilst
its activity in the cytoplasmic fractions did not differ (p>0.05). Staining
of HXK II, VDAC and mitochondria in the cells showed large areas of
colocalisation upon control conditions. Interestingly, colocalisation
was significantly reduced when cells were treated with the Hsp90 inhibitor. Furthermore, treatment with 17-DMAG resulted in a decreased
expression of HXK II in the mitochondrial fraction in cells and tissues.
Determination of the expression of HXK I and III in cancer cells and
tissues showed a slight decrease in HXK III expression in cytoplasmic
fraction whilst there was no change in mitochondrial fraction in either
protein.
Conclusion. Results so far show that targeting Hsp90 affects glucose metabolism in cancer cells via inhibition of VDAC incorporation into the
mitochondrial membrane and in consequence disabling HXK II-VDAC
binding. Hsp90 inhibitors might, therefore, play a role in treatment
concepts targeting the Warburg effect in human cancer.
B23 – 0337
Genetic analysis for SDH mutations (SDH-B, SDH-C and SDH-D) in
paraganglioma patients
*T. Cohnert1, J. Fruhmann1, S. Koter1, A. Baumann1, J. Geigl2
1
Medizinische Universität Graz, Klin. Abt. für Gefäßchiurgie, Graz,
Österreich, 2Medizinische Universität Graz, Institut für Humangenetik, Graz,
Österreich
Introduction. Paraganglioma represent rare tumours of the head and
neck. They originate from the neural crest cells and can occur from the
skull base to the pelvic floor. Many cases are sporadic. However, the hereditary cases are most often seen in Von Hippel Lindau Disease, MEN 2
or neurofibromatosis. Recently succinate dehydrogenase mutations
(SDH) have been described in paraganglioma and phaechromocytoma
patients.
Patients and methods. 51 patients (pts.) were operated on 60 Paragangliomas (PGL) of the neck (carotid body tumors) between January 1988
and July 2011. Prospectively collected clinical data were analyzed retrospectively. In 2006 genetic analyses were started for succinate dehydrogenase mutations (SDH; SDH-B, SDH-C and SDH-D). Follow-up was
completed. All patients were contacted and genetic testing as well as genetic family counselling were offered. Statistical data are given as mean
values and standard deviation.
Results. 51 pts. (36 female, 15 male) were operated at a mean age of
53.9+16.6 years (range 24–80 years). In 9 pts. (4 female, 5 male) there
were bilateral tumors. After a mean follow-up of 94 months (range
1–263 months = 21 years 11 months) 6 pts. had died. 45 pts. were alive,
3 pts. did not agree to genetic testing and one patient was currently not
available for testing (moved abroad). Of the tested 41 pts. no mutation
was detected in 20 pts. (17 female, 3 male). In 21 pts. a total of 14 SDH-D
mutations, 2 SDH-B mutations and 1 SDH-C mutation were found. Additional 4 pts. showed abnormalities in SDH-C that need further investigation. In summary in 17 of 41 pts. (17/41=41.5%) SDH mutations were
confirmed. In all 9 patients with bilateral tumors SDH-D mutations
were detected.
Conclusions. Long-term survival after surgical removal of paraganglioma of the neck is not limited. Genetic testing is mandatory in patients
with bilateral tumors or positive family history and strongly recommended in all other PGL patients. When a SDH mutation is diagnosed,
regular clinical and ultrasound investigations, MRI of the head and
neck, thorax, abdomen and pelvis are recommended for diagnosis or
exclusion of multiple tumor localizations as well as phaechromocytoma. In addition genetic exploration of patients’ families and counselling
should be offered.
B24 – 0480
Two novel splice variants of the transcriptional co-repressor
Daxx with different p53-regulating properties
N. Wethkamp1, S. Funke1, C.V. Suschek2, E. Grinstein3, S. Heikaus1, H.E. Gabbert1, *C. Mahotka1
1
Heinrich Heine Universität – Klinikum, Institut für Pathologie, Düsseldorf,
Deutschland, 2Heinrich Heine Universität – Klinikum, Klinik für Unfallchirurgie, Düsseldorf, Deutschland, 3Heinrich Heine Universität – Klinikum,
Klinik für Kinder-Onkologie, -Hämatologie und -Immunologie, Düsseldorf,
Deutschland
Aims. Deregulation of apoptosis is involved in several diseases including cancer, characterized by an abnormally prolonged cell survival.
The ubiquitously expressed protein Daxx is implicated in apoptosis but
whether its function is pro- or anti-apoptotic is still controversially discussed. Daxx is involved in transcriptional control of several genes and
it comprises domains including a regulatory C-terminus which is responsible for the interaction with numerous proteins such as p53, PML,
or HSP27.
Methods. RT-PCR, expression cloning, retroviral transfections, confocal fluorescence microscopy, western blotting, immunoprecipitations,
flow cytometry, luciferase reporter gene assays, apoptosis assays, etc.
Results. Here we describe the identification and characterization of two
novel variants of Daxx termed Daxx-β and Daxx-γ which are generated by alternative splicing. Alternative splicing results in a truncated
regulatory C-terminus in both proteins. As a consequence, Daxx-β
and Daxx-γ show a markedly decreased affinity to PML, which in turn
is associated with a different subnuclear localization of these proteins
compared to Daxx. While Daxx is mainly localized to PMLoncogenic
domains (PODs) Daxx-β and Daxx-γ display a distinct distribution pattern. Furthermore, Daxx-β and Daxx-γ show a decreased affinity to p53
also due to the truncated C-terminus. We provide evidence that the p53
recruitment into PODs is Daxx isoform dependent. The decreased affinity of Daxx-β/-γ to p53 and PML results in a diffuse localization of p53
throughout the nucleus. In contrast to Daxx, Daxx-β and Daxx-γ are
unable to repress p53-mediated transcription.
Conclusion. Therefore, alternative splicing of Daxx as a regulator of p53regulated/dependent gene expression might indicate an additional level
in the cellular apoptosis network.
Palliativmedizin/ Supportivtherapie
Best of Poster – Palliativmedizin/ Supportivtherapie
B25 – 0058
Randomized placebo-controlled double-blind study of modified
methylphenidate on cancer-related fatigue (CRF)
*M.E. Heim1, S. Kuhnt2, R. Schwarz2, W. Abenhardt3, B. Lathan4, K. Verpoort5,
S. Siehl6, C. Ose7, A. Engels8, J.-U. Rüffer9
1
Universität Göttingen, Rosdorf, Deutschland, 2Universität Leipzig, Leipzig,
Deutschland, 3Onkologische Praxis, München, Deutschland, 4Onkologische
Praxis, Dortmund, Deutschland, 5Onkologische Praxis, Hamburg, Deutschland, 6Onkologische Praxis, Kassel, Deutschland, 7Universitätsklinikum
Essen, Inst. f. Med. Informatik, Biometrie u. Epidemiologie, Essen, Deutschland, 8Medice Pütter GmbH, Iserlohn, Deutschland, 9Deutsche Fatigue
Gesellschaft, Köln, Deutschland
Introduction. CRF is the most prevalent symptom of cancer patients
(pts) following treatment, can persist for months or even years, and significantly reduces usual functioning and health related quality of life.
There is no standard treatment for CRF, initially a comprehensive assessment and the treatment of possible causative factors, such as anemia
or hypothyroidism is recommended. Nonpharmacological treatments,
such as individualized exercise programs, psychoeducational and cognitive-behavioral interventions are the backbone of CRF therapy. Pharmacological treatment with the psychostimulant methylphenidate showed inconclusive results in several phase II and III studies.
Patients and methods. Tumor pts without active disease suffering from
CRF (MFI-score >40) were randomized into a treatment and a placebo
group. The treatment duration was 3 weeks with modified release methylphenidate starting with 20 mg in the 1st week, and dose escalation
to 40 mg, and 60 mg in the 2nd and 3rd week in case of inadequate
treatment effect. Treatment results were evaluated by patient reported
outcome measures with MFI, EORTC-QLQ-C30, HADS, and by the
clinical global impression (CGI) of the physician at baseline, week 3 and
6, and for MFI and CGI additionally at week 2 and 3. Primary endpoint
was the general fatigue in the MFI. A total of 67 pts (46 women, 21 men,
mean age 48 years) were randomized, 53 could be evaluated, 25 in the
treatment, 28 in the placebo group. Mean fatigue duration was 4 and
2.5 years.
Results. In the intention to treat analysis there was a mean reduction
of the general fatigue score of the MFI of 22 points (verum) and 13 points (placebo), in the per protocol analysis of 25 and 16 (not significant).
There was a significant difference in the CGI for therapeutic efficacy in
favor of methylphenidate. Single pts had an impressive advantage of the
treatment with methylphenidate. No significant differences could be
observed for anxiety and depression, and the EORTC-subscales, except
for the cognitive function subscale, which was significantly improved
in the verum group.
Conclusion. In accordance with other studies we could not observe
a significant improvement of CRF in the MFI with methylphenidate.
However significant better results for the intervention group could be
observed in the therapeutic efficacy in the CGI and for the cognitive
function in the EORTC-QLQ-C30. Differences in both groups and subgroup analysis will be discussed to explain the results.
Abstracts
B26 – 0071
Occupational rehabilitation after partial laryngectomy
*D. Wollbrück1, H. Danker1, E.F. Meister2, A. Meyer1
1
Universität Leipzig, Medizinische Fakultät, Medizinische Psychologie und
Medizinische Soziologie, Leipzig, Deutschland, 2Klinikum St. Georg, HNOKlinik, Leipzig, Deutschland
Purpose. Improvements in early detection and treatment of laryngeal
cancer have let to an increase of numbers of cancer survivors. Against
this background two questions arise for patients after partial laryngectomy: I. How does the work status of patients with partial laryngectomy
change? II. Which factors are associated with a successful occupational
rehabilitation?
Methods. Since 2007, all patients in Middle Germany, who underwent
a partial laryngectomy due to laryngeal carcinoma, were contacted in
a multi-centre longitudinal study. Patients were questioned at different
time points (t1= preoperative; t2=2 weeks after partial laryngectomy;
t3=12 weeks after operation; t4=1 year postoperative). For this presentation, all patients were included, who were interviewed until December
2010 and were under the age of 65 at t1 (n=38). Instruments used were
the Quality of Life Questionnaire of the European Organization of Research and Treatment of Cancer (EORTC QLQ-C30), single questions
(importance of having a job) and sociodemographic (age, professional
career) and medical data (tumour stage; use of rehabilitation).
Results. I. Employment rate one year postoperatively (40%) has decreased in comparison to preoperatively (63%), while the group of patients
who are no longer available for the job market (due to retirement annuity or disability pension) has increased (from 21% at t1 to 36% at t4). All
patients who worked one year post surgery had already been working
preoperatively. The perceived extent of limitation in the context of work
and daily activities has increased (from 26% at t1 to 84% at t4). II. The
return to work one year postoperatively is correlated with the professional career (Rho=0.41*, p=0.04). All other factors show no significant
correlation.
Conclusion. Blue-collar workers return to work significantly less often
than white-collar/self-employed workers. Being able to re-enter the
workforce and to take an active part in the occupational life should be
both a matter of the affected patients and of public interest. The introduced findings could contribute to further discussion on how to adapt
the specific work situations of blue-collar workers so that a return, if not
to the same job, at least to an alternative job may be within the realms of
possibility for the affected patients.
B27 – 0145
Somato-psychosocial caring program to improve symptoms
in cancer patients with stem cell transplantation (HSCT) – first
results of a prospective non randomized intervention study
*H. Schmidt1, P. Jahn1,2, S. Böse1, A. Bauer1, A. Lau3, O. Stoll3, H.-J. Schmoll2,
C. Mauz-Körholz2, O. Kuß4, M. Landenberger1
1
MLU Halle, Institut für Gesundheits- und Pflegewissenschaft, Halle,
Deutschland, 2Universitätsklinikum Halle, Halle, Deutschland, 3MLU Halle,
Department Sportwissenschaft, Halle, Deutschland, 4MLU Halle, Institut für
Medizinische Epidemiologie, Biometrie und Informatik, Halle, Deutschland
Objective. Patients with hematopoietic stem cell transplantation
(HSCT) suffer from a range of symptoms including mucositis, fatigue
and mobility/activity deficits. This single center prospective non randomized clinical study examined whether an evidence-based interdisci-
plinary caring program would improve global health status and reduce
somatic symptoms in patients with HSCT.
Method. Patients with HSCT, age >14 years and written informed consent were eligible. The intervention group received modified care consisting of three modules based on counseling and exercise focusing
mobility/activity enhancement, prevention of oral mucositis and nutritional support. Control group patients received standard care. Primary endpoint was global HRQoL measured by EORTC QLQ C30 at
discharge. Secondary endpoints were symptoms measured by EORTC
symptom-scales, physical activity (kcal per week) and use of resources
e.g. duration of hospitalization.
Results. 82 patients participated (control group n=42, intervention
group n=37, average age of 52.6±12.7 years, 69.9% male). Baseline characteristics were balanced between both groups except ECOG-status which
was significantly lower for patients of the intervention group (p<0.01).
All a priori specified covariates were included in the final regression
model. At discharge statistically significant improvement could neither
be shown for global health-related quality of life nor physical functioning nor fatigue but specific symptoms like dyspnoea and nausea/emesis were reported being significantly less severe by patients of the intervention group and duration of hospitalization was significantly shorter.
Regarding physical activation patients in the intervention group were
more active during hospitalization and reported significantly higher
satisfaction with counselling concerning means to enhance their activity. However this level of activity was not maintained after discharge.
Content analysis of the sports therapists’ records showed that 48% of the
patients expressed anxiety and sadness during training sessions while
the main obstacle for activity was the physical condition with fever and
weakness (48% of the patients).
Conclusion. Even though the expected statistically significant improvement of HRQoL could not be achieved by the intervention, some symptoms were reduced and increased activity during hospitalization was
achieved. Cost beneficial effects might be achieved by shorter hospitalization periods.
B28 – 0177
Standardizing early integration of palliative care
*J. Gaertner1,2,3, S. Frechen1, J.-P. Glossmann2,4, M. Hallek2,4, N. Harbeck2,5,
J. Wolf2,4, R. Wuerstlein2,5, R. Voltz1,2,3, C. Ostgathe6
1
University Hospital of Cologne, Department of Palliative Medicine, Cologne, Deutschland, 2University Hospital of Cologne, Center for Integrated
Oncology Cologne Bonn, Cologne, Deutschland, 3Clinical Trials Center
Cologne, BMBF 01KN1106, Cologne, Deutschland, 4University Hospital of Cologne, Department of Internal Medicine I, Cologne, Deutschland, 5University
Hospital of Cologne, Department of Senology, Cologne, Deutschland, 6University of Erlangen, Division of Palliative Medicine, Erlangen, Deutschland
Background. The integration of palliative care (PC) early in the disease trajectory of life limiting diseases is explicitly recommended by the
World Health Organisation (WHO). This recommendation was included in the administrative directives for principles of cancer care in
our institution in 2006. From then on, the early integration (EI) of PC
should be provided by a PC hospital support team (PCST).
Objective. To evaluate the implementation of EI of PC, specifically, to
assess (i) at what point in the disease trajectory the patients were first
provided PC and (ii) whether the concept became increasingly accepted
after one year.
Methods. A retrospective systematic chart analysis was performed. The
first PC consultation was analyzed to assess the patient’s performance
status and symptom burden. The assumption was that seeing patients
relatively early in the disease trajectory would be reflected by seeing
atients that were not already (i) in a reduced performance status or (ii)
p
experiencing symptoms that are indicators for advanced disease (e.g.
dyspnoea).
Results. During the first two years of the project, 862 patients were consulted by the PCST. Generally, patients were already in a reduced physical state (ECOG 3 & 4: 40%) and experiencing burdening symptoms
(e.g. dyspnoea 27%) on the initial PCST consultation. After a one-year
period, the number of burdening symptoms presented at first PC consultation decreased significantly from seven to three (p<0.001), and the
PCST tended to be increasingly requested for psychosocial interventions (p=0.069).
Conclusion. Though after one year of the project patients generally received PC support earlier in the disease trajectory and non-PC physicians increasingly recognized PC competencies for psycho-social issues, the adoption of the WHO recommendation alone did not suffice to
integrate PC early in the course of illness. As a consequence, standard
operating procedures (SOPs) for EI of PC as part of comprehensive-cancer-care have been developed and implemented for 20 (hemato-)oncological diseases to facilitate EI integration of PC by providing clinical
and logistic guidance and reduced terminological confusion.
Seltene Tumoren
Best of Poster – Seltene Tumoren
B29 – 0013
Design and development of nanocarrier for efficient drug delivery into the brain
*A. Orthmann1,2, R. Zeisig2, I. Fichtmer1,2
1
Max Delbrück Centrum, Experimentelle Pharmakologie, Berlin, Deutschland, 2EPO GmbH Berlin-Buch, Berlin, Deutschland
The success in the treatment of brain cancer or brain metastases by chemotherapy is very limited because of the efficient blood-brain barrier
(BBB) which prevents most drugs from reaching tumour cells in the
brain. An encapsulation of cytostatic drugs into liposomal nanocarrier
may help to overcome the tight cell layer of the BBB and to enhance the
therapeutic effect.
The aim of the study was to develop Trojan Horse Liposomes (THL) for
an improved drug transport of anticancer drugs across the BBB to enhance the anti-tumour effect. In a first part we optimized the membrane properties of vesicles with respect to a better passive uptake by and
transport through a tight cell barrier in vitro. In the second part, the
most efficient liposomes were surface modified for an active targeting
using a 19-mer peptide sequence (Angiopep) to increase specific uptake
and trans-cellular transport. It was already shown that Angiopep passes the BBB by a physiological transcytosis process mediated by the low
density lipoprotein receptor related protein (LRP) receptors expressed
on the surface of the BBB and brain cancer cells.
In this study we could demonstrate in vitro that the liposomal nanocarrier with an optimised composition of the lipid membrane (L2) and the
Angiopep ligand, bound to the liposomal surface, significantly improved cellular uptake by epithelial (MDCK II), endothelial (bEnd.3), breast cancer (MT-3) and glioama (U373 MG) cells. Transcytosis through a
tight cell barrier using the MDCK II model demonstrated that the highest amount of calcein passed through the cell layer was induced by the
THL-L2 formulation.
In vivo studies using a human xenograft brain metastasis model (MT-3
breast cancer) in nude mice showed already a significantly better antitumour effect of Mitoxantrone loaded L2-liposomes compared to the
free drug. In addition, clearly fewer side effects like gastrointestinal
complications, weight loss and dehydration were observed. The thera-
peutic effect was further improved if THL-L2 liposomes were used, resulting in an additional tumour volume reduction as compared to L2.
Our results demonstrate that the obstacle in the chemotherapeutic treatment of brain tumours and metastases in the brain can be overcome
by liposomal nanocarrier with carefully composed bilayer and surface
modification with the Angiopep sequence to obtain an improved transport through the BBB.
B30 – 0129
Molecular dissection of the impact of frequent genetic alterations on the response of head and neck cancers to anti-epidermal
growth factor receptor-directed therapies
*M. Pogorzelski1, S. Kasper1, S. Tusche2, S. Ting2, F. Breitenbücher1,
T.C. Gauler1, K.W. Schmid2, M. Schuler1
1
Universitätsklinikum Essen, Innere Medizin (Tumorforschung), Essen,
Deutschland, 2Universitätsklinikum Essen, Institut für Pathologie und
Neuropathologie, Essen, Deutschland
Introduction. Monoclonal antibodies and tyrosine kinase inhibitors
(TKI) targeting the EGFR are approved or under investigation for
the systemic treatment of patients with head and neck squamous cell
cancers (HNSCC). However, primary and acquired resistance against
EGFR-targeted therapies are frequently observed. Mutational activation of the EGFR signalling cascade as well as molecular changes caused by HPV infection are the most abundant oncogenic alterations in
HNSCC, and it is currently unclear whether these events determine the
response to anti-EGFR therapies. Against this background we have used
preclinical cancer models to study the impact of activated PI3K/AKT
and RAS/RAF/MAPK pathways or HPV16 oncoprotein expression on
the response to anti-EGFR therapies in vitro and in vivo.
Methods. Cetuximab- and erlotinib-sensitive cancer cells were retrovirally transduced to express HPV16 oncoproteins E6 and E7, conditionally active AKT and RAF-1, or a RASG12V mutant. Functional transgene
expression was confirmed by immunoblot analysis and PCR. HPV16positive cancer cells and cells harboring endogenously mutated PIK3CA
or RAS were used as alternative models. Cell proliferation, induction
of apoptosis, clonogenic survival and tumor growth in immune-compromised mice were analyzed in relation to treatment with anti-EGFR
antibodies or TKIs.
Results. Activation of the PI3K/AKT and the RAS/RAF/MAPK pathways strongly protected cancer cells against anti-proliferative and
pro-apoptotic effects of anti-EGFR therapies in vitro and in vivo. Mechanistically, this resistance was mediated by changes in the expression
of anti-apoptotic proteins and could be overcome by co-treatment with
specific inhibitors of EGFR downstream signaling. In contrast, ectopic
expression of HPV16 oncoproteins E6 or E7 sensitized EGFR-positive
cancer cell lines to anti-EGFR therapies and to chemotherapy.
Conclusion. Activation of the PI3K/AKT and the RAS/RAF/MAPK pathways functionally interfere with the activity of anti-EGFR therapies in
vitro and in vivo. In contrast, expression of HPV16 oncoproteins sensitizes cells to cetuximab, erlotinib and chemotherapy. Currently, analyses
of HNSCC patients treated with anti-EGFR antibodies are ongoing to
study the predictive value of these molecular alterations.
Supported by the Wilhelm Sander-Stiftung (2005.136.3), the IFORES
program of the Medical Faculty of the University Duisburg-Essen and
the Wiedenfeld-Stiftung.
Abstracts
B31 – 0218
Comparison of Cyclophosphamide versus Ifosfamide containing
adjuvant chemotherapy (CTX) in Ewing sarcoma (ES) patients:
results of the randomized standard risk (SR) cohort of EUROE.W.I.N.G. 99 Trial
B32 – 0424
Meningiomas of the base-of-skull: long term results and patient
self-reported outcome in 507 patients treated with precision
photon radiotherapy in a single institution
*U. Dirksen1, A. Ranft1, M.-C. Le Deley2, J. Whelan3, M. Paulussen4, O. Oberlin5, I. Lewis6, J. Michon7, R. Ladenstein8, B. Brennan9, P. Marec Bérard10,
H. van den Berg11, L. Hjorth12, C. Douglas13, I. Judson14, M. van Glabekke15,
A. Craft16, H. Jürgens1, *U. Dirksen1, A. Ranft1, M.-C. Le Deley2, J. Whelan3,
M. Paulussen4, O. Oberlin5, I. Lewis6, J. Michon7, R. Ladenstein8, B. Brennan9,
P. Marec Bérard10, H. van den Berg11, L. Hjorth12, C. Douglas13, I. Judson14,
M. van Glabekke15, A. Craft16, H. Jürgens1
1
UKM, Pädiatrische Hämatologie und Onkologie, Münster, Deutschland,
2
Institut Gustave Roussy, Biostatisique, Paris, Frankreich, 3University
College Hospital, Medical Oncology, London, UK, 4Vestische Kinderklinik,
Datteln, Deutschland, 5Institut Gustave Roussy, Oncologie Pédiatrique,
Paris, Frankreich, 6St.James University Hospital, Leeds, UK, 7Institut Curie,
Paris, Frankreich, 8St. Anna Children’s Hospital and Research Institute, Wien,
Österreich, 9Royal Manchester Children’s Hospital, Manchester, UK, 10Centre
Léon Bérard, Lyon, Frankreich, 11Academic Medical Center, Emma Children’s
Hospital, Amsterdam, Niederlande, 12Lund University Hospital, Lund,
Schweden, 13CCLG Data Centre, Leicester, UK, 14University of Birmingham,
Birmingham, UK, 15European Organisation for Research and Treatment of
Cancer Headquarters, Brussels, Belgien, 16The Royal Marsden NHS Foundation Trust, London, UK
Background. Anthracyclines and alkylating agents and are the backbone of worldwide used chemotherapeutic regimens in ES. Ifosfamide and
cyclophosphamide have different toxicity profiles and unknown relative
efficacy. The EURO-E.W.I.N.G.99 R1 trial for SR patients, compared two
consolidation regimens combining ifosfamide (I) or cyclophosphamide
(C) with vincristine (V) and actinomycin D (A) (VAI vs VAC).
Methods. SR patients with localized ES and either good histological response to induction chemotherapy or tumor size <200 ml and resection
at diagnosis or radiotherapy alone for local treatment were randomized
for 7 VAI cycles with I=6 g/m2/cycle or 7 VAC cycles with C=1.5 g/m2/
cycle. The non-inferiority analysis was performed with a limit of noninferiority set at −8.5% for 3-y event-free survival (EFS). Overall, 806 pts
were included to achieve 80% power with 1-sided alpha =5%. 91.4% confidence intervals (CI) are given for this final analysis.
Results. 856 pts were recruited from 202 centers in 11 European countries
between 02/2000 and 08/2010: 424 patients received VAI and 432 VAC.
Median FU was 4.6 y, 3-y EFS was 77.1 respectively 76.0%. The 3-y EFS
difference was –1.1% (–6.3; +4.2), hazard ratio of event =1.06 (0.83; 1.36),
hazard ratio of death =1.05 (0.78; 1.41; intention to treat). Results were
similar in the per protocol population. Major modifications of Ctx were
significantly more frequent in the VAI (13%) than in the VAC arm (6%)
due to toxicity and inferior compliance. Thrombocytopenia was more
common in the VAC arm, grade 2–4 acute tubular renal toxicity in the
VAI arm (31 vs 16%).
Conclusions. The efficacy of the two alkylating agents tested in the treatment of ES is similar. Late effects studies regarding renal and gonadal
toxicity are ongoing.
*S.E. Combs1, S. Adeberg1, J.-O. Dittmar1, S. Rieken1, D. Habermehl1, T. Welzel1, P.E. Huber1, J. Debus1
1
Universitätsklinikum Heidelberg, RadioOnkologie, Heidelberg, Deutschland
Purpose. To evaluate long-term results and patients‘ self-reported outcome of high-precision photon radiotherapy for meningiomas of the skull
base with respect to tumor control, side effects and quality of life.
Methods and materials: Between 1985 and 2010, we treated 632 consecutive patients with meningiomas with fractionated stereotactic radiotherapy (FSRT) or intensity modulated radiotherapy (IMRT). Of these,
507 (80%) tumors were located in the skull base region. All patients were
prospectively enrolled in a continuous and regular follow-up program
including thorough clincial-neurological assessment as well as contrastenhanced imaging. Tumor classification was performed by reviewing
all images acquired for treatment planning. Most tumors extended into
several regions of the skull base. Main locations included the sphenoid
wing, sphenoorbital region, cavernous sinus as well as petroclival region. Treatment was delivered using a 6 MV linear accelerator (Siemens, Erlangen, Germany) using FSRT in 376 patients (74%) and IMRT
in 131 patients (26%). A median total dose of 57.6 Gy (range 25–68 Gy)
was prescribed in median single doses of 1.8 Gy. To evaluate long-term
toxicity as well as quality of life, we sent out a detailed questionnaire
to all patients for evaluation within this anaysis. Special focus was set
on long-term sequelae including visual deficits, cranial nerve deficits,
headaches, fatigue or any other symptoms impairing overall quality of
life (QOL).
Results. Overall treatment was well tolerated and very few acute side effects were observed, including alopecia, skin erythema, conjunctivitis,
headache or fatigue. Of the 507 patients, 340 patients (67%) responded
and sent back the questionnaire. Of note, 51% of the patients reported
visual impairment prior to radiotherapy, which was diplopia in 53%.
During follow up, diplopia and visual field deficits were the symptoms
showing the largest range of improvement. Overall QOL was unchanged in 47.7% of the patients after RT, and 37.5% showed an improvement
in QOL during follow-up. Only 11% reported a reduction on QOL after
RT; in these patients, 5 suffered from cancer with metastases, 5 reported
severe arthritis, cardiac disease or other associated with higher age, in
2 patients a tumor recurrence had occurred, and in 8 patients symptoms
associated with the skull base meningioma, such as double vision, gait
disturbance or facial nerve impairment impacted QOL. Only 9% of the
patients reported new symptoms after radiotherapy, which were not always in connection to the treated skull base meningioma. Overall, 84%
of the patients reported no long-term side effects and no new symptoms.
Local control was 98% at 1 year, 95% at 3 years, 94% at 5 years and 88% at
10 years. Patients with benign histology showed a significant higher local control than atypical or anaplastic meningiomas (p<0.0001). Overall
survival was 95% at 5 years and 90% at 10 years.
Conclusion. Patients’ self-reported outcome confirms the convincing
results with respect to tumor control and QOL after precision photon
radiotherapy in skull base meningiomas.
Versorgungsstrukturen/Qualitätssicherung
Best of Poster – Versorgungsstrukturen/
Qualitätssicherung
Qualitätssicherung
B34 – 0179
Trends of population-based breast cancer survival in Germany
and the US: decreasing discrepancies
B33 – 0098
Comparison of psychosocial outcomes of breast and colorectal
cancer patients treated in certified cancer centres vs. non-certified treatment units
*B. Holleczek1, H. Brenner2
1
Saarland Cancer Registry, Saarbrücken, Deutschland, 2Division of Clinical
Epidemiology and Aging Research, German Cancer Research Center,
Heidelberg, Deutschland
*G. Weißflog1, S. Singer1, G. Klinitzke2, E. Kleinert1, C. Wittekind3, E. Brähler1,
J. Ernst1
1
Universität Leipzig, Medizinische Psychologie und Medizinische Soziologie, Leipzig, Deutschland, 2Universitätsklinikum Leipzig AöR, Klinik und
Poliklinik für Psychosomatische Medizin und Psychotherapie, Leipzig,
Deutschland, 3Tumorzentrum am Universitätsklinikum Leipzig e. V., Leipzig, Deutschland
Background. Population-based studies have revealed both higher cancer
survival in the US than in Germany and substantial improvement of
cancer prognosis in these two countries in the past. This populationbased study aims at comparing most recent 5-year survival of breast
cancer (BRC) patients and preceding trends in Germany and the US.
Material and methods. Women with invasive BRC (ICD-10: C50) from
Germany (Saarland) and the US (SEER 13 registries) diagnosed and
followed up through 1977 and 2008 were included (in total 21,796 and
617,882 patients, respectively). Period analysis was used to derive most
up-to-date 5-year relative survival (RS) for subsequent calendar periods
of 4 years between 1981 and 2008 according to age (1–69 and 70+ years
at diagnosis) and stage (localized, local/regional spread, metastasized,
unknown).
Results. Between 1981 and 2008, age standardized RS has steadily improved in Germany and the US from 65% and 75% to 83% and 89%, respectively. In 2005–2008, no differences in age specific RS were observed
for the US, but RS of elderly patients was only 75% compared to 88% for
younger patients in Germany. Over time, the gap in RS between Germany and the US has almost disappeared for younger patients (from 8 to
1% unit), but remained unchanged for elderly patients (13% units). Most
recent age standardized RS of localized BRC was 98% in both countries.
RS of locally/regionally spread and metastasized BRC was 79% and 24%
in Germany and 84% and 27% in the US, respectively in 2005–2008. Since 1993–1996, the differences in RS have decreased by 5 and 7% units for
localized and locally/regionally spread BRC, but increased by 4% units
for metastasized BRC. If adjusted for stage mix, the difference in RS has
almost disappeared over time.
Conclusion. Differences between 5-year RS of BRC patients in Germany
and the US have decreased over time. Similar RS is now observed for
patients below the age of 70 years and localized BRC, but in Germany
RS is still inferior for elderly patients and advanced disease. Differences
in the health care systems, implementation and utilization of organized
screening, delivery of cancer care as well as population characteristics
may account for the observed differences in survival. Encouraging, the
survival of BRC patients has improved in Germany to a much greater
extent than in the US, albeit challenges remain for the care of elderly
patients and advanced disease in both countries.
Purpose. In Germany, breast and colorectal cancer patients are increasingly being treated in certified cancer centres. To date, there are no
research findings investigating potential differences in clinical, sociodemographic and psychosocial outcomes (patient satisfaction, quality
of life, and psychosocial distress) between patients treated in certified
cancer centres and patients treated in non-certified units.
Methods. In a cross-sectional study, socio-demographic, disease-related (e.g. UICC stage), and psychosocial data of patients with breast or
colorectal cancer were assessed in a postal survey. The questionnaire
included the following standardised instruments: for patient satisfaction the Hamburger Fragebogen zum Krankenhausaufenthalt (HFK),
the EORTC Quality of Life Questionnaire – Core instrument (EORTC
QLQ-C30) and for psychosocial distress the Hospital Anxiety and Depression Scale (HADS).
Results. A total of 1,925 persons were enrolled into the study. 101 persons were excluded from this initial sample (48 could not be located, 42
died in the meantime, 14 were cognitive impaired). Of the remaining
1,821 patients, a total of 950 cancer patients participated in the survey
(return-rate: 52%, 666 patients with breast cancer and 284 patients with
colorectal cancer). The mean age of respondents was 64 years. Patients
with breast and colorectal cancer treated in certified cancer centres differed not to patients treated in non-certified units with respect to clinical and socio-demographic data. In both groups, patient satisfaction
was generally high. There are only few differences in patient satisfaction
and its subdimensions (e.g. overall judgement was lower in breast cancer patients who were treated in a certified breast cancer centre; satisfaction with the sub-dimension medical care is higher in colorectal cancer
patients in certified colorectal cancer centres). There were no differences
between both groups in psychosocial distress (anxiety and depression),
but colorectal cancer patients in certified cancer centres experienced
impaired quality of life.
Conclusion. With respect to these empirical findings, there is evidence
of particular (but not general) differences in psychosocial outcomes in
comparison between certified cancer centres and non-certified units.
These results must be validated in future studies involving further parameters (e.g. guideline-adherence, compliance), and advanced designs
(longitudinal approach).
Abstracts
Qualitätssicherung
Qualitätssicherung
B35 – 0283
Effects of a longitudinal intervention study on physical activity
and functional capability in workaday and occupational following oncological rehabilitation
B36 – 0408
Results of the 2010 patient survey in Breast Care Centers
*H. Kähnert1, A.-K. Exner1, B. Leibbrand2, I. Biester3, D. Gharaei4, C. Niehues5,
M. Trapp6
1
Salzetalklinik, IFR, Norderney – Bad Salzuflen, Bad Salzuflen, Deutschland,
2
Salzetalklinik, Onkologie, Bad Salzuflen, Deutschland, 3MediClin Rose
Klinik, Onkologie, Horn-Bad Meinberg, Deutschland, 4Klinik Porta-Westfalica, Onkologie, Bad Oeynhausen, Deutschland, 5Median Kliniken am
Burggraben, Onkologie, Bad Salzuflen, Deutschland, 6Median Klinik am
Park, Onkologie, Bad Oeynhausen, Deutschland
Introduction. Physical activity (PA) plays a major role in the prevention
and rehabilitation of breast cancer patients. Although many patients
may develop an intention to change their PA, they might not act accordingly. Based on the Health Action Process Approach, volitional
factors like action-/coping planning serve to mediate between exercise
intention and later PA. The study investigates the effectiveness of the
INOP-intervention (Individuelle Nachsorge onkologischer Patienten)
focusing on action- and coping planning to change PA and thus functional capability in workaday (FCW) as well as occupational (FCO) over
six months.
Methods. The sample consisted of 450 breast cancer patients who underwent an oncological rehabilitation. They were randomly assigned to
the control (CG) or intervention group (IG) and were interviewed with
a questionnaire at the beginning (t1), at the end (t2) and 6 months after
the rehabilitation (t3). While the CG received the conventional care, the
IG additionally received the INOP intervention (consisting of a seminar, a counseling interview during the clinical setting and/or a phone
interview 3 months after discharge). Analysis of covariance was applied
to investigate differences between CG and IG regarding the action-/coping planning, the PA, FCW and FCO (IRES-3 questionnaire).
Results. Compared to the CG the action-/coping planning of the IG
increased from t1 to t3. The IG patients reported significantly higher
planning activities to t2 (p<0.05) and t3 (p<0.05). Further analysis demonstrated the mediating mechanism of planning activities in the
maintenance of PA 6 months after discharge. At t3 participants in the
IG differed from those in the CG regarding PA (p<0.01). From t1 to t3
the IG patients increased their PA on average by 71 min per week and
the CG on average 10 min per week. Furthermore IG patients were also
considerably less limited in their FCW (p=0.05) and FCO (p<0.01) than
CG patients at t3.
Conclusion. The present study provides evidence that INOP is a useful
intervention to enhance physical activity and thus functional capability
of breast cancer patients at least 6 months after discharge. Presently a
follow up questionnaire is carried out to investigate whether these effects can be retained for 12 months. The INOP-intervention is brief, well
documented and can be implemented in a clinical setting and post-rehabilitations support.
Supported by: Institut für Rehabilitationsforschung, Norderney.
*C. Kowalski1, L. Ansmann1, H. Pfaff1
1
Universität zu Köln, IMVR, Köln, Deutschland
Introduction. Breast Care Centers that were accredited according to the
German Cancer Society criteria were offered to participate in a standardized patient survey in 2010 that was conducted by the Institute for
Medical Sociology, Health Services Research and Rehabilitation Science of the University of Cologne.
Methods. Patients were included if they (1) had undergone inpatient surgery for newly-diagnosed breast cancer between 22 March and 30 November 2010; (2) at least one malignancy; and (3) at least one post-operative histologic evaluation. Shortly before being discharged from the
hospital, the patients were asked to give written consent to be included
in the survey by the hospital staff. Once patients had given their consent, medical personnel from the centers provided the research team
with clinical information about the patients. The questionnaire was sent
out to the patients within a week of receiving their written consent. The
Cologne Patient Questionnaire- Breast Cancer (CPQ-BC) was used,
which assesses a number of aspects of hospital care as perceived by the
patients, among them provider-patient interaction, the disease-specific
information provided, the quality of organization, and room amenities.
Results. 128 of 195 Breast Care Centers and 160 of 251 hospitals participated in the study. 8226 patients consented to the survey. The questionnaires of 7301 patients could be included in the analyses. Overall,
patients were satisfied with their hospital stay. Especially with regard to
the medical treatment and the cleanliness only few patients were dissatisfied. Trust in nurses and doctors were particularly high, too. However, there is room for improvement for a number of issues, for example
with regard to the provision of information and patient involvement in
decision making. In addition, for a number of indicators substantial differences were found between the hospitals.
Conclusion. Involving more than 7000 patients from 160 hospitals, the
study is among the largest breast cancer specific patient surveys in Europe. The results of the survey provide information on the breast centers’ development and can be used by the centers’ surgery locations for
benchmarking purposes, to identify strengths and weaknesses, and to
take actions. Results from North Rhine-Westphalia demonstrate that
the patient survey results can be used successfully since 2005.
Urologische Tumoren
Best of Poster – Urologische Tumoren
B37 – 0005
A novel stereotactic prostate biopsy system integrating preinterventional MRI and live US fusion
*T.H. Kuru1, M. Roethke2, H.-P. Schlemmer2, M. Hohenfellner1, B.A. Hadaschik1
1
Universitätsklinik Heidelberg, Klinik für Urologie und Kinderurologie,
Heidelberg, Deutschland, 2DKFZ Heidelberg, Abteilung für Radiologie,
Purpose. To develop an effective way to precisely diagnose prostate cancer employing a novel prostate biopsy system which integrates preinterventional MRI with periinterventional ultrasound for perineal navigated prostate biopsies.
Patients and methods. 106 men with suspicion of prostate cancer (median age 66 yrs, PSA 8.0 ng/ml, prostate volume 47 ml) underwent multiparametric 3T-MRI. Suspicious lesions were marked on the MRI and
the data were transferred to the novel biopsy system. Using a custommade biplane TRUS probe mounted on a stepper, 3D-ultrasound data
were gathered and fused with the MRI. As a result, suspicious MRI-lesions were superimposed over the TRUS-data. Next, 3D-biopsy planning
was performed including systematic biopsies from the peripheral zone
of the prostate. Perineal biopsies were taken under live US-imaging and
the precise location of each biopsy was documented in 3D. Feasibility,
safety, and cancer detection were evaluated.
Results. Prostate cancer was detected in 63 out of 106 patients (59.4%).
A positive correlation between MRI findings and histopathology was
found in 68.9% (71/103). In MRI-lesions marked as highly suspicious,
the detection rate was 95.8% (23/24). Target registration error of the first
2461 biopsy cores was 1.7 mm. Regarding adverse effects, two patients
experienced urinary retention and one patient a perineal hematoma.
Urinary tract infections did not occur.
Conclusions. Perineal stereotactic prostate biopsies guided by the combination of MRI and ultrasound allow effective examination of suspicious MRI-lesions. Each biopsy core taken is documented accurately
for its location in 3D enabling MRI-validation and tailored treatment
planning. The morbidity of the procedure was minimal.
B38 – 0233
Basal Differentiation Marker KRT14 Identifies High-Risk Bladder
Cancer Patients
*J.-P. Volkmer1,2, D. Sahoo2, R.K. Chin2, P.L. Ho3, C. Tang2, A.V. Kurtova3,
S.B. Willingham2, S.K. Pazhanisamy3, H. Contreras-Trujillo2, T. Storm2,
Y. Lotan4, A. Beck2, A. Alizadeh2, G. Guilherme3, S. Lerner3, M. van de Rijn,2,
L. Shortliffe2, K. Chan3, I. Weissman2
1
Uniklinik Düsseldorf, Urologie, Düsseldorf, Deutschland, 2Stanford University, Institute for Stem Cell Biology & Regenerative Medicine, Stanford, USA,
3
Baylor College of Medicine, Houston, USA, 4UT Southwestern, Urology,
Dallas, USA
Background. Pathological stage and grade are the standard for assessing prognosis of bladder cancer (BC). Grade provides a description of
BC differentiation based on broad histological criteria. We sought to
determine whether a molecular classification of differentiation could
improve BC prognostics.
Methods. We developed a biologically supervised computational approach, utilizing pre-existing gene-expression datasets, to predict differentially expressed genes during BC differentiation. Tumor cells corresponding to each differentiation state were isolated from patient BCs
by fluorescence-activated cell sorting and their relative tumorigenic and
differentiation potential were validated by xeno-transplantation. An association between the identified molecular markers with patient survival was validated in three independent pre-existing BC gene expression
datasets and two independent patient tissue datasets by immunohistochemistry.
Results. We identified keratin and corresponding cell-surface marker
expression patterns that putatively define three differentiation states
in BCs: basal (KRT14+KRT5+KRT20−/CD90+CD44+CD49f+), intermediate (KRT14−KRT5+KRT20−/CD90-CD44+CD49f+), and differentiated
(KRT14−KRT5−KRT20+/CD90−CD44−CD49f+). These differentiation states revealed three subtypes of BC (basal, intermediate, differentiated).
Only the most primitive cells within each subtype formed xenograft
tumors and differentiated to all downstream cell compartments. KRT14
marks the basal differentiation state and is associated with significantly
worse patient survival in 3 independent gene expression (p<0.001) and
two independent protein expression (p<0.001) datasets with a total of
943 patients. Multivariate analysis revealed that the prognostic power of
KRT14 is independent of established clinical and pathological variables.
Conclusions. We identified three novel differentiation states and corresponding subtypes in BC each with a distinct tumor initiating cell
population. Moreover, KRT14, which marks the basal subtype, was a
robust marker for BC patient survival independent of established pathological and clinical variables.
B39 – 0400
Serum analysis to define predictive protein signatures specific
for TKI-therapy response in patients with metastatic renal cell
carcinoma
*M. Walter1, A. Szendröi2, N. Kröger1, C. Bode1, T. Steiner1,3, F. von Eggeling4,
O. Kniemeyer5, P. Zipfel6, I. Romics2, M.-O. Grimm1, K. Junker1
1
University Hospitals Jena, Department of Urology, Jena, Deutschland,
2
Semmelweis University, Department of Urology, Budapest, Ungarn,3Helios
Hospital Erfurt, Department of Urology, Erfurt, Deutschland, 4University
Hospitals Jena, Institute of Human Genetics and Anthropology, Jena,
Deutschland, 5Hans-Knöll-Institute, Department of Molecular and Applied
Microbiology, Jena, Deutschland, 6Hans-Knöll-Institute, Department of
Infection Biology, Jena, Deutschland
Objectives. Renal cell carcinomas (RCC) represent 3% of all carcinomas
but are the most common malignancies of the kidney. Localized disease
can be treated by surgery while in patients with advanced or metastatic disease (mRCC) systemic therapy is induced. For this purpose the
European Association of Urology (EAU) published recommendations
including the tyrosine kinase inhibitors (TKIs) Sunitinib and Sorafenib
as therapy options. Both agents lead to primary clinical benefit in the
majority of patients while some others show no response and undergo
progressive disease. Recognition of these patients would optimize individual treatment and also avoid high costs for health care system. For
this reason reliable predictive biomarker are absolutely necessary. The
aim of this study is to establish protein signatures predictive for primary therapy response to Sunitinib and Sorafenib.
Materials and methods. We examined serum samples from mRCC-patients before TKI-therapy and after 3 months (26 Sunitinib, 23 Sorafenib). Primary response after 3 months was evaluated by RECIST. Mass
spectrometry based and gel based techniques were used for protein analysis: Surface-enhanced laser desorption/ionisation time-of-flight mass
Abstracts
spectrometry (SELDI-TOF MS) and multiplex-two-dimensional fluorescence gel electrophoresis (Multiplex-2DE) provided protein candidates
separating samples into primary clinical benefit (CB) and primary progressive disease (PD). Identification of these candidates was performed
by peptide mass fingerprinting. Western Blot and ELISA were carried
out for quantification.
Results. Protein pattern specific for primary PD could be generated by
SELDI-TOF MS and biostatistics. Multiplex-2DE revealed i.a. serum
amyloid A (SAA) as differentially expressed protein. Pre-therapeutic
SAA-concentrations were significantly different between CB and PD in
Sunitinib-treated patients but were not for Sorafenib. Comparison of
therapeutic SAA-concentrations after 3 months resulted in significant
differences for both drugs. High SAA-levels are representative for primary PD.
Conclusion. Our data show that pre-therapeutic serum is well-suited to
establish protein signatures for TKI-therapy response prediction based
on the used techniques. Selection of patients for personalized medicine seems possible. In this ongoing study further candidates from the
detected protein signature have to be identified and validated on an independent patient cohort.
B40 – 0431
Influence of morbidity on health-related quality of life after
open retropubic radical prostatectomy
*B. Löppenberg1, C. von Bodmann1, M. Brock1, T. Eggert1, J. Palisaar1,
J. Noldus1
1
Ruhr-Universität Bochum Marienhospital Herne, Klinik für Urologie und
Neuro-Urologie, Herne, Deutschland
Introduction and Objectives. Standardized assessment of complications
following open retropubic prostatectomy (ORRP) results in overall
complication rates of about 30%.The influence of medical and surgical
complications on health-related quality of life (HRQOL) has not been
investigated. Objective was to evaluate the influence of complications,
continence and erectile dysfunction on HRQOL one year after ORRP.
Methods. Medical and surgical complications of ORRP were assessed
prospectively within 30 days postoperative. They were graded according to the Clavien-Dindo classification retrospectively. HRQOL was
assessed preoperatively and one year after ORRP using the EORTCQLQ C30 questionnaire. Pre- and postoperative results were compared
by using the Wilcoxon rank test. HRQOL of patients without complications were compared to patients who had complications using the
Mann Whitney-U test. A p<0.05 was considered statistically significant.
Results. Between August 2003 and September 2009 2899 patients
underwent ORRP for clinically localized prostate cancer in a single
institution. Patients with available pre- and postoperative data sets
(n=856, 33.6%) were enrolled in the analysis. Overall complication
rate was 25.7% (n=220). Low-grade (Clavien-Dindo 1–2) or high-grade (Clavien-Dindo 3–5) complications occurred in 23.6% (n=202) and
5.0% (n=42), respectively. In general the subjective global health status
(GHS) improves after ORRP (70.5±21.99 vs. 74.5±19.7, p<0.0001). Overall-, low- or high-grade complications influence several symptom- and
functional scales significantly. The postoperative GHS of patients who
had a complication in comparison to patients who had no complication is worse (75.4±19.3 vs. 71.3±20.5, p=0.004). In patients with highgrade complications global health-status is even worse than preoperatively (70.5±21.99 vs. 68.6±24.5, p=0.183). Compared to incontinent
patients GHS was higher in continent patients (78.6±17.8 vs. 64.3±20.5,
p<0.0001) and patients without erectile dysfunction have higher GHS
scores (83.7±15.7 vs. 73±19.8, p<0.0001).
Conclusions. In general global health status improves after ORRP.
Complications have a significant impact on postoperative HRQOL,
however clinical impact is low. Incontinence and erectile dysfunction
have a statistically significant and clinical considerable deteriorating
effect on postoperative quality of life.
GI-Tumoren
Discussed Poster – GI-Tumoren
D1 – 0093
Interaction of the CXC-chemokines SDF-1 and I-TAC in the
regulation of tumor growth and angiogenesis of colorectal
cancer metastases
*K. Rupertus1, M.D. Menger2, J. Sinistra2, O. Kollmar3
1
Universitätsklinikum Tübingen, Medizinische Klink II, Tübingen, Deutschland, 2Universität des Saarlandes, Institut für Klinisch-Experimentelle Chirurgie, Homburg/Saar, Deutschland, 3Universitätsklinikum des Saarlandes,
Abteilung für Allgemeine Chirurgie, Viszeral-, Gefäß- und Kinderchirurgie,
Homburg/Saar, Deutschland
Background. Recent studies have demonstrated that the chemokine
SDF-1 and its receptors CXCR4 and CXCR7 are involved in metastasis and angiogenesis of colorectal cancer. Whereas the SDF-1-mediated
signaling via CXCR4 and CXCR7 promotes angiogenesis and tumor
progression, the second ligand for CXCR7, I-TAC, also exerts angiostatic impulses through CXCR3. Results from previous studies suggest
that in colorectal carcinoma, the balance between SDF-1 and I-TAC determines the angiogenic switch within newly established metastases.
In the present study, we therefore studied the interaction of SDF-1 and
I-TAC in an in vivo model of colorectal cancer metastasis.
Material and methods. For in vivo studies, GFP-transfected CT26.WT
colorectal cancer cells were implanted into the dorsal skinfold chamber of syngeneic BALB/c mice (n=40).The animals were randomized
into 5 groups (n=8). In the first group, I-TAC was locally applied on the
tumors 5 days after tumor cell implantation (I-TAC). The second group
received intraperitoneal injections with a neutralizing anti-I-TAC antibody starting at the day of tumor cell implantation and every second
day thereafter (α-I-TAC). The third group was treated with a neutralizing anti-SDF-1 antibody (α-SDF-1), the forth group received alternate
injections with both antibodies (α-I-TAC/SDF-1). One group received
sham treatment and served as control. Increase of tumor size [mm2],
neovascularization [cm/cm2] and tumor cell migration [n/field] were
studied using intravital fluorescence microscopy during an observation period of 14 days.
Results. Local application of I-TAC significantly stimulated tumor
growth (4.20±0.64 mm2 vs. 2.67±0.31 mm2 increase of tumor area)
compared to controls without affecting tumor neovascularization
and tumor cell migration. Blockade of I-TAC-mediated signaling by a
neutralizing antibody significantly reduced tumor cell migration but
did not influence tumor growth and neovessel formation. Blockade
of SDF-1-mediated signaling had no effect on tumor growth, neovascularization and tumor cell migration. Combined blockade of I-TAC
and SDF-1 by alternate application of neutralizing antibodies almost
completely abrogated tumor vessel formation leaving tumors poorly
vascularized 14 days after tumor cell implantation (19.28±8.36 cm/cm2
vs. 140.28±30.68 cm/cm2). Concomitantly, tumor growth was reduced
compared to the other groups. Tumor cell migration was not affected.
Conclusion. The results show that there is a close interaction between
the SDF-1 and I-TAC-mediated signaling pathways in the regulation
of angiogenesis of colorectal carcinoma. Our data indicate that I-TAC
counteracts the anti-angiogenic effects expected after SDF-1-blocka-
de and vice versa. Therefore, blockade of the SDF-1-pathway can only
become a successful anti-angiogenic approach in tumor therapy with
respect to I-TAC-mediated signaling.
D2 – 0223
Anti-neoplastic activity of Taurolidine in pancreatic cancer – in
vitro study of different pancreatic cancer cell lines
*M. Buchholz1, A. Flier1, S. Hahn2, D. Bulut3, W. Uhl1, A. Chromik1
1
St. Josefs Hospital, Chirurgie, Bochum, Deutschland, 2Ruhr Universität,
Bochum, Deutschland, 3St. Josefs Hospital, Bochum, Deutschland
Introduction. Taurolidine (TRD) – a compound derived from the aminosulfoacid Taurine – has been shown to exert anti-neoplastic activity
in vitro in several malignant cell lines (e.g. glioblastoma, and colorectal
cancer). However, human pancreatic cancer cells have not been tested
for susceptibility against TRD induced cell death. The aim of this project was therefore to evaluate the anti-neoplastic activity of TRD in different pancreatic cancer cell lines in vitro.
Material and methods. Five pancreatic cancer cell lines (AsPC-1, BxPC3, HPAF II, MiaPaca-2 and Panc1) were incubated with increasing concentrations of TRD (10, 100, 250, 500 und 1000 µmol/l) for 6 h, 12 h, 24 h
and 48 h. Different methods were used to receive a systematic analysis
of several aspects of anti-neoplastic actions induced by TRD. Cytotoxic
and anti-proliferative activities were evaluated by colorimetric MTTand ELISA based BrdU-assays, respectively. The TRD related apoptosis
induction was examined by FACS-analysis (AnnexinV-FITC/Propidiumiodide). Dose dependent growth curves during exposure of TRD over
a certain period of time were rendered using a real-time cell analyzer
(xCelligence, Roche). To compare the effects of TRD with a standard
chemotherapeutic agent for pancreatic cancer, gemcitabine was used as
control treatment (concentrations: 0.01, 0.1, 1, 10, 100 µmol/l).
Results. TRD showed a strong cytotoxic and anti-proliferative effect
in all pancreatic cancer cells with maximal reduction of cell viability
to 10% and proliferation to 15%, as shown in the MTT-and BrdU assay,
respectively. The FACS analysis resulted in a strong apoptotic response upon stimulation by TRD leading to a maximal apoptotic effect of
40–50%. Among all concentrations, TRD 250 µM caused the strongest
anti-neoplastic activity. The results of the real-time growth curve experiments confirmed the results. Interestingly, gemcitabine was less effective compared to TRD in all cell lines.
Conclusions. In this systematic analysis, it could be demonstrated for
the first time that TRD exerts anti neoplastic activity in different pancreatic cancer cell lines. The results indicate that TRD operates with
different mechanisms, e.g. inhibition of proliferation, direct cell toxicity
and induction of apoptosis. As the most effective TRD concentration,
250 µmol/l was determined, which was also superior to gemcitabine.
Further studies are necessary to evaluate the in vivo capacity of TRD in
pancreatic cancer.
D3 – 0259
KRAS, BRAF and PI3K mutations in rectal cancer
*P. Jo1, K. Jung2, J. Salendo1, T. Beissbarth2, M. Spitzner1, H.A. Wolff3,
L.C. Conradi1, M. Grade1, J. Gaedcke1, H. Becker1, M. Ghadimi1
1
Universitätsmedizin Göttingen, Abteilung für Allgemein- und Viszeralchirurgie, Göttingen, Deutschland, 2Universitätsmedizin Göttingen, Abteilung
für Medizinische Statistik, Göttingen, Deutschland, 3Universitätsmedizin
Göttingen, Abteilung für Strahlentherapie und Radioonkologie, Göttingen,
Deutschland
Background. The heterogeneous response in locally advanced rectal
cancer (RC) treated with a 5-FU based radiochemotherapy (RCT) is still
a considerable clinical dilemma. The pretherapeutic identification of
responders would allow a patient adjusted therapy. Mutations within
the MAPK and PI3K pathway were previously shown to activate the pathways. However, data on their clinical impact are rare, especially with
respect to the exchange dependent level of activation.
Materials and methods. Mutation profile of KRAS, BRAF and PI3K was
assessed in 192 patients with RC. All patients were treated and followedup within the CAO/ARO/AIO-94 and -04 trial of the German Rectal
Cancer Study Group. Analyses compromised exons 2, 3 and 4 for KRAS,
exon 15 for BRAF and exons 9 and 20 for PI3K. Mutations were assessed
using bidirectional Sanger Sequencing. In case of differing results a primer extension analyses (SNaPshot Multiplex Kit Applied Biosystems,
Foster City, CA) was applied for definite decision.
Results. No typical (V600E) BRAF mutation was identified. 85 (44%)
tumors revealed a KRAS mutation, 22 (11%) showed a mutation in PI3K.
In 55% (12 out of 22) of the tumors KRAS and PI3K mutations occurred simultaneously. Those patients harboring both mutations revealed
a significantly worse 3- and 5-year disease free survival (p=0.02). KRAS
mutation was significantly associated with a lower number of postoperative lymph node positivity (ypN+; p=0.05). However, tremendous differences occurred between the different type of amino acid exchanges
(p<0.01). While patients with a G13D mutation barely experience ypN+
(5%), half of the patients suffering a G12V mutated tumor experience
postoperative lymph node metastasis.
Conclusion. For KRAS a differentiation regarding the amino acid exchange should be aimed and their clinical meaning should be further
analysed. Mutations of both KRAS and PI3K are present in more than
half of the PI3K mutated tumors. It deciphers a distinct subtype of RC
that is associated with a more aggressive course of disease.
Abstracts
D4 – 0274
Preoperative chemoradiation for resectable adenocarcinom of
the pancreas (ISRCTN 78805636): results of a randomized trial
D5 – 0304
CpG island methylator phenotype infers a poor prognosis in
locally advanced rectal cancer
*H. Golcher1, H. Witzigmann2, L. Marti3, J. Lange3, W. Bechstein4, C. Bruns5,
H. Jungnickel2, J. Hauss6, S. Schreiber7, T. Brunner8, G. Grabenbauer9, S. Merkel1, R. Fietkau10, W. Hohenberger1
1
Universitätsklinikum Erlangen, Chirurgie, Erlangen, Deutschland,
2
Krankenhaus Dresden-Friedrichstadt, Allgemein- und Viszeralchirurgie,
Dresden, Deutschland, 3Kantonsspital St. Gallen, Chirurgie, St. Gallen,
Schweiz, 4Universitätsklinikum Frankfurt/Main, Allgemein- und Viszeralchirurgie, Frankfurt/Main, Deutschland, 5Universitätsklinikum München-Großhadern, Chirurgie, München, Deutschland, 6Universitätsklinikum Leipzig,
Department Operative Medizin, Leipzig, Deutschland, 7Universitätsklinikum Leipzig, Unfall-, Wiederherstellungs- und Plastische Chirurgie, Leipzig,
Deutschland, 8Gray Institute for Radiation Oncology and Biology, Oxford,
UK, 9Praxis für Radiologische Diagnostik, Radioonkologie und Nuklearmedizin (DiaCura Coburg), Strahlentherapie, Coburg, Deutschland, 10Universitätsklinikum Erlangen, Strahlentherapie, Erlangen, Deutschland
*P. Jo1, K. Jung2, M. Grade1, L.C. Conradi1, H.A. Wolff3, J. Kitz4, J. Rüschoff5,
A. Hartmann6, H. Becker1, T. Beissbarth2, A. Müller1, M. Ghadimi1, R. Schneider-Stock6, J. Gaedcke1
1
Deutschland, 4Universitätsmedizin Göttingen, Abteilung für Pathologie,
Göttingen, Deutschland, 5Pathologie Nordhessen, Kassel, Deutschland,
6
Universitätsklinikum Erlangen, Abteilung für Pathologie, Erlangen,
Deutschland
Introduction. Standard treatment for resectable pancreatic carcinoma is
primary surgery, and median overal survival time [mOS] for patients
[pts] with resected pancreatic cancer is about 20 months. But still most
pts die from local relapse or metastases. Therefore, we investigated in
a randomized controlled trial whether preoperative chemoradiation
[CRT] in resectable pancreatic carcinoma is superior compared to primary resection.
Patients and methods. Pts with histologically proven ductal adenocarcinoma of the pancreatic head encircling peripancreatic vessels for 180°
were randomized into two groups: Group A: primary surgery, Group B:
preoperative chemoradiation (55.4 Gy; gemcitabine/cisplatin), followed
by surgery 6 weeks later. In 2005 a protocol amendment suggested adjuvant chemotherapy (gemcitabine). The primary endpoint was mOS.
Results. Between 01.06.2003 and 31.12.2009, 73 pts were randomised in
8 centres (A: n=37, B: n=36). Due to slow recruitment the trial was closed early (planned n=254). By 25.7.11 data of 68 pts (A/B: n=34) could
be evaluated, 3 pts withdrew consent (A/B: n=2/1), 1 centre did not sent
data (A/B: n=1). The allocated therapy was received by 33 pts in Group A
and 30 pts in Group B. 1 pt (A) developed sepsis and died before surgery.
4 pts refused the allocated CRT and underwent primary surgery. Another 4 pts (B) did not undergo surgery due to obvious tumor progression
after CRT. Tumor resection was performed in 24 pts (A) and in 20 pts
(B) by intention-to-treat-analysis. Explorative laparotomy revealed locally unresectable tumor in 6 pts (A/B n=4/2) and distant metastasis
in 13 pts (A/B n=5/8). The R0-resection rate was 67% (16/24 pts) in A
and 90% (18/20 pts) in B (p=0.083, fisher exact test). One patient (A)
died postoperatively due to perioperative myocardial infarction/multiorgan failure in hospital. Postoperative complications were comparable
in both groups. mOS was 14.4 months (A) and 17.4 months (B; p=0.90).
mOS after tumor resection was 18 months and 25 months respectively
(p=0,63). For pts whose tumors were not resected mOS was 9.5 months
(A) and 8.2 months (B; p=0.84; similar figures for per-protocol analysis).
Conclusion. The results for the primary endpoint mOS of this trial were
not statistically significant due to low patient numbers. Instead, both
groups had comparable survival figures for resected as well as for notresected disease. There was a trend for a higher rate of clear resection
margins after CRT and CRT helped to de-mask the biology of the tumor
sparing pts with rapidly progressive disease from surgery.
Introduction. Locally advanced rectal cancers are treated with preoperative radiochemotherapy (RCT). However, subsets of patients have no
benefit from preoperative treatment. Since epigenetic modifications,
including DNA methylation, may influence response to neoadjuvant
treatment we studied the CpG island methylator phenotype (CIMP) in
patients who received a 5-fluoruracil based RCT.
Material and methods. One-hundred and fifty patients with locally
advanced rectal cancer, treated within a phase III clinical trial (CAO/
ARO/AIO-94 and -04), were included in this analysis. CIMP was assessed by methylation specific PCR (MSP) using RUNX3, SOCS1, NEUROG1, IGF2 and CACNA1G as marker panel. Loss of mismatch repair
gene (MMR) expression was assessed by immunohistochemistry for a
subset of patients. KRAS and BRAF mutation status were available from
previous studies.
Results. The CIMP status could be established in all (n=150) patients.
Fifteen (10%) revealed CIMP positivity (≥3 methylated promoters), whereas 135 patients (90%) where classified as CIMP negative. Analysis for
MMR status did not reveal any microsatellite instability (MSI). A single mutation of the BRAF gene (D594G) was detected. The KRAS gene
(exon 1, 2, and 3) was mutated in 65 tumors (43%) but was not correlated
to a specific CIMP status. Three- and 5-year disease-free survival was
notably worse in CIMP positive patients (56% and 0% vs. 80% and 75%;
p<0.01) suggesting an increased likelihood of poor clinical outcome
(Hazard Ratio 5.5; 95%-CI: [2.1, 13.9]).
Conclusion. CIMP positivity, defined by methylation of at least three
specific gene promoters, is an infrequent event in locally advanced rectal cancer. However, it increases the likelihood of distant metastases.
Therefore, the CIMP status may be included as a molecular marker for
the identification of high-risk patients and might contribute to individual treatment stratification.
D6 – 0382
Searching for predictive molecular markers for chemoradioimmunotherapy with interferon-alpha and 5-fluorouracil of
pancreatic cancer patients
Discussed Poster – Mammakarzinom/
*T. Rusch1, S. Bulashevska2, J. Werner1, A.V. Bazhin1
1
Universitätsklinikum Heidelberg, Chirurgische Klinik, Heidelberg, Deutschland, 2Deutsches Krebsforschungszentrum, Division of Theoretical Bioinformatics, Heidelberg, Deutschland
D7 – 0163
The power of DNA double-strand break repair testing to predict
breast cancer susceptibility
Background and aims. Nowadays the importance of individualised therapy finds its way more and more into the awareness of scientists and
medical doctors. Pancreatic carcinoma has a particularly poor prognosis with a median survival of 6 months. The standard treatment today is
surgical resection and subsequent adjuvant chemotherapy. This is possible in about 20% of all patients, and results in a median survival of over
20 months. A recent multicenter trial on intensified adjuvant chemoradioimmunotherapy with interferon-alpha, the CapRi trial, also could
not increase survival compared to standard chemotherapy, 5-fluorouracil alone. Nevertheless the outcome of over 30 months median survival
represented the best ever reported outcome for patients with resected
pancreatic cancer in a randomized trial. The main aim of the work was
to identify predictive molecular markers for patients’ selection for chemoradioimmunotherapy with interferon-alpha.
Methods. RNA from the frozen tumor tissues of patients with higher
and lower overall survival (OS) was isolated and used for gene expression profiling with Illumina technology. Bioinformatics was applied to
select differentially expressed genes. The selected gene candidates were
further validated by real-time PCR. Survival analysis with gene candidates as predictors was applied to find predictive markers with respect
to OS and disease-free survival (DFS).
Results. 12 gene candidates were selected from the Illumine array data
as potential candidates for their subsequent evaluation as predictive
markers. Expression level of these genes was measured with Real-Time
PCR. Afterwards we applied the Cox Proportional Hazard model on
the 12 selected genes to identify the significant predictors of the OS and
disease-free survival (DFS). Highly significant predictors for the OS of
the patients appeared to be GAGE5 (p =0.0099), as well as MAP3K2 (p
=0.055) and RTEL1 (p =0.06). 3 genes were detected to be highly significant predictors for the DFS: GAGE5 (p =0.0088), MAP3K2 (p =0.02444)
and TCEA1 (p =0.0304).
Conclusion. Expression level of GAGE5, MAP3K2 and RTEL1 has been
found to be predictive for the OS, and GAGE5, MAP3K2 and TCEA1 –
for the DFS of patients undergoing chemoradioimmunotherapy. These
markers should be prospectively evaluated in a future clinical trial.
M. Keimling1, M. Deniz1, D. Varga1, H. Schrezenmeier2, R. Kreienberg1, I. Hoffmann3, J. Koenig3, *L. Wiesmüller1
1
Universität Ulm, Universitätsfrauenklinik, Ulm, Deutschland, 2Universität
Ulm, Abt. Transfusionsmedizin, Ulm, Deutschland, 3Universität Mainz,
IMBEI, Mainz, Deutschland
Purpose. All breast cancer susceptibility genes have been linked to DNA
double strand break (DSB) repair. However, these genes explain only a
small fraction of the familial risk. To identify novel markers that may
serve as indicators for breast cancer risk, we performed DSB repair
analysis in cohorts of predisposed women, cancer patients, and healthy
women.
Methods. We previously developed a GFP-based test system for detection of mechanistically distinct DSB repair changes caused by predisposing mutations. Here, we analyzed DSB repair using three pathway-specific substrates in peripheral blood lymphocytes (PBLs) from 35 female
members of families with defined history of familial breast and/or ovarian cancer, 175 female breast cancer patients, and 245 healthy women
without previous cancer and without family history of breast cancer. A
logistic model was fitted for each variable to determine association of
repair changes with breast cancer/risk.
Results. We found increases of the error-prone mechanisms non-homologous end joining (NHEJ) and single-strand annealing (SSA) in
women with familial risk and breast cancer patients (risk: p=0.0001–
0.0022; cancer: p=0.0004–0.0042). Young age (<50) at initial diagnosis of breast cancer, which could be indicative of genetic predisposition, was associated with elevated SSA frequencies using two different
substrates, amounting to similar odds ratios (ORs) as for familial risk
(risk: OR= 2.61–4.05, p=0.0007–0.0045; young patients: OR=2.54–4.46,
p=0.0059–0.0095).
Conclusions. In conclusion, detection of distinct DSB repair activities in
PBLs could be a method to estimate breast cancer susceptibility beyond
the limitations of genotyping and to predict responsiveness to therapeutics targeting DSB repair-dysfunctional tumors.
Gynäkologische Tumoren
D8 – 0175
Immunoglobulin kappa C as a plasma cell derived prognostic
and predictive factor in breast cancer
*M. Schmidt1, B. Hellwig2, Z. Chen1, S. Hammad3, D. Böhm1, A. Lebrecht1,
S. Gebhard1, M. Gehrmann4, H. Kölbl1, J. Hengstler3
1
Universitätsmedizin, Frauenklinik, Mainz, Deutschland, 2Technische Universität, Institut für Statistik, Dortmund, Deutschland, 3Technische Universität, Leibniz-Institut für Arbeitsforschung (IfADo), Dortmund, Deutschland,
4
Bayer, Leverkusen, Deutschland
Background. In recent literature, the humoral immune system is shown
to strongly influence breast cancer prognosis. These findings may lead
to improved prediction of prognosis and therapeutic concepts.
Abstracts
Methods. We analyzed the prognostic impact of a B-cell derived gene
signature, including the most representative marker of this signature,
immunoglobulin kappa C (IGKC), in gene expression profiles of 1810
breast carcinomas. Protein and RNA levels of IGKC were examined in
paraffin embedded tissue of 330 node-negative breast cancer patients.
Finally, the origin of IGKC expression was determined using immunostaining and confocal fluorescence microscopy. Prognosis was analyzed
with Cox regression, Kaplan-Meier analysis, Brier scores and meta-analyses.
Results. IGKC as a single gene similarly predicts better prognosis
in node-negative breast cancer not treated in the adjuvant setting
(HR=0.81; p<0.001) and response to anthracycline-based chemotherapy (HR=1.41; p<0.001) as a previously described 60 gene-based B-cell
signature. The association of IGKC with prognosis was observed in all
molecular subtypes (e.g. ER+, ER−, HER2+) of breast cancer, and was
confirmed by qRT-PCR and immunostaining of paraffin embedded tumors. Confocal fluorescence microscopy showed that IGKC was exclusively expressed by tumor-infiltrating plasma cells.
Conclusion. IGKC is expressed in tumor-infiltrating plasma cells and
has an independent prognostic and predictive impact in breast cancer.
D9 – 0257
Detection of circulating tumor cells in patients with primary
breast cancer: Comparison of two analytical methods
*J. Jückstock1, B. Jäger1, B. Rack1, J. Salmen2, U. Ortmann2, R. Lorenz3,
M. Rezai4, T. Beck5, A. Schneeweiss6, T. Zwingers7, M.W. Beckmann8,
K. Friese1, W. Janni2
1
Frauenklinik der LMU Campus Innenstadt, Gynäkologie und Geburtshilfe,
München, Deutschland, 2Klinikum der Heinrich Heine-Universität, Gynäkologie und Geburtshilfe, Düsseldorf, Deutschland, 3Frauenärztliche Gemeinschaftspraxis Lorenz-Hecker-Wesche, Braunschweig, Deutschland, 4Luisenkrankenhaus GmbH & Co. KG, Gynäkologie und Geburtshilfe, Düsseldorf,
Deutschland, 5RoMed Klinikum Rosenheim, Kliniken der Stadt und des
Landkreises Rosenheim GmbH, Gynäkologie und Geburtshilfe, Rosenheim,
Deutschland, 6University Hospital Heidelberg, Heidelberg, Deutschland,
7
Estimate GmbH, Augsburg, Deutschland, 8Frauenklinik der Universität
Erlangen, Gynäkologie und Geburtshilfe, Erlangen, Deutschland
Background. Evidence for circulating tumor cells (CTCs) as a prognostic marker both in metastatic and in early breast cancer (BC) has been
established earlier. Detection of CTCs is included in some clinical trials.
Patients and methods. SUCCESS A compared FEC-Docetaxel vs.
FEC-Docetaxel-Gemcitabine and 5 vs. 2 years of treatment with zoledronic acid in early BC patients (pts) with node positive or high-risk
node negative disease. Two different techniques to detect CTCs were
prospectively evaluated in diverse but comparable subgroups. In 3515
samples the CellSearch® System (Veridex, Warren, USA) was used for
CTC detection. Immunomagnetic enrichment with an EPCAM-antibody was followed by labeling with monoclonal antibodies specific for
cytokeratin (8, 18, 19) and leukocytes (CD45). 2165 samples were evaluated with a manual immunocytochemistry (MICC) protocol. Cytospins
were prepared after mononuclear cell enrichment based on Oncoquick®
centrifugation (greiner bio-one, Frickenhausen, Germany). Staining
was performed with the monoclonal pancytokeratin antibody A45-B/
B3 (Micromet, Munich, Germany) and the APAAP technique. The cutoff value for positivity was ≥1CTC. All specimens were evaluated by two
independent investigators.
Results. CTCs were examined in a total number of 3243 pts before and
after chemotherapy (CHT). The two subgroups evaluated with either
method were well-balanced regarding tumor size, grade, lymph node-
status, hormone receptor, and Her2 expression. In univariate analyses
we found no significant correlation between CTC positivity and one of
these clinico-pathological parameters using CellSearch or MICC. Before adjuvant CHT 21.3% (424 out of 1994) and 21.1% (264 out of 1249)
of the pts were CTC positive using CellSearch® or MICC, respectively,
with a mean CTC level of 5.9 (range: 1–827) and 3.1 (range: 1–256). Immediately after CHT 21.9% and 16.5% of the pts were positive for CTCs.
The mean CTC level decreased to 3.0 (range: 1–124) using CellSearch®
and 2.1 (range: 1–23) using MICC. In the CellSearch® group there was a
significant correlation between the presence of CTCs before CHT and
disease progression (p=0.0044) as well as survival (p=0.0001), whereas
CTCs detected by MICC were not associated with outcome (p=0.3143
and p=0.0801).
Conclusion. We found comparable incidence of CTCs before and after
adjuvant CHT with the CellSearch® System and MICC. Prognostic relevance, however, could only be shown for CTCs detected with the CellSearch® System.
D10 – 0300
The Oncotype DX® Recurrence Score® Assay impacts adjuvant
therapy recommendations for ER-positive (ER+), node negative
(N0) and node positive (N+) early breast cancer – final results of
the German decision impact study
*S. Kümmel1, W. Eiermann2, M. Rezai3, T. Kühn4, M. Warm5, K. Friedrichs6,
A. Schneeweiss7, S. Markmann8, H. Eggemann9, J. Hilfrich10, C. Jackisch11,
I. Witzel12, H. Eidtmann13, M. Kaufmann14, J.-U. Blohmer15
1
Kliniken Essen-Mitte, Brustzentrum, Essen, Deutschland, 2Rotkreuzklinikum, Frauenklinik, München, Deutschland, 3Luisenkrankenhaus,
Brustzentrum, Düsseldorf, Deutschland, 4Klinikum, Frauenklinik, Esslingen,
Deutschland, 5Krankenhaus Holweide, Frauenklinik, Köln, Deutschland,
6
Brustzentrum, Hamburg, Deutschland, 7Universitätsklinikum, Nationales Tumorcentrum, Heidelberg, Deutschland, 8Universitätsklinikum,
Frauenklinik, Rostock, Deutschland, 9Universitätsklinikum, Frauenklinik,
Magdeburg, Deutschland, 10Eilenriedeklinik, Hannover, Djibouti, 11Klinikum,
Frauenklinik, Offenbach, Deutschland, 12Universitätsklinikum, Frauenklinik,
Hamburg, Deutschland, 13Universitätsklinikum, Frauenklinik, Kiel, Deutschland, 14Universitätsklinikum, Frauenklinik, Frankfurt, Deutschland, 15Sankt
Gertrauden-Krankenhaus, Frauenklinik, Berlin, Deutschland
Introduction. Oncotype DX® is validated as a prognostic and predictive
marker in ER+ early breast cancer (EBC). Results regarding its clinical
use and impact on treatment decisions have been published predominantly for N0 disease and for US clinical practice. To explore the effect
of the Recurrence Score (RS) on adjuvant decision-making in German
clinical practice and to prospectively evaluate its effect in N+ EBC we
performed a study in 15 German centers.
Methods. Patients (pts) with ER+, HER2-negative N0 (pN0) and N+ (N1,
1–3 positive lymph nodes) EBC and no contraindication for chemotherapy were eligible. Physicians’ adjuvant treatment recommendations and
their confidence in these as well as patients’ decisional conflicts were
assessed before and after knowledge of the RS using standardized questionnaires. Pharmacoeconomic analyses were performed based on actual treatment data.
Results. Overall 379 pts were recruited. In 11 pts Oncotype DX could not
be performed and 2 pts dropped out leaving 366 evaluable pts. Of these,
244 (66.7%) were N0 and 122 (33.3%) N+. Overall, 54.1% had low, 38.0%
intermediate and 7.9% high RS values. Initial recommendations changed in 33.1% of all, 30.3% of N0 and 38.5% of N+ pts, and in 36.4% of pts
with low, 30.9% with intermediate and 20.7% with high RSs. In 21.6% of
all, 18.4% of N0 and 27.9% of N+ pts a recommendation for adjuvant che-
moendocrine therapy (CHT) was changed to endocrine therapy (HT)
and in10.7% of all, 11.5% of N0 and 9.0% of N+ from HT to CHT. In 25%
of all, 22% of N0 and 39% of N+ pts initially recommended HT the postRS recommendation changed to CHT; in 38% of all, 39% of N0 and 37%
of N+ pts initially recommended CHT it changed to HT. Physicians’
confidence increased in 45.1% of all (p=0.047), 44.7% of N0 and 45.9% of
N+ cases. There was a moderate improvement of the decisional conflict
score which was statistically significant for all pts (p=0.029) and the low
RS subgroup (p=0.003). Net reduction in adjuvant chemotherapy usage
was 19.1% in all, 14.0% in N0 and 27.9% in N+ pts. The incremental costeffectiveness ratio associated with the use of the test was € 442/life year
and considering the societal perspective € 155/life year.
Conclusions. Results of our study suggest an impact of the RS on adjuvant treatment decision making in ER+ EBC in German clinical practice resulting in a significant net reduction of adjuvant chemotherapy
usage. The effect was more pronounced for patients with node positive
disease.
D11 – 0381
Comparison of the ER, PR and HER/2neu status changes in primary and relapsed breast cancer
*R. Mavrova1, J. Radosa1, A. Mayer2, R.-M. Bohle2, E.-F. Solomayer1, I. JuhaszBöss1
1
Uniklinik Homburg, Frauenklinik, Homburg /Saar, Deutschland, 2Uniklinik
Homburg, Pathologie, Homburg/ Saar, Deutschland
Question. We analyzed the changes in the estrogene (ER) and progesterone (PR) receptor, and HER/2neu status of primary and relapsed breast
cancer in patients suffering from a relapse and we searched for possible
causes.
Methods. We analyzed the data of 68 patients with a relapse detected at
the Saarland University Hospital during the last 5 years. We compared
the receptor status of the primary tumor to the receptor status of the
relapse.
Results. 44 of 68 (65%) patients analyzed showed a positive ER and PR
status in the primary tumor. Overall we notices 16 switches in ER status
(23%) and 23 switches in PR status (34%). The switches occurred from
negative status to positive status and vice versa. A trend of switch from
hormone receptor positive status towards negative status could be observed. In contrast the Her2/neu status changed from negative to positive in each case.
Conclusion. The hormone and Her2/neu receptor status can vary strongly between primary tumor and relapse in breast cancer in the same patient. It is to be noted that there are more switches in PR than in ER status. In our patients collective the occurrence of receptor status switches
were independent of hormone therapy after the initial diagnosis.
D12 – 0407
Multivariate analysis of obesity and survival in patients with
node-positive primary breast cancer: The ADEBAR trial
*C. Hagenbeck1, W. Janni1, B. Rack2, P. Hepp1, U. Andergassen2, N. Harbeck3,
J. Neugebauer2, K. Annecke4, A. Wischnik5, W. Simon6, M. Rezai7, T. Fehm8,
A. Schneeweiss9, P.A. Fasching10, B. Gerber11, T. Zwingers12, H. Sommer2,
K. Friese2, M. Kiechle4
1
Universitätsklinik Düsseldorf, Frauenklinik, Düsseldorf, Deutschland,
2
Ludwig-Maximilians-Universität, Frauenklinik, München, Deutschland,
3
Universitätsklinik, Frauenklinik, Köln, Deutschland, 4Technische Universität
München, Frauenklinik, München, Deutschland, 5Klinikum Augsburg, Frauenklinik, Augsburg, Deutschland, 6Robert-Bosch-Krankenhaus, Frauenklinik, Stuttgart, Deutschland, 7Luisenkrankenhaus, Düsseldorf, Deutschland,
8
Universitätsklinikum Tübingen, Frauenklinik, Tübingen, Deutschland,
9
Universitätsklinikum Heidelberg, Nationales Centrum für Tumorerkrankungen, Heidelberg, Deutschland, 10Universitätsklinik Erlangen, Frauenklinik, Erlangen, Deutschland, 11Universitätsklinik Rostock, Frauenklinik,
Rostock, Deutschland, 12Estimate, Augsburg, Deutschland
Background. The prevalence of obesity increases throughout most industrialized countries. Epidemiological studies have shown not only an
increase in breast cancer (BC) among obese women but also an adverse
impact of obesity on BC survivors. This analysis focuses on the impact
of obesity on high risk BC patients (pts) treated within the ADEBAR
study protocol.
Methods. The ADEBAR Trial compared 4 cycles of EC followed by
4 cycles of Doc vs. 6 cycles of FEC (120) in pts with primary BC (≥4LN).
1500 pts have been accrued from Sep/01 through May/05. For this analysis data of 1361 pts have been analyzed about the impact of obesity
on disease free survival. Therefore pts have been grouped to be either
underweight (BMI <18.5 kg/m2), normal weight (BMI: 18.5–25kg/m2),
overweight (25–30 kg/m2).
Results. 13 pts (1.0%) were underweight, 557 pts (40.9%) were normal
weight, 491 pts (36.1%) were overweight, 300 pts (22.0%) were obese at the
time of study enrolment. After a follow-up period of 60 months 87.5%
of the underweight group, 70.4% of the normal weight group, 70.7% of
the overweight group and 58.6% of the obese group were alive with no
signs of recurrent disease (χ2=9.355; p<0.0249). In univariate analysis
also overall survival was significantly worse in the obese pts group
(p=0.014). There was no significant difference in disease free survival
as well as in overall survival between patients with normal weight and
moderate overweight, respectively. In multivariate analysis, stratified
for tumor size, lymph node status, histopathological grading, hormone
receptor status, age, menopausal status and type of chemotherapy, no
BMI between 25 and 30, but a BMI greater than 30 was predictive for a
significant higher risk for death (adjusted hazard ratio 1.67 [1.14–2.45],
p=0.008). Additionally, a significant incremental effect for every BMI
point could be shown, with an increased hazard ratio of 0.7 % for every
kg per square meter.
Conclusions. In conclusion, the results of this analysis confirm previous
data regarding the detrimental impact of obesity on the survival of BC
patients in this homogeneous group of individuals with high risk disease undergoing chemotherapy.
Abstracts
Discussed Poster – Molekulare Onkologie
D14 – 0168
The role of TGF-b1 dependent L1CAM expression in malignant
transformation of intestinal epithelial cells
D13 – 0125
Expression of p53D133 isoforms in novel papillary urothelial
cancer cell lines
B. Struck1, E.-M. Feldmann1, F. Bergmann2, E. Grage-Griebenow1, C. Geismann3, P. Altevogt4, H. Schäfer3, *S. Sebens1
1
Department of Internal Medicine I, Institute for Experimental Medicine,
Kiel, Deutschland, 2University of Heidelberg, Institut of Pathology, Heidelberg, Deutschland, 3Department of Internal Medicine I, Laboratory for Molecular Gastroenterology & Hepatology, Kiel, Deutschland, 4German Cancer
Research Center, Translational Immunology D015, Heidelberg, Deutschland
*A. Koch1, J. Hatina2, H. Rieder3, R. Stoer4, W.A. Schulz1
1
Heinrich Heine Universität, Forschungslabor Urologische Klinik, Düsseldorf, Deutschland, 2Charles University, Department of Biology, Pilzen,
Tschechische Republik, 3Heinrich Heine Universität, Inst. f. Humangenetik
und Anthropologie, Düsseldorf, Deutschland, 4Universitätsklinikum Erlangen, Pathologie, Erlangen, Deutschland
Commonly used urothelial cell lines are mostly derived from invasive
urothelial tumors, whereas cell lines derived from papillary tumors are
rare. To expand the repertoire of papillary derived cell lines, we have
established two novel lines BC61 (pTaG2) and BC44 (papillary part of a
pT4G3 carcinoma) using a specifically adapted culture technique. Both
cell lines presented karyotypes typical of progressive papillary urothelial cancers including monozygosity of chromosome 9. Accordingly, CDKN2A at 9p21 was homozygously deleted as in many papillary
and invasive urothelial carcinomas. An oncogenic mutation of FGFR3
(S249C) characteristic of low grade papillary urothelial tumors was detected in BC61 but not BC44. Likewise typical of such tumors BC61 had
wild-type (wt) TA-p53, whereas p53 was initially undetectable in BC44.
The TP53 gene contains alternative promoters from which several isoforms are transcribed. In particular, p53D133 isoforms expressed from
promoter p2 were shown to inhibit wt p53 function in several tumors.
We therefore studied p53 expression with Do-6 antibody detecting
TA-p53 and others (PAB240, Do-12) detecting several isoforms. BC61
had a normal level of nuclear wt p53 and weak expression of other p53
isoforms, whereas exclusively p53D isoforms were detectable in BC44.
Western blot and PCR identified these isoforms as p53D40 and D133.
In an extended set of urothelial cancer cells and tissues, D133 was expressed mostly in additional papillary urothelial tumor cell cultures,
but also individual invasive cancer tissues. Methylation and sequencing
analysis of the TP53 gene p1 promoter and gene in BC44 revealed neither mutations nor hypermethylation as potential causes of the promoter
shift.
In invasive urothelial carcinomas p53 is typically inactivated by missense or nonsense mutations in one allele with loss of the second wild-type
allele, whereas mutations are much rarer in papillary tumors. We show
that some urothelial carcinomas predominantly or exclusively express
p53 isoforms from the p2 promoter that do not exhibit the full spectrum
of p53 functions. Alternative promoter usage may therefore constitute
a further mode of p53 inactivation in urothelial carcinomas and might
compromise p53 function particularly in papillary tumors, where point
mutations in the gene are rare.
Background. Inflammatory bowel disease (IBD) patients have an increased risk to develop colorectal cancer (CRC), particularly after longduration of the disease. Chronic inflammation of the intestinal mucosa
is characterized by a marked enrichment of immune cells such as macrophages and a plethora of cytokines and growth factors e.g. Transforming growth factor-beta 1 (TGF-b1). In colorectal cancer tissues, the
adhesion molecule L1CAM has been detected associating with metastatic spread and poor prognosis of CRC patients. Moreover, L1CAM
induces apoptosis protection and chemoresistance as well as motility
of tumor cells.
Aim. The present study investigates the role of TGF-b1 and macrophages
in the upregulation of L1CAM in intestinal epithelial cells and its functional consequences.
Methods and results. We demonstrate by immunohistochemistry that
colonic tissues from IBD patients are already characterized by considerable L1CAM expression in intestinal epithelial cells particularly in
the presence of macrophages compared to normal non-inflammatory
colon tissues. When cocultured with in vitro generated macrophages
the transcription factor Slug and L1CAM are upregulated in the human
colonic cell line NCM460 along with a Slug- and L1CAM-dependent
increase of cell motility and apoptosis resistance against Irinotecan and
Trail. Pharmacological interference with TGF-b1 signaling abolished
the elevated expression of Slug and L1CAM in cocultured NCM460
cells and decreased cell migration and apoptosis protection. Chromatin
immunoprecipitation (ChIP) and luciferase assays revealed that direct
binding of Slug to the L1CAM promoter is essential for gene activation
and upregulation of L1CAM expression in NCM460 cells.
Conclusion. These data provide new insights into the mechanisms by
which IBD promotes malignant transformation of intestinal epithelial
cells and underscore the role of L1CAM in this scenario.
D15 – 0211
Targeting fibroblast growth factor receptor (FGFR) system impairs angiogenic signaling in gastric cancer, endothelial cell and
periycytes
*C. Moser1, C. Hackl1, H.J. Schlitt1, E.K. Geissler1, S.A. Lang1
1
Universitätsklinik Regensburg, Klinik und Poliklinik für Chirurgie, Regensburg, Deutschland
Background. Expression of FGFRs has been associated with poor prognosis in gastric cancer patients at least in part via activation of MAPK/
Erk and PI3K/Akt signaling. In addition, activation of FGFRs is a crucial event in induction of tumor angiogenesis through regulation of
endothelial cell/pericyte motility and survival. Therefore, we sought to
evaluate the effects of targeting FGFR on gastric cancer cells as well as
endothelial cells and pericytes.
Methods. Human gastric cancer cells (TMK-1, KKLS), endothelial
cells (ECs), pericytes (vascular smooth muscle cells, VSMCs) and the
FGFR inhibitor BGJ398 (Novartis Oncology, Basel) were used for the
experiments. Effects of BGJ398 on tumor growth and chemoresistance
were determined by MTT assays. For evaluation of cancer cell motility,
modified Boyden chambers were used. Signaling pathways affected by
BGJ398 treatment were assessed by Western blot analyses. Conditioned
media from gastric cancer cells was used to determine effects of FGFR
blockade by BGJ398 on ECs and VSMCs.
Results. Targeting FGFR with BGJ398 impaired in vitro growth of gastric cancer cells in a dose-dependent manner. Furthermore, activation
of Akt and Erk in cancer cells was effectively blocked while expression
of HIF-1α and c-Myc was reduced. In addition, treatment with BGJ398
led to marked inhibition of constitutive tumor cell migration and invasion (p<0.05). Interestingly, interference with FGFR signaling enhanced
antiproliferative effects of oxaliplatine and 5-FU in cancer cells. In ECs
and VSMCs, targeting FGFR with BGJ398 led to a significant inhibition
of cell growth and motility even upon stimulation with conditioned
media (p<0.05).
Conclusion. Inhibition of FGFR signaling with BGJ398 disrupts oncogenic signaling, impairs tumor cell motility and improves chemosensitivity in gastric cancer cells. Moreover, antiangiogenic effects might
be mediated via direct effects on ECs and pericytes. Hence, molecular
targeted therapy against FGFR may be a promising approach to improve
current treatment concepts in gastric cancer patients.
D16 – 0214
Influence of zoledronate and denosumab on osteoblast-breast
cancer cell interactions
*T. Kaiser1, I. Teufel1, D. Wallwiener1, G. Klein2, T. Fehm1
1
Universitätsklinikum, Frauenklinik, Tübingen, Deutschland, 2Universitätsklinikum, Zentrum für Medizinische Forschung, Tübingen, Deutschland
Background. Zoledronate, a nitrogen-containing bisphosphonate, and
denosumab, a fully humanized monoclonal antibody against receptor
activator of NF-κB ligand (RANKL), are current therapeutic treatments
for breast cancer patients with bone metastases. The development of
bone metastases is a multistep process that involves interactions between tumor cells and normal host components of the bone marrow
microenvironment. Emerging evidence suggests that the interplay of
breast cancer cells with both RANKL-expressing osteoblasts, key mediators of osteoclastogenesis, and osteoblast-derived extracellular matrix structures is critical to the metastatic process. This relationship may
contribute to the tumor cell colonization of bone, invasive behavior, and
eventual tumor progression. However, the mechanisms how zoledronate and denosumab modulate the crosstalk between breast cancer cells
and osteoblasts still remain poorly characterized.
Methods. The influence of zoledronate and denosumab on osteoblastbreast cancer cell interactions was investigated in cell adhesion and
migration assays using CAL72 or primary osteoblasts and breast cancer
cell lines with different metastatic potential.
Results. Breast cancer cells revealed a strong attachment to several extracellular matrix components expressed by osteoblasts. The subsequent
incubation of attached cells with 100 µM zoledronate for 72 h resulted
in a prominent reduction of tumor cell binding to collagen type I, fibronectin, defined laminin isoforms and tenascin-C, whereas incubation
with 10 µg/ml denosumab did not affect the adhesive behavior of tumor
cells. In addition, cell-cell adhesion analyses indicated that zoledronate
was able to decrease the attachment of breast cancer cells to osteoblasts.
Furthermore, the conditioned media of osteoblasts strongly enhanced
the migration of the invasive breast cancer cells compared to the conditioned media of osteoclast-like cells and stromal cells, suggesting that
exclusively osteoblasts release factors that significantly increase tumor
cell migration. Interestingly, exposure to zoledronate inhibited osteoblast-induced tumor cell migration in a concentration-dependent manner, while denosumab had no inhibitory effect.
Conclusion. In summary, zoledronate, but not denosumab affects osteoblast-induced breast cancer cell abilities including tumor cell adhesion
and migration. Our data provide further insights into the antiresorptive
effect of zoledronate on bone metastasis.
D17 – 0492
Hsa-miR-214 and hsa-miR-199a expression increases tumor
invasion in breast cancer
*S. Schultz1, H. Bartsch2, B. Kootz1, K. Sotlar2, K. Petat-Dutter2, M. Bonin3,
S. Poths3, M. Walter3, O. Riess3, D. Wallwiener1, T. Fehm1, H. Neubauer1
1
Eberhard-Karls-University Tübingen, Department of Obstetrics and Gynecology, Tübingen, Deutschland, 2Ludwig-Maximilians-University Munich,
Institute for Pathology, Munich, Deutschland, 3Eberhard-Karls-University
Tübingen, Microarray Facility Tübingen, Tübingen, Deutschland
Aims. The ductal carcinoma in situ (DCIS) of the breast is considered to
be the pre-invasive form of the invasive ductal breast carcinoma (IDC).
The analysis of molecular mechanisms is an important prerequisite for
the understanding of tumor progression. The aim of this project is (1)
the identification and validation of differentially expressed microRNAs
(miRNAs) (2) to validate their functional relevance in tumour cell invasion.
Material and methods. Formalin fixed and in paraffin embedded (FFPE)
tissue of 15 IDC breast cancer tissue samples with DCIS component was
selected from the tissue banks of the Institute for Pathology in Munich. Tissue sections were prepared, stained with hematoxylin-eosin
and the epithelial cells were isolated by laser capture microdissection
(LCM). 200 ng RNA were extracted, hybridized to the Universal Bead
miRNA-chip (Illumina) and bioinformatically evaluated. Differentially
expressed miRNAs were identified. The expression of the miRNAs was
validated by qRT-PCR (miScript PCR system, Qiagen). Invasion assays
were performed with the invasive breast cancer cell lines TMX2-28
and MDA-MB-231. To that aim cells were transfected with miRNA-inhibitors (Ambion) and seeded to MatrigelTM (BD Bioscience) coated
membranes (ThinCertTM Cell culture Inserts, Greiner). The number of
invading cells was compared to mock transfected controls.
Results. Microarray analysis provided 44 miRNAs which are differentially expressed between DCIS and IDC components of the same tumor
tissue. Differential expression was validated for 5 miRNAs using two
sample sets, the technical validation set (15 samples) and an independent validation set (26 samples). Two candidate miRNAs, hsa-miR-214
and hsa-miR-199a are up regulated in invasive tumor cells of IDC with
a DICIS component. Knock down of hsa-miR-214 and hsa-miR-199a
reduces the invasiveness of the breast cancer cell lines TMX2-28 and
MDA-MB-231 by 60–80%.
Conclusion. We identified progression-specific candidate miRNAs by
combining LCM and microarray analysis of FFPE breast cancer tissues.
Hsa-miR-214 and hsa-miR-199a are potential progression markers.
Abstracts
Seltene Tumoren
D18 – 0498
The Wnt transcription factor TCF4 mediates resistance of colorectal cancer cells to (chemo-)radiotherapy
Discussed Poster – Seltene Tumoren
*M. Grade1, E. Kendziorra1, K. Ahlborn1, M. Spitzner1, C. Eimer1, M. RaveFränk2, J. Gaedcke1, G. Emons1, H. Becker1, T. Ried3, T. Pukrop4, M. Ghadimi1
1
Universitätsmedizin Göttingen, Klinik für Allgemein- und Viszeralchirurgie, Göttingen, Deutschland, 2Universitätsmedizin Göttingen, Klinik für
Strahlentherapie und Radioonkologie, Göttingen, Deutschland, 3National
Cancer Institute, Genetics Branch, Bethesda, Deutschland, 4Universitätsmedizin Göttingen, Klinik für Hämatologie und Onkologie, Göttingen,
Deutschland
D19 – 0276
Histologic diagnoses in persistently swollen cervical lymph
nodes
Background. The clinical response of locally advanced rectal cancers
to preoperative chemoradiotherapy is very heterogeneous. We recently profiled a series of responsive and resistant rectal carcinomas using
gene expression microarrays and identified TCF4, a key effector of the
Wnt/β-catenin pathway, as over-expressed in resistant tumors. The aim
of this study was to explore the functional relevance of TCF4 for mediating treatment resistance.
Methods. Three colorectal cancer cell lines (SW837, SW480, and HT-29)
were transfected with two different shRNA-vectors targeting TCF4.
After establishing stable single-cell clone (SCC) populations, selected
clones were irradiated at 0, 1, 2, 4, 6 and 8 Gy. γH2AX staining was used
to evaluate DNA double strand repair after irradiation, and changes
in cell cycle distribution were analyzed before and after radiation. βcatenin/TCF signaling activity was assessed using the TOP-FLASH/
FOP-FLASH reporter assay.
Results. RNAi-mediated silencing of TCF4 led to a significant radiosensitization in SW837 and SW480, whereas no effect was observed in
HT-29. Well-fitting, we observed significantly more γH2AX foci 24 h
after radiation in SW837 SCCs compared to HT-29 SCCs, pointing to an
impaired DNA damage repair in SW837 SCCs. Furthermore, in SW837
SCCs, but not in HT-29 SCCs, we noticed a change in the cell cycle distribution towards radiosensitive cell cycle phases before radiation, and
compromised cell cycle control after radiation. Analysis of the reporter
assay revealed that SW837 cells shower high β-catenin/TCF signaling
activity compared to HT-29 cells.
Conclusion. TCF4 was found to be over-expressed in resistant rectal carcinomas, and its RNAi-mediated silencing caused a significant radiosensitization, mediated by DNA damage repair deficiencies and impaired cell cycle control. Thus, we have uncovered a novel role of the Wnt
transcription factor TCF4 for mediating radioresistance. Moreover,
these data suggest that TCF4 is a potential therapeutic target to sensitize
resistant tumor cells to radiation.
*W. Laffers1, K. Eggert1, H.-U. Schildhaus2, F. Bootz1, A.O. Gerstner1
1
Universität Bonn, Klinik für HNO-Heilkunde/Chirurgie, Bonn, Deutschland,
2
Universität Köln, Institut für Pathologie, Köln, Deutschland
Background. Biopsy and histological examination of persistently enlarged cervical lymph nodes represent a major health care issue and have
high impact on further clinical therapy. Tertiary health centers are
faced with an increased demand for diagnostic work-up of persistently swollen cervical lymph nodes in order to rule out malignancy. We
performed a retrospective study from I/2000 to VI/2008 to identify
patients referred to us for diagnostic biopsy and to document the histopathological result.
Methods. Patients with a diagnostic biopsy but neither clinical signs of
head and neck cancer nor other malignancies were identified within the
records. Patient characteristics and histopathological diagnosis were
retrieved from the system.
Results. Within that period 326 patients were identified (146 female,
180 male). 123 patients (38%; 44 female, 79 male) had a malignancy: 61
with metastatic disease and 62 with malignant lymphoma, the youngest
15 years and the oldest 92 years old.
Conclusions. Persistently swollen cervical lymph nodes should trigger a
thorough clinical examination and prompt biopsy for histopathological
work-up.
D20 – 0281
The endogenous nicotinamide adenine dinucleotide precursor
quinolinic acid confers resistance of glioma to oxidative stress
*F. Sahm1, A. von Deimling1, W. Wick2, M. Platten2
1
Institut für Pathologie, Abt. Neuropathologie, Heidelberg, Deutschland,
2
Abt. Neuroonkologie, Heidelberg, Deutschland
Background. Quinolinic acid (QA) is a product of tryptophan degradation and may serve as a precursor for nicotinamide adenine dinucleotide (NAD) synthesis, an enzymatic step catabolized by quinolinic acid
phosphoribosyltransferase (QPRT) as a source for energy. Pathologic
accumulation of QA has been found in Alzheimer’s and Huntington’s
disease. In these conditions QA is thought to be toxic for neurons by
activating the N-methyl-D-aspartate (NMDA) receptor and inducing
oxidative stress. The role of QA in glioma biology is unclear till date.
Methods. QA accumulation and expression patterns of the QA producing enzyme 3-hydroxyanthranilate oxygenase (HAAO) and QA metabolizing QPRT were analyzed in diffusely infiltrating glioma of the
World Health Organization (WHO) grades II, III and IV by immunohistochemistry. Immunofluorescent double-labelling with CD68 and
glial fibrillary acid protein (GFAP) was applied to assess HAAO and
QPRT expression in different cell populations within the tumor. Real
time-quantitative polymerase chain reaction and western blot analysis were performed to analyze HAAO and QPRT expression levels in
the human glioma cell lines U251, A172 and the human astrocyte cell
line CRL-8621. Effects of QA on oxidative stress conditions induced
by 100 µM hydrogen peroxide and NAD synthesis inhibition by 10 nM
FK866 were determined by crystal violet viability assay and western blot
for markers of apoptosis.
Results. There was QA accumulation in human gliomas, which is associated with a malignant phenotype. Expression of the QA producing
enzyme HAAO was confined to microglial cells in glioma tissue. QPRT
expression correlates with glioma malignancy, determined by WHO
grade and is upregulated in recurrent tumors after radio-chemotherapy compared to specimens of untreated primary lesions. Human malignant glioma cells but not non-neoplastic astrocytes express QPRT
and utilize QA for NAD synthesis when de novo NAD synthesis was
blocked. QA protects malignant glioma cells but not non-neoplastic astrocytes from apoptosis induced by NAD depletion or oxidative stress.
Conclusion. There is QA expression in neoplastic astrocytes and a WHO
grade-dependent expression of QPRT as well as induction in treated,
recurrent tumors. Our data indicate that neoplastic transformation in
astrocytes is associated with a switch in NAD metabolism by exploiting microglia-derived QA as a source of energy and thereby increasing
the resistance to oxidative stress. These findings have implications for
therapeutic approaches inducing intracellular NAD depletion such as
alkylating agents or direct NAD synthesis inhibitors.
D21 – 0371
The role of relative lymphocyte count as a new biomarker for
the effect of catumaxomab on overall survival in patients with
malignant ascites: follow-up results from a phase ll/lll study
*M.M. Heiss1, M. Ströhlein1, C. Bokemeyer2, D. Arnold3, S.L. Parsons4, M. Ott5,
E. Schulze6, H. Lindhofer7, D. Seimetz5, M. Hennig5
1
Cologne-Merheim Medical Center, Cologne, Deutschland, 2University
Hamburg-Eppendorf, Clinic for Oncology/Haematology and Stemcell
Transplantation, Hamburg, Deutschland, 3Martin Luther University Halle,
Clinic for Internal Medicine IV, Halle, Deutschland, 4Nottingham University
Hospitals NHS Trust, Nottingham, UK, 5Fresenius Biotech GmbH, Munich,
Deutschland, 6Fresenius Biotech GmbH, Medical Affairs, Munich, Deutschland, 7TRION Pharma GmbH, Munich, Deutschland
Background. Catumaxomab (anti-EpCAM x anti-CD3) is approved in
the EU for the intraperitoneal treatment of malignant ascites in patients
with EpCAM-positive carcinomas. Here we report the follow-up overall
survival (OS) results including long-term survival for the pivotal phase II/III randomized study in patients with malignant ascites due to different epithelial cancers. In addition, the impact of relative lymphocyte
count in peripheral blood before treatment (RLC) as a new biomarker
for the efficacy of catumaxomab therapy was tested on the basis of a
separate small hypothesis-generating study.
Methods. Survival analyses were performed for the safety set of the pivotal trial (paracentesis + catumaxomab [catumaxomab]: n=157; paracentesis alone [control]: n=88) including only patients who received at
least one dose of catumaxomab. In order to identify patients with pronounced OS benefit, the impact of treatment and RLC was evaluated
using the Cox model. For group comparisons, the Kaplan-Meier method and log-rank test were applied.
Results. Follow-up results showed a statistically significant benefit in OS
for catumaxomab-treated patients compared with controls (p=0.0219,
HR=0.649). The 6-month OS rate in these patients was 28.9% compared
with 6.7% for the control group. In addition, higher RLC had a positive impact on OS (p<0.0001). In patients with a RLC >13% (n=159: 100
catumaxomab; 59 control), catumaxomab treatment was associated
with a more pronounced beneficial effect on OS vs controls (p=0.0072,
HR=0.518), with a median/mean OS benefit of 31/131 days and an increased 6-month survival rate of 37.0% vs 5.2% in the control group. Regarding the time to first paracentesis patients with a RLC ≤13% (p<0.0001,
HR=0.159) and>13% (p<0.0001, HR=0.182) had a similar benefit from
catumaxomab treatment.
Conclusions. Intraperitoneal treatment with catumaxomab significantly
improved OS in patients with malignant ascites due to EpCAM-positive
carcinomas. A RLC >13% at start of treatment was a significant biomarker for a prolonged OS outcome with catumaxomab therapy and should
lead to further investigation into the immunology of this clinical observation.
D22 – 0379
Podoplaninexpression in oralen Plattenepithelkarzinomen
*M. Kreppel1,2, M. Scheer1,2, U. Drebber3,2, I. Wedemeyer3,2, H.-T. Eich4,
J.E. Zöller1,2
1
Universitätsklinik Köln, Klinik für Mund-, Kiefer- und plastische Gesichtschirurgie, Köln, Deutschland, 2Centrum für Integrierte Onkologie,
Köln, Deutschland, 3Universitätsklinik Köln, Institut für Pathologie, Köln,
Deutschland, 4Universitätsklinik Münster, Klinik für Strahlentherapie,
Münster, Deutschland
Fragestellung. Trotz verbesserter therapeutischer Möglichkeiten hat
sich die Überlebenswahrscheinlichkeit von Patienten mit fortgeschrittenen oralen Plattenepithelkarzinomen in den letzten 30 Jahren nicht
wesentlich verbessert. Die Ursache hierfür ist überwiegend ein lokoregionäres Therapieversagen. Aktuelle Studien weisen auf die Bedeutung
molekularer Faktoren für die Prädiktion und Prognose bei oralen Plattenepithelkarzinomen hin. Dem muzinähnlichen Glykoprotein Podoplanin, das maßgeblich an der Lymphangiogenese beteiligt ist, scheint
dabei eine besondere Bedeutung zuzukommen. Ziel unserer Untersuchungen war es, zum einen den Einfluss von Podoplanin auf die Prognose und das Metastasierungsverhalten und von oralen Plattenepithelkarzinomen und andererseits den Wert als Marker für das Ansprechen
des Tumors auf eine präoperative Radiochemotherapie zu untersuchen.
Methoden. Gegenstand der Untersuchungen waren 150 Patienten mit
oralen Plattenepithelkarzinomen, von denen 63 mit einer präoperativen (neoadjuvant) Radiochemotherapie und 87 mit einer primären
Operation gefolgt von einer adjuvanten Radiochemotherapie behandelt
wurden. Die Podoplaninexpression wurde semiquantitativ immunhistochemisch bestimmt. Die Podoplaninexpression wurde mit verschiedenen klinisch-pathologischen Parametern korreliert, zudem wurde
der Einfluss auf das Gesamtüberleben und die lokoregionäre Kontrolle
untersucht.
Ergebnisse. Sowohl bei den neoadjuvant behandelten als auch bei den
primär operativ behandelten Patienten konnte sowohl univariat als
auch multivariat ein starker Einfluss der Podoplaninexpression auf
das Gesamtüberleben nachgewiesen werden (p<0,001). Die Podoplaninexpression wies eine hochsignifikante Assoziation mit dem pN- und
dem ypN-Status auf (p<0,001 und p=0,004). Zudem war eine starke Podoplaninexpression mit einer geringen Rate an Komplettremissionen
nach neoadjuvanter Radiochemotherapie assoziiert (p=0,013).
Schlussfolgerungen. Podoplaninexpression in oralen Plattenepithelkarzinomen hat einen negativen prognostischen Einfluss und ist zudem
mit dem Auftreten von zervikalen Lymphknotenmetastasen assoziiert.
Außerdem scheint die Podoplaninexpression hilfreich zu sein, um das
Ansprechen von oralen Plattenepithelkarzinomen auf eine neoadjuvante Radiochemotherapie vorherzusagen.
Abstracts
D23 – 0447
Prognostic impact of Survivin in oral squamous cell carcinomas
*C.B. Keschke1, M. Kappler1, U. Bilkenroth2, J. Schubert1, H. Taubert1,
A.W. Eckert1
1
Martin-Luther-Universität Halle-Wittenberg, MKG-Chirurgie, Halle(Saale),
Deutschland, 2Institut für Pathologie, Eisleben, Deutschland
Introduction. Oral Squamous cell carcinomas (OSCC) are one of the ten
most common human tumors. However, the 5-year survival rate stagnates at almost 50% since 40 years. For a better prognostic calculation
of patients with OSCC as well as for stratification to an individualized
therapy more promising prognostic markers are necessary. The aim of
the present investigation was to analyze the prognostic impact of Survivin in OSCC, an inhibitor of apoptosis.
Materials and methods. 72 patients with oral squamous cell carcinomas
were enrolled for the study. Tumor specimens were stained for Survivin
using a standard immunohistochemical technique. Expression of Survivin was determined by assessing semi-quantitatively the percentage
of decorated tumor cells and the staining intensity. All stained tumor
specimens were viewed at magnifications of 100× and 200× by three independent investigators and correlated with clinicopathological data.
Statistical analyses were performed using χ2-test, KAPLAN-MEIERanalysis, the log-rank-test and multivariate Cox’s proportional-hazards
regression analysis.
Results. The patient’s median age was 59 years (ranging from 23 to 83 years). There were 45 T1/T2-tumors and 27 patients suffered from advanced T3/T4-forms. Twenty-four were well, 33 moderately and 15 poorly
differentiated. Forty-five patients were only surgically treated the other
27 had a combination of surgery and radiotherapy. Survivin had an impact on prognosis in OSCC of all patients (RR=2.5, p=0.0026). The Cox’s
regression analysis (adjusted to tumor size and tumor grade) revealed
that patients, whose tumors highly expressed Survivin had a 6.83-fold
increased risk of tumor related death in the operated group (p=0.0015).
Conclusion. Survivin is a member of the IAP-family (inhibitor of apoptosis) and can be considered as an independent prognostic marker in
OSCC. In summary, increased levels of Survivin are significantly correlated with poor prognosis of OSCC patients. We therefore suggest that
expression of this protein can be used for an early diagnosis. Immunohistochemical stainings for Survivin should complete the diagnostic
concept (TNM system, grading) at the beginning.
D24 – 0482
Moguntinones – new selective inhibitors for treating solide
tumours
*A. Müller1, S. Plutizki2, K. Khillimberger1, G. Dannhardt2, M. Moehler1
1
Universitätsmedizin Mainz, I. Med. Klinik, Mainz, Deutschland, 2Johannes
Gutenberg Universität, Pharmazie, Mainz, Deutschland
Introduction. Moguntinones are new innovative, synthetic designed
small molecules, which are a combination of three natural products.
These patent-protected kinase inhibitors were invented by the Institute of Pharmacy and our Department of Internal Medicine, Mainz. The
substances displayed a new generation of targeted inhibitors for tumour
progression, angiogenesis suppression and resistance blockage.
Methods. The substances were analysed by kinase assays and HET-CAM
as well as in vitro in four human colon cancer (HT-29, HCT-116, DLD1, SW480) and two gastric cancer cell lines (MKN-45, AGS) for RNA
and protein expression levels (RT-PCR, Western blot, ELISA, FACS).
Different viability and apoptosis assays were performed in the tumour
cells, which were incubated with Moguntinones and different cytostatic
drugs. Additionally, intracellular signalling pathways were analysed.
In vitro data were further verified in a human xenograft NOD/SCID
mouse model.
Results. Moguntinones showed clear anti-angiogenic effects in HETCAM assays and inhibitory activities in IC50 kinase assays. After generating additional substances with little structural changes and better
biological effects, these Moguntinones alone induced apoptosis only in
higher concentrations (>10 µM). Furthermore, stronger synergistic effects for induction of apoptosis were observed in lower concentrations
(<10 µM) in combination with classical cytostatic drugs like irinotecan.
These effects could not be seen in HUVEC. The signalling pathways
AKT, GSK3b or FAK were totally inhibited in incubated tumour cells.
The in vivo mouse model again showed significant reductions in tumour growth and tumour weight. Even more, comparable suppressive
effects of Moguntinones in KRAS, BRAF and PI3KCA-mutated colon
and gastric cancer cell models were identified.
Conclusion. Our in vitro and in vivo data clearly showed significant proapoptotic, anti-angiogenic and anti-proliferative effects of Moguntinones in different human gastrointestinal cancer cells. The experiments
argue for a high potency of these substances to complement standard
combinations and to overcome possible tumour resistance mechanisms. Thus, the consortium aims to develop these substances in clinical phase I studies.
Supportivtherapie/Palliativmedizin
Discussed Poster – Supportivtherapie/
Palliativmedizin
D25 – 0047
Who benefits from systematically provided information about
professional psychosocial-help offers? An experimental investigation
*R. Schiel1
1
Nationales Centrum für Tumorerkrankungen, Psychoonkologische Ambulanz am NCT, Heidelberg, Deutschland
There seems to be a big gap between the level of psychological consequences of cancer illness reported in the literature and the actual level
of requests for professional psychosocial help. It has been shown that
only approximately 50% of all cancer patients in the hospital even know
that psychosocial-help offers exist. Although the knowledge about these
offers is certainly a pre-condition of requesting them.
Therefore we hypothesized that providing systematic information about psychosocial-help offers (cancer information service, social work
and psychooncology) can influence the knowledge of and the request
for these offers. Furthermore, we were interested in the moderating role
of the level of psychological consequences, age and education.
To test these hypotheses, a randomized controlled prospective study
was realized at the Universitätsklinikum Heidelberg. Participants were
96 breast cancer patients currently taking part in radiation therapy. A
analysis of covariance was used to investigate the influence of the level
of psychological consequences, age, and education on the knowledge of
and the request for psychosocial offers.
The results showed that the manipulation of providing versus not providing additional information about psychological-help offers was effective. The experimental group had more knowledge about psychosocial
offers than the control group. The knowledge about cancer information
service increased significantly, knowledge about social work and psychooncology increased but not on a significant level. There was no sig-
nificant difference between the two groups in the later request for these
offers.
Additionally, a remarkable relation between education and knowledge
of psychosocial-help offers was found. Patients with a higher level of
education also showed a better knowledge about the offers, independent
of their group membership. Concerning the request for help it could
be shown that patients with higher degree of education profited more
from the information given, therefore requesting professional help offers more often.
In summary the findings demonstrate that systematically providing information about psychosocial-help offers can influence the knowledge
of and the request for these offers. This seems to be especially the case
for patients with higher levels of education.
Palliativmedizin
Palliativmedizin
D26 – 0079
Decision making at the end of life: Cancer patients’ treatment
preferences and prevalence of advance directives
*J. Hilbig1,2, *S. Sahm3,1
1
Goethe-Universität, Institut für Geschichte und Ethik der Medizin, Frankfurt, Deutschland, 2Capio Mathilden Hospital, Klinik für Innere Medizin,
Büdingen, Deutschland, 3Ketteler Krankenhaus, Medizinische Klinik I,
Offenbach, Deutschland
Introduction. Advanced directives (AD) are promoted as a means to ensure patient’s autonomy in case they are no longer able to decide themselves. Little is known about cancer patients’ capacity to express their
treatment preferences in advance and the prevalence of ADs. As part
of a project to evaluate attitudes with respect to ADs we examined treatment preferences and presence of ADs in cohort of cancer patients.
Method. Cancer patients (CP) were interviewed using a structured
questionnaire that had been established before (Sahm et al 2006). All
CPs had proven diagnosis of neoplastic disease of various stages. The
questionnaire included items inquring CPs treatment preferences (in
case of severe non-curable disease), presence of an AD, as well as demographic data and information about CPs’ current state of health. Association with demographic and health data were calculated using χ2-test.
Results. 100 CPs inlcuded, 51 male, mean age 68 yrs. Site of disease: 51
colorectal, 8 pancreas, 1 CUP syndrome, 3 breast cancer, 3 ovary, 9 esophagus, 8 stomach, 1 thyroid, 2 renal cell, 5 prostrate, 10 lung, 3 other
(double specification possible). 11 (11%) CPs had an AD fulfilled. Treatment preferences with respect to particular options are given in table 1.
The presence of AD was not associated to sex, general health state or
frequency of pain (p>0.05).
Tab. 1 D26-0079
i.v. fluid
Artificial nutrition
Antibiotic treatment for pneumonia
Analgesia if
consciousness will
be affected
Chemotherapy/
dialysis
Artificial ventilation
Conclusion. Prevalence of ADs amongst CPs is low. Many CPs are not
able to make decisions in advance as they are unsure about their preferences. In case pain management will affect consciousness a considerable amount of responders refuse that treatment signifying retaining
autonomy as the more important value. Artificial ventilation is rejected
overwhelmingly while i.v. fluid is favoured by a majority. The high proportion of answer not known proves a lack of information amongst CPs
which treatment may be comforting (or too burdensome) at the end of
life. To have CPs fulfilling an AD may be not be of value if they have not
been informed appropriately about the respective goals of various treatment options. Other strategies such as advanced care planning should
be adopted to manage care and sustain CPs’ autonomy at the end of life.
n
Wish to
be treated
Refusal
Not
known
100
100
100
73
16
36
2
35
28
25
49
36
100
82
6
12
100
31
19
50
100
3
70
27
D27 – 0269
Optimism and habitual coping as predictors of group psychotherapy effectiveness for women after treatment for breast cancer
*K. Teich1, C. Hamm2, A. Hamm1, H. Freyberger2
1
Institut für Psychologie, Physiologische und Klinische Psychologie/Psychotherapie, Greifswald, Deutschland, 2Universitätsklinikum, Klinik für
Psychiatrie und Psychotherapie, Greifswald, Deutschland
Purpose. After treatment for breast cancer psychotherapy helps enhancing the well-being and quality of life of the patients. Several programs
have been conducted for this purpose but the effectiveness of psychological intervention on cancer patients’ outcomes varies considerably.
The aim of the present study is to contribute to the improvement of psychological intervention programs by identifying individual differences
that help understand who benefits from such programs and who does
not. The study focused on differences in optimism, habitual coping, and
social support (SS) and examined effects on health-related quality of life
(HRQL), states of mood, anxiety, and depressive symptoms.
Methods. Data were collected from twenty-four Western Pomeranian
women (mean age: 50 years) receiving an adapted 10-week version of
the cognitive behavioral therapy (CBT) based intervention program BSMART by Antoni in a group setting. Participants filled in questionnaires assessing optimism, habitual use of coping strategies, and SS and
completed pre- and post-assessments on HRQL, states of mood, anxiety, and depressive symptoms.
Results. The intervention improved reports of vigour, physical, emotional, and functional well-being and reduced reports of anxiety, depressive symptoms, numbness, fatigue, and irritability. The effects remain
stable after three months. Furthermore, amount of improvement depended on two personality variables. Correlation analysis showed that
reduction in depressive symptoms was higher in the less optimistic patients (r=0.51), and in participants with a less avoidance (r=0.44) and a
more emotion-oriented coping style (r=−0.43). Vigour increased more
in participants with a less avoidance (r=−0.49) and a more emotionoriented coping style (r=0.42). Emotional well-being increased (r=0.49)
and anxiety decreased (r=−0.45) more in patients with a emotion-oriented coping style. No such effects emerged for SS.
Conclusions. The adapted CBT group intervention helped Western Pomeranian women in coping with the diagnosis breast cancer. The intervention was especially effective for less optimistic patients and participants with a less avoidance-oriented and a more emotion-oriented
coping style. The results suggest that the effectiveness of psychological
programs could be enhanced by accounting for differences in personality traits that eventually lead to tailored interventions for breast cancer
patients.
Abstracts
Palliativmedizin
Palliativmedizin
D28 – 0457
Changes in quality of life, anxiety, and depression of women
with and without breast-reconstruction undergoing oncological
rehabilitation: A prospective multi-center study
D29 – 0474
Psychosocial predictors of long-term survival in cancer patients
undergoing radiotherapy
*J. Giesler1, H.H. Bartsch1, J. Weis1
1
Klinik für Tumorbiologie, Institut für Reha-Forschung und Prävention,
Freiburg, Deutschland
Objectives. Research on quality of life and subjective well-being of women with breast cancer undergoing oncological rehabilitation after
breast reconstruction is sparse. Similarly, not much is known about the
specific needs and expectations these patients might have regarding rehabilitation. Therefore, we surveyed breast cancer patients with (n=129)
and without (n=155) post-mastectomy breast reconstruction with respect to quality of life, anxiety, depression, and satisfaction with the
outcome of surgery at the beginning, the end, and 6 months after the
end of rehabilitation in 7 rehabilitation clinics.
Method. Quality of life was measured by the QLQ C-30 and the BR23 of the EORTC, anxiety and depression were assessed by the HADS.
Quality of life facets specifically related to breast reconstruction were
measured through items addressing sequelae of reconstruction as well
as patients’ satisfaction. In addition, information on selected medical
and demographic variables was obtained. Data were analyzed by 2 (with
vs. without breast reconstruction) ×2 (time of assessment) repeated
measures ANOVAs. Since patient groups differed by age (M=50.9 vs.
M=56.4 years, p<0.001), age served as a covariate in some of the analyses. All results presented here are based on the data collected at the
beginning and the end of rehabilitation.
Results. Group comparisons revealed almost no significant group differences in quality of life. However, patients with reconstruction scored
significantly higher on sexual functioning (p<0.005) and experienced
less depression than women without reconstruction (p<0.05). While
there were no significant interactions between the factors group and
time, quality of life (QLQ C-30), anxiety, and depression improved
significantly across time (all p-values <0.001). Most domains and symptoms measured by the BR-23 also changed significantly (most p-values <0.001) with improvements most pronounced in body image and
side effects of systemic therapy.
Conclusions. Comparable to a review by Lee et al. (2009) we found almost
no significant differences in quality of life and subjective well-being between women with and without breast reconstruction undergoing oncological rehabilitation. That patients generally improved significantly
may indicate that rehabilitation has been equally effective. However,
patients from both groups continue to score markedly lower on many of
the EORTC functioning scales than an age-matched comparison group
of the German normal population (Schwarz & Hinz, 2001). Therefore, it
remains to be seen whether there will be any further changes 6 month
after rehabilitation. Identifying potential interventions specifically tailored to women with (or without) breast reconstruction also will require
further analyses taking additional variables into account.
*A. Dinkel1, B. Marten-Mittag1, P. Herschbach1, S. Sehlen2
1
Klinikum rechts der Isar, TU München, Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie, München, Deutschland, 2Klinikum
Großhadern, Universität München, Klinik und Poliklinik für Strahlentherapie und Radioonkologie, München, Deutschland
Background. Despite many attempts to identify stable prognostic psychosocial factors for survival after the diagnosis of cancer, current evidence is still equivocal. One limitation of many studies is the focus on
the predictive power of only one psychosocial variable. Thus, the purpose of this study was to investigate the prognostic value of several psychosocial factors for long-term survival in cancer patients, controlling
for relevant sociodemographic and medical variables.
Methods. Data were gathered in routine radiotherapy practice during
44 months. The analyses are based on 938 patients for whom data were
available. Baseline psychosocial distress, depression, health-related
quality of life (HRQOL), and life satisfaction were assessed using the
Questionnaire on Distress in Cancer Patients (QSC-R23), the Self-Rating Depression Scale (SDS), the Functional Assessment of Therapy-General (FACT-G) questionnaire, and the Questions on Life Satisfaction
(FLZM). Patients were followed for up to 10 years. Kaplan-Meier plots
and Cox proportional hazards models were used to investigate associations between sociodemographic, clinical, psychosocial factors and
overall survival (OS).
Results. Patients’ median survival time was 35 months (95% CI 28.9–
41.1). Significant multivariate predictors of OS were age, health insurance type, functional status, cancer site, and cancer stage. Controlling for
these variables, HRQOL was the only significant psychosocial predictor
of survival (hazard ratio 0.988, CI 0.979–0.997, p=0.009).
Conclusion. This study shows that psychosocial factors are associated
with survival after cancer diagnosis. Among several psychosocial factors HRQOL is the most important predictor for long-term survival in
cancer patients.
Discussed Poster – Versorgungsstrukturen/
Qualitätssicherung
Abstract withdrawn
D30 – 0073
Disclosing information about randomized clinical trials: A difficult and time consuming tasks for oncologists – results of a time
efficient communication skills training evaluated in randomized
controlled design
*A. Wünsch1, T. Gölz1, G. Ihorst2, H. Bertz3, K. Fritzsche4
1
Universitätsklinikum Freiburg, Psychoonkologischer Dienst der Abt.
Psychosomatische Medizin und Psychotherapie sowie Innere Medizin 1,
Freiburg, Deutschland, 2Universitätsklinikum Freiburg, Studienzentrum,
Freiburg, Deutschland, 3Universitätsklinikum Freiburg, Innere Medizin I
(Hämatologie und Onkologie), Freiburg, Deutschland, 4Universitätsklinikum Freiburg, Psychosomatische Medizin und Psychotherapie, Freiburg,
Deutschland
Background and Objectives. Disclosing information about randomized
clinical trials (RCT) is one of the hardest communication tasks for physicians and it is time consuming. Physicians have to address complex
information, e.g. explaining randomization, and they have to respect
patients’ rights to come to a free and uncoerced decision concerning
participation. A Communication Skills Training (CST) was developed
to train physicians to convey key information about RCT adequately, to
respect patients’ rights and to be time efficient. (1) Can a CST improve
communication skills about conveying key information about clinical
trials? (2) Does this CST change the amount of time needed for consultations about RCTs?
Methods. We developed a time efficient CST, based on the experience of
Jenkins (2005) and Brown (2004, 2007). First, individual learning goals
of participating physicians were derived from a video assessment. Then,
these learning goals were used in role play with actor-patients in a CST
to train each physician. For evaluation, 40 physicians were randomly
assigned to training or waiting control group. Training success was evaluated by blinded rater using a specific checklist to evaluate video-recorded standardized consultations with actor-patients. Duration of the
consultation was assessed before and after the training.
Results. (1) Results show significant improvements in content specific communication skills of trained physicians. (2) By the time of the
conference final data about time changes of these consultations will be
presented.
Conclusions. The developed CST is the first CST, which can show improvements in communication skills conveying key information about
clinical trials evaluated in a randomized controlled design. It addresses
ethical and legal standards, patient needs in understanding complex
information and especially physicians’ needs in having a time efficient
training for this difficult matter. This CST should be integrated as a
standard training for physicians who disclose information about RCT.
Qualitätssicherung
D31 – 0173
Quality assurance of oral Xeloda® chemotherapy by a mobile
phone application
*M. Welslau1, S. Haase2, A. Jakob3, N. Marschner4
1
Praxis Dr. Klausmann, Dr. Welslau, Aschaffenburg, Deutschland, 2IFETH Ltd.
& Co GbR, Hamburg, Deutschland, 3Gemeinschaftspraxis für Hämatologie
& Onkologie Offenburg, Offenburg, Deutschland, 4Praxis für Interdisziplinäre Hämatologie & Onkologie, Freiburg, Deutschland
Oral chemotherapy needs active cooperation of patient, physician and
health personnel concomitant with time-consuming elucidation and
supervision to assure effective therapy. The mobile phone-based project
P-com-X was started to support patients suffering from colon-CA, gastric-CA, and mamma-CA to provide therapeutic safety during Capecitabine (Xeloda®) oral chemotherapy. Real-time monitoring by a mobile
phone may improve compliance and sense of therapy safety along with
less personnel deployment.
From 03/2008 to 03/2009 n=17 patients (3m/14f, age range 23–87 years)
treated by Xeloda® of its approved indication in 4 oncologic centres in
Germany (Berlin, Duisburg, Freiburg, Aschaffenburg) were evaluated in this study. Two patients were in adjuvant therapy, 7 patients in
first-line (metastasized), 6 patients in second-line (metastasized) and
2 patients were in third-line treatment or more. Ten patients received
monotherapy, 7 patients combination therapy (CAPOX, CAPIRI, Bevacizumab, Xeloda®/Herceptin®, Xeloda®/Lapatinib).
Customary mobile phones were programmed with specially developed
Xeloda® documentation software. Within this software patients recorded general condition, side effects and their feeling of mentoring by the
mobile phone application twice daily. Real-time data submission to the
supervising medical centre allowed direct call-back by the physician if
intervention was required. The project was approved by the Bavarian
Chamber of Physicians Ethical Committee. All patients gave written
informed consent.
2546 treatment days from 17 patients were evaluable. This corresponds
to 119 cycles of Xeloda® treatment (3–14 cycles) while the documentation
time varied between 49–267 days. For general condition data evaluation
revealed no difference between treatment days and treatment-free interval. Due to adverse effects intervention was necessary only in 7.7% of
treatment days and hospitalisation could be avoided during the surveillance. Compliance amounted to 100%. The mobile phone application
allowed quick and realistic record of patients’ quality of life.
Patients felt safe and well assisted on 98% of all reviewed days during
Xeloda® therapy by the mobile phone application. None of the elderly
patients reported about handling problems. Evaluation of the therapy
monitoring by the mobile phone application demonstrated considerably improvement of compliance and allowed rapid intervention at arising toxicities. Furthermore, it showed multicentre applicability.
Abstracts
Qualitätssicherung
D32 – 0193
Quality of life in patients with thyroid cancer during rehabilitation compared to the German general population
*S. Singer1, T. Lincke2, E. Gamper3, K. Bhaskaran4, S. Schreiber5, A. Hinz5,
T. Schulte6
1
Bergische Universität Wuppertal, Gesundheitspsychologie, Wuppertal,
Deutschland, 2Universität Leipzig, Nuklearmedizin, Leipzig, Deutschland,
3
Medizinische Universität, Innsbruck, Österreich, 4London School of Hygiene and Tropical Medicine, Epidemiology, London, UK, 5Universität Leipzig,
Medizinische Psychologie, Leipzig, Deutschland, 6Rehabilitation Clinic, Bad
Oexen, Deutschland
Background. Since patients with thyroid cancer have a very good prognosis overall, clinicians may often assume that their quality of life is
comparable to the general population. We hypothesized that quality of
life of thyroid cancer patients is lower compare to the general population while controlling the effect of age and gender.
Methods. At the beginning of their stay at an inpatient rehabilitation clinic, a cohort of n=121 patients with thyroid cancer were assessed using
the quality of life core questionnaire of the European Organisation for
Research and Treatment of Cancer (EORTC QLQ-C30). Data for comparison were derived from a representative German community sample
with n=2037.
Results. The patients reported significantly more problems than the
community sample participants independently of gender and age effects in all but two domains, namely constipation and diarrhoea. The
strongest effects of the group (patients vs. general population) were
found in the following domains: insomnia (B=−43.7, p<0.001), fatigue
(B=−38.0, p≤0.001), and role functioning (B=29.7, p≤0.001). Significant
interactions between age and group occurred in the social functioning,
role functioning, fatigue, nausea/vomiting, and financial difficulties
domains. Quality of life was unrelated to the stage of the disease, except
in the physical function and global health status domains.
Conclusions. Patients with thyroid cancer at the beginning of inpatient
rehabilitation often experience more problems than controls from
community samples, independently of their age and gender. Clinicians
should be aware of the fact that quality of life is not directly related to
the severity of the cancer prognosis.
Qualitätssicherung
D33 – 0237
Oncofertility: Experience with cryopreservation and transplantation of ovarian tissue
*R. Dittrich1, A. Mueller1, L. Lotz1, I. Hoffmann1, M.W. Beckmann1
1
Universitätsklinikum Erlangen, Frauenklinik, Erlangen, Deutschland
Introduction. Cryopreservation of ovarian tissue with subsequent retransplantation following a period of recurrence-free survival is a promising new technique for fertility preservation in patients facing gonadotoxic treatment. Thirteen pregnancies have been reported worldwide
from this procedure and it can be expected that in the near future more
and more cancer patients who have been cured of their disease are likely to request reimplantation of cryopreserved ovarian tissue. However,
there are still many unanswered questions regarding the best place to
retransplant ovarian tissue, the longevity of the ovarian tissue and the
risk of recurrent cancer as a result of autotransplantation. This recita-
tion summarizes the Erlangen expertise on cryopreservation and transplantation of ovarian tissue following 6 retransplantations.
Method. Ovarian tissue from 6 cancer patients (n=3 hodgkin, n=2 anal
cancer, n=1 breast cancer) were cryopreserved with slow freezing protocols prior to chemo- and/or radiotherapy to preserve fertility for a future pregnancy. After cancer remission, the cryopreserved ovarian tissues
were retransplantated orthotopically in the vicinity of the ovary.
Results. All 6 patients regained ovarian function between 8 and
24 weeks (mean 16 weeks) after transplantation, as shown by follicle development and estrogen production. All women have had regular menstrual cycles after transplantation and in four patients oocytes from the
transplantated ovarian tissue could be retrieved and fertilized even without hormonal stimulation. The life span of the transplanted tissue has
been between 6 months and still functioning after 13 months.
Conclusion. Cryoperservation and autotransplantation of ovarian tissue is an encouraging method of re-establishing menstrual cycles and
achieving pregnancy in woman with iatrogen POF. We believe that
ovarian cortex cryopreservation should be offered before gonadotoxic
chemo or radiotherapy in all cases where there is a high risk of POF
and where emergency IVF is not possible. However due to the fact that
reports of pregnancy after ovarian tissue transplantation are still scarce,
the procedure requires more intensive investigation and other factors
such as uterine damage due to pelvic radiotherapy during cancer treatment need to be considered in order to optimize the preservation of
fertility. Further information about fertility saving strategies gives the
network Fertiprotekt (www.fertiprotekt.de).
Qualitätssicherung
D34 – 0411
Cancer information needs, topics of interest, information
resources and respective expectations in the German public – a
population based survey
*A. Gaisser1, R. Hagmann1
1
Deutsches Krebsforschungszentrum, Krebsinformationsdienst, Heidelberg, Deutschland
Background. Cancer patients and their family consistently express high
information needs. Also, 75% of users of hotline and email service of
the cancer information service are patients and next of kin. To evaluate
information needs, topics of interest, preferred resources and respective expectations in the general public a population based survey was
conducted.
Methods. In December 2010 a sample of 1852 persons over age 16 and
an additional sample of 395 individuals affected by cancer (patients,
relatives or close friends) who have not used the KID before was interviewed face to face by trained interviewers. The 15 questions presented
covered the following issues: if and on which cancer topics respondents
ever sought information, topics where more information would be appreciated, preferred resources, expectations regarding quality and presentation and to which extent they want to be informed and participate
in medical decisions in case of disease.
Results. Between 50 and 60% of respondents want to be well informed
and to participate in decisions in case of disease, patients more so. Over
two thirds – and 100% of patients – have sought cancer information
at least once. Topics of highest interest in the general public were risk
factors, prevention and early detection, among those affected it was
treatments, side effects, aftercare, but also prevention. Preferred resources were doctors and social network. For younger and better educated
respondents the internet ranked first. Overall, only two thirds were satisfied with the information they got. Expected quality criteria of information resources are: in detail, reliable and independent, individually
relevant, up-to-date, comprehensible, free of charge, with the opportunity to speak to somebody. Few have used independent counselling
and information services, but 37–45% would do so if they needed information again.
Conclusions. The internet is already a major source of health information, but does not provide tailored information and has not widely reached the older age groups. Overall person to person settings, first of all
with a doctor, are preferred. Counselling services can come up to that
preference, too. They have to stress independence and to cover a broad
range of topics, including complementary medicine, to reach the potential target groups. People of younger age and lower education, especially
if not affected in any way, seem to have no considerable interest in cancer related information and don’t seek it.
Qualitätssicherung
D35 – 0468
Proxy assessment of quality of life (QoL) before and after radiotherapy for brain metastases: results of a prospective study
using the DEGRO brain module
*D. Steinmann1, D. Vordermark2, H. Geinitz3, G. Ernst4, M. Hipp5, M. Theodorou3, A. Bayerl6, U. Eichenseder-Seiss6, H.-J. Wypior7, R. Aschoff8, C. Schäfer5
1
MHH, Strahlentherapie, Hannover, Deutschland, 2M.-Luther-Universität,
Strahlentherapie, Halle/Saale, Deutschland, 3TU, Strahlentherapie, München, Deutschland, 4MHH, Medizinische Psychologie, Hannover, Deutschland, 5Universität, Strahlentherapie, Regensburg, Deutschland, 6Hospital,
Strahlentherapie, Krems, Österreich, 7Hospital, Strahlentherapie, Landshut,
Deutschland, 8St.-Josef-Hospital, Strahlentherapie, Gelsenkirchen-Horst,
Deutschland
Purpose. Quality of life (QoL) studies in patients undergoing palliative
cancer treatment are difficult to perform due to poor performance status of patients and their limited ability to complete questionnaires. Proxies of such patients could give useful informations about patients’ QoL.
We applied a newly developed questionnaire, the DEGRO brain module
(DBM), in a prospective QoL study of patients undergoing radiotherapy
for brain metastases and compared results to scores obtained with validated patient-completed instruments.
Materials and methods. From 01/2007 to 06/2010 n=166 patients with
previously untreated brain metastases were recruited at 14 centers in
Germany and Austria. The EORTC-QLQ-C15-PAL and the brain module BN20 were used to assess QoL in patients at the start of treatment
(T0) and at 3 months (T3mo). At the same timepoints 141 of their proxies
estimated the QoL with the new DEGRO brain module (DBM), a tenitem questionnaire rating the general condition as well as functions and
impairment by symptoms in areas relevant to patients with brain metastases. QoL scores were compared between patients and their proxies as
well as between the two timepoints by calculation of the Spearman-Rho
correlation coefficient and by comparison of group means.
Results. At T3mo, 85 of 141 patients (60%) with initial response by a
proxy were alive. 67 of these patients (79% of 3-month survivors) and
65 proxies completed the second set of questionnaires. After 3 months,
QoL significantly deteriorated in all items of proxy-assessed QoL except
headache. Correlations between self-assessed and proxy-assessed QoL
were high in single items like nausea, headache and fatigue and in total
scores of the whole questionnaires at both points in time (r=0.57–0.78).
Conclusions. The high correlation between self assessment and proxy
ratings for the total questionnaire and for single items of physical symptoms as well as a similar change over time for both approaches suggest
that in patients with brain metastases, proxy assessment using the DBM
questionnaire can be an alternative approach to obtain QoL data when
patients are unable to complete questionnaires themselves.
General Poster
GI-Tumoren
0017
The Janus face of neoadjuvant therapy: the pelvic-perineal
morbidity
*J. Bunse1, H. Hollerbuhl1, F. Fritze1, K. Gellert1
1
Sana Klinikum Lichtenberg, Klinik für Allgemein- und Viszeralchirurgie,
Berlin, Deutschland
Introduction. In elevating neoadjuvant radiochemotherapy to being the
standard therapy for localized advanced rectal cancer (S3-guidelines),
the risks and side effects of biologically highly-active therapy inevitably accumulate and pose a significant challenge to both surgeon and
wound therapist. Both the immunosuppression caused by the cancer
and increasingly the localized radiation treatment effects of aggressive neoadjuvant therapy regimens play a part in the general postoperative risks. Other relevant risk factors are catabolism, which is present
in almost all cases, hypoproteinemia and age-related multi-morbidity
(such as atherosclerosis, diabetes and hypertonus). With regard to modern wound management, it seems necessary to adjust the therapeutic
strategy – based on good documentation – to the individual needs of
the patient, taking into consideration the methods available for wound
therapy such as VAC therapy, biological surgery and novel wound dressings. It is equally important, however, to balance out the catabolic state
and achieve prompt patient mobilization. A positive physician-patient
relationship is required during long periods of hospitalization in order
to maintain good adherence.
Method. 120 patients (2004–2008) with rectal cancer were retrospectively divided into two groups: patients (n=60) with neoadjuvant therapy [short-term radiotherapy (RT) and long-term radiochemotherapy
(RCHT) respectively] vs. patients who had undergone surgery without
neoadjuvant therapy. From the period between 2008 and 2010, four patients with particularly complicated sacral wound healing were retrospectively extracted.
Results. The evaluation of the two groups (neoadjuvant vs. non-adjuvant) shows an increase of almost double the rate of disorders of wound
healing in the group of patients with rectum amputation and pre-treatments. A particularly vulnerable group in terms of complicated healing
processes is women, as the anatomical boundary between the vagina
and the rectum (the rectovaginal fascia) may fall victim to the oncological resection or debridement subsequent to a sacral cavity infection,
resulting in the formation of a cloaca.
Discussion. The irradiated infected sacral cavity poses a big challenge to
surgeons and patients and requires courses of therapy adjusted to the
individual which include surgical debridement as well as all available
wound therapy options. Success is usually achieved only very slowly and
often requires changes in strategy at a very early stage. The psycho-social guidance of the patients makes very high demands of the attending
team of doctors. This can only be ensured by an interdisciplinary team.
Abstracts
0051
Trastuzumab in combination with standard chemotherapy as
first-line treatment for patients with HER2-positive metastatic
gastric cancer: safety findings from the German non-interventional observation study HerMES
*S.-E. Al-Batran , C.V. Hannig , D. Pott , C. Tirier , C. Lerchenmüller , E. Moorahrend4, H. Kröning5, S. Hegewisch-Becker6, V. Petersen7, M. Königsmann8,
E. Böcher9, T. Hamm9, K.-U. Däßler10, M. Groschek11, C. Maintz11, C. Hinske11,
W. Schneider-Kappus12, V. Kächele12
1
Krankenhaus Nordwest, Klinik für Onkologie und Hämatologie, Frankfurt,
Deutschland, 2Schwerpunktpraxis für Hämatologie und Onkologie, Bottrop, Deutschland, 3Gemeinschaftspraxis für Hämatologie und Onkologie,
Münster, Deutschland, 4Onkologische Praxis, Porta Westfalica, Deutschland, 5Schwerpunktpraxis für Hämatologie und Onkologie, Magdeburg,
Deutschland, 6Internistische Praxisgemeinschaft Eppendorf, Hamburg,
Deutschland, 7Onkologische Schwerpunktpraxis, Heidenheim, Deutschland, 8Onkologische Schwerpunktpraxis und Tagesklinik am Diakoniekrankenhaus Henriettenstiftung, Hannover, Deutschland, 9Gemeinschaftspraxis, Soest, Deutschland, 10Onkologische Schwerpunktpraxis,
Freital, Deutschland, 11Hämatologisch-Onkologische Praxis, Würselen,
Deutschland, 12Praxis für Hämatologie und interdisziplinäre Onkologie,
Ulm, Deutschland
1
2
2
2
3
Background. The ToGA trial, an international multicenter phase III clinical study involving 24 countries globally, has recently shown that the
anti-HER2 humanized monoclonal antibody trastuzumab is effective
in prolonging survival in HER2-positive carcinoma of the stomach and
the gastroesophageal junction (GEJ). However, few data are available on
trastuzumab when used as part of routine clinical practice in Germany.
Methods. This non-interventional observation study was conducted to
evaluate the efficacy, safety and feasibility of trastuzumab in previously
untreated patients with HER2-positive metastatic gastric cancer (MGC)
in Germany. Data from all patients with MGC who received trastuzumab were recorded in detail on standardized forms (eCRF) until they
had developed disease progression or for a maximum of 12 months of
trastuzumab therapy.
Results. Between April 2010 and June 2011, data from 50 patients were
collected. All patients were evaluable for safety. Baseline patient characteristics were as follows: median age 59.5 years (range 29–88); gender
(male 66%; female 34%); ECOG PS (0: 28%; 1: 46%; 2: 16%; 3: 6%); distant
metastases (92%); liver metastases (48%), lymph node metastases (38%);
peritoneum metastases (24%); lung metastases (12%); bone metastases
(12%). The median duration of trastuzumab treatment was 3.3 months
(range 0–10.6). The median trastuzumab dose per patient and cycle was
6.2 mg/kg BW. Only 27% of patients received trastuzumab according to
the label in combination with cisplatin and fluoropyrimidine (5-FU or
capecitabine), the remainder received trastuzumab either as monotherapy (8%) or in other combinations: cisplatin, 5-FU and leukovorin (12%);
5-FU, leukovorin, oxaliplatin and docetaxel (10%); 5-FU, leukovorin and
oxaliplatin (8%); capecitabine (6%); 5-FU, cisplatin and docetaxel (4%).
The most common adverse events (AEs, all grades) were as follows:
nausea (8%), diarrhoea (8%), vomiting (8%), and fatigue (6%). The most
common grade 3/4 AEs were nausea (4%), vomiting (4%), fatigue (4%),
diarrhoea (2%), and urinary tract infection (2%).
Conclusions. Trastuzumab, administered either as monotherapy or in
combination with standard chemotherapy, is well tolerated in the routine treatment of MGC. These findings support those from the ToGA
trial and suggest that treatment with trastuzumab should be regarded
as standard of care for patients with HER2-positive MGC.
0059
Tumor response and clinical outcome in advanced gastrointestinal stromal tumors under sunitinib therapy: comparison of
RECIST, Choi and volumetric criteria
*N. Schramm1, M. Schlemmer2, E. Englhart1, C. Becker1, M. Reiser1, F. Berger1
1
Klinikum der Universität München, Institut für Klinische Radiologie, München, Deutschland, 2Klinikum der Universität München, Medizinische Klinik
und Poliklinik III, München, Deutschland
Purpose. For patients with metastatic gastrointestinal stromal tumor
(GIST) under imatinib it has been demonstrated that radiological response according to Choi criteria also taking into account CT density
changes correlates better than RECIST with early therapy response and
disease-specific survival (DSS). Purpose of the study was the comparison of RECIST, Choi and volumetric radiological response in GIST-patients under 2nd-line-sunitinib-therapy with correlation to DSS.
Methods. 20 patients with baseline-CT of the abdomen under imatinib
obtained follow-up-CTs 3 months and 1 year after change to sunitinib.
Therapy response was evaluated according to RECIST, Choi and volumetric criteria (PR: decrease ≥40%, PD: increase ≥33%). The response
categories respectively were: partial response (PR), stable disease (SD)
and progressive disease (PD). Response according to the different assessment systems was correlated to the DSS of the patients.
Results. The mean DSS (in months) of the response groups 3 months
after therapy change was: RECIST: PR (0/20); SD (17/20): 29.2 (months);
PD (3/20) 11.6/Choi: PR (10/20) 27.9; SD (8/20) 26.4; PD (2/20) 13.5 /
Volumetry: PR (4/20) 29.7; SD (11/20) 28.4; PD (5/20) 17.2. Reponse
groups after 1 year of sunitinib showed the following mean DSS: RECIST: PR (3/20) 33; SD (9/20) 28.2; PD (8/20) 20.3 /Choi: PR (10/20) 21.3;
SD (4/20) 39.6; PD (6/20) 23.9 /Volumetry: PR (6/20) 27.0; SD (5/20) 35.9;
PD (9/20) 19.3. Patients classified as PR after 1 year according to Choi
and volumetry had a shorter DSS than patients classified as SD.
Conclusion. In our GIST-patient collective Choi and volumetric criteria
could detect responders with prolonged survival time under sunitinib
only in the early follow-up but not in the later course of disease. These
results have to be verified in larger patient cohorts. Our data provide
support for the assumption that Choi criteria might not be appropriate
to select GIST-patients with prolonged survival in later follow-up examinations.
0072
Gene markers of progression of Barrett’s metaplasia to carcinoma
*Q. Wang1, M. Fehlker1, M. Vieth2, P.-M. Schlag3, T. Wex4, P. Malfertheiner4,
W. Kemmner1
1
MDC-Berlin Buch, Surgical Oncology, Berlin, Deutschland, 2Klinikum
Bayreuth, Pathology, Bayreuth, Deutschland, 3Charité – Universitätsmedizin, Comprehensive Cancer Center, Berlin, Deutschland, 4Magdeburg
University, Gastroenterology, Magdeburg, Deutschland
Background. The incidence of esophageal adenocarcinoma has increased strongly during the past 30 years and 5-year survival remained poor
at approximately 20%. Esophageal adenocarcinoma develops through
a multistage process. Barrett’s esophagus metaplasia is considered to
be the key precursor lesion of esophageal adenocarcinoma. The aim of
this study is to generate and validate biomarkers to stratify patients with
Barrett’s esophagus in terms of their risk for developing cancer.
Patients and methods. We studied gene expression profiling of 59 frozen specimens, consisting of esophageal squamous epithelium from 18
healthy subjects, 20 specimens from patients with Barrett’s epithelium
and 21 cases of esophageal Barrett’s adenocarcinoma, by whole genome
microarray analysis. Laser capture microdissection technique was applied to procure cells from defined regions of Barrett’s metaplasia and
esophageal Barrett’s adenocarcinoma. Microarray results were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in
a second and independent cohort consisting of 12 healthy cases, 20 Barrett’s epithelium, 8 intermediate dysplastic BE closed to esophageal adenocarcinoma and 10 esophageal Barrett’s adenocarcinomas. Furthermore, immunohistochemistry was performed on a third independent
cohort consisting of 12 normal squamous esophagus samples, 12 esophageal adenocarcinoma cases and 12 Barrett’s esophagus samples, five
of which were close to esophageal Barrett’s adenocarcinoma, representing Barrett’s esophagus at high risk for developing adenocarcinoma.
Results. Microarray analysis showed that 1176 genes were significantly
differentially expressed in esophageal Barrett’s adenocarcinoma compared to squamous esophagus epithelium. In a second step, the expression profile of Barrett’s esophagus metaplasia was compared to esophageal Barrett’s adenocarcinoma and squamous epithelium resulting in a
short list of 16 genes which were differentially expressed among all three
groups. Hierarchical clustering of the samples based on the expression
of these 16 genes allowed a clear discrimination of NE, BE and EAC.
Validation of the microarray results in an independent patient cohort
by qPCR confirmed these results. This analysis showed that in particular the genes CTHRC1, INHBA, PROCR and ADH7 were significantly
differently expressed between NE, BE and EAC. Furthermore, immunohistochemistry showed that CTHRC1 and INHBA were only high in
EAC and BE located close to EAC on protein level.
Conclusions. This study identified novel biomarkers to predict esophageal Barrett’s adenocarcinoma at its Barrett’s esophagus precursor
stage, not only in original cohort, but also in validation cohorts. These biomarkers can be determined by quantitative expression analysis,
which will complement conventional semi-quantitative immunohistochemical analysis in the future. However, further efforts are needed to
understand the contribution of these genes to Barrett’s carcinogenesis.
0089
Resection vs. transplantation as curative treatment options for
hepatocellular carcinoma in cirrhosis – Systematic review and
metaanalysis
*A. Proneth1, F. Zeman2, S. Bhoorie3, V. Mazzaferro3, E.K. Geissler1,
H.J. Schlitt1, A.A. Schnitzbauer1
1
Uniklinikum Regensburg, Klinik und Poliklinik für Chirurgie, Regensburg,
Deutschland, 2Uniklinikum Regensburg, Zentrum für Klinische Studien,
Regensburg, Deutschland, 3National Cancer Institute, Istituto Nazionale
Tumori Fondazione IRCCS, Gastrointestinal Surgery and Liver Transplantation Unit, Milano, Italien
Objective. To systematically review the literature on resection (Rx) and
liver transplantation (LT) for hepatocellular carcinoma (HCC) in patients with Child A cirrhosis.
Background. Hepatocellular Carcinoma is the fifth most neoplasm
worldwide. Current standard curative therapeutic strategies include
resection and liver transplantation with or without prior bridging with
ablative procedures. Organ shortage leads to discussion whether HCC
should be transplanted or whether resection can achieve similar results.
Methods and aims. A systematic review of various databases (Pubmed,
PICO, MEDLINE, Cochrane and Library for RCT) was performed. Studies investigating Rx vs. LT, and Rx or LT only, and in which patients
were regarded to be both resectable and transplantable between 1998
and 2011 were included in the analysis. The primary endpoint was overall survival (OS). Secondary endpoints were disease free survival (DFS)
as well as prognostic factors (AFP, tumor size and number, micro- and
macrovascular invasion, stadium of cirrhosis, MELD-score, bridging
therapies etc.). The results should serve as a decision-making basis to
either transplant or resect the patient primarily in case of HCC-diagnosis.
Results. Database research revealed a total 843 hits. To date there is no
existing randomized controlled trial (RCT) investigating Rx vs. Tx for
HCC. A total of 71 publications were eligible for statistical evaluation.
OS and DFS data for LT and Rx differ significantly between groups fa-
voring LT. However, surrogate predictive markers for outcome reveal a
lower microvascular invasion, a better differentiation, less microsatellites, smaller tumors and lower pre-treatment AFP values in patients
being transplanted.
Conclusion. Current evidence in literature does not allow a meaningful
comparison between patient collectives undergoing Rx or LT for HCC.
There are no data from randomized controlled trials. Analyses do not
compare patients in a comparable tumor stadium. A RCT in patients
without contraindications for transplantation or resection and comparable surrogate characteristics should be initiated investigating the
hypothesis that resection of HCC achieves similar results than transplantation.
0122
Implementation of adjuvant treatment in routine care of colorectal cancer – data of a population-based sample
*A. Schlesinger-Raab1, S. Schrodi1, R. Emeny1, R. Eckel1, G. Schubert-Fritschle1, J. Engel1
1
Tumorzentrum München (TZM), Tumorregister München (TRM), München,
Deutschland
Introduction. In 2004, the first national S3 guideline for the diagnosis,
therapy and aftercare of colorectal patients was implemented in Germany, and the first update was released in 2008. Adjuvant chemotherapy is
recommended in colon cancer with UICC stage III. Neoadjuvant radiation therapy is recommended in rectal cancer with UICC II/III.
Objective. The study aim was to evaluate guideline compliance for adjuvant treatment of patients with colorectal cancer and to determine
possible influences on survival in a population-based sample.
Methods. The Munich Cancer Registry (MCR) records all cancer patients treated in the registration area that covers upper Bavaria, with
4.5 million inhabitants, since 2007. Data from almost 45,000 cases of
patients with colorectal cancer, diagnosed between 1988 and 2008 were
analysed. The distribution of adjuvant therapies was analysed in regard
to associations with time, age and tumour-related factors. Survival as
outcome parameter was examined by the Kaplan-Meier method and
Cox proportional hazard modelling.
Results. Stratification into two decades (1988–1997, 1998–2002) showed
the demographic ageing, the proportion of patients 80 years and older
increases from 15 to 20% over these two time periods. The proportion of
male patients increased as well from 53 to 56%. UICC stage distribution
was quite stable. Documentation improved continuously; missing values in tumour-related variables were less than 10%. The realisation of
adjuvant chemotherapy in colon cancer stage III improved from 30%
in the years before 1998 to almost 50% after 1998 and is still improving
year by year. Only 16% of stage II rectal cancer patients were treated with
neoadjuvant radiation before 1998 and about 70% after 1998. In stage III
patients, the proportions improved from 53% to about 80%. A slight
improvement in relative survival can be seen in rectal cancer patients:
about 3% points in 10-year relative survival. Thus, since 1998 colon and
rectal cancer have the same prognosis with 65% and 57% probability for
5- and 10-year relative survival, respectively.
Conclusion. The guideline recommendations concerning adjuvant and
neoadjuvant therapies continue to be brought into practice, especially
in UICC III in rectal cancer patients. Their increasing implementation
may be a reason for improvement in survival in rectal cancer patients.
Abstracts
0131
The impact of multimodal treatment on long-term quality of life
in patients with rectal carcinoma. Results of the CAO/ARO/AIO-94
study
*S. Merkel1, M.-T. Villanueva1, W. Hohenberger1, T. Liersch2, H. Becker2,
R. Raab3, C. Rödel4, R. Sauer5
1
Universitätsklinikum Erlangen, Chirurgische Klinik, Erlangen, Deutschland,
2
Universitätsmedizin Göttingen, Klinik für Allgemein- und Viszeralchirurgie, Göttingen, Deutschland, 3Klinikum Oldenburg, Klinik für Allgemeinund Visceralchirurgie, Oldenburg, Deutschland, 4Universitätsklinikum
Frankfurt am Main, Klinik für Strahlentherapie und Onkologie, Frankfurt
am Main, Deutschland, 5Universitätsklinikum Erlangen, Strahlenklinik,
Erlangen, Deutschland
Introduction. The German multicenter study CAO/ARO/AIO-94 compared preoperative chemoradiotherapy with postoperative chemoradiotherapy (CRT) in locally advanced rectal cancer. Preoperative CRT
was found to improve local control and was associated with reduced
acute toxicity but did not improve survival. The aim of our study was
to compare quality of life in the long-term survivors after a median of
11 years (range: 8–15 years).
Patients and methods. Until 2010 of 799 participating patients, 340 patients (42.6%) had died and 8 patients (1.0) were lost to follow-up. 359
(79.6%) of the 451 long-term survivors (8–15 years) completed the quality
of life questionnaires of the EORTC, the QLQ-C30 and its new colorectal module, the QLQ-CR29: 190 patients who had preoperative CRT,
109 patients who received postoperative CRT and 60 patients of the
postoperative treatment arm without receiving CRT due to overstaging,
understaging, postoperative complications or denial. The QLQ-CR29
permits a combined analysis of patients with and without a stoma even
in bowel function. Median age of the 237 men and 122 women was 71 years (range: 43–88 years). For comparisons the Mann-Whitney U test and
the Kruskal-Wallis one-way of variance were used.
Results. Significant differences between the three groups were found in
social functioning, diarrhea, stool frequency, faecal incontinence, flatulence, bloated feeling, embarrassing bowel movements, abdominal
pain, urinary frequency and dysuria. Patients without CRT indicated
more favourable statements in most measures, followed by patients with
preoperative CRT, while patients with postoperative CRT stated the
most unfavourable results. Impotence was rated highest of all symptom
scales but without differences between the primary treatment groups.
Age, sex, tumour site and stoma were found to be additional factors influencing significantly quality of life in several aspects.
Conclusion. Multimodal treatment, especially preoperative CRT reduces the rate of locoregional recurrences. The indication for multimodal
treatment has to be based on evidence based criteria, because long-term
survivors complain about reduced quality of life, especially with respect
to bowel function and defecation. However, long-term quality of life was
found to be superior after preoperative CRT when compared to postoperative CRT.
0133
Locoregional recurrence in rectal carcinoma: Long-term results
of the German multicenter study CAO/ARO/AIO-94
*S. Merkel1, M.-T. Villanueva1, W. Hohenberger1, T. Liersch2, H. Becker2,
R. Raab3, C. Rödel4, R. Sauer5
1
2
Universitätsmedizin Göttingen, Klinik für Allgemein- und Viszeralchirurgie, Göttingen, Deutschland, 3Klinikum Oldenburg, Klinik für Allgemeinund Visceralchirurgie, Oldenburg, Deutschland, 4Universitätsklinikum
Frankfurt am Main, Klinik für Strahlentherapie und Onkologie, Frankfurt
am Main, Deutschland, 5Universitätsklinikum Erlangen, Strahlenklinik,
Introduction. The German multicenter study CAO/ARO/AIO-94 of locally advanced rectal cancer showed in 2004 after a median follow-up of
46 months in the intention-to-treat-analysis, that preoperative chemoradiotherapy (CRT) compared with postoperative CRT improved local
control (6% vs 13% locoregional recurrences) and reduced acute toxicity,
but did not improve survival (74% vs 76%). Now we report long-term
results after a median follow-up of 11 years (8–15 years).
Methods. Until 2010 of 799 participating patients, 340 patients (42.6%)
had died and 8 patients (1.0) were lost to follow-up. 764 patients treated
with curative intent (M0/M1, R0/R1) were selected for analysis: 386 patients after preoperative CRT, and 378 in the postoperative CRT arm
(132 of these did not receive any postoperative treatment due to overstaging, understaging, complications or denial. An as-treated analysis was
performed to estimate 10-year rate of locoregional recurrences and to
evaluate treatment and prognosis of those patients.
Results. The 5- and 10-year rates of locoregional recurrences of all patients were 7.2% and 8.5%. These rates differed significantly (p=0.008)
between the preoperative CRT (4.2% and 6.3%) and the postoperative
CRT arm (10.4% and 10.7%) after the long-term follow-up. In multivariate analysis, R1-resection was the most adverse factor for locoregional
recurrences. Late locoregional recurrences (≥60 months after primary
treatment) were seldom in our study with 7 out of 58 recurrences: five in
the preoperative arm and two in the postoperative CRT arm. In general,
the treatment choice for locoregional recurrences depended on primary
treatment. Radiotherapy or CRT was administered in 7/41 patients (17%)
who had former CRT and in 12/17 patients (71%) with primary surgery
alone (p<0.001). R0-resection of locoregional recurrence was possible
in 2/20 patients (10%) with preoperative CRT as primary treatment, in
6/21 patients (29%) with postoperative CRT and in 7/17 patients (41%)
wthout any CRT of the primary tumour (p=0.091). The observed 2-year
overall survival rates of the 58 patients with locoregional recurrences
were: 15.8% in 20 patients after preoperative CRT as primary treatment,
14.3% in 21 patients with primary postoperative CRT and 58.8% in 17 patients with primary surgery alone (because of overstaging, complications, denial etc., p=0.001).
Conclusions. Even after a median follow-up of 11 years, preoperative
chemoradiotherapy remains superior to postoperative chemoradiotherapy with respect to locoregional recurrences. In this arm few more late
recurrences developed. The prognosis of these rare cases however, was
poor.
0134
Hyperthermia induced by nanotherapy for oesophageal and
pancreatic cancer
*B. Rau1, M. Steinbach2, M. Hünerbein2, J.-T. Ollek3, A. Jordan3
1
Charité Campus Mitte, Klinik für Allgemein-, Thorax- und Gefäßchirurgie,
Berlin, Deutschland, 2Helios Klinken Buch, Berlin, Deutschland, 3Magforce,
Berlin, Deutschland
Background. In the literature is postulated, that hyperthermia enhances
the effect of radio- and chemotherapy. Intra-tumorally instilled superparamagnetic ironoxide nanoparticles (NanoThermR) inducing localized hyperthermia are a potential option to further improve cancer
treatment. Oesophageal (OC) and pancreatic cancer (PC) have a poor
outcome regarding overall and progression free survival. The objective
of this study was to show that NanoThermR can be applied safely in
incurable OC and PC and effectively induce interstitial hyperthermia.
Methods. The method comprised direct injection of the nanoparticles
into the tumor. Instillation was controlled by CT scan prior to exposure to the magnetic field. Hyperthermia was applied synchronously or
directly before chemotherapy. Patients were subsequently exposed to
an alternating magnetic field which stimulates the nanoparticles causing interstitial heat needed for effective thermotherapy. Altogether
17 patients with OC (11) and PC (6) were treated with nanoparticles in
combination with chemo- or chemoradiotherapy. Temperature was
monitored via thermometry catheter placed at the tumor. Treatment
emergent toxicities were records according to the common Toxicity
Criteria (CTC).
Results. Mean tumor volume was 27.3 and 42.3 cm3 in OC and PC, respectively. Placement of the nanoparticles was feasible in all tumors.
Temperature at the tumor could not be measured in OC. Instead mean
simulated temperatures based on the distribution of the nanoparticles
determines by post-instillation CT was 42.8°C. In PC temperatures
were successfully measured at the tumor yielding 40.0°C on average.
Occurrence of the treatment emergent CTC grade 3 and 4 toxicity was
low. Hot spots during treatment were observed in every patient.
Conclusion. NanoThermR therapy in combination with chemo- or chemoradiotherpy was feasible and reasonably well tolerated even in this
late-stage patient population. To optimize the NanoThermR application
procedure and to improve the quality of temperature measurement as
well as to show efficacy of the therapy in combination with current therapy options in OC and PC further investigations are planned.
0141
Identification of predictive molecular markers for chemoradiation by ICPL proteom amalysis in rectal carcinomas
*R. Croner1, M. Sevim2, P. Jo3, V. Schellerer1, E. Naschberger4, M. Stürzl4,
W. Hohenberger1, F. Lottspeich2, J. Kellermann2
1
2
Max-Planck Institut Martinsried, Proteinanalytik, Martinsried, Deutschland, 3Universitästklinkum Göttingen, Chirurgische Klinik, Göttingen,
Deutschland, 4Universitästklinkum Erlangen, Abteilung für Molekulare und
Experimentelle Chirurgie, Erlangen, Deutschland
Background. Neodajuvant chemoradiation (CRT) is an established procedure in rectal carcinomas to increase sphincter preservation and to
decrease local tumor recurrence (9.6%). But only 53% of the carcinomas
respond with tumor regression, while 8–15% show complete response.
Molecular markers may be an option to identify responder from nonresponder prior to CRT.
Material and methods. Tumor biopsies from 20 rectal carcinomas were
harvested prior to CRT (CAO/ARO/AIO-04). After laser microdissektion (LCM) of the specimens, proteins were isolated. The samples of CRT
responders (rCRT; n=10) and CRT non reponders (nCRT; n=10) were
pooled regarding their postoperative histopathological tumor regression rate (Dworak). Isotope Coded Protein Label (ICPLTM) was perfor-
med of the LCM specimen’s proteom to identify differential proteins
between rCRT and nCRT.
Results. From all tumor biopsies a sufficient amount of material could be
harvested during LCM to perform ICPLTM. The isolated protein lysate
was of good quality and ICPLTM worked well. We identified 43 differentially expressed proteins between the rCRT and nCRT group. These
proteins belonged to the tumor stroma, immune system and gluthation
metabolism.
Conclusions. ICPLTM is a sufficient technology to identify differentially
expressed proteins in rectal carcinoma biopsies. The identified markers
may be potential candidates for CRT prediction, but their clinical value
has to be validated during further analysis.
0151
Evaluation of sorafenib in combination with local microtherapy
guided by gadolinium-EOB-DTPA enhanced MRI in patients with
inoperable hepatocellular carcinoma
*J. Ricke1, K. Schütte2, O. Rosmorduc3, A.L. Jacob4, J. Lammer5, C. Verslype6,
B. Sangro7, J. Walecki8, H.-J. Klumpen9, B. Peynircioglu10, S. Yalcin11, C. Bartolozzi12, H. Amthauer1, P. Malfertheiner2
1
Universität Magdeburg/ Medizinische Fakultät, Radiologie und Nuklearmedizin, Magdeburg, Deutschland, 2Universität Magdeburg, Klinik für
Gastroenterologie, Hepatologie und Infektiologie, Magdeburg, Deutschland, 3Hôpital Saint Antoine, Service d’Hepatologie, Paris, Frankreich, 4Universitätsspital, Klinik für Radiologie und Nuklearmedizin, Basel, Schweiz,
5
Medizinische Universität, Interventional Radiology, Wien, Österreich,
6
Medizinische Universität, Digestive Oncology, Wien, Österreich, 7Clinica
Universitaria and CIBEREHD, Liver Unit, Pamplona, Spanien, 8Centralny
Szpital Kliniczny, MSWiA, Department of Radiology, Warszawa, Polen,
9
Academic Medical Center, Oncology, Amsterdam, Niederlande, 10Haceteppe University of Medicine, Department of Radiology, Ankara, Türkei,
11
Haceteppe University of Medicine, Medical Oncology, Ankara, Türkei,
12
University of Pisa, Department of Radiology, Pisa, Italien
Background. Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with an increasing incidence rate. Tumour stage
at diagnosis, liver function and general health status are the most important prognostic factors for the individual patient. Treatment strategy
in early HCC aims at the local removal of the tumor and represents a
potentially curative treatment option [resection, liver transplantation
or local ablation using percutaneous ethanol injection (PEI) or radiofrequency ablation (RFA)]. In intermediate and advanced stages of
HCC patients receive treatment with palliative intent [transarterial
chemoembolisation (TACE), Yttrium-90-radioembolisation (SIRT)
or systemic therapy with sorafenib]. Studies with the combined use of
locoregional and systemic therapy with their potential of a beneficial
synergism are few and conducted in a small number of patients.
Methods. This phase II study (SORAMIC) is composed of three sub-studies with the following primary objectives: (1) In patients in whom local
ablation is appropriate to determine if sorafenib in combination with
radiofrequency ablation (RFA) prolongs the time-to-recurrence in comparison with RFA + placebo. Primary endpoint (PEP): time to recurrence, n=290 pts. (2) In patients in whom RFA is not appropriate (palliative
treatment group) to determine if the combination of yttrium-90-microspheres (SIRT) + sorafenib improves the overall survival in comparison to sorafenib alone. PEP: overall survival, n=375 pts. (3) To test the
diagnostic and staging accuracy of Gd-EOB-DTPA enhanced MRI with
contrast-enhanced multisclice CT. PEP: correct stratification of patients
to a palliative versus local ablation treatment strategy; n=830 pts.
Results. This trial has already started with 34 out of 830 patients enrolled until July, 18th 2011 and will recruit in 41 European centers in 14
countries. Preliminary results regarding the feasibility of these treatments within such a complex trial design under academic sponsorship
will be presented. Safety data after at least 2 months of treatment with
Abstracts
sorafenib/placebo for the first 20 patients did not indicate an increased
toxicity for the combination of local microtherapy and sorafenib.
Conclusion. Findings will provide insight in the synergism of local microtherapy and systemic treatment in patients with HCC. The complex
trial design with three separate study sections with own PEP will additionally define the optimal imaging staging modality.
0152
Progression free survival and overall survival in patients with
metastastic gastrointestinal stromal tumor (GIST) treated with
sorafenib as 3rd- or 4th-line therapy
*U. Bitz1, D. Pink1, J. Rahm1, A. Koepke1, P. Reichardt1
1
HELIOS Klinikum Bad Saarow, Klinik für Hämatologie und Onkologie,
Sarkomzentrum Berlin-Brandenburg, Bad Saarow, Deutschland
Background. There is no approved treatment option for patients with
unresectable or metastastic GIST with resistance to imatinib and sunitinib. Results of phase II trials indicate an efficacy of the multi-tyrosinkinase-inhibitor sorafenib in this population.
Methods. We performed a retrospective analysis of all patients with metastastic GIST treated with sorafenib in our institution regarding their
progression free survival and overall survival. All of these patients had
suffered disease progression to imatinib and sunitinib, some of them
had also been treated with everolimus and/or nilotinib. Response to
treament was assesed using CT-Scans and RECIST-criteria every three
months.
Results. 37 patients (median age 53 years [33–75 years]) treated with
sorafenib 800 mg daily were included in our analysis. Primary sites
of GIST were small intestine (42%), stomach (30%), duodenum (15%),
unknown (10%) and rectum (3%). 35 patients were eligible for response evaluation. 3 patients (9%) had a partial remission, 19 patients (54%)
showed stable disease, resulting in a disease control rate (PR + SD) of
63%. 13 (37%) patients showed no response to treatment. Median progression free survival (mPFS) was 5 months (0–38 months). mPFS in patients with at least stable disease was 8,5 months (4–38 months). Median
overall survival since start of treatment was 10 months (1–38 months),
82 months (21–158 months) since first diagnose of GIST and 76 months
(10–126 months) since first diagnose of metastasis. Main toxicities during treatment were skin reactions (rash, hand and foot-syndrome), hypertension, diarrhea and fatigue. In 24% of the patients a dose reduction
due to toxicity was necessary.
Conclusion. To our knowledge this is the largest collection of patients
with metastastic GIST treated with sorafenib by a single institution,
that has been reported so far. In the majority of patients with intensively
pretreated metastatic GIST, treatment with sorafenib can at least lead to
stabilisation of disease. Our results are comparable to those of phase II
trials from South Korea und the USA. The conduction of randomised
prospective trails is necessary for further evaluation.
0180
Investigating the relationship between quality of life (QoL) and
tumour response in patients (pts) with metastatic colorectal
cancer (mCRC) receiving FOLFIRI plus panitumumab (pmab) as
first-line therapy: an exploratory analysis of study 314
*M. Karthaus1, J. Thaler2, R. Hofheinz3, L. Mineur4, H. Letocha5, R. Greil6, E.
Fernebro7, E. Gamelin8, A. Baños9, C.-H. Köhne10
1
Department of Hematology, Oncology and Palliative Medicine, Klinikum
Neuperlach/ Klinikum Harlaching, München, 2 Department of Hematology
and Medical Oncology, Klinikum Wels-Grieskirchen, Wels, 3 Day treatment
centre at the Interdisciplinary Tumour Centre Mannheim, Universitätsmedizin, Mannheim, 4 Radiology and Oncology Centre, Institut SainteCatherine, Avignon, 5 Department of Oncology, County Hospital, Västerås,
63
rd Medical Department, University Hospital, Salzburg, 7 Department of
Oncology, University Hospital, Lund, 8 Department of Medical Oncology
and Oncopharmacology, Centre Paul Papin, Angers, 9 Department of Biostatistics, Amgen, Uxbridge, 10 Department of Hematology and Oncology,
Onkologie Klinikum, Oldenburg
Introduction. Study 314 was a phase II, single-arm, multicentre study
assessing the efficacy/safety of first-line FOLFIRI plus pmab in pts with
mCRC, stratifying by KRAS tumour status. Here, we explored the relationship between QoL and tumour response.
Methods. FOLFIRI and pmab (6 mg/kg) were administered every 14
days until disease progression, unacceptable toxicity or consent withdrawal. EUROQOL EQ-5D Index scores were recorded at screening,
then every 8 wks until wk 32, every 3 months thereafter until disease
progression, and 56 days after stopping study treatment (referred to as
the safety follow up visit). EQ-5D scores range from −0.594 to 1 (1 being
equal to perfect health). A change of ≥0.08 was considered to be clinically meaningful. Data were analyzed descriptively by best overall response and by tumour KRAS status (wild type [WT] or mutant [MT]).
Results. In those pts with higher baseline EQ-5D scores, a trend for better tumour response was observed. In those pts who achieved complete or partial response, the difference in EQ-5D score between the WT
group and the MT group surpassed the clinically meaningful threshold
at wk 8 and wk 24.
Tab. 2 Mean (SE) change in EQ-5D score from baseline
Mean (SE)
baseline
score
n
Wk 8
n
Wk 16
n
Wk 24
n
PD
WT
PD
MT
SD
WT
SD
MT
CR or PR
WT
CR or PR
MT
4
3
25
26
45
22
0.720
(0.178)
3
+0.047
(0.047)
1
−0.240
(–)
0.588
(0.205)
2
−0.087
(0.122)
1
−0.327
(–)
0
–
0.790
(0.034)
23
+0.015
(0.030)
19
−0.007
(0.073)
9
+0.111
(0.046)
5
+0.172
(0.081)
15
0.812
(0.034)
43
+0.049
(0.032)
39
+0.067
(0.031)
33
+0.053
(0.028)
15
+0.019
(0.037)
19
0.817
(0.052)
21
−0.036
(0.052)
22
+0.018
(0.045)
19
−0.027
(0.033)
8
−0.015
(0.080)
14
−0.034
(0.085)
+0.048
(0.042)
−0.019
(0.038)
1
−0.311
(–)
2
0
–
1
0.833
(0.039)
23
−0.023
(0.044)
20
+0.024
(0.039)
10
+0.014
(0.073)
3
+0.195
(0.195)
13
−0.087
(0.343)
+0.000
(–)
−0.040
(0.060)
0.000
Wk 32
n
Safety
follow up
visit
n
CR complete response, PD disease progression, PR partial response, SD
stable disease, SE standard error.
Conclusions. Those pts with WT KRAS mCRC who responded to pmab
appeared to maintain their EQ-5D score over time. These results suggest that the relationship between QoL and tumour response in this
treatment setting should be further investigated, perhaps in a larger
patient population.
0183
Inhibition of portal branch ligation-induced extrahepatic tumor
growth by rapamycin
*S. Dold1, S. Senger1,2, B. Huber2, J. Sperling1, M.D. Menger2, M.K. Schilling1,
O. Kollmar1
1
Universität des Saarlandes, Klinik für Allgemeine Chirurgie, Viszeral-,
Gefäß- und Kinderchirurgie, Homburg/Saar, Deutschland, 2Universität des
Saarlandes, Institut für Klinische & Experimentelle Chirurgie, Homburg/
Saar, Deutschland
Background. Portal branch ligation (PBL) is a frequently used procedure
to achive curative resection of initially unresectable tumors by inducing liver regeneration in the unligated liver lobe. However, PBL induces
tumor growth within the ligate part of the liver. The mTOR inhibitor
rapamycin (RAPA) has been shown to exhibit potent anti-tumor activities. Therefore, we analyzed the effect of RAPA on tumor growth and
angiogenesis under the conditions of PBL-associated liver regeneration.
Materials and methods. Tumor growth was studied using GFP-transfected CT26.WT colorectal cancer cells implanted into the dorsal skinfold
chamber of BALB/c-mice. Directly after tumor cell implantation, PBL
of the left liver lobe was performed. The animals were treated daily with
PBS as control and with RAPA (1.5 mg/kg) starting at day 0 or day 5
after PBL (n=8 each group). Tumors were analyzed for angiogenesis and
tumor growth via intravital fluorescence microscopy at defined time
points until day 14 after PBL.
Results. Extrahepatic tumor growth was markedly reduced by PBL
compared non-PBL controls. Interestingly, RAPA treatment starting
at day 0 significantly inhibited tumor growth compared to PBL-controls (1.35±0.56 mm2 vs. 3.86±1.28 mm2). RAPA treatment starting at
day 5 did not influenced tumor growth within the observation period
(2.98±0.35 mm2 vs. 3.86±1.28 mm2). The inhibition of tumor growth was
associated with a significantly decreased macro and microvascular density within the tumor border (6.5±2.7 cm/cm2 vs. 63.0±19.4 cm/cm2) as
well as tumor center (6.3±2.9 cm/cm2 vs. 72.4±29.8 cm/cm2) compared
with controls. This inhibitory effect on the angiogenesis of the tumors
was seen in both RAPA treatment groups.
Conclusion. RAPA treatment is capable of inhibiting angiogenesis and
tumor growth of colorectal metastasis during PBL-associated liver regeneration. Moreover, our experimental data indicate that an early onset
of RAPA-therapy after PBL has a more potent anti-tumoral effect.
0185
After major liver resection cilostazol stimulates liver regeneration but not growth of residual colorectal liver metastases
*M. Strowitzki1, M.R. Moussavian2, S. Dold2, M. von Heesen2, M.K. Schilling2,
M.D. Menger1, O. Kollmar2
1
Universität des Saarlandes, Institut für Klinische & Experimentelle Chirurgie, Homburg/Saar, Deutschland, 2Universität des Saarlandes, Klinik für
Allgemeine Chirurgie, Viszeral-, Gefäß- und Kinderchirurgie, Homburg/
Saar, Deutschland
Background. Liver resection is still the accepted gold standard of treatment for liver tumours. The resectability rate for liver tumors is about
20–30% in normal livers, but reduced in patients with impaired liver
function caused by neoadjuvant chemotherapy, steatosis or cirrhosis. In
spite of improvements in adjuvant chemotherapy and increasing surgical confidence and expertise, the parameters determining how much
liver can be resected have remained largely unchanged. Major liver resection for primary or secondary liver tumors can lead to postoperative
liver dysfunction or even liver failure. Therefore, this study analyzed
whether cilostazol, a selective phosphodiesterase-III inhibitor, is capable to improve hepatic perfusion and liver regeneration after 70% hepatectomy and influences tumor growth of colorectal metastases within
the remnant liver.
Methods. Sprague-Dawley-rats were pre-treated with cilostazol (5 mg/
kg bw) or glucose solution. After 5 days animals underwent either 70%
hepatectomy or sham operation. Additional animals (WAG-rats) received placebo- or cilostazol-treatment followed by 70% hepatectomy or
sham operation and subcapsular implantation of 5×105 CC531-colorectal cancer cells.
Results. In sham-operated animals cilostazol-treatment resulted in an
improved hepatic blood flow and an elevated hepatic microcirculation
(692±17 vs. 431±24aU). After hepatectomy cilostazol-treated animals
showed improved portal venous flow and hepatic microcirculation
(893±33 vs. 651±54aU). Liver regeneration was found enhanced by cilostazol-treatment over the whole observation period, as indicated by
significantly increased number of PCNA-expressing hepatocytes (day
3: 21±2 vs. 12±1 cells/HPF) and augmentation of recovered liver mass at
day 6. Tumor volume in cilostazol-treated animals was not different to
controls after 7 respectively after 14 days.
Conclusion. We could demonstrate that cilostazol-treatment efficiently improves hepatic perfusion and stimulates liver regeneration after
70% hepatectomy. No coincidental stimulation of tumor growth could
be observed. Thus, cilostazol may represent an appropriate therapy to
improve liver function after extended hepatectomy for colorectal liver
metastases.
0187
Comparison of three putative methylation markers for the early
detection of colon cancer
*C. Gerecke1, Y. Löwenstein1, I. Fait1, B. Scholtka1
1
Universität Potsdam/IEW, Ernährungstoxikologie, Nuthetal, Deutschland
Background. Colon Cancer is one of the most frequent occurring cancers in the western civilization. Thus it is one of leading causes of cancer
related deaths. Colorectal cancer mortality can be reduced significantly
by early detection of premalignant adenomas and early staged cancers.
Therefore it is necessary to develop sensitive non-invasive screening
tests. In the past few years it has become clear that abnormal hypermethylation of tumorsuppressor linked gene promoters, resulting in loss of
gene expression, is one of the early events in colonic carcinogenesis. To
evaluate a marker panel including methylated marker genes for an early
detection of colon cancer we analyzed the methylation status of the gene
promoters of integrin alpha subunit 4 (ITGA4), tissue factor pathway
inhibitor II (TFPI2) and vimentin (VIM) in paired patient tissue and
stool samples as well as in stool samples from healthy individuals.
Methods. In this present study we analyzed samples of 4 inflamed tissue
(IT), 13 hyperplastic polyps (HP), 50 adenomas (Ad) and 9 colorectal
carcinomas (CRC). Additionally, stool samples derived from 5 healthy
individuals and from 5 CRC patients were studied. The isolated genomic
DNA was converted by sodium bisulphite treatment and subsequently
analyzed by nested methylation-specific PCR (nMSP) encompassing
the respective promoter regions of ITGA4, TFPI2 and vimentin.
Results. The nMSP revealed a methylated promoter of the ITGA4-gene
in 3/4 IT, 13/13 HP, 44/50 Ad and 8/9 CRC. In 4/5 CRC patient stool samples a methylated ITGA4 promoter was detected. None of the healthy
stool samples were methylated in the ITGA4-promoter. A methylated
TFPI2-promoter was found in 1/4 IT, 4/13 HP, 32/50 Ad and 8/9 CRC. In
4/5 CRC patient stool samples we detected a methylated TFPI2 promoter as well. However, no healthy stool sample contained a methylated
Abstracts
TFPI2-promoter. A methylated VIM-promoter was detected in 3/4 IT,
8/13 HP, 36/50 Ad and in 4/9 CRC. In stool samples from CRC patients
we discovered in 2/5 individuals a methylated VIM-promoter whereas
no healthy sample was methylated.
Conclusion. Because of the high methylation frequency of inflamed tissue it is concluded that the methylation analysis of VIM and ITGA4 is
no suitable biomarker for early detection of colon cancer and premalignant adenomas. However, our findings suggest that the TFPI2 methylation is a proper biomarker with a good specificity and sensitivity.
0188
Quality of life and intestinal symptoms and after multimodal
therapy of rectal cancer
*H. Geinitz1, A. Seidl1, R. Thamm1, R. Rosenberg2, F. Lordick3, M. Fuchs4,
W. Heitland5, F. Zimmermann1, M. Molls1
1
Technische Universität München, Klinik für Strahlentherapie, München,
Deutschland, 2Technische Universität München, Chirurgische Klinik,
München, Deutschland, 3Technische Universität München, III. Medizinische
Klinik, München, Deutschland, 4Klinikum München Bogenhausen, Klinik für
Gastroenterologie, München, Deutschland, 5Klinikum München Bogenhausen, Klinik für Chirurgie, München, Deutschland
Purpose and objective. This cross sectional study was carried out in order to assess quality of life (QOL) and intestinal symptoms and after
multimodal therapy of locally advanced rectal cancer.
Materials and methods. 216 patients with neoadjuvant or adjuvant radiochemotherapy and surgery for stage III rectal cancer were assessed at a
median of 62 months (16–137 m.) after the end of radiochemotherapy.
Intestinal symptoms and fecal continence were evaluated with standardized instruments. Quality of life assessment was carried out with
the EORTC QLQ-C30 and the colorectal module CR38.
Results. 164 patients had received preoperative RChT (45 Gy with continous 5-FU) and 52 patients postoperative RChT (50.4 Gy with 5-FU
continously or bolus). As compared to the age and gender adjusted German general population (Schwarz and Hinz; Eur J Cancer 2001) quality
of life was significantly compromised in younger patients (50–60 years
old) affecting in particular role functioning, emotional functioning,
cognitive functioning, social functioning and fatigue, while in older
patients (>60 y.) QOL-reduction was less pronounced and involved
mainly social functioning. The most prevalent fecal symptoms were:
diarrhoea (80%), flatulence (75%) and tenesmus (15%). In patients without a colostomy (n=152) only 18% reported a perfect fecal continence. Incontinence involved mainly gas (73%) and liquid stool (66%) with
16% reporting incontinence for solid stool. 46% of the non-colostomy
patients reported to wear pads because of fecal incontinence and 49%
were unable to delay defecation for more than 15 minutes. Patients with
low lying tumors (p=0.006) and those with reoperation because of
anastomotic leakage (p=0.041) experienced more incontinence. Global
QOL (p=0.041), physical functioning (p<0.001) and role functioning
(p<0.001) were significantly lower in colostomy patients as compared
to non-colostomy patients. Higher (above median) incontinence score
values were associated with lower global QOL (p=0.002) as well as lower role functioning (0.014), cognitive functioning (p<0.001) and social
functioning (p<0.001).
Conclusion. Survivors after multi-modality treatment of rectal cancer
have an impaired QOL especially those below the age of 60. Anorectal
function after combined radiochemotherapy and sphincter-preserving
surgery is suboptimal especially in patients with low-lying tumours.
0216
Assessment of the clinical utility of an improved blood-based
Septin9 test for early detection of CRC in patients with co-morbidities
*V. Schellerer1, R. Tetzner2, H. Golcher1, G. Weiss2, R. Stöhr3, A. Hartmann3,
W. Hohenberger1
1
Universitätsklinik Erlangen, Allgemein- und Viszeralchirurgie, Erlangen,
Deutschland, 2Epigenomics AG, Berlin, Deutschland, 3Universitätsklinik,
Pathologisches Institut, Erlangen, Deutschland
Objectives. Early detection of colorectal cancer (CRC) decreases CRC
mortality significantly, although compliance to CRC screening is low.
The availability of a blood-based test is expected to improve CRC screening compliance. The Septin9 methylation biomarker (mSEPT9) has demonstrated sensitivity for CRC of around 70% at a specificity of around
90% in multiple studies of CRC patients and colonoscopy-verified negative individuals. Laboratory-developed tests based on mSEPT9 are now
available in the United States and Canada and a molecular diagnostic
blood test for mSEPT9, Epi proColon, has been available as a CE-marked kit for over a year in Europe. A second generation product, Epi proColon 2.0 Early Detection Assay, has demonstrated improved CRC sensitivity of around 90% without compromising the 90% specificity value.
In order to investigate the biological background of the approximately
10% positive test results observed in clinical controls, a study has been
set up to explore potential association of mSEPT9 positivity with patient
co-morbidities and/or medications commonly used in the population
over 50 years of age.
Methods. Plasma specimens from 230 colonoscopy-verified negative
individuals consecutively enrolled at local gastroenterologists’ sites as
well as specimens from 30 CRC cases will be tested for mSEPT9 according to the manufacturer’s instructions. The mSEPT9 test positivity in
patients with co-morbid conditions (cardiovascular diseases, malignant
diseases other than CRC, other gastrointestinal diseases or other chronic conditions) as well as in patients undergoing treatment using drugs
from pre-defined therapeutic classes will be statistically evaluated for
deviations from the global test performance measures.
Results and conclusion. The test results will provide a first assessment of
the impact of common medications and current co-morbidities on the
positivity of the Septin9 test. The results of this initial screen for interfering conditions and cross-reactants, will trigger further research aimed
at a deeper understanding of the clinical utility of the Septin9 test.
0217
Tumour associated fibroblasts present with higher adhesion
ability than normal tissue associated fibroblasts
*V. Schellerer1, M. Langheinrich1, R. Croner1, W. Hohenberger1, M. Stürzl2,
E. Naschberger2
1
Universitätsklinik Erlangen, Allgemein- und Viszeralchirurgie, Erlangen,
Deutschland, 2Universitätsklinik Erlangen, Abteilung für Molekulare und
Experimentelle Chirurgie, Erlangen, Deutschland
Background. Progression of colorectal cancer is strongly associated with
angiogenesis and other desmoplastic reactions, e.g. inflammation, of
the surrounding tissue. For elucidating epigenetic effects on the desmoplastic tissue we successfully isolation fibroblasts from human colorectal cancer and uninvolved colon tissue of the same patient.
Materials and methods. Tumour (TAF) and Normal tissue associated
fibroblasts (NAF) of 16 patients with CRC were isolated from operation
specimens and cultivated. With Isolated fibroblasts immunocytochemical stainings with Vimentin, I-CAM-1, CK-20, CD45, CD 31 as well as
an adhesion assay with U937 were performed.
Results. By immunocytochemical staining isolated fibroblasts were
positive for Vimentin and negative for CK-20, CD31 and CD45. Hereby the contamination by epithelial, endothelial and hematopoietical
cells was excluded. Immuncytochemically differences between TAF
and NAF were detectable by ICAM-1 staining. In 15 of 16 TAF cultures
ICAM-1 was higher expressed compared to corresponding NAF cultures. After stimulation of cultures with interleucin-1β also 14 of 16 TAF
cultures presented with higher ICAM-1 levels than corresponding NAF
cultures. Performing an U937 adhesion assay also unstimulated and
with tumor necrosis factor stimulated TAF cultures showed a higher
adherence than corresponding stimulated and unstimulated NAF cultures.
Conclusions. The isolation of TAF and NAF is possible and fibroblasts
present with differences although in vitro cultivation. Isolated fibroblast
present as a useful tool for further functional investigations of the desmoplastic tissue of CRC.
0222
cDNA-microarray gene expression analysis in different malignant pancreatic cancer cell lines after induction of apoptosis
induced by Taurolidine (TRD)
*M. Buchholz1, A. Flier1, S. Hahn2, D. Bulut3, W. Uhl1, A. Chromik1
1
St. Josefs Hospital, Chirurgie, Bochum, Deutschland, 2Ruhr Universität,
Bochum, Deutschland, 3St. Josefs Hospital, Bochum, Deutschland
Introduction. The originally anti-infective agent Taurolidine (TRD) has
been shown to have cell death inducing properties, but the mechanism
of its action is largely unknown. The aim of this study was to identify
potential common target genes modulated at the transcriptional level
following TRD treatment in different malignant pancreatic cancer cell
lines
Material and methods. Five different malignant human pancreatic cancer cell lines (AsPC-1, BxPC-3, HPAF II, MiaPaca-2 and Panc1) were
incubated with TRD (250 µmol/l) and Povidon 5%, which served as
control. After 2 h incubation, gene expression analysis was carried out
using the Agilent -microarray platform to indentify early genes which
displayed conjoint regulation following the addition of TRD in all pancreatic cancer cell lines. Agilant’Feature Extraction Software was used
to analyze acquired array images. Further data processing was performed using the GeneSpring GX11.01 software package. Following the
data sets were reduced by filtering the raw signal intensity value ≥50
and a quantile normalization of raw data. (T-test was used to examine
the hypothesis that there was no difference in expression between the
TRD treatment group and the Povidon control group). Candidate genes
were analyzed by Ingenuity Pathways Analysis and selected genes were
validated by qRT-PCR and Western Blot.
Results. Among cell death associated genes with the strongest regulation in gene expression (factor x5–x60), we identified a broad range of
pro-apoptotic proteins, e.g. pro-apoptotic transcription factors (EGR1,
EGR2, EGR4, ATF3) as well as genes involved in proliferation (c-FOS,
DUSP1). Furthermore, inhibitors of the JAK/STAT signaling pathway
(SOCS1), genes involved in oxidative stress response (ADM) as well
as pro-apoptotic proteins of GADD family (GADD45B, GADD45A,
GADD34) were identified. The results of the validation by qRT-PCR and
Western Blot confirmed the prior results.
Conclusions. This is the first conjoint analysis of potential early target
genes of TRD which was performed simultaneously in different malignant pancreatic cancer cell lines. The increased expression of several
pro-apoptotic proteins of various origins indicates that TRD might be
involved in different signal transduction pathways leading to apoptosis
in pancreatic cancer cell lines. However, further functional studies are
necessary to elucidate the exact mechanism and relative contribution of
death inducing pathways of TRD.
0230
Molecular repair mechanisms and chemoresistance in hyperthermic intraperitoneal chemotherapy in patients with peritoneal
carcinosis
*M. Vetterlein1, M. Lazariotou1, T. Grimmig1, N. Matthes1, M. Faber1, C.-T. Germer2, J. Pelz2, A.M. Waaga-Gasser1, M. Gasser2
1
Universitätsklinikum Würzburg, Chirurgische Klinik I, Molekulare Onkoimmunologie, Würzburg, Deutschland, 2Universitätsklinikum Würzburg,
Chirurgische Klinik I, Würzburg, Deutschland
Background. In patients with isolated peritoneal carcinosis (PC) of
gastric, colorectal and ovarian cancer hyperthermic intraperitoneal
chemotherapy (HIPEC) represents a promising treatment option integrated into multimodal concepts. We analyzed relevant heat shock proteins (HSPs) that confer resistance to physical stress like hyperthermia
as well as specific multidrug resistence (MDR) genes in patients with
PC.
Methods. Patients with different adenocarcinomas and additional PC
that underwent HIPEC therapy between 09/09 and 03/11 in our department (gastric, colorectal and ovarian cancer) were included in the study.
HIPEC therapy was performed under specific conditions (1hr permanent chemotherapeutical flux via external pump into the abdominal cavity after resection of relevant tumor masses with elevated temperature
up to 43°C). Tumors before and after HIPEC therapy were analyzed for
HSPs, ABC transporter and CD133 expression by immunohistochemistry, Western Blot, and RT-qPCR. Additionally, HT29 tumor cells were
exposed in vitro to different conditions of hyperthermia up to 43°C for
60 minutes and comparably analyzed. Tumor cells were counted and
studied for apoptosis.
Results. HSP70/72, HSP90 and CD133 expression was upregulated in the
investigated tumors, in particular post HIPEC therapy. Upregulated
protein and gene expression was also shown for MDR genes ABCB5,
ABCG2 and ABCC5. Hyperthermia induced upregulated protein and
gene expression in HT29 tumor cells dependent on incubation temperature, mainly for HSPs observed in western blot, immunohistochemistry
and RT-qPCR. Furthermore, cell viability decreased with increasing
incubation temperature.
Conclusions. Therapeutic approaches like HIPEC to achieve antiproliferative and apoptosis inducing cellular effects in patients with PC seem
to be negatively influenced by highly conserved HSP mechanisms as
well as multidrug resistance genes. Studying HSP and MDR expression
profiles both in patient tumors and in vitro are valuable tools to further
clarify the effects of hyperthermia and chemotherapeutical agents in
context with the treatment of HIPEC therapy in the affected patients.
0232
PDGF stimulates proliferation in colorectal cancer
*M. Faber1, N. Matthes1, M. Kim2, T. Grimmig1, C.-T. Germer2, M. Gasser2,
A.M. Waaga-Gasser1
1
Background. Platelet derived growth factor (PDGF) plays an important
role in angiogenesis of several cancer types. It induces cell migration
and proliferation in stromal cancer tissue and is a key target in cancer
metastasis therapy. Aim of our study was to analyze the Mitogen-activated protein kinase (MAPK)-pathway in colon cancer cells stimulated
by PDGF for putative future therapeutic interventions in colorectal cancer (CRC).
Methods. The human colorectal cancer cell line HT-29 was cultured and stimulated with PDGF-BB over the time periods of 5, 10, 15,
30 and 60 minutes. Cell protein and RNA extracts were analyzed by
Western Blot and RT-PCR for PDGF-receptor-β and for proteins of the
MAPK-pathway. To determine effects on proliferation HT-29 cells were
Abstracts
c ultured on a Matrigel layer and stimulated with PDGF over two weeks
and cell count and colony formation were analyzed.
Results. Western blot analysis and RT-PCR revealed no relevant PDGFreceptor-β in HT-29 cells. Nevertheless, stimulation of PDGF-BB resulted in an upregulation of downstream MAPK-pathway events in
Western Blot analysis and in an increased proliferation in the matrigel
assay. After two weeks of stimulation with PDGF cell count as well as
colony forming significantly increased compared to unstimulated cell
populations.
Conclusions. PDGF-receptor-β expression has been described in cancer
stromal tissues. We could show for the first time that in the absence
of its receptor, stimulation with PDGF-BB results in activation of the
MAPK-pathway and consecutive proliferation in colon cancer cells.
Our results suggest that PDGF activates MAPK and cancer cell proliferation by an alternative signaling route.
0245
CAES/ CAMIC- Zentralregister: “Okkultes Gallenblasenkarzinom”.
Analyse der Prognosefaktoren nach Auswertung von mehr als
700 Fällen
*T. Goetze1, V. Paolucci1
1
Ketteler-Krankenhaus, Chirurgische Klinik, Offenbach, Deutschland
Background. The incidental gallbladder carcinoma (IGBC) is a cancer
first discovered by the pathologist after cholecystectomy. The indication
for the operation was a benign disease. The indication for early radical
re-resection (ERR) is debated in the recent literature and the S3 guidelines. According to the S3 guidelines a ERR is recommended in T2 and
more advanced carcinomas. Recent data of the literature, the German
Registry, and even international guidelines, e.g. National Comprehensive Cancer Networks show that patients with T1b carcinomas do profit
from an ERR. Another important prognostic factor that has to be discussed in context with ERR is the lymph node status.
Methods. For data analysis we used „The German Registry“ ( CAES/
CAMIC- Zentralregister: „Okkultes Gallenblasenkarzinom“, der deutschen Gesellschaft für Chirurgie) . For getting the data a questionnaire
was sent to all German surgical clinics. The data are actualised in a period of 3 months. All patients of the registry have been treated according
to the S3 guidelines.
Results. To date more than 700 patients have been registered and 684
cases of IGBC are calculated by the statistics. In 29 patients with T1a
carcinomas there was no ERR. In 6 cases of T1a carcinomas there was
an ERR. In 28 of 84 patients with T1b tumors there was a ERR. The 5
year- survival rate shows a significant prognostic survival benefit for
T1b- tumors with ERR, but there is no prognostic benefit for T1a carcinomas after ERR. All of the liver resections have been combined with a
lymph node dissection of hepatoduodenale ligament. The liver resection
in cases of T1b tumors was 16× a wedge resection, 6× a IVb/V resection
and 5× another kind liver resection technique was used. The wedge resection shows a 5 year survival of 84%, the IVb/V resection 75%. Patients
with positive lymph nodes show a worse prognosis compared with nodal negative IGBC’s in all stages.
Discussion. The analysis of more than 700 cases of IGBC of the German registry shows, a significant benefit for T1b patients with ERR. For
patients with T1a carcinomas a simple cholecystectomy is enough. The
positive nodal status is a significant negative prognostic factor in T1–3
tumors. Patients with radical re-resection show always a better survival
than without. Liver resection and lymph node dissection of the hepatoduodenal ligament has to be highly recommended up to T1b.
0256
Analysis of tumor cell dissemination gives evidence for peripheral tumor initiating cells in colorectal cancer
*M. Kim1, M. Frank2, N. Frank2, T. Grimmig3, C.-T. Germer1, A.M. Waaga-Gasser3, M. Gasser1
1
Universitätsklinikum Würzburg, Chirurgische Klinik I, Würzburg, Deutschland, 2Children‘s Hospital, Harvard Medical School, Boston, USA, 3Universitätsklinikum Würzburg, Chirurgische Klinik I, Molekulare Onkoimmunologie, Würzburg, Deutschland
Background. Recent findings suggest that tumor initiating cells beside
differentiated tumor cells are responsible for disseminated tumor disease. This study evaluates CD133, a marker described for tumor initiating
cells, together with ABCB5 and ALDH1 as putative additional markers
in peripheral blood and bone marrow of patients with colorectal cancer
(CRC).
Methods. Expression of CD133, ABCB5, a chemoresistance mediator,
ALDH1, and Lgr5 were analyzed in cells from peripheral blood of patients with CRC (n=105, UICC stages I–III) and completed 5-year followup by RT-qPCR. A cohort of 26 healthy individuals served as controls.
Bone marrow aspirates (n=24) were analyzed for further evidence of
cancer cell migration in this compartment.
Results. CD133 and ABCB5 expression in peripheral blood cells was
upregulated in patients with CRC even at early tumor stages (p<0.001
respectively). Expression levels highly correlated with each other
(p=0.0001 respectively). ABCB5 expression in bone marrow and expression of CK20 for differentiated tumor cells in the peripheral blood
negatively influenced overall survival (p=0.027 and p=0.03).
Conclusions. Molecular signature expression in peripheral blood indicates a migrating tumor cell subset with chemoresistant and putative
stem-like characteristics as an early event during tumor development
in CRC. This may be responsible for tumor relapse and development of
metachronic metastases. Expression of ABCB5 in bone marrow significantly influenced patient survival pointing to a specific chemoresistance in this disseminated cell subset. This may have significant influence
for future treatment strategies.
0258
Relevance of Toll-like receptor 7 and 8 for tumor growth in pancreatic cancer
*N. Matthes1, T. Grimmig1, C.-T. Germer2, A.M. Waaga-Gasser1, M. Gasser2
1
Background. Toll-like receptors as activators of inflammatory processes
in association with malignant diseases have been evaluated differently
and their underlying mechanisms are only partly clarified. Therefore
the aim of this study was to determine the presence of TLR7 and -8,
and their importance for the growth behavior of pancreatic cancer in
more detail.
Methods. The pancreatic cancer cell lines PANC-1 and MIA PaCa 2 were
transfected with siRNAs to induce a gene knockdown either for TLR7
or TLR8. TLR expression was shown by Western Blot and RT-qPCR.
Resiquimod (R848) was used to stimulate the TLR7 and 8 downstream
signaling cascade and phosphorylated intermediates were examined by
Western blot. In addition, Matrigel studies were also conducted.
Results. TLR7 and 8 transcripts in both untreated cell lines were only
weakly detectable. Stimulation via the TLR agonist R848 resulted in increased expression of phosphorylated Erk1/2. Further analysis showed
at this point an activation of the expressed opioid growth factor receptor (OGFr) through R848, whereby the activation of TLR7/8 and tumor
cell apoptosis can be bypassed.
Conclusions. The expression of intracellular occurring TLR7 and 8 in
the investigated cell lines is in contrast to their detected expression in
clinical tumors less present. Further in vitro analysis of a specifically
induced expression seems to be relevant to develop clinical strategies
for increased tumor cell apoptosis in pancreatic cancer with detected
increased TLR expression patterns.
0288
Outcome of surgical and interventional therapy of patients with
hepatocellular carcinoma
*T. Förtsch1, W. Hohenberger1, S. Merkel1, V. Mueller1, R. Croner1
1
Universität Erlangen, Chirurgische Klinik, Erlangen, Deutschland
Introduction. Hepatocellular carcinoma (HCC) represents the fifth most
common malignant tumor worldwide with a rising incidence especially
in the western countries. Our retrospective analysis compares outcome
and survival of patients with HCC, who were treated at the department
of surgery of University of Erlangen from 1998–2008, by the means of
different possibilities of treatment. In addition risk factors like pT classification, tumor size and lymph node dissection are tested for their prognostic influence on survival.
Material and methods. At our department 260 patients (231 male, 29
female) with HCC were treated from 1998–2008. Thereof 96 patients
received a removal of the tumor by liver resection; on 23 patients with
small HCC a liver transplantation (LTx) was performed. 71 patients were
treated by an interventional therapy (radiofrequency ablation, chemoembolization). Because of advanced liver cirrhosis or advanced tumor
stage only a supportive palliative therapy was done in 70 patients.
Results. The 1-, 3- and 5-year survival rates for all patients who underwent surgery amounted to 75%, 50% and 37%. Comparing the group of
liver resected patients with patients who underwent LTx, the survival
rates resulted in 70%, 46% and 32% vs. 85%, 64% and 59% (log-rank test
p=0.007). In patients who have received interventional therapy without
surgical resection, the 1-, 3-, and 5-year survival rates were 58%, 25% and
17% (log-rank test compared to all operated patients p<0.001). The survival rates of only palliative treated patients were 37%, 13% and 2% (logrank test compared to the remaining patients, p<0.001). The pT category
was found to have no influence on the survival of liver resected patients
(p=0.222), the performance of lymph node dissection in the conduct of
tumor resection also had no difference in patient survival (p=0.5). In
contrast, a significant difference was found in tumor size. Patients with
tumors who had a diameter of less than 5 cm showed a significant advantage of survival (p=0.015, 1-, 3-, 5-year survival rate of 71%, 55%, 43%
vs. 62%, 34%, 20%.).
Conclusion. According to our analysis, there is an advantage of survival
on patients with small HCC tumors who underwent LTx compared to
liver resection. The pT stage and the performance of lymph node dissection during surgery showed no effect on survival, whereas patients with
tumor size >5 cm had significantly worse survival rates.
0295
Pancreatic cancer – Epidemiological and clinical results in southern Germany
*G. Schubert-Fritschle1, A. Schlesinger-Raab1, R. Eckel1, R. Emeny1, J. Engel1
1
Deutschland
Background. Pancreatic cancer incidence and mortality rates are increasing slowly [1]. Prognosis remains very unfavourable. Currently radical
resection followed by adjuvant chemotherapy is the only chance for improved survival.
Objective. The study aim was to evaluate changes in epidemiological
measures, and to analyse clinical aspects such as stage, histology, or
grading, as well as characteristics of cancer care and its outcome.
Methods. The Munich Cancer Registry (MCR) records all cancer patients treated in the registration area that covers Upper Bavaria, with
4.5 million inhabitants, since 2007. Data from almost 5000 cases of patients with pancreatic cancer, diagnosed between 1998 and 2009 were
analysed. The distributions of prognostic factors was analysed with
regard to associations with time, age, tumour-related factors and therapeutic procedures. Survival as outcome parameter was examined by the
Kaplan-Meier method and Cox proportional hazard modelling.
Results. Pancreatic cancer ranks in incidence at position 10 for men
and position 9 for women, yet in mortality statistics it ranks at position
4 for both men and women. “Cancer in Germany” (1) estimates 6380
new male cases per year, corresponding to a crude incidence of about
15.8/100,000 (for females 6980 and 16.6/100,000). Observed incidences
for Upper Bavaria are in part higher [2]. Median age at diagnosis differs
for men (70 y) and women (76 y). Stage distribution is characterized
by a low proportion of pT1/2 cases (15%). Correspondingly, survival for
pancreatic cancer in general is low (5-year relative survival 5.7%). The
median relative survival for pT2-4 patients is 11 months (0.9 y). Only
pT1 patients reach an average survival of 2.4 years. These results do not
include neuroendocrine pancreatic tumours with a favourable median
5-year relative survival of 5.8 years. Cox proportional hazard models
primarily identified the prognostic relevance of TNM, grading and age,
as well as surgery and chemotherapy.
Conclusion. Population based data from the Munich Cancer Registry
were analysed to identify prognostic variables for pancreatic cancer.
There are entities with better prognosis, e.g. patients with stage pT1 or
patients with neuroendocrine pancreatic tumours. This analysis also
demonstrates the importance of clinical cancer registries and their role
in quality assurance.
1. Krebs in Deutschland 2005/2006. Häufigkeiten und Trends. 7. Ausgabe. Robert Koch-Institut (Hrsg) und die Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg). Berlin, 2010
2. Tumorregister München http://www.tumorregister-muenchen.de/
facts/base/base_C25__G.pdf, 30. Juni 2011
0308
Whole genome expression profiling to predict outcome in rectal
cancer
*J. Gaedcke1, P. Jo1, K. Jung1,2, T. Beissbarth2, H.A. Wolff3, L.C. Conradi1,
T. Liersch1, M. Grade1, H. Becker1, M. Ghadimi1
1
Deutschland
Background. The heterogeneous response in locally advanced rectal
cancer (RC) treated with a 5-FU based radiochemotherapy (RCT) is still
a considerable clinical dilemma. We therefore aimed to predict outcome
in RC after preoperative RCT using whole genome expression profiling
that was previously demonstrated to be a powerful tool in stratifying
cancer.
Materials and methods. After assessment of RNA quality and tumor
content in preoperative biopsies RNA of 208 patients with RC were hybridized on Agilent® 44K whole genome oligo microarrays. For 181 patients corresponding mucosa was available that was analyzed as well.
All patients were treated within the CAO/ARO/AIO-94 and -04 trial
of the German Rectal Cancer Study Group. As surrogate parameter for
prognosis we primarily used postoperative lymph node status.
Results. To assess outcome after therapy 31,183 probes remained for
classification of lymph node status. For the two groups (nodal positive,
n=61; nodal negative, n=147) 52 genes were found to be expressed significantly different. Training classifiers with the 100 most differentially
expressed genes in LOOCV, the average classification accuracy was 71%
[95% confidence interval (CI): (65%, 78%)], the positive predictive value was 51% [95% CI: (38%, 63%)] and the negative predictive value was
81% [95% CI: (73%, 88%)]. Survival data were available for 191 patients.
Abstracts
edian disease free survival (DFS) was 23.2 months revealing 3700 difM
ferentially regulated probes (q≤0.005).
Conclusion. Whole genome expression analyses enable a correct prediction of lymph node negativity after preoperative RCT in 81%. Although
validated by LOOCV these data still need an independent validation
that is currently ongoing. The high number of differentially regulated
probes for DFS is promising to find a predictive profile.
0311
Influence of multimodality treatment on the immune system of
patients with esophageal cancer
*T. Herbold1, E. Bollschweiler1, A. Worring1, H. Alakus1, W. Schröder1, A. Hölscher1, R. Metzger1
1
Universität zu Köln, Allgemein-, Viszeral- und Tumorchirurgie, Köln,
Deutschland
Introduction. Neoadjuvant radiochemotherapy (RTx/CTx) is an important part of the multimodality treatment in locally advanced esophageal
cancer. Analyzed were the effects of neoadjuvant radiochemotherapy
on the immune status of patients with esophageal cancer.
Patients and methods. In this prospective study 86 patients (m: 71, w: 15)
with locally advanced esophageal cancer (uT3/4) were included. Median
age was 59 years (min: 31, max: 78). 27 patients had a squamous cell carcinoma (SCC), 59 patients an adenocarcinoma (AC) of the esophagus.
All patients underwent induction therapy with 5-FU, CDDP and 40 Gy.
Analysis of the cellular immune system (leucocytes, lymphocytes, CD3, CD4-, CD8-, CD16-, CD19-, CD25-, CD56-, HLA-DR-bearing cells)
was performed before and 3 weeks after induction therapy.
Results. The neoadjuvant radiochemotherapy resulted in a significant
decrease of leucocytes, lymphocytes and subgroups. Pathologic low values after induction therapy were detected in 19% of the patients for leucocytes, in 20% for thrombocytes, in 61% for lymphocytes, in 76% for B
cells, in 37% for T cells, in 31% for T helper cells, in 33% for T suppressor
cells, in 30% for NK cells. The posttherapeutic results reflect the preoperative status of the cellular immune system.
Conclusion. In our cohort of patients with locally advanced esophageal
cancer (uT3/4) neoadjuvant radiochemotherapy results in a significant
decrease of immune competent cells particularly in lymphocytes. However, we didn’t observe any case of aplasia caused by induction therapy. In consideration of a demanding surgical procedure this would be
unfavorable.
0323
GPI-anchored tissue inhibitor of matrix metalloproteinase-1
(TIMP-1) inhibits tumor growth in fibrosarcoma and pancreatic
cancer
*Q. Bao1, H. Niess1, R. Djafarzadeh2, Y. Zhao1, B. Schwarz1, K.-W. Jauch1,
P.J. Nelson2, C.J. Bruns1
1
Campus Großhadern, LMU, Department of Surgery, Munich, Deutschland,
2
LMU, Medical Policlinic, Clinical Biochemistry Group, Munich, Deutschland
Background. The family of tissue inhibitors of metalloproteinases
(TIMPs) exhibit diverse physiological/biological functions including
the moderation of tumor growth, metastasis, and apoptosis. TIMP-1
is a secreted protein that can be detected on the cell surface through
its interaction with surface proteins. The diverse biological functions
of TIMP-1 are based, in part, on the kinetics of TIMP-1/MMP/surface
protein interactions. Proteins anchored by glycosylphosphatidylinositol
(GPI), when purified and added to cells in vitro, are incorporated into
their surface membranes. A GPI anchor was fused to TIMP-1 to generate a reagent that could be added directly to cell membranes and thus
deliver defined concentrations of TIMP-1 protein on any cell surface independent of protein-protein interaction.
Methods. We produced and purified a fusion protein based on the tissue
inhibitor of matrix metalloproteinase-1 linked to a glycosylphosphatidylinositol anchor (TIMP-1-GPI). TIMP-1-GPI was exogenously added
to the human fibrosarcoma cell (HT1080) and murine pancreatic cancer
cells (Panc02) culture medium. Fluorescent staining assays, proliferation assays, clonogenic assays, migration assays, and apoptosis assays
were performed comparably with rhTIMP-1 and vehicle treatment. In
a homogenetic subcutaneous pancreatic cancer mouse model, TIMP1-GPI, rhTIMP-1, and vehicle were applied locally, and their effects on
tumor growth were investigated.
Results. TIMP-1-GPI showed better incorporation with cell membranes
compared to TIMP-1. As the concentration of TIMP-1-GPI increased
(2–14 ng/ml), the proliferation rates of both cancer cell lines were significantly inhibited. The inhibition effects were enhanced by incubation
time prolongation. While control rhTIMP-1 protein did not significantly affect proliferation of HT1080 and Panc02 cells at the concentration
(14 ng/ml) tested, the GPI-anchored TIMP-1 protein showed a pronounced suppression of cancer cell clone formation and migration. Furthermore, TIMP-1-GPI induced significant higher percentage of apoptotic
cells than rhTIMP-1 and control group, the sequentially combination of
TIMP-1-GPI and chemotherapy (Doxorubicin) had synergetic effects of
inducing apoptosis. In addition, TIMP-1-GPI can inhibit HT1080 sidepopulation cells with Hoechst staining. Treatment of Panc02 tumors
implanted in C57BL/6 mice with local applied TIMP-1-GPI, control
rhTIMP-1 protein, or vehicle showed a significant inhibition of tumor
growth following treatment with TIMP-1-GPI.
Conclusion. Compared with rhTIMP-1, exogenous administration of
TIMP-1-GPI result in transient morphological changes of tumor cells
including better incorporation of TIMP-1 in the cell membrane, pronounced inhibition of proliferation, clone formation, migration, and
enhancement of side-population cells, inducing more apoptotic cells
either as single reagent or combined with chemotherapy. In vivo, TIMP1-GPI significantly inhibited tumor growth. GPI-anchored TIMP-1 may
represent a more effective version of the protein for cancer therapy.
0344
Ulcerative colitis-associated carcinogenesis depends on alternatively activated “M2 macrophages” – from mice to men
R. Kesselring1, M. Martin1, P. Ruemmele2, H.J. Schlitt1, *S. Fichtner-Feigl1
1
Universität Regensburg, Klinik und Poliklinik für Chirurgie, Regensburg,
Deutschland, 2Universität Regensburg, Institut für Pathologie, Regensburg,
Deutschland
The pathogenesis of human ulcerative colitis (UC) is characterized by
the presence of IL-13-producing Natural Killer T cells (NKT cells). One
major complication of UC is the development of colitis-associated colorectal cancer. In these studies we determined the role of alternatively
activated „M2 macrophages“ in a new mouse model of colitis-associated
carcinogenesis based on chronic Oxazolone-colitis in combination with
an initial i.p. azoxymethane (AOM) injection. Further, we verified these
results through the immunological analysis of surgical specimens obtained from 6 patients with UC-associated colon cancer.
We could show that chronic Oxazolone-colitis was mediated by colonic
alpha-galactosyl-ceramide+CD1+ NKT-cells producing IL-13 and therefore resembles the immunological characteristics of human UC. Colon cancer development in this model was dependent on the presence of
F4/80+CD11bhighGr1low macrophages producing IL-6 and EGF. Those
cells inherited phenotypic characteristics of IL-13-stimulated alternatively-activated “M2 macrophages”. To elucidate the importance of these
“M2 macrophages”, we conducted bone marrow chimera studies and
demonstrated that innate immune signaling through MyD88 in “M2
macrophages” is the key event for the production of tumor supporting
factors like IL-6 and EGF. In surgical specimens obtained from patients
with UC-associated colon cancer we verified those experimental findings. We consistently found a dense accumulation of IL-13-producing
NKT cells inside the tumors. In addition, in this IL-13-dominated tumor
micromilieu CD14+ and CD68+ antigen-presenting cells accumulated
intensively and those antigen-presenting cells demonstrated an alternatively activated “M2 phenotype” by the expression of CD163 and CD205.
In conclusion, we could demonstrate that in an experimental UC model, as well as in human UC, pathogenic IL-13-producing NKT cells
accumulate in the tumor micromilieu of UC-associated colon cancers.
This immunologic situation inside the tumor microenvironment of
mice and men induces tumor promoting M2 macrophages. Therefore
M2 macrophages represent a potential target for future therapeutic strategies.
0353
Pancreatic cancer cells expressing stem cell markers survive
Gemcitabine treatment in vitro
*K. Quint1, P. Di Fazio1, R. Montalbano1, M. Ocker1
1
Philipps Universität Marburg, Institut für Chirurgische Forschung, Marburg, Deutschland
Introduction and objectives. The prognosis of pancreatic carcinoma patients remains among the worst of all solid tumors. Response rates to
the standard chemotherapeutic regimens remain low and tumors recur
frequently. In recent years, subpopulations of cells have been identified
in various solid tumors, which express stem cell associated markers and
are associated with increased resistance against radiochemotherapy. In
this study, we address the question whether chemotherapy leads to a
selection of resistant cancer stem cells and whether the epithelial-tomesenchymal transition (EMT) is associated with chemoresistance.
Materials and methods. Panc-1 and Capan-1 cells were continuously incubated with 10 µM Gemcitabine for up to 6 days. Vital cells were counted after one, 3 and 6 days after trypan blue staining. Gene expression of
the early developmental markers and stem cell associated genes PDX-1,
SHH, CD24, CD44, CD133, EpCAM, CBX7 and OCT4, EMT markers
Slug, Snail and Twist were quantified using qPCR. PDX-1, SHH, CBX7,
Oct-4, CD133, Ki-67, E-Cadherin and β-catenin were stained by immunocytochemistry.
Results. After 3 days, Gemcitabine treatment reduced viable cell numbers to less than 10% of the untreated controls. mRNA levels of all investigated genes showed a time-dependent increase in both cell lines
compared to the untreated controls (normalized n-fold gene expression
for Panc-1/Capan-1, respectively): PDX1: 13.3/4.1; SHH: 24.1/2.0; CD24:
1.7/47.3; CD44: 17.4/3.2; CD133: 20.2/7.8; EpCAM: 3.1/15.9; CBX7: 3.1/3.5;
OCT4: 4.2/13.4, Snail: 6.4/6.4, Slug: 15.2/3.5. Immunocytochemistry confirmed gene expression for Oct-4, SHH, PDX-1, CD133, E-Cadherin and
β-catenin. The majority of surviving cells stained positive for Ki-67.
Conclusion. Cells surviving six days of high-dose Gemcitabine treatment
express increased levels of stem cell and EMT markers and retain their
proliferative capacity. These data suggest a selection of cancer stem cells
which could be responsible for tumor recurrence in the clinical setting.
0355
Mutation analysis of the metastasis-inducing gene MACC1 and
association with colon cancer metastasis
*F. Schmid1, K. Klockmeier2, S. Burock3, P.M. Schlag3, U.S. Stein4
1
Max-Delbrück-Center for Molecular Medicine, Berlin, Deutschland, 2Freie
Universität Berlin, Berlin, Deutschland, 3Charité Comprehensive Cancer
Center, Berlin, Deutschland, 4Experimental and Clinical Research Center, a
joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine, Berlin, Deutschland
Colorectal cancer is one of the most common cancer diseases in the
Western world. About 90% of cancer deaths arise from the formation
of metastases. Recently, the new gene MACC1 (metastasis-associated
in colorectal cancer 1) was identified as a prognostic marker for colon
cancer metastasis. Tumors, which developed later metastases, showed a
significantly higher MACC1 expression compared to non-metastasizing
tumors. The 5-year survival rate for patients with a high MACC1 expression was only 15% compared to 80% for subjects with a low MACC1
expression. It was shown that MACC1 is a key-regulator of Met (met
proto-oncogene) expression that plays a decisive role in epithelial-mesenchymal transition, cell motility, invasiveness and metastasis. In this
study, we analyzed the mutation status of the genes MACC1 and Met in
human colorectal tumors. We wanted to evaluate if mutations in these
genes are associated with expression modulation of MACC1 and Met,
as well as with clinicopathological data, particularly with the metastasis
formation. We sequenced the genomic coding exons of MACC1 and the
exons of the juxtamembrane and the tyrosine kinase domain of Met. We
detected in a test set of 60 tumors the Met variants T1010I and R988C
in only two tumors. We identified in the same test set three MACC1
single nucleotide polymorphisms (SNPs): L31V, S515L and R804T. Additionally, we screened them in a validation set of further 94 tumors. We
found them almost as frequent as in the test set. L31V occurs in 13%, SNP
S515L in 48% and SNP R804T in 84% of all 154 tumors. We correlated
the MACC1 SNPs to sex, age, tumor grade, tumor stage, lymph node
metastasis and metachronous metastases and did not find a significant
correlation. In order to evaluate the biological abilities of the SNPs we generated plasmids containing MACC1 SNPs by site-directed mutagenesis.
Colon cancer cells were transfected with these constructs. MACC1 SNPs
had no impact on the migratory, proliferative or wound healing abilities
of the cells. So far, MACC1 mutation analysis even when combined with
MACC1 expression data does not improve the prediction of colon cancer
metastasis.
0365
Capecitabine-induced cardiotoxicity associated with complete
remission in a rectal cancer patient treated with neoadjuvant
radio-chemotherapy
*N. Henze1, J. Kuhfahl1, S. Wagner1
1
Klinikum Deggendorf, Med. Klinik II, Deggendorf, Deutschland
Background. Neoadjuvant radiochemotherapy is the therapeutic standard in patients with locally advanced rectal cancer. Infusional or oral
5-FU-derivatives form the basis of chemotherapy. Cardiotoxicity is a
rare but clinically important side effect of 5-FU. Here we report a case
with complete histomorphologic remission despite dose reduction caused by severe capecitabine-induced cardiotoxicity.
Case report. A 63-year-old male patient (80 kg, 168 cm) with rectal
cancer (uT3, G3, uN+, cM(HEP); UICC IV) and six hepatic metastatic
cancer lesions (maximum diameter 32 mm) was presented to the local
tumour board. A curatively-intented neoadjuvant radiochemotherapy
with capecitabine and oxaliplatin combined with 50.4 Gy pelvine radiation was recommended as consensus decision. Five days after initiation of capecitabine (3000 mg/d) rapidly increasing cardiostenotic
pain and dyspnoea developed. Coronary artery disease was excluded by
percutaneous coronary arterial angiography. Stenocardiac symptoms
dissolved after stopping of cabecitabine. Thus the diagnosis of cabecitabine induced coronary spasms was established. Re-treatment with
cabecitabine in a 50% reduced dose was started using prophylaxis with
nitrate. Oxaliplatin was given in unchanged dosage. Neoadjunvant radiochemotherapy then could be applied as planned without any further
complaints. Total mesorectal excision (TME) and simultaneous hepatic
resection of all intraoperatively detectable lesions was performed [ypT0,
yV0, yL0, yN0 (0/15)]. Histopathologic examinations revealed no vital
cancer cells in colonic and hepatic resection material.
Conclusion. Capecitabine may rarely induce coronary spasms. After
exclusion of coronary artery disease, therapy can be restarted at individually adapted dose. Despite dose reduction complete remission may
be induced which could suggest a special tumour response to 5-FU in
such patients.
Abstracts
0385
Immune status in patients with esophageal squamous cell carcinoma and adenocarcinoma
*R. Metzger1, E. Bollschweiler1, T. Herbold1, W. Schöder1, A. Worring1,
H. Alakus1, A.H. Hölscher1
1
Uniklinik Köln, Allgemein-, Viszeral- und Tumorchirurgie, Köln,
Deutschland
Introduction. Esophageal cancer comprises the tumor entities squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the esophagus. Epidemiology, etiology and tumorbiology are different in both SCC
and AC. Consequently the two histological subtypes are considered to
be different tumors. Patients with AC usually are overweight and report
on a long history of reflux. Contrary, patients with SCC usually are smokers and have an abuse of alcohol leading to cirrhosis and malnutrition.
The immune status was analyzed and compared in patients with SCC
and AC; the influence of alcohol and malnutrition was evaluated.
Patients and methods. In this prospective cohort study 86 patients
(m: 71, w: 15) with locally advanced esophageal cancer (uT3/4) were included so far. Median age was 59 years (min: 31, max: 78). 27 patients
had SCC, 59 patients had AC. As part of the initial staging comparative
analysis of the cellular immune status (leucocytes, lymphocytes, CD3-,
CD4-,CD8-, CD16-, CD19-, CD25-, CD56-, HLA-DR-bearing cells) was
performed in all patients.
Results. Pretherapeutic values were detected in a pathological range in
3.5% oft he patients for leukocytes, in 3.5% for thrombocytes, in 7% for
lymphocytes, in 7% for B cells, in 5.8% for T cells, in 3.5% for T helper
cells, in 11.6% for T suppressor cells, in 5.9% for NK-cells.
Conclusions. Despite a locally advanced oncological disease and different risk factors the immune system in patients with esophageal cancer
was not significantly compromised. Comparing the different tumor
subtypes SCC and AC no significant difference was detectable regarding the immune system.
0395
Cancer stem cells and chemoresistance in oesophageal cancer
*Y. Zhao1, B. Schwarz1, S. Gros2, A. Renner1, J. Mysliwietz3, J. Ellwart3, P. Camaj1, Q. Bao1, E. Yecebas2, J. Izbicki2, C. Bruns1
1
Klinikum Großhadern, LMU Munich, Munich, Deutschland, 2Department of
Surgery, University Hamburg-Eppendorf, Hamburg, Deutschland, 3Institute
of Molecular Immunology, Helmholtz Center for Environment and Health,
Munich, Deutschland
Introduction. Side population (SP) cells – potential cancer stem cells
(CSC) – are known to be resistant to chemotherapy and more likely to
cause epithelial-to-mesenchymal transition (EMT). We examined the
existence of the SP subpopulation in 5 human oesophageal cancer cell
lines. In addition, corresponding 5-FU, Cisplatin and Sorafenib resistant cell lines were developed in order to evaluate the potential contribution of SP-CSC to chemotherapy resistance of oesophageal cancer.
Methods. OE19, OE21, OE33 and PT1590 (derived from a primary tumor) as well as LN1590 (derived from a corresponding lymph node with
micro-metastasis) were analyzed in this study. Cells resistant to 5-FU,
Cisplatin, and Sorafenib were identified via IC-50 determination after
long-term in vitro exposure. The SP subpopulation was detected and
sorted by Hoechst 33342 staining as previously described. ABCG2 and
CD133 expression was detected by FACS, immunofluresence staining,
and RT-PCR in both SP and Non-SP populations and EMT markers (ECadherin, ZEB1 and Vimentin) were evaluated at the protein level.
Results. Five esophageal cell lines showed different chemo-sensitivity
and processed different metastatic potential in vitro. Neither LN1590
nor PT1590 had detectable SP cells, while the percentage of SP cells in
OE19, OE21, and OE33 cells was 17.07%, 0.83% and 8.82%, respectively.
Sorted OE19 SP cells were more resistant to 5-FU and Cisplatin than
OE19 non-SP cells. Colony formation assay showed significant higher
clonogenic capabilities of the SP population in OE19, OE21, and OE33.
All chemotherapy-resistant oesophageal cell lines contained an enriched SP subpopulation with enhanced efflux capacity.
Conclusions. Further in vivo studies are necessary to elucidate SP stemlike characteristics. SP cells purified from oesophageal cancer cell lines
harbor cancer stem-like properties and may be related to metastasis,
therapeutic-resistance, and EMT stimulation in oesophageal carcinoma. Identifying new molecular targets against chemotherapy resistant
CSCs might potentially result in more effective anti-cancer strategies.
0398
Measurements of 5-FU level in serum of patients with gastrointestinal cancer: 5-FU levels in blood reflect 5-FU dose applied
(24 h CIV) Response to 5-FU therapy reflects AUC values and 5-FU
dosage
*M. Blaschke1, M. Nischwitz1, G. Ramadori1, S. Cameron1
1
UM Göttingen, Gastroenterologie und Endokrinologie, Göttingen,
Deutschland
Introduction. 5-Fluorouracil (5-FU) is the base of most combination chemotherapies for gastrointestinal tumors. It is generally well tolerated,
but side-effects might require dose-adjustment. As chemotherapy-induced adverse events might not be specific for the 5-FU component of
the chemotherapy-combination, the knowledge of 5-FU serum levels
might help to attribute these side effects to the 5-FU compound.
Methods. 5-FU serum levels (n=230) in 30 patients with gastrointestinal
cancer treated with 5-FU containing infusional therapy were monitored using the Saladax 5-FU PCMTM- Immunoassay. Patients received
different 5-FU regimens based on a 24 or 48-hour AIO treatment-schedule using a Baxter pump. Blood was taken before and towards the end
of the infusion (21-23h), when 5-FU concentrations are at a steady-state
level. In 14 patients long term measurements of 5-FU levels over up to
50 weeks and up to 18 measurements per patient were obtained.
Results. Care has to be taken with blood sample collection before the
pump is empty, placement on ice and prompt centrifugation of the samples. 5-FU concentrations did increase with elevated 5-FU doses. Intraindividual variation in 5-FU plasma concentration was negligible. One
third of our patients reached AUC-values within the proposed range of
20–25 mgh/l (Gamelin 2008): 3 patients achieved AUC-levels <18 mgh/l,
5 patients achieved AUC-levels between 18 and 25 mgh/l and 6 patients
had AUC-levels >25 mgh/l. There was a tendency to better response in
patients receiving higher 5-FU doses and therefore obtaining higher
AUC-levels (>20 mgh/l). Side effects could not necessarily be attributed to 5-FU concentrations, as they did not correlate with the measured
5-FU concentrations.
Conclusions. The measurement of 5-FU plasma concentrations leads to
reproducible results in our test system. Our preliminary data show that
5-FU concentrations are dose-dependent with low intraindividual variability. The measurement of 5-FU plasma concentrations may in the
future allow to optimize the 5-FU dose and to identify the cause of toxicity.
0402
Prognosis in colon cancer
*K. Oeckl1, W. Hohenberger1, S. Merkel1, M. Langheinrich1
1
Chirurgische Universitätsklinik, Allgemeinchirurgie, Erlangen, Deutschland
From 1978 to 2004 1453 patients from our ERCRC with solitary colon
carcinoma were selected and the data analysed for local recurrence, distant metastasis and 5-year survival-rate.
The 5-year rate of local recurrence was 4.8 % (95% CI 3.6–6.0). Local recurrence occurred in median 20 months after primary therapy. In univariate analysis it was significantly elevated at tumors with advanced pT
and pN category, high tumor stadium, high grade tumors, tumors with
extramural venous invasion and emergency presentation with emergency operation. In multivariate analysis we analysed three risc factors:
pN-category (relative risk 8.6 in pN2-tumors), grading of tumor tissue
(relative risk: 8.6 in high grade tumors) and emergency presentation (relative risk: 1.6 in emergency operation).
The 5-year rate of distant metastases was 19.2 % (95% CI 17.0–21.4). In
univariate analysis we found significantly factors in advanced pT and
pN category, tumor stadium, grading, extramural venous invasion and
emergency presentation as well as lymphatic invasion and in patients
without adjuvant chemotherapy. Independent factors in multivariate
analysis were pT and pN category, tumor stadium, extramural venous
invasion and emergency presentation.
The 5-year survival rate of all patients was 84.4 %. Similar to local recurrence significant factors in univariate analysis were an advanced pT and
pN category, tumor stadium and grading, extramural venous invasion
and emergency presentation. In multivariate analysis we found advanced pT and pN category and emergency presentation as independent
factors.
At contemplating the independent risk factors advance pT and pN category and emergency presentation are the most important factors. Using
better prevention and early diagnosis the tumor can be diagnosed and
treated in an earlier tumor stage. A sophisticated operation technique
and performing the operation by a specialized surgeon with high experience can improve prognosis. In our data we can see, that prognosis is
considerably better since introduction the method of CME (complete
mesocolic exczsion) in 1995. (Exemplary 10,4% of local recurrence in
stadium III tumors in 1978–1984, 4.9 % local recurrence in 2000–2004.)
0416
Therapy resistance in HCC is modulated by IL-29 and Rapamycin
*E.B. Schwarz1, Y. Zhao1, F. Beigel2, J. Mysliwietz3, J.W. Ellwart3, S. Brand2,
K.-W. Jauch1, C.J. Bruns1
1
Universitätsklinikum der LMU München Campus Großhadern, Chirurgie,
München, Deutschland, 2Universitätsklinikum der LMU München Campus
Großhadern, Med II, München, Deutschland, 3Helmholtz Center for Environment and Health, Institute of Molecular Immunology, München,
Deutschland
Background. HCC is the fifth leading cause of cancer-related death
worldwide. Patients with advanced HCC rarely benefit from the available first-line therapies. Second line therapies are often associated with
development of resistance. Thus, it is essential to gain deeper knowledge of HCC tumor biology, in particular the significance of cancer stem
cells and their impact on therapy resistance, to develop novel therapeutic strategies. Therefore, we investigated in vitro and in vivo the
effects of interleukin-29 (IL-29) and the mTOR-inhibitor Rapamycin
on different cancer stem cell subpopulations in HCC. Our aim was to
characterize CSC markers on sensitive and Sorafenib-resistant human
HCC cells (Huh7) and to demonstrate the therapeutic effects of IL-29
and Rapamycin.
Methods. For in vitro experiments sensitive and Sorafenib-resistant
(Huh7-SoR) Huh7 cells were used. To characterize CSC surface markers FACS and immunoﬂuorescence staining for SP (side population),
CD133, CD44, ABCG2 were performed. Cell viability, migration, colony
formation and apoptosis of sensitive and Sorafenib-resistant Huh7 cells
were analyzed under treatment of IL-29 and Rapamycin.
Results. We could demonstrate a significant dose-dependent inhibition
of cell proliferation in both Huh7 and Huh7-SoR cells under IL-29 treatment. The Huh7 SP subpopulation increased after 72 h of therapy with
Sorafenib at IC50-concentrations and enriched with long term therapy
after 3 months (5,19% vs. 12,9%). The CD133+ and CD44+ double positive
subpopulation significantly increased in Huh7-SoR compared to sensitive Huh7 cells over the same treatment period. Interestingly, Rapamycin reduced the SP subpopulation in sensitive Huh7 and Huh7-SoR
cells more effectively than IL-29. Inhibition of colony formation in both
sensitive Huh7 and Huh7-SoR cells was more pronounced following
treatment with Rapamycin compared to IL-29. Immunofluorescence
stainings showed similar results.
Conclusions. There is an obvious effect of IL-29 treatment on sensitive
and Sorafenib-resistant Huh7 cells. However, with respect to different
cancer stem cell subpopulations Rapamycin was a more effective inhibitor in vitro. Therefore, mTOR inhibition seems to open new possibilities
for second line therapy in HCCs.
0427
microRNA signature for the chemoradiosensitivity in colorectal
cancer cell lines
*J. Salendo1, M. Spitzner1, P. Jo1, F. Kramer2, T. Beissbarth2, H.A. Wolff3,
M. Grade1, H. Becker1, B.M. Ghadimi1, J. Gaedcke1
1
Universitätsmedizin Göttingen, Allgemein- und Viszeralchirurgie, Göttingen, Deutschland, 2Universitätsmedizin Göttingen, Medizinische Statistik,
Göttingen, Deutschland, 3Universitätsmedizin Göttingen, Strahlentherapie
& Radioonkologie, Göttingen, Deutschland
Background. Preoperative 5-fluorouracil-based chemoradiotherapy is
the standard treatment for locally advanced rectal carcinomas. However, the individual tumor response is very heterogeneous, ranging from
complete resistance to regression. Recently, it has been shown that microRNAs (miRNAs) play a key role in the initiation, progression and
therapy response of cancer. Therefore, the identification of miRNAs as
predictive markers for response remains very crucial.
Materials and methods. Previously, we established in vitro models for
studying the molecular basis of this heterogeneous tumor response. 12
colorectal cancer cell lines were exposed to 3 µM of 5-fluorouracil and
2 Gy of radiation. The pretherapeutic miRNA expression profiles of these cell lines were assessed using 60 K Agilent Human miRNA Microarray. Differences in treatment sensitivity of the cell lines and miRNAs
expression were then correlated.
Results. Using a linear model analysis, we identified 36 miRNAs whose
expression levels correlated significantly with the heterogeneous sensitivity of the cell lines to chemoradiotherapy (p<0.05). Some of the most
significant miRNAs were miR-320, miR-486-5p, miR-452 and miR-224,
which have previously been related to carcinogenesis. The microarray
measurements were independently validated for a subset of these genes
using semi-quantitative real-time PCR. Target prediction of the identified miRNAs revealed mRNAs that were previously identified to be
associated to therapy resistance.
Conclusion. This study demonstrates for the first time a miRNA expression profile for chemoradiosensitivity in colorectal cancer cell lines.
We identified a subset of miRNAs which might play a crucial role in
regulating response to chemoradiotherapy. We further expect that the
validation of their targets will disclose response mechanisms and could
serve to identify a priori resistant primary tumors.
0430
Inflammation in gastric adenocarcinoma of the cardia. What is
the role of tumor infiltrating lymphocytes?
*M. Haas1, L. Distel2
1
Charité, Institut für Radiologie, Berlin, Deutschland, 2Universitätsklinik
Erlangen, Strahlenklinik, Erlangen, Deutschland
Background and aims. Recently, the immunoenvironment of human
malignancies has come more and more into focus. The underlying
question is how malignant tumors achieve escape from immunosurveillance. In this context, regulatory T-cells (Treg) are considered a
key player. They have the ability to hamper host anti-tumor immunity
and therefore were investigated with much diligence in several human
malignancies. The aim of the present study was to assess their role in
gastric adenocarcinoma of the cardia along with other subsets of tumor
Abstracts
infiltrating lymphocytes (TIL). Additionally, immunogenic factors of
the gastric tumors at hand were to be investigated.
Methods. Tumor samples of 52 patients with gastric adenocarcinoma of
the intestinal subtype located at the cardia were assessed using tissue
microarrays. The relationship between subtypes of tumor infiltrating
immune cells (CD3+, CD8+, CD20+, CD68+, GranzymeB+, FoxP3+
and CXCR3+) in different histologic compartments and no evidence of
disease (NED) – survival was investigated. To further understand the
specific immunogenic tumoral environment human epidermal growth
factor receptor 2 (Her2) overexpression and Ebstein-Barr virus (EBV) –
status of the carcinomas were determined and set into relation to TIL
infiltration.
Results. A strong compartmentalization with high TIL counts in the tumoral stroma as compared to low intratumoral infiltration was noted.
In the stromal compartment, an association of high FoxP3+ regulatory T cells with long NED-survival was observed, while high stromal
CD68+/FoxP3+ ratios were linked to shorter NED-survival times. Her2
overexpression/amplification had no correlation to TIL infiltration,
whereas EBV infection showed an association with both intratumoral
and stromal CD8+ cell accumulation. Stromal CXCR3+ T cell infiltration equalling Th1 cell infiltration showed an inverse correlation to T
category.
Conclusion. The association of Treg with improved outcome might be
due to an inhibition of carcinogenic inflammatory processes. CD68+
macrophages on the other hand are possible promoters of carcinogenesis. The diminishing CXCR3+ T cell infiltration with increasing T
category suggests a subversion of Th1 immunoresponse in cancer progression. This underlines the important role of inflammation for early
carcinogenesis.
0435
Circulating microRNAs in rectal cancer
*J. Salendo1, P. Jo1, T. Beissbarth2, M. Spitzner1, H.A. Wolff3, L.C. Conradi1,
M. Grade1, H. Becker1, B.M. Ghadimi1, J. Gaedcke1
1
Universitätsmedizin Göttingen, Allgemein- und Viszeralchirurgie, Göttingen, Deutschland, 2Universitätsmedizin Göttingen, Medizinische Statistik,
Göttingen, Deutschland, 3Universitätsmedizin Göttingen, Strahlentherapie
& Radioonkologie, Göttingen, Deutschland
Background. The identification of response in locally advanced rectal
cancer (RC) to a 5-FU based chemoradiotherapy is a crucial step towards an individualization of the therapy. The impact of microRNAs
(miRNAs) on progression or resistance in cancer has recently been described. Although their impact in patients’ blood has recently been described in different cancer types data in rectal cancer are scarce.
Materials and methods. miRNAs were extracted from patient and healthy control plasma including C. elegans miRNA mimics for the normalisation process. Each miRNA was detected using SYBR-Green based
miScript PCR system from Qiagen. 15 differentially regulated miRNAs
that were retrieved from the comparison of rectal cancer and normal
tissue based on miRNA microarray analyses were analysed in a first set
of 17 patients. All patients were treated within the CAO/ARO/AIO-94
and -04 trial of the German Rectal Cancer Study Group. Additionally,
14 age and gender matched healthy controls were analysed. In a second
set of 46 controls and 122 patients a subset of miRNAs was validated and
analysed on postsurgical blood specimens.
Results. 5 of the 15 analyzed miRNAs turned out to be significantly
down regulated in plasma compared to healthy controls (miR-17, miR18b, miR-20a, miR-31 and miR-193a-3p). Subsequently, a second set of
patients was analysed and two of the previously identified miRNAs
could be validated in this independent cohort. Interestingly, all miRNAs were downregulated in the RC patients. Comparing pretherapeutical and postsurgical expression 4 out of 5 miRNAs were significantly
differentially expressed.
Conclusion. This study demonstrates for the first time the differential
expression of plasma miRNAs in RC patients compared to healthy controls. To assess the impact of miRNAs on response or prognosis prediction these results will be correlated to the clinical data and a more
comprehensive approach will be undertaken.
0440
Isolation and characterisation of different stem cell-like subpopulations in an esophagus ascites
*S. Stoelting1, H. Ungefroren1, H. Lehnert1, F. Gieseler1
1
UK S-H, Campus Lübeck, Med. Klinik I, Onkologie, Lübeck, Deutschland
Background. First indication for the existence of cancer stem cells
(CSCs) was made by J. Dick et al in 1994. They identified the presence
of CSCs in acute lymphatic leukaemia. CSCs represent only 1% of the
tumor but appear to be the only cells that are able to generate a new
tumor. CSCs were discussed as the origin of tumor resistance and metastases. So far CSCs would be isolated and characterized only from solid
tumors. Basack et al. (2009) detected cells similar to stem cells with specific markers in a NSCLC pleura effusion for the first time. Until know
it is not clear whether only one population of stem cell like cells exist in
maligne effusions or different subpopulations with stem cell characters.
For the time being no data about the behaviour of those cells have been
determined.
Material and methods. We detected CSCs from an esophagus ascites
with stemgent alkaline phosphatase staining kit II and characterised
different subpopulations with stem cell markers by separating CD133+,
CD133+/Lin- and TRA-1-60+ cells with the miltenyi separating kits.
These cells had been cultured with the esophagus CSC medium from
cell system and analysed by determined surface marker (e.g. CD133)
with FACS, quantitative gene expression of stem cell transcription
factors (Oct3/4, Sox2, Nanog, cMyc), expression of microRNA (system
bioscience) and their behaviour of migration under TGFβ stimulation.
Results. After separation of different cell subpopulations with stemness
from an esophagus ascites we cultured the cells under specific conditions for CSCs. We obtained differences in gene expression of stem cell
markers (e.g. Oct3/4, Nanog) and also for microRNA. We also obtained
differences in migration behaviour. Under TGFβ stimulation TRA-160+ cells showed migration, in contrast the migration of CD133+ and
CD133+/Lin− cells have been inhibited.
Discussion. We demonstrated that cells with stemness not only exist
within solid tumors but also in ascites. These cells exhibit markers like
CD133 which describe for CSCs and TRA-1-60 which describes for pluripotent stem cells. The quantitative analysis of specific transcription
factors and microRNA indicates that only the subpopulation of TRA1-60+ cells feature a stem cell potential and maybe play an important
role in metastases. This hypothesis is supported by the observance that
only the TRA-1-60+ cells showed migration under TGFβ stimulation.
The presented data clarify the importance of understanding CSCs and
to generate a treatment.
0444
Generating scFv antibodies against pancreatic carcinoma from
naïve human Phage Display Libraries for clinical application
*E.-M. Siepert1
1
Helmholtz Institute for Applied Biomedical Engineering, Experimental
Medicine and Immunotherapy, Aachen, Deutschland
Pancreatic carcinoma (PC) is an aggressive form of cancer characterized
by its high potential for metastasis and thus resulting in a low survival
rate. As the initial stages of this disease are almost asymptomatic, early
detection, before metastasis occurs, is challenging because no reliable
detection tools for early diagnosis and treatment of PC are available. In
patients with metastasis the average survival rate of 5 years is less than
5%. Therefore, the need to develop tumour-specific therapies and tools
for early diagnosis is significant. The aim of this study was to develop an
immunotherapeutic approach for targeted diagnosis and treatment of
pancreatic cancer by using highly specific human antibody fragments
(scFv). Using the Phage Display Technology highly specific scFv were
generated from the naïve human Tomlinson phage library in a two-step
panning strategy with depletion on human peripheral blood lymphocytes (PBL) followed by a positive selection on the metastatic pancreatic
cancer cell line (L3.6pl). Monoclonal phage ELISA identified 16 unique
positive binders which were subsequently expressed in eukaryotic cells
(HEK293T) as scFv-SNAP-tag fusion proteins. The SNAP-tag® is a novel
tool for site specific conjugation of any benzylguanine-labeled molecule
to a given protein, providing the imaging of tumor cells in vitro and in
vivo. IMAC-purified fusion proteins were analyzed by protein ELISA
and flow cytometry for their binding specificity on several pancreatic
cancer cell lines. Eight clones were identified as recognizing L3.6pl cells
with cross-reactivity to other pancreatic cancer-derived cell lines. To
validate the selective binding of these clones to human pancreatic cancer cells, frozen primary tissue sections from patients with pancreatic
carcinoma were used and selective binding of at least one individual clone to tumor cells over normal cells was shown. All clones are currently
being tested for their ability for internalization in order to identify candidate clones for development of immunotoxins eliminating pancreatic
cancer cells.
0454
The systematic assessment of health information on colorectal
cancer screening in Germany
*M. Dreier1, B. Borutta1, G. Seidel1, S. Kramer1, I. Kreusel1, J. Töppich2,
E.M. Bitzer3, M.-L. Dierks1, U. Walter1
1
Medizinische Hochschule Hannover, Institut für Epidemiologie, Sozialmedizin und Gesundheitssystemforschung, Hannover, Deutschland,
2
Bundeszentrale für gesundheitliche Aufklärung (BZgA), Köln, Deutschland, 3Pädagogische Hochschule, Freiburg, Deutschland
Objective. The informed choice to attend or not attend colorectal cancer
screening tests (fecal occult blood test FOBT, screening colonoscopy)
may be supported by evidence-based health information. The aim was
to assess whether written health information on colorectal cancer screening meet the criteria of evidence-based health information.
Methods. The development of a criteria list included the following steps:
systematic literature review in 8/2010 in relevant electronic databases
(including Medline, Embase, search period from 2000) and Internet,
identification of recommendations and assessment tools for health information, extraction of the criteria, summary of the criteria by topics,
review by external experts, modification. In 8/2010 major players in
Germany were asked for leaflets via email.
Results. The criteria list was based on 16 documents with recommendations and 17 tools for health information and contains a total of 235
criteria in the following categories: formal issues, information on the
target disease, information on screening-colonoscopy/FOBT, readability and comprehensibility, layout, neutrality, correctness of the information. Input of free text ensures the transparency. An accompanying
manual supports the assessment by giving the correct answers, based
on systematic reviews, HTA reports, and guidelines. Eighteen flyers and
13 brochures on colorectal cancer screening were identified and assessed. It turned out that information was often not given (including risks,
quantification of the benefits), false information were given (“screening
results in a gain in life years in any case”), benefits and risks of the procedure were not be represented in a balanced way, and information was
partly misleading, e.g. the accuracy of colonoscopy was circumscribed
as the safest kind of prevention, which could be misunderstood as a low
risk of the procedure.
Discussion. An evaluation concept was developed and applied, which
goes beyond previous tools by considering not only the presence but
also the correctness of information. It also allowed the detailed detection of missing information, distorted presented benefits and risks as well
as of false and misleading information. The requirements for evidencebased patient information were currently not met by most of the offered
leaflets in Germany. The results may be used to revise existing leaflets
or to develop new health information on colorectal cancer screening.
0465
Solid pseudopapillary tumor of the pancreas: a new name for an
old enigmatic, but universally recognized entity
*N. Vassos1, A. Agaimy2, P. Klein1, W. Hohenberger1, R. Croner1
1
Universitätsklinikum Erlangen, Chirurgische Klinik, Erlangen, Deutschland, 2Universitaetsklinikum Erlangen, Pathologisches Institut, Erlangen,
Deutschland
Background. Solid pseudopapillary tumor (SPT) of the pancreas is an
infrequently-encountered tumor, typically affects young women without significant symptoms. Its behavior is relatively indolent and largely benign.
Material and methods. We report a case series of four patients with SPT
of pancreas, who were treated at our hospital between 2008 and 2011.
The clinical, pathological and immunohistochemical parameters as
well as the therapy and follow-up were investigated retrospectively.
Results. All four patients were female whose ages ranged between 15 and
42 years. Two patients were presented with abdominal pain, one patient
with abdominal mass and one with acute abdominal signs following
blunt trauma. The tumor’s size ranged between 1 and 16 cm. Two of them
were diagnosed preoperatively through a percutaneous needle biopsy
and the other two underwent surgery because of the high clinical and
radiological suspicion of SPT. By immunohistochemistry, all four cases
were stained strongly for vimentin, progesterone-receptor and beta-catenin and variably with pankeratin and neuroendocrine markers. The
proliferation index (Ki-67) was less than 2%. The patients underwent
surgical resection of the tumor and after a follow-up period between 3
and 36 months, all of them were alive with no evidence of disease.
Conclusion. SPT of pancreas should be considered in the differential diagnosis of any solid or partly cystic pancreatic or upper abdominal mass,
particularly in young females. The tumor has a low malignant potential
and the treatment of choice consists of surgical resection. Adequate surgical intervention is associated with an excellent prognosis.
0466
Management of liver metastases of gastrointestinal stromal
tumors (GISTs)
*N. Vassos1, A. Agaimy2, W. Hohenberger1, R. Croner1
1
Universitätsklinikum Erlangen, Chirurgische Klinik, Erlangen, Deutschland, 2Universitätsklinikum Erlangen, Pathologisches Institut, Erlangen,
Deutschland
Introduction. Liver metastases and/or peritoneal dissemination are the
main clinical manifestations of advanced GISTs. With the advent of tyrosine kinase inhibitors (TKI), the role of surgery in management of
advanced GISTs has radically changed. The effectiveness of TKI-therapy has provided an increasing proportion of GIST-patients with liver
metastases who are candidates for potentially curative therapy.
Material and methods. We herein present our experience about management of liver metastases of GISTs, investigating in retrospective analysis
clinical, macro-/microscopic and immunohistochemical criteria, surgical or TKI therapy and follow-up in these cases.
Results. Within a 10-year period (2000–2009), 85 patients with GISTs
were referred to our institution. In 24 patients (28.2%) metastatic disease was disclosed. Of these, 10 patients (11.7%; M:F=1:1) were rendered
to have liver metastases. The mean age was 59 (range: 35–75) years. The
primary GISTs were located in stomach (40%) and in small intestine
Abstracts
(60%), expressed CD117 and/or CD34. Liver metastases were commonly
multiple, distributed in both lobes (70%) and detected synchronously
with primary tumor (n=4) or metachronously (n=6). The period of time
between diagnosis of GIST and metachronous liver metastases ranged
from 23 to 76 (mean period: 36.3) months. All patients with liver involvement were considered to treatment with imatinib. The liver metastases
were estimated as resectable in 4 cases (R0). In recurrent (2/4, 50%) or
resistant cases, other treatments were carried out, including radiofrequency ablation (RFA) and sunitinib or nilotinib therapy. During a
mean follow-up of 52.6 months (range: 7–111 months), death for progressive disease occurred in 2 cases (20%). Eight patients (80%) were alive;
five of them remained free of disease and the other three have maintained disease with partial response or stabilization.
Conclusion. The liver is a common metastatic site for GISTs. Appropriate
initial evaluation remains of paramount importance for selecting the
correct treatment strategy. Combining surgery with TKI treatment is
the most effective management for GIST patients with liver metastases. For unresectable disease, RFA, hepatic artery chemoembolization
(TACE), TKI therapy, or any combination of these treatments can be
considered. Multidisciplinary management of this disease is important
for both curative and palliative treatment in these patients.
0483
Tumorinfiltrierende regulatorische T-Lymphozyten als prognostische Marker mit therapeutischer Relevanz beim Rektumkarzinom
*T. Borschitz1, D. Wohland1, E. von Stebut2
1
Deutsche Klinik für Diagnostik, Chirurgie und Koloproktologie, Wiesbaden, Deutschland, 2Universitätsmedizin Mainz, Core Facility-Histologie,
Dermatologie, Mainz, Deutschland
Fragestellung. Die Behandlung von Rektumkarzinomen erfordert eine
stadiengerechte, optimierte Therapie. Dabei entscheiden Histologie/
Eindringtiefe/Lymphknotenmetastasen sowohl über das Operationsverfahren (lokale vs. radikale Exzision), als auch (neo-)adjuvante Therapien. Ziel dieser Untersuchung war es, zu evaluieren, inwiefern die
Infiltration des Tumors mit immunmodulierenden T-Lymphozyten
prognostisch relevant und in Therapieentscheidungen einzubeziehen
ist.
Methode. Getrennt nach Lymphknotenmetastasen (n=40 N+/n=40 N0)
wurden Tumorschnitte von 80 Patienten (8% T1, 44% T2, 46% T3, 3% T4)
mit einem Follow-up von ≥5 Jahren untersucht, die nicht neoadjuvant
behandelt wurden. Sechs Patienten (8%) wiesen im Verlauf Lokalrezidive (LR) auf, 14 (18%) synchrone und 10 (13%) metachrone Fernmetastasen (M). Es wurden tumorinfiltrierende CD4+/CD8+ Lymphozyten,
CD57+ NK-Zellen sowie FoxP3+ bzw. CD25+ regulatorische T-Zellen
(Treg) immunhistochemisch dargestellt. Durch Auszählen aller positiven Zellen und Mittlung von 5 repräsentativen Gesichtsfeldern/Tumor wurde die jeweilige Infiltrationsdichte quantifiziert und statistisch
mittels Mann-Whitney-U-Test auf Unterschiede hinsichtlich T-Kategorie, Lymphknotenstatus (N0/N+), Grading (G) und LR-/M-Auftritt
untersucht. Unterschiede im Gesamtüberleben (GSÜ) wurden mit LogRank-Test und Cox-Regression ausgewertet.
Ergebnisse. Färbungen gegen CD4, CD8, CD57 und CD25 wiesen keine Unterschiede in den jeweiligen Verteilungen auf. Die FoxP3+ TregDichte war bei T1 Karzinomen am höchsten und nahm mit zunehmender T-Kategorie signifikant ab (T1/2 vs. T3/4 p=0,002). Gleiches ergab
sich für N+ und M1 gegenüber N0 (p=0,033) bzw. M0 Karzinomen (synchrone p=0,006/metachrone p=0,04/kombiniert p=0,004). Außerdem
fanden sich bei „high-grade“- (G3–4) signifikant weniger FoxP3+ Tregs
als bei „low-grade“- (G1–2) Karzinomen (p=0,012) und schließlich für
hohe Treg-Infiltrationsdichten ein signifikant längeres GSÜ (p<0,001
im univariaten Log-Rank-Test). Dies bestätigte sich auch in der multivariaten Cox-Regressionsanalyse, wenn zusätzlich alle anderen Lymphozyten-Infiltrationen berücksichtigt wurden (p=0,029).
Schlussfolgerungen. Hohe FoxP3+ Treg-Infiltrationen sind beim Rektumkarzinom hinsichtlich Lymphknotenstatus, Grading, Metastasierung und Gesamtüberleben als prognostisch günstig einzustufen und
können für Therapieentscheidungen herangezogen werden. Um diese
Ergebnisse zu untermauern, sind Untersuchungen an größeren Patientenkollektiven notwendig.
0486
Neoadjuvant chemoradiation with surgery of the primary tumour in stage UICC IV rectal carcinomas
*F. Stirkat1, S. Merkel1, J. Göhl1, W. Hohenberger1, R. Croner1
1
Friedrich-Alexander Universität Erlangen-Nürnberg, Chirurgische Klinik,
Background. The preoperative chemoradiation and resection of the
primary tumour in stage UICC IV rectal carcinomas is controversially
discussed. We compared survival and outcome of patients with stage
UICC IV rectal carcinomas and synchronous liver metastases undergoing either primary tumour resection or no primary tumour resection
after neoadjuvant chemoradiation with or without liver resection.
Material and methods. We selected 75 patients who underwent treatment
for stage UICC IV rectal carcinomas and synchronous liver metastases
(LM) between 1995 and 2010 from the Erlangen Registry for Colorectal
Carcinomas. The median age of patient was 58 years (range 45–78). All
patients received neoadjuvant chemoradiation (CRT) with 5-FU based
chemotherapy and local tumour irradiation (50.4 Gy). The median follow-up was 20 months (range 2–189). Survival was compared in patients
who underwent A) tumour resection of the primary tumour after CRT
and staged resection of LM, B) tumour resection of the primary tumour
after CRT and no resection of LM, C) no tumour resection of the primary tumour after CRT and no resection of LM .
Results. Eighteen patients (A; 24%) received a staged liver resection after
surgery for the primary tumour, 44 patients (B; 58.7%) were operated
only on the primary tumour and 13 patients (C; 17.3%) received no tumour resection at all. Thirty-three patients (53.2 %) received a anterior
rectal resection, 20 patients (32.3 %) received abdomino-perineal excision (APE) and 6 patients (9.7%) an intersphincteric resection. All patients received total meseorectal exzision. Liver surgery was performed in
18 patients (24%). Time between rectal and liver surgery was 6.1 months
(range 2–13). Median survival was 33.5 months in group A, 17.8 months
in group B and 13.2 months in group C. Difference in survival was significant (p<0.05) between group A and B and group A and C. No significance could be calculated between group B and C (p=0.25). Survival
in group A and B was not dependent on the number of liver metastases.
Conclusions. The upfront target in the management of stage UICC IV
rectal carcinoma with LM should be a complete tumour resection. Nevertheless patients may benefit from primary tumor resection alone
which could generate prolonged survival. Chemoradiation alone without any surgery should be considered for local tumor control in a palliative setting only.
Hauttumoren
0022
R1-Status bei fazialen Basalzellkarzinomen – Realität oder
Mythos
*L. Tischendorf1
1
Praxis MKG-Chirurgie, Praxis, Halle, Deutschland
Fragestellung. Aktuelle Leitlinien für die Behandlung von Basalzellkarzinomen (BCC) fordern den Einsatz der mikroskopisch kontrollierten
Chirurgie und der sekundären Defektabdeckung speziell im Gesichtsbereich. Diese Ansicht ist wissenschaftlich nicht ausreichend belegt, vor
allem nicht durch randomisierte kontrollierte Studien. Wir analysierten 2 Fragen: 1.) Ist der R1-Status realistisch beurteilbar? 2.) Was ist der
prognostische Wert des R1-Status?
Material und Methodik. Ergebnisse der operativen Behandlung fazialer
BCC (649 stationär 1948–1982 retrospektive R1-Bewertung, 847 ambulant 1993–2007 prospektive R1-Bewertung). Berechnungen der Rezidivwahrscheinlichkeit (Kaplan-Meier) in Abhängigkeit von R1-Status.
Ergebnisse. 1.) R1-Status beträgt bei unvorbehandelten BCC: 9% bzw.
3%, bei rezidivierten: 8% bzw. 19%. 2.) Rezidivwahrscheinlichkeit ist 26fach (unvorbehandelte BCC) bzw. 3-fach (rezidivierte BCC) höher bei
R1-Status. Nachgewiesen werden Tumorreste in 30–85%. 3. R1-Status
beeinflusst Überleben nicht. Allerdings treten in 30% Zweitgeschwülste
auf und die Lebenserwartung verkürzt sich im Vergleich zur Normalpopulation um 5 Jahre.
Schlussfolgerungen. 1.) R1-Status beeinflusst Prognose nur begrenzt auf
das Rezidivverhalten. 2.) Mikroskopisch kontrollierte Chirurgie bildet
(auch in vereinfachten Modifikationen) R1-Status im lateralen Bereich
sicher ab und kann die onkologische Sicherheit erhöhen. 3.) Verzögerte
Defektabdeckungen bleiben seltenen Ausnahmefällen vorbehalten.
0027
Sensitization of melanoma cells for TRAIL-induced apoptosis by
the kinase inhibitor indirubin is mediated through upregulation
of p53 and death receptors
*A. Berger1, S.-A. Quast1, M. Kunz2, P. Langer3,4
1
Charité – Universitätsmedizin Berlin, Klinik für Dermatologie und Allergologie, Berlin, Deutschland, 2University Hospital of Leipzig, Department of
Dermatology and Allergy, Leipzig, Deutschland, 3University of Rostock, Institute of Organic Chemistry, Rostock, Deutschland, 4University of Rostock,
Leibniz Institute of Catalysis e.V., Rostock, Deutschland
Background. No effective therapy is available for metastatic melanoma
so far. An anti-tumour activity of indirubin is known from traditional
Chinese medicine, and its derivative 8-Rha-beta has been described as
a cyclin-dependent kinase inhibitor. However, the molecular basis underlying 8-Rha-beta-induced apoptosis remained elusive. TNF-related
apoptosis-inducing ligand (TRAIL) is known to trigger apoptosis in a
variety of human cancer cells, while normal cells are largely spared.
However, prevalent or inducible resistance prevented its efficient use in
cancer therapy so far. TRAIL resistance in melanoma cell lines is frequently associated with downregulation of its agonistic receptors DR4
and DR5.
Methods. TRAIL-sensitive melanoma cell lines A-375 and Mel-HO
were compared to permanently resistant MeWo and Mel-2a as well as
to cell lines selected for death ligand resistance A-375-TS, Mel-HO-TS
(TRAIL-selected) and A-375-CS, Mel-HO-CS (selected with an agonistic CD95 antibody, CH-11, for resistance to the death ligand CD95L).
Results. Both death ligand-sensitive cell lines (A-375 and Mel-HO) responded with enhanced apoptosis to combinations of death ligands
(TRAIL, CH-11) with 8-Rha-beta. The indirubin was further able to
sensitize resistant Mel-2a and A-375-TS (DR4+, DR5+) for death ligand-
induced apoptosis. In contrast, MeWo and Mel-HO-TS (DR4−, DR5+)
remained without effect. The unraveling of proapoptotic signaling
pathways in A-375-TS revealed strong enhancement of the effector caspase-3 in the combination. Significant loss of the mitochondrial membrane potential, release of cytochrome c and apoptosis-inducing factor
(AIF) as well as processing of caspase-9 was evident for activation of
intrinsic apoptosis pathways. On the other hand, enhanced surface expression of DR4 and DR5 as well as processing of initiator caspase-8 was
indicative for activation of extrinsic apoptosis pathways. Remarkably,
this combination was able to overcome an apoptosis block due to ectopic Bcl-2 overexpression. The effects may be explained by downregulation of antiapoptotic proteins Mcl-1 and XIAP as well as by activation of
the master regulator p53 seen in course of 8-Rha-beta treatment.
Conclusions. Apoptosis resistance to TRAIL may be overcome by kinase
inhibitors, and the indirubin 8-Rha-beta appears as a promising therapeutic strategy for melanoma cells, dependent on their expression of
TRAIL receptors.
0032
Sensitization of melanoma cells for death ligand-induced apoptosis by the potassium channel inhibitor TRAM-34 correlates
with the intrinsic pathway and SMAC release
*S.-A. Quast1, A. Berger1, N. Buttstädt2, K. Friebel2, R. Schönherr2, *J. Eberle1
1
Charité – Universitätsmedizin Berlin, Klinik für Dermatologie und Allergologie, Berlin, Deutschland, 2Universität Jena, Zentrum für molekulare
Biomedizin, Jena, Deutschland
Introduction. Melanoma only poorly responds to chemotherapy, and the
death ligand TRAIL, which mediates apoptosis via TRAIL-R1/DR4 and
TRAIL-R2/DR5, appears as a promising therapeutic strategy. However,
prevalent and inducible TRAIL resistance may limit its clinical use in
melanoma cells. Potassium channels as KCa3.1 are involved in tumor
progression and may serve as additional targets.
Material and methods. Functional expression of KCa3.1 in melanoma
cells is demonstrated by quantitative RT-PCR analysis and patch-clamp
recordings. We prove that TRAM-34, a selective KCa3.1 inhibitor,
strongly enhanced TRAIL sensitivity of melanoma cells and overcomes
prevalent and inducible TRAIL resistance. Unraveling the signaling
pathways revealed that TRAM-34 was able to overrule the lack of caspase-3 processing in selected TRAIL-resistant cells. Disruption of the
mitochondrial membrane potential and the release of proapoptotic mitochondrial factors such as SMAC clearly indicate the involvement of
the mitochondrial apoptosis pathway. Importantly, TRAM-34 mediated enhancement of the TRAIL-induced apoptosis was critically dependent on the expression of either Bax or Bak, as shown in genetic models,
and apoptosis was abrogated in Bax/Bak double knockout cells as well
as by overexpression of the antiapoptotic Bcl-2 protein Bcl-2.
Conclusion. Taking into account the physiological role of death ligands
in immune surveillance, sensitization of melanoma cells for death ligands may be supportive for an anti-tumor immune response. The data
prove the critical role of the mitochondria in TRAIL resistance and present a new strategy for TRAIL sensitization based on the targeting of
potassium channels. Furthermore, combinations with the potassium
channel inhibitor TRAM-34 may help for a breakthrough of TRAILmediated strategies in melanoma.
Abstracts
0251
Mechanism analysis of melanoma chemosensitization by
MIDGE-mediated hTNF-alpha gene transfer in combination with
vindesine
*D. Kobelt1, J. Aumann2, M. Schmidt3, M. Schroff3, I. Fichtner4, P.M. Schlag5,
W. Walther2
1
MDC Berlin Buch, Chirurgie/chirurgische Onkologie, Berlin, Deutschland, 2Experimental and Clinical Research Center, a joint cooperation
between the Charité Medical Faculty and the MDC for Molecular Medicine,
Chirurgie/chirurgische Onkologie, Berlin, Deutschland, 3MOLOGEN AG,
Berlin, Deutschland, 4MDC Berlin Buch, Experimental Pharmacology, Berlin,
Deutschland, 5Charité University Medicine, Charité Comprehensive Cancer
Center, Berlin, Deutschland
Non-viral vectors are frequently used for clinical gene therapy trials.
Compared to viral vectors they offer a better safety profile due to their
limited ability to integrate or to provoke immune reactions. Besides
long known plasmids as gene transfer vectors there are novel non-viral
vectors available. Among those, the MIDGE vector technology (Mologen, Berlin, Germany) offers the smallest vectors for transient gene
transfer. They are linear double stranded DNA molecules with end-sealing loops at their ends. Using those vectors it is possible to avoid the
transfer of any unnecessary genetic material like ORIs, CpG islands or
resistance genes besides the expression cassette.
In our in vitro experiments using luciferase reporter gene we showed,
that the MIDGE vector is superior compared to plasmid vectors. In
different human melanoma (A375, MeWo, SKMEL-5, SK-MEL-28) and
colon carcinoma (HCT116, SW480) cell lines, reporter gene expression
increased up to 10-fold after equimolar transfection and >100-fold after
equimolar electroporation compared to the parental plasmid harboring
the identical expression cassette. This increase was due to an enhanced
transgene expression when using MIDGE vectors as shown by expression studies at the mRNA level by qRT-PCR. For a therapeutic approach
we were combining the MIDGE based gene transfer of human tumor
necrosis factor alpha (hTNF-alpha) with vindesine in vitro and in vivo.
The equimolar gene transfer by transfection/electroporation in vitro or
in vivo jet-injection gene transfer in melanoma xenotransplants showed
improved MIDGE-mediated transgene expression. The hTNF-alpha
gene transfer led to an up to 10-fold reduction of the vindesine IC50 in
vitro. Analyzing the mechanism of enhanced cell killing using lactate
dehydrogenase (LDH) release assay and caspase 8, 9, 3/7 activation assays we showed in vitro, that particularly an accelerated activation of
caspases leads also to accelerated apoptosis.
The in vivo tumor growth was significantly reduced by MIDGE-based
hTNF-alpha gene transfer in combination with i.v. vindesine treatment.
Additionally, the MIDGE vector showed a good safety profile with low
systemic leakiness and fast clearance of the vector after intratumoral
jet-injection. The MIDGE vector demonstrated its great potential for
future clinical application in tumor gene therapy.
0321
Bone morphogenetic protein and nodal induce epithelial-mesenchymal transition in melanoma cells and confer a neural crest
phenotype to melanocytes in vitro and in vivo
*C. Busch1, C. Garbe1
1
Universitäts-Hautklinik, Dermatologische Onkologie, Tübingen, Deutschland
During embryonic development, TGF-β family members nodal and
bone morphogenetic protein-2 (BMP-2) induce an epithelial-mesenchymal transition (EMT) in the neural crest. Here we demonstrate numerous effects of BMP-2, BMP-7 and nodal, their antagonists noggin and
lefty, and the nodal receptor (Alk4/5/7) antagonist SB431542 on melanoma cells and melanocytes.
There was no effect on cell cycle or cell proliferation. In melanoma cells
aggregate formation was reduced by agonist treatment and increased
by antagonists. Migration and invasion were increased by agonists and
blocked by antagonists. Western Blot analyses showed a down-regulation of neural crest proteins Slug and SOX9 upon antagonist treatment.
mTOR signalling was also inhibited by antagonists. In epidermal skin
reconstructs invasion of melanoma cells was reduced by antagonists.
BMP-2 and nodal induced invasiveness in radial growth phase melanoma cells in epidermal reconstructs. In vivo, the SB431542 entirely
abrogated neural crest migration of SKMel28 cells upon transplantation into the chick embryonic neural tube. Cytoplasmatic expression of
nodal was confined to melanoma cells performing EMT. Noggin and
SB431542 significantly inhibited invasion of BLM melanoma cells in a
newly established in vivo model of brain metastasis in the chick embryo.
Agonists (BMP-2, BMP-7, nodal) conferred a neural crest phenotype
to primary human melanocytes: They reduced adhesiveness, induced
migration and invasion in vitro, induced neural crest-specific proteins
Slug and SOX9, and mTOR signalling. In vivo BMP-2 and nodal induced EMT in melanocytes transplanted into the chick embyonic neural
crest, thus behaving like melanoma cells in the same experimental setup.
Expression of nodal and its receptors were determined in a newly-generated melanoma tissue microarray. Expression of nodal receptors significantly increased from nevi to primary melanoma. Further, BMP-2
levels were determined in plasma of 40 melanoma patients and healthy
controls. BMP-2 levels were significantly higher in plasma of patients
with a short survival time when compared to long-term survivors.
In summary, we highlight that BMP and nodal are crucial for melanoma cell invasiveness in vitro and in vivo. Plasma level of BMP-2 turned
out to be a novel biomarker for rapid disease progression in melanoma
patients. Together, we are able to demonstrate that BMP and nodal represent highly crucial therapeutic targets to prevent melanoma progression.
0357
The BRAFV600E kinase inhibitor vemurafenib induces endoplasmic reticulum stress-mediated apoptosis in BRAFV600E mutated
melanoma cells
*D. Beck1, H. Niessner1, D. Kulms2, C. Garbe1, F. Meier1
1
Universität Tübingen, Dermatologische Onkologie, Tübingen, Deutschland, 2Universität Stuttgart, Institute of Cell Biology and Immunology,
Stuttgart, Deutschland
Background. In a previous study, we observed that the pan-RAF inhibitor sorafenib induces upregulation of endoplasmic reticulum (ER)
stress-related genes and apoptosis in melanoma cells in vitro. In this
study, we investigated whether vemurafenib, which selectively inhibits
the BRAFV600E kinase and demonstrates potent antitumor activity in
melanoma patients with the BRAFV600E mutation, induces ER stressmediated apoptosis.
Methods and results. The BRAFV600E kinase inhibitor vemurafenib inhibited growth, induced caspase-dependent apoptosis and upregulated
the ER stress-related genes p8, CHOP, ATF4, ATF3 and TRB3 mRNA
levels exclusively in BRAFV600E mutated melanoma cell lines. Apoptosis was correlated with the induction of the proapoptotic BH3-only protein Bim-particularly Bim short, which is linked to ER stress-mediated
apoptosis. Western blot analysis showed that vemurafenib increases the
protein levels of the ER stress marker CHOP in BRAF mutated but not
in NRAS mutated melanoma cells. Furthermore, electron microscopy
showed typical morphological signs of ER stress, in particular significant swelling of the endoplasmic reticulum lumen of BRAFV600E
mutated melanoma cells treated with vemurafenib. siRNA inhibition
of ATF4 diminished melanoma cell apoptosis induced by vemurafenib.
Furthermore, classical ER stress inducers such as thapsigargin and tunicamycin potently inhibited growth, induced apoptosis and suppressed
invasive tumor growth of melanoma cells. Moreover, both thapsigargin
and tunicamycin upregulated p8 and CHOP and induced apoptosis in
vemurafenib-resistant melanoma cells.
Conclusions. These data suggest that the BRAFV600E kinase inhibitor
vemurafenib induces apoptosis in BRAFV600E mutated melanoma
cells through upregulation of ER stress-related genes.
Lungentumoren
0097
A multi-centric, open-label, phase II study investigating the combination of RAD001 (everolimus) with paclitaxel and carboplatin
in first line treatment of patients with advanced (stage IV) Large
Cell Lung Cancer with neuroendocrine differentiation (LCNEC)
*C. Grohé1, O. Zaba1, N. Reinmuth2, I. Nimmrich3, J. Stieglmaier4, C. May4,
M. Serke5, M. Thomas2
1
Evangelische Lungenklinik Berlin, Pneumologische Klinik, Berlin, Deutschland, 2Thoraxklinik am Universitätsklinikum Heidelberg, Onkologie der
Thoraxtumoren, Heidelberg, Deutschland, 3i.A. Novartis Pharma GmbH,
Berlin, Deutschland, 4Novartis Pharma GmbH, Nürnberg, Deutschland,
5
Lungenklinik Hemer, Abt.Pneumologie III, Hemer, Deutschland
Neuroendocrine tumors (NET) of the lung can be divided into typical
carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). LCNEC, which
accounts for approximately 3% of all lung cancers, progresses rapidly, is
aggressively metastatic, and exhibits a poor prognosis, with currently
no curative treatment option. Upcoming targeted therapies such as angiogenesis inhibitors, tyrosine kinase inhibitors, and mTOR inhibitors
are discussed as promising approaches to improve outcome of LCNEC.
RAD001 (everolimus) is an inhibitor of mTOR, a component of the PI3/
AKT/mTOR pathway known to be dysregulated in numerous human
cancers. RAD001 is approved for treatment of metastatic renal cell cancer and known to be effective in pancreatic neuroendocrine tumors.
In the presented trial for advanced (stage IV) LCNEC patients, RAD001
is combined with carboplatin and paclitaxel, a standard chemotherapy
routinely used in both non-small cell lung cancer (NSCLC) and smallcell lung cancer (SCLC) patients. The primary objective of this study
is to evaluate the efficacy of this treatment in patients with advanced
LCNEC. The primary endpoint is the proportion of patients progression-free after three months. Main inclusion criteria are histologically
confirmed stage IV LCNEC (at least positive for one of the neuroendocrine markers CD56, Synaptophysine, Chromogranine A), measurable
disease according to RECIST, adequate bone marrow, renal, and liver
function. Main exclusion criteria are symptomatic CNS metastases, prior treatment for advanced LCNEC, and any severe other medical condition. Patients receive four cycles of combined treatment and are allowed
to continue with RAD001 treatment as long as they benefit from treatment. The trial is open for recruitment and seeking 85 patients at 10 sites
in Germany. The study design will be presented in detail.
In summary, a combined therapy of carboplatin and paclitaxel with the
mTOR inhibitor RAD001 might be a promising approach for more efficient treatment of LCNEC patients.
0123
Active participation in a sports club has a protective effect on the
development of lung cancer in smokers
*A. Schmidt1, J. Jung1, N. Ernstmann1, E. Driller1, M. Neumann2, A. Staratschek-Jox3, C. Schneider4, J. Wolf5, H. Pfaff1
1
Universität Köln, Institut für Medizinsoziologie, Versorgungsforschung
und Rehabilitationswissenschaft der Humanwissenschaftlichen Fakultät
und Medizinischen Fakultät der Universität zu Köln, Köln, Deutschland,
2
Medical Department of the Private University of Witten/Herdecke,
Gerhard Kienle Institute for Medical Theory, Integrative and Anthroposophic Medicine, Integrated Curriculum for Anthroposophic Medicine
(ICURAM), Witten, Deutschland, 3University Bonn, LIMES (Life and Medical
Sciences Bonn), Genomics and Immunoregulation, Bonn, Deutschland,
4
University Hospital of Cologne, Department III for Internal Medicine, Köln,
Deutschland, 5University Hospital of Cologne, First Department of Internal
Medicine, Molecular Tumour Biology and Tumour Immunology & Centre
for Integrated Oncology (CIO), Köln, Deutschland
Background. This study analyzes the effect of social networks and participation in a sports club on the development of lung cancer in patients
who smoke. Our hypothesis is that study participants lacking social
support are at a greater risk for lung cancer than those who have social
support.
Methods. Data for the study were taken from the Cologne Smoking
Study (CoSmoS), a retrospective case-control study examining potential psychosocial risk factors for the development of lung cancer. Our
sample consisted of n=158 participants who had suffered lung cancer
and n=144 control group participants. Both groups had a history of
smoking. Data on social support were collected by asking participants
whether they participate in a sports club and about the number of
friends and relatives in their social environment. In addition, sociodemographic data and data on pack years were collected to control for
potential confounders. Logistic regression was used for the statistical
analysis.
Results. The results revealed that participants who participate in a
sports club are at a lower risk for lung cancer than those who do not
(n=302; adjusted OR=0.435; CI=0.222–0.853). Number of friends and
relatives had no statistically significant influence on the development
of the disease.
Conclusions. The results of the study suggest that there is an association
between smokers who have suffered lung cancer and participation in a
sports club. In the study sample, participation in a sports club seemed
to have a greater protective effect than a social network of friends and
relatives.
0149
Pulmonary neuroendocrine tumours: prevalence in 1244 resected patients and analysis of patient characteristics, smoking
habits and tumour stage
*E.-R. Walburga1
1
Kliniken der Stadt Köln, Lungenklinik, Köln, Deutschland
Objective. Neuroendocrine tumours of the lung can be divided in typicalcarcinoid (TC), atypical carcinoid (AT), large cell neuroendocrine
carcinoma (LCNEC) and small cell lung carcinoma (SCLC). Apart from
SCLC which accounts for 20–25% of pulmonary tumors, carcinoids and
LCNEC are rare tumors with a reported prevalence of approximately
3% among surgically resected lung cancers. Generally speaking there
is only little information on the prevalence of neuroendocrine tumors
in resected patients so that we would like to present the data collected
our institution.
Patients and method. Retrospective analysis of 1244 surgically resected lung cancer patients in our institution between January 2007 and
Abstracts
ecember 2010. For patients with a diagnosis of TC, AT and LCNEC we
D
compared the data in terms of age, sex, smoking habits and tumor stage.
Results. Among the resected patients 17 (1.7%) were diagnosed with TC,
6 with AT (0.6%) and 25 patients with LCNEC (2.5%). A mixed histology
of LCNEC and SCLC was found in 8 out the 25 patients with a LCNEC.
LCNEC highly correlated with smoking (all were smokers) and the patients were diagnosed at a later stage compared to those with carcinoids.
Patients with TC and AT happened more likely to be women, neversmokers and were mainly diagnosed in stage I. There was no significant
difference in age between these groups.
Conclusions. Neuroendocrine tumours of the lung are rare. Retrospective analysis of this data allows us to differentiate between these patients
in terms of prognosis. The importance of clinical trials is underlined
especially for patients with LCNEC as they have a poor prognosis. Two
new clinical Trials are initiated to examine the efficacy and safety of
Pasireotid LAR (SOM230) and Everolimus (RAD 001) in the treatment
of LCNEC.
0367
Expression profiling of serum microRNAs in non-small cell lung
cancer
S. Kaduthanam1,2, T. Muley2, M. Meister2, J.C. Brase1, M. Johannes1, S. Gade1,
F.F. Herth3, H. Dienemann4, H. Sültmann1, *R. Kuner1
1
DKFZ/NCT, AG Krebsgenomforschung, Heidelberg, Deutschland, 2Thoraxklinik, University of Heidelberg, Translational Research Unit, Heidelberg,
Deutschland, 3Thoraxklinik, University of Heidelberg, Department of Pneumology and Critical Care Medicine, Heidelberg, Deutschland, 4Thoraxklinik,
University of Heidelberg, Department of Thoracic Surgery, Heidelberg,
Deutschland
Introduction. Lung cancer is the leading cause of cancer related death
worldwide. At the time of diagnosis, about 40% of non-small cell lung
cancer (NSCLC) patients already have metastases, which lead to a worse
prognosis. Detection of NSCLC at early stage and the subsequent surgical resection strongly increase the 5-year survival rate. However, even
for early-stage tumor diagnosis, the outcome is critically determined by
metastatic spread: About 30–50 % of patients encounter a recurrence
after surgery for lung cancer. At the time of diagnosis, those patients
might benefit from additional treatment like chemotherapy and radiation. The aim of the study was to identify serum microRNAs associated
with early relapse of NSCLC patients.
Methods. The study included serum from 231 patients with NSCLC
diagnosis, chronic obstructive pulmonary disease (COPD) or healthy
controls. Upon RNA extraction, qRT-PCR based microRNA screening
using low-density arrays (667 microRNAs) was performed from a subset
of 40 patients. Several microRNA candidates were further validated in
an independent patient cohort. Moreover, microRNA expression was
compared between serum and tissues of the same NSCLC patients including matched tumor and normal specimens.
Results. The screening experiment suggested six circulating microRNAs to be associated with NSCLC relapse. Two serum microRNAs
could be validated in an independent cohort to be differentially abundant between patients with early and late relapse. The abundance of
microRNAs was also found to be influenced by the non-malignant lung
disease COPD, which represent a risk factor for lung cancer. Moreover,
microRNAs were found to be similarly abundant in serum and tissues
of NSCLC patients.
Conclusion. In this study, we have found promising circulating microRNAs associated with early relapse of NSCLC. The abundance of microRNA biomarkers can be influenced by other lung diseases like COPD.
0432
Debulking surgery followed by adjuvant chemoradiation in
malignant pleural mesothelioma
*S. Bölükbas1, M. Eberlein2, A. Fisseler-Eckhoff3, D. Ghezel-Ahmadi1, J. Schirren1
1
2
Carver College of Medicine, Division of Pulmonary, Critical Care and Occupational Medicine, Iowa City, USA, 3Dr. Horst Schmidt Klinik, Institut für
Pathologie und Zytologie, Wiesbaden, Deutschland
Objective. To investigate the effectiveness of extended debulking surgery in terms of lung-sparing radical pleurectomy (RP) within a standardized multimodality treatment of malignant pleural mesothelioma
(MPM).
Methods. All patients with histologically proven MPM and without
prior treatment for MPM were assessed for trimodality therapy in a
prospective, non-randomized study from November 2002 to December 2008: RP (visceral and parietal pleurectomy) followed by 4 cycles
of chemotherapy (Cisplatin/Pemetrexed) and radiation of the intervention sites (21 Gy in 3 fractions). Primary end-point was overall survival.
Secondary end-points were progression-free survival (PFS), patterns of
recurrence, morbidity and mortality.
Results. Fifty-two out of 135 consecutive patients were included in the
study. Forty-nine patients (94%) completed the trimodality therapy.
Surgical morbidity and mortality were 23.1% (12/52) and 1.9% (1/52),
respectively. Primary histology was epithelial (80.8%). Macroscopic
complete resection (MCR) could be achieved in 65.4%. Thirty patients
(57.7%) had advanced disease at International Mesothelioma Interest
Group (IMIG) stages III/IV. Mean follow-up was 26.9 months. Median
survival was 26.3 months. One- and 5-year-survival rates were 76% and
33%, respectively. Mean PFS was 21.5 months. The sites of failure were
locoregional (28/51, 54.9%), distant (10/51, 19.1%) and both (2/51, 3.9%).
Significant survival differences were seen for MCR vs. incomplete resections (p<0.0001), IMIG stages I/II vs. III/IV (p=0.011) and nodal disease
N0 vs. N1-2 (p=0.005). Histology (p=0.5), gender (p=0.7) and age (p=0.6)
had no significant impact on survival. When the Cox proportional hazards model was applied, MCR was the only significant prognostic factor (p<0.001).
Conclusions. Debulking surgery in terms of lung-sparing RP is associated with promising long-term survival, morbidity and mortality within
a multimodality therapy concept. MCR is the most important prognosticator in this study. Further investigation for the locoregional control of
the disease is warranted because of the high rate of locoregional failure.
0439
En-bloc resection of non-small cell lung cancer invading the
spine
*J. Schirren1, T. Dönges1, M. Melzer2, R. Schönmayr2, M. Eberlein3,
S. Bölükbas1
1
2
Dr. Horst Schmidt Klinik, Neurochirurgie, Wiesbaden, Deutschland,
3
Carver College of Medicine, Division of Pulmonary, Critical Care and Occupational Medicine, Iowa City, USA
Objectives. The aim of the study was to illustrate our surgical en-bloc
approach and to evaluate the outcome and survival of non-small cell
lung cancer (NSCLC) invading the spine.
Methods. All patients undergoing lung resection with en bloc hemivertebrectomy or total vertebrectomy for NSCLC were retrospectively
reviewed from our prospective database of between January 2003 and
December 2008 in an individualized multimodality treatment concept.
Kaplan-Meier method was applied to estimate survival. Log-rank analyses were used for comparisons of two groups.
Results. Twenty-eight patients with NSCLC invading the spine (aged
58.9±12.9 years) were identified at a single center. Eight of those patients
0464
Benefit from inpatient oncological – pulmonary rehabilitation in
lung cancer patients
sis and cancer progression, suggesting that DNA methylation analysis
may be a valuable source of biomarkers. Hypermethylation of SHOX2
in bronchial lavage has previously been shown in a case control study
with more than 500 patients to be a clinically useful tumor marker for
identifying subjects with lung carcinoma, especially if histological and
cytological findings after bronchoscopy are ambiguous. To facilitate the
use of SHOX2 DNA methylation in a diagnostic setting, the CE IVD
“Epi proLung BL Reflex Assay” was developed and the biomarker was
validated in an independent patient population.
Methods. The developed assay for measuring SHOX2 DNA methylation
in bronchial aspirates is based on two major steps: generation of bisulfite
converted template nucleic acids from patient samples followed by subsequent determination of SHOX2 biomarker methylation by real-time
PCR. Individual kits for DNA preparation, real-time PCR analysis and
work flow control were developed.
Results. The results describe the “Epi proLung BL Reflex Assay” as a
robust and reliable diagnostic tool for identifying patients with lung
cancer using Saccomanno-fixed bronchial lavage specimens (AUC [95%
CI]=0.95 [0.91–0.98], sensitivity 78% [69–86]/specificity 96% [90–99]).
Conclusions. The “Epi proLung BL Reflex Assay” allows for the accurate
analysis of SHOX2 DNA methylation in Saccomanno-fixed bronchial
lavage specimens from patients undergoing first-time bronchoscopy for
suspected lung cancer. The test result is indicated for use by physicians
as an aid in diagnosis of lung cancer adjunct to existing clinical and
pathological information.
*S. Korfee1, K. Wollina1, D. Grimmer1, J. Mehrholz1, B. Erdmann-Reusch1,
C. Lotze1
1
Klinik Bavaria Kreischa, Hämotologie/Onkologie, Kreischa, Deutschland
Lymphome/Leukämien/pädiatrische Tumoren
were inoperable at the time of diagnosis. Twenty patients underwent
resection with en bloc hemivertebrectomy (n=16) or total vertebrectomy (n=4). Induction chemotherapy was given to 6 patients (30%). Complete resection rate (R0) was achieved in 16 patients (80%). Morbidity
and mortality rates were 40% and 0%, respectively. Adjuvant radiation
(n=14) or chemoradiation (n=6) were administered with 66 Gy. The
mean survival was 46.0 months. Five-year survival for patients who
underwent surgery (n=20) was 47%. Inoperability was associated with
poorer survival (14.0 months; p=0.004). Sublobar resections (p=0.002)
and incomplete resections (p=0.02) were negative prognostificator. A
trend towards prolonged survival were observed in patients with adjuvant chemoradiation (p=0.088), hemivertebrectomy (p=0.062) and
age <70 years (p=0.076), respectively.
Conclusions. En-bloc lung resections with hemivertebrectomy or total
vertebrectomy offer promising long-term survival in highly selected
patients with NSCLC invading the spine within multimodality treatment concepts. Acceptable morbidity and mortality can be achieved in
these extended resections in specialized centers. Patients aged ≥70 years should be selected very cautiously for surgery. Sublobar resections
should be avoided whenever possible.
Introduction. Patients with lung cancer are often burdened by physical
and functional impairments. The major role of pulmonary rehabilitation in Lung Cancer patients is to improve their functional status. The
aim of this study was to investigate the impact of multidisciplinary pulmonary rehabilitation on pulmonary function, capillary blood gases
and general condition of lung cancer patients.
Methods. We analysed the data of 110 patients with local, local advanced
and metastatic lung cancer who received oncological pulmonary rehabilitation in our hospital retrospectively. Clinical symptoms und functional impairments were assessed. Pulmonary function tests (in 71 pts),
capillary blood gases (in 58 pts) and Karnofsky Indeces (in 109 pts) were
available from the beginning and the end of rehabilitation.
Results. A statistic significant improvement of parameters of capillary
blood gases (pO2 and SO2) and general condition (Karnofsky Indices)
were observed. Elderly patients (≥70 years) had results comparable to
the younger patients. No limitation of improvement of these parameters
was observed in patients with local advanced und metastatic disease.
Conclusion. Lung cancer patients benefit from inpatient oncological
pulmonary rehabilitation. These benefits are independent of age und
stage of disease.
0469
SHOX2 DNA methylation – a validated biomarker for detecting
lung cancer in bronchial aspirates
C. Ivascu1, *D. Dietrich1, J. Field2, V. Liebenberg3, B. Schmidt4, T. Schlegel1,
N. Flemming1, S. Rausch1, J. Distler1, M. Fleischhacker5, T. Liloglou2, O. Raji2
1
Epigenomics AG, R&D, Berlin, Deutschland, 2The University of Liverpool,
Department of Molecular and Clinical Cancer Medicine, Liverpool, UK, 3Metanomics Health GmbH, Berlin, Deutschland, 4Universitätsklinik und Poliklinik für Innere Medizin I, Halle, Deutschland, 5Charité –Universitätsmedizin,
Medizinische Klinik m.S. Hämatologie Onkologie, Berlin, Deutschland
Aims. DNA methylation plays an important role in fundamental biological processes such as development and cellular differentiation.
DNA methylation has been shown to play a major role in carcinogene-
0118
The assessment of physical activity in pediatric cancer patients
*C. Winter1, C. Müller1, M. Brandes2, A. Brinkmann1, C. Hoffmann3, J. Hardes4,
G. Gosheger4, J. Boos3, D. Rosenbaum1
1
Universitätsklinikum Münster, Funktionsbereich Bewegungsanalytik,
Münster, Deutschland, 2Universität, Sportwissenschaft, Oldenburg,
Deutschland, 3Universitätsklinikum Münster, Pädiatrische Hämatologie und
Onkologie, Münster, Deutschland, 4Universitätsklinikum Münster, Klinik
und Poliklinik für Allgemeine Orthopädie und Tumororthopädie, Münster,
Deutschland
Background. Recently, the importance of being physically active during
cancer treatment is well-recognized and an established part of additional care. This is especially true for adults but it is increasingly acknowledged in the treatment of childhood cancer. However, so far physical
activity (PA) has rarely been assessed and only self-reports were used
that are known to be inconsistent and subjective. In the present study
accelerometry was used to quantify PA adding precision and objectivity
to the measures. The purpose of the present study was to provide baseline data on the extent of activity restrictions, the influence of inpatient
treatment and the possible influence of cancer entity.
Methods. A total of 80 patients, 29 with bone tumor, 20 with leukemia,
15 with lymphoma and 12 with brain tumor as well as 45 healthy control subjects of comparable age were included in the study. Patients were
between 5 and 18 years of age an all undergoing cancer treatment. The
amount and intensity of PA were assessed using the StepWatch 3™ Activity Monitor, which is a uniaxial ankle-worn accelerometer. Both, inpatient stays and home-stays were recorded.
Results. Patients reached only 23% of the control group’s amount of
activity during inpatient stays and 40% during home-stays. At home
patients assembled 42% more steps than during inpatient stays. Patients with bone tumors were the least active group. Differences between
groups and settings are even greater considering the intensity of activity
were patients hardly show any activity on a moderate to high level of
activity.
Abstracts
Discussion. Patients undergoing cancer treatment experienced severe
reductions in their level of PA. Inpatient stays especially affected PA due
to being restricted on the ward. Patients with a bone tumor showed the
greatest limitations which is attributable to the consequences of surgery.
Patients were at an increased risk for sustained inactivity. Consequently patients being restricted to the ward and especially patients with a
bone tumor should receive special attention to prevent inactivity related
negative health effects. This baseline data emphasizes the need for interventions individually tailored to the patients’ well-being. While wellestablished in adult cancer treatment, this has not yet been sufficiently
taken into account in children. The method used in the study could be
an appropriate tool to compare different cancer entities, points in time
and the effects of intervention.
0207
Costs of Posaconazole compared to standard prophylaxis in patients with a high-risk of invasive fungal diseases: an economic
analysis from the Cologne Cohort of Neutropenic Patients
*S. Heimann1, O.A. Cornely1, H. Wisplinghoff2, M.J.G. Vehreschild1, B. Franke1,
J.-P. Glossmann1, J. Vehreschild1
1
Uniklinik Köln, Klinik I für Innere Medizin, Köln, Deutschland, 2Uniklinik
Köln, Institut für Medizinische Mikrobiologie, Immunologie und Hygiene,
Köln, Deutschland
Background. Prior trials have demonstrated efficacy and effectiveness
of posaconazole in the prophylaxis of invasive fungal diseases (IFD)
in high-risk patients. Controversy exists about the cost effectiveness of
posaconazole prophylaxis in neutropenic patients with a high risk of
invasive fungal diseases. We performed an analysis comparing the direct costs of posaconazole prophylaxis against topical polyene (thrush)
prophylaxis in patients with acute myelogenous leukemia (AML) and
myelodysplastic syndrome (MDS).
Methods. Data of AML/MDS patients receiving remission-induction
chemotherapy were extracted from the Cologne Cohort of Neutropenic
Patients to compare hospital costs of patients before (2003–2005) and
after (2006–2008) introduction of posaconazole prophylaxis. All cases
were part of an earlier analysis demonstrating effectiveness of posaconazole over topical prophylaxis [Vehreschild et al., J Antimicrob Chemother. 2010 Jul;65(7):1466–71]. Duration on general ward, intensive
care unit, mechanical ventilation, diagnostic procedures and all antiinfective drugs were included into the cost analysis.
Results. Patient groups were well matched according to age, gender,
underlying disease, and duration of neutropenia. The average costs per
patient in the posaconazole group (n=76) and the topical polyene group
(n=81) were 23,235 € (95% CI: 19,722–26,749 €) and 26,531 € (95% CI:
21,887–31,175 €) per patient, respectively. Average daily treatment costs
were 495 € (95% CI: 434–555 €) and 508 € (95% CI: 433–582 €). Antifungal treatment costs were nominally lower in the posaconazole group
(6,773 € [95% CI: 5,187–8,360 €] vs. 7,419 € [95% CI: 5,062–9,775 €]). The
costs for other anti-infectives were also numerically decreased in the
posaconazole group (4,845 € [95% CI: 4,019–5,671 €] vs. 5,402 € [95%
CI: 4,507–6,297 €]). Average duration of ICU stays were 1.79 (95% CI:
0.68–2.90) days per patient for the posaconazole group compared to 3.83
(95% CI: 1.53–6.13) days per patient in the topical polyene group. Costs
for diagnostic procedures were 611 € (95% CI: 478–744 €) and 653 € (95%
CI: 552–754 €) per patient, respectively.
Conclusions. In our hospital, there was a trend towards cost-saving by
posaconazole prophylaxis in patients receiving remission-induction
chemotherapy. These cost savings were demonstrated in all aspects taken into consideration, including overall treatment costs as well as cost
of anti-infective and antifungal medication.
0234
Bedeutung von CT-Größe und -Dichte (“size and attenuation
CT-SACT”) von residuellen Raumforderungen nach spezifischer
Therapie follikulärer Non-Hodgkin-Lymphome
*M. Horger1, D. Spira1
1
Eberhard-Karls-Universität Tübingen, Radiologie, Tübingen, Deutschland
Ziel. Evaluation der CT-Dichte-Ratio von residuellen Tumormanifestationen bei Patienten mit follikullären Non-Hodgkin-Lymphome (FL)
am Ende der Therapie verglichen mit den Ausgangsbefunden und Ermittlung deren prognostischer Bedeutung.
Material und Methodik. Es konnten retrospektiv über das hauseigene
digitale Datenarchiv im Zeitraum 2002–2010, 52 konsekutive Patienten
mit FL welche am Ende der Therapie noch residuelle Lymphommanifestationen beibehalten hatten und sich sowohl in der Primärdiagnostik als auch zum Therapieabschluss einer kontrastmittelangehobener
Ganzkörper-CT unterzogen hatten, identifiziert werden. Eine Schwächungsratio, definiert als Quotient von CT-Dichte zwischen Tumor und
umliegender Muskulatur (HU) wurde anschließend für beide Zeitpunkte berechnet. Die Größe der analysierten Lymphommassen wurde
als Produkt von Länge und Breite dieser Befunde registriert. 28 von 52
Patienten wurden dann im weiteren Verlauf über ≥2 Jahre nach Therapieabschluss kontrolliert und die Ergebnisse mit dem rezidivfreien
Intervall korreliert.
Ergebnisse. AR und Tumorgröße nahm signifikant ab im Vergleich Ausgang- zu Endtreatment-Untersuchung bei Respondern (n=51; p<0,05).
Eine Zunahme sowohl von AR als auch Größe wurde im Gegenteil in
Fällen von Frührezidive oder bei Non-Respondern registriert (n=10;
p<0,05). 8 von 28 Patienten sprachen zunächst auf die Therapie an, entwickelten jedoch ein Rezidiv innerhalb der nächsten 2 Jahre. Die mittlere Dauerzeit bis zum Rezidiv betrug 13,5 Monate (Spanne: 5–24 Monate). AR gemessen zum Zeitpunkt der letzten Kontrolle präsentierte
sich signifikant niedriger bei Patienten die im weiteren Verlauf ≥2 Jahre
stabil blieben (n=20) verglichen mit Patienten die in diesem Zeitraum
rezidivierten (n=8; p<0,05). Für eine AR≥1 zum Zeitpunkt der letzten
CT-Kontrolle die Spezifität und Sensitivität für ein Rezidiv innerhalb
von 2 Jahren erreichte 85%, respektive 63%.
Schlussfolgerung. CT-Dichtemessungen von residuellen Lymphommanifestationen bei Patienten mit FL am Abschluss der Therapie ist hilfreich für die Risikostratifizierung eines Frührezidives innerhalb der
nächsten 2 Jahre.
0253
Value of medical information for children on the web
*A. Winkel1, F. Ückert1
1
Institut für medizinische Informatik, Internettechnologie, Münster,
Deutschland
Background. Every year, approximately 1800 German children contract
cancer. Meanwhile, the internet is established as an easy accessible source of information. Thus, especially as far as serious diseases are concerned, the importance of the internet as source of information rises every
day. The aim of this study is to examine how children suffering from
cancer and their families acquire information on their respective diseases. In addition, the study focuses on the requirements which an online
presence has to fulfil and to what extend “KONI” met these demands.
Methods. We contacted paediatric-oncologic patients in written form –
at the date of the interview aged eight to fourteen – who underwent treatment in the years between 1994 and 2006 and their parents. The participants were asked about their use of the internet and their demands
on web based information on paediatric-oncologic diseases. 63 children
and 63 parents paticipated in the interview. In a second, web based survey, we evaluated to what extend the demands mentioned above were
met. 64 children and 149 adults took part in the second survey.
Discussion. In the surveys part of this study, children and adults as well
stated they had an enormous interest in finding further information on
the disease they were confronted with. Furthermore, data from various
other studies of the past indicates the existence of two facts about patient orientated health education to keep in mind: First of all, the internet as a source of growing importance as provider of health-related information. Second, the difficulties of lay people, especially children, to
comprehend texts including high quality medical information. “KONI”
and its design can be an online-presence solving the difficulties resulting from these two facts.
Conclusion. For the benefit of children of the enormous potential of the
internet as a source of information it is of tremendous importance to
enable them to understand the content. Therefore, it is very important
to design web pages eligible for youth. KONI can be a website meeting
this expectation.
0302
Durable complete remissions in a pivotal phase 2 study of SGN35 (brentuximab vedotin) in patients with relapsed or refractory
Hodgkin lymphoma (HL)
*A. Younes1, A.K. Gopal2, S.E. Smith3, S.M. Ansell4, J.D. Rosenblatt5, K.J. Savage6, J.M. Connors6, A. Engert7, E.K. Larsen8, D.A. Kennedy8, E.L. Sievers8,
R. Chen9
1
University of Texas, MD Anderson Cancer Center, Houston, USA, 2University of Washington, Cancer Research Center, Seattle, USA, 3Loyola University,
Medical Center, Maywood, USA, 4Mayo Clinic, Rochester, USA, 5University,
Miami, USA, 6BC Cancer Agency, Center for Lymphoid Cancer, Vancouver,
Kanada, 7University Hospital, Cologne, Deutschland, 8Seattle Genetics, Inc.,
Bothell, USA, 9City of Hope National Medical Center, Duarte, USA
Introduction. CD30 expression by Reed-Sternberg cells is a defining feature of HL. SGN-35 comprises an anti-CD30 antibody conjugated by a
plasma-stable linker to the potent antimicrotubule agent, monomethyl
auristatin E (MMAE). SGN-35 selectively induces apoptotic death of
CD30+ cells by binding, internalizing, and releasing MMAE.
Methods. A pivotal, phase 2, single-arm, multicenter study evaluated the efficacy and safety of SGN-35 in patients (pts) with relapsed
or refractory HL after autologous stem cell transplant (auto-SCT). Pts
received SGN-35, 1.8 mg/kg q3 weeks (wks) as a 30-min. outpatient IV
infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per an independent review facility (IRF) according
to Cheson 2007.
Results. 102 pts were enrolled; 53% female, median age was 31 yrs (range
15–77). Pts had received a median of 3.5 (range 1–13) prior systemic therapies excluding auto-SCT. 71% of pts had primary refractory disease and
42% had not responded to their most recent prior therapy. ORR per IRF
was 75% (76 of 102 pts) with complete remissions (CRs) in 34% of pts
(n=35). At the time of database lock (August 2010), median duration of
follow up from first dose was approx. 9 months (for responders). Median
duration of response for pts with CR per IRF has not yet been reached
(range 0.3+ to 61.4+ wks); follow up continues and 6+ months of additional data will be available for presentation. Treatment-related AEs of any
grade in ≥15% pts were peripheral sensory neuropathy, nausea, fatigue,
neutropenia, and diarrhea. AEs ≥ grade 3 in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia.
Conclusions. With manageable AEs, single-agent SGN-35 induced objective responses in 75% of pts with relapsed or refractory HL. In this
heavily pretreated population, 35 of 102 pts (34%) achieved a durable CR,
with more than 65% of pts remaining in CR.
0312
Molecular monitoring, response and adherence to treatment
in outpatients with chronic myeloid leukemia in chronic phase
(CML-CP) treated with imatinib: 42-month follow-up results of a
non-interventional study
*H. Tesch1, M. Welslau2, C. Spohn3, K. Blumenstengel4, U. von Verschuer5
1
Onkologische Gemeinschaftspraxis am Bethanien Krankenhaus, Frankfurt/M, Deutschland, 2Onkologische/Diabetologische Gemeinschaftspraxis Klausmann/Welslau, Aschaffenburg, Deutschland, 3Onkologische
Gemeinschaftspraxis, Halle, Deutschland, 4Onkologische Gemeinschaftspraxis, Eisenach, Deutschland, 5Onkologische Gemeinschaftspraxis, Essen,
Deutschland
The availability of imatinib has changed the treatment paradigm in
CML. Long-term benefits from imatinib in terms of overall survival,
increasing response and decreasing disease progression have been confirmed by data from the 7-year update of the phase III IRIS (International Randomized Study of Interferon vs STI571). However, good patient
adherence is mandatory to achieve maximal treatment benefit and to
avoid imatinib resistance. Estimation of BCR-ABL transcript levels by
quantitative polymerase chain reaction (qPCR) is the method of choice for monitoring therapeutic efficacy and prognosis. The aim of this
non-interventional study was to evaluate molecular response of patients
with CML-CP by qPCR with respect to adherence during treatment
with imatinib. A total of 514 outpatients from 56 centers, mainly hematology/oncology practices and outpatient clinics were included. Patients
received imatinib according to the prescription information and physician‘s decision. 4.1% of the patients belonged to the high risk, 42.7% to
the intermediate risk and 41.8% to the low risk group (Hasford prognostic score). Molecular monitoring was performed in 91.3% of the patients.
Major molecular response (BCR-ABL transcript reduction >3 log), was
observed in 34.5% of the patients, no BCR-ABL transcripts at all were
detected in 50.1%, and a minor molecular response <3 log was observed in 8.0% of the patients. Since almost all patients were molecularly
monitored, cytogenetic monitoring was performed in only 38.6% of the
patients of whom 74.0% reached complete and 13.6% partial cytogenetic
response. In parallel with molecular response, treatment adherence rate
was high with 99.3% of the patients adhering to the prescribed medication. Accordingly, plasma imatinib levels were within or above the
therapeutic range in 88.2% of the patients who had been tested (n=34).
In general, patients showed good tolerance to imatinib consistent with
the known tolerability profile. 59.6% of the patients did not report any
adverse effects. Main side effects were edema, anemia, and gastrointestinal complaints. In conclusion, the 42-month follow-up of this non-interventional study further highlights the value of molecular monitoring
as a standard procedure also for outpatient care. Patients with CML-CP
demonstrate high treatment adherence that translates into a molecular
response comparable to that in clinical studies.
0313
Monitoring of deferasirox treatment in patients with transfusion-dependent iron toxicity due to myelodysplastic syndromes:
correlation of serum ferritin with liver iron concentration noninvasively determined by MRI
*H. Tesch1
1
Onkologische Gemeinschaftspraxis am Bethanien Krankenhaus, Frankfurt/M, Deutschland
Iron toxicity damages various tissues and organs such as liver, heart
and pancreas. In Germany, myelodysplastic syndromes (MDS) are the
leading cause for transfusion-dependent iron toxicity. Liver iron concentration (LIC) has been shown to reflect total body iron burden. The
aim of the present non-interventional study is to monitor iron toxicity
during iron chelation therapy with deferasirox and to analyze the acceptance and feasibility of LIC monitoring by MRI in everyday practice
Abstracts
in MDS patients with transfusion-dependent iron overload. The study
is currently being conducted in approx. 100 hematology/oncology institutions in Germany. Patients are being treated with deferasirox according to established guidelines and the prescribing information.
Iron overload is assessed by serum ferritin measurement as well as by
MRI-LIC determination if routinely performed. Moreover, the number
of blood transfusions, co-medication, safety and efficacy of deferasirox
as well as adherence to treatment are assessed. For patients, in whom
no bone marrow biopsy is performed, cytogenetic analysis of CD34+
cells from peripheral blood can be requested at a reference institution.
Patients are evaluated before starting therapy and after about 3, 6, 9,
12, 18, and 24 months of treatment. Between March 2010 and the first
interim analysis with data cut-off in May 2011 82 of 250 planned patients
were prospectively enrolled. Mean patient age was 73.9±10.0 years. Median serum ferritin levels before treatment were 1751±1483 ng/ml. Most
patients were classified as IPSS low (15%) or intermediate 1 (29%). Median deferasirox dose was 135±590 mg/day. Further data from the first
interim analysis will be presented. These data will reflect medical care
of MDS patients in Germany with respect to the monitoring of iron
chelation therapy and may provide evidence for a potential role of LIC
determination by MRI.
0334
Physical performance status as independent predictor for cancer-related fatigue and physical functioning in allogeneic stem
cell-transplanted patients
*D. Vandenbergh1, M. Bohus2, P. Dreger3, R. Schwerdtfeger4, D. Jäger5,
C. Ulrich1, N. Rea1, J. Wiskemann5,1
1
National Center for Tumor Diseases (NCT) and German Cancer Research
Center (DKFZ), Heidelberg, Preventive Oncology, Heidelberg, Deutschland,
2
Central Institute of Mental Health, Mannheim, Deutschland, 3University
Clinic Heidelberg, Department of Hematology, Oncology, and Rheumatology, Heidelberg, Deutschland, 4German Clinic for Diagnostic, BMT Unit,
Wiesbaden, Deutschland, 5National Center for Tumor Diseases (NCT) and
University Clinic Heidelberg, Medical Oncology, Heidelberg, Deutschland
Introduction. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a medical treatment with many and severe side effects. Nevertheless, for many patients with hematologic malignancies it is the last
and only chance for cure. Due to the malignancy itself and prior treatment many patients have already impairments in physical functioning
when the transplantation process starts [Morishita et al. 2011 (1)]. Moreover patients suffer from Cancer-Related Fatigue (CRF) and an even
further reduced physical functioning after being transplanted [Hacker
et al. 2006(2)]. We hypothesized that reduced physical performance before allo-HSCT is an independent predictor for patients’ physical functioning (PF) and their CRF status 6–8 weeks after transplantation.
Methods. We evaluated the physical performance status of n=60 patients. We used the 6 min walk distance (6 MWD) as a marker for the
patients’ cardiovascular fitness. Arm strength (elbow flexors and extensors, shoulder abductors) and leg strength (hip abductors and flexors,
knee flexors and extensors) were measured using a Hand-Held-Dynamometer and were jointly used to calculate a general Force Index (FI).
CRF and physical functioning were evaluated using subscales of the
EORTC-QLQ-C30 quality of life questionnaire. For regression analyses
we defined 6 MWT and FI as independent variables and CRF and PF as
dependent variables. p-values <0.05 were considered significant.
Results. We observed that measured physical performance can explain
32% of variance of questionnaire-assessed physical functioning with a
significant p-value for the 6 MWD (p=0.002), but not for strength tests.
Using 6 MWD and FI as individual, independent predictors explained
less variance (6 MWT R2=0.29, FI R2=0.20) but both were statistically
significant (6 MWD p<0.001, FI p<0.001). Up to 24% of CRF variance
can be explained by physical performance measures, most significantly
so by FI (p=0.009). Again both 6MWD and FI were significant indepen-
dent predictors, but explained less variance (6 MWD R2=0.11 p=0.012,
FI R2=0.23, p<0.001).
Discussion. The results support the hypothesis that the physical performance of patients prior to allo-HSCT is a predictor for important
subjective outcomes after allo-HSCT. The finding that physical functioning is more influenced by cardiovascular fitness and fatigue more by
muscular strength supports the importance of both, aerobic training
and strength training, for patients undergoing allo-HSCT even prior to
treatment begin.
1. Morishita S et al (2011) Impaired physiological function and healthrelated QOL in patients before hematopoietic stem-cell transplantation.
Support Care Cancer [Epud ahead of print]
2. Hacker ED et al (2006) Fatigue and physical activity in patients
undergoing hematopoietic stem cell transplant. Oncol Nurs Forum
33(3):614–24
0335
Fatigue in patients prior to allogeneic stem cell tranplantation. Is
there utility for exercise interventions?
*R. Nies1, M. Bohus2, P. Dreger3, R. Schwerdtfeger4, D. Jäger5, C. Ulrich1,
G. Huber6, J. Wiskemann1,5,
1
National Center for Tumor Diseases (NCT) and German Cancer Research
Center (DKFZ), Devision of Preventive Oncology, Heidelberg, Deutschland,
2
Central Institute of Mental Health, Mannheim, Deutschland, 3University
Clinic, Heidelberg, Deutschland, 4German Clinic for Diagnostic, Wiesbaden,
Deutschland, 5National Center for Tumor Diseases (NCT) and University
Clinic, Devision of Medical Oncology, Heidelberg, Deutschland, 6Institute
for Sports und Sport Science, University, Heidelberg,Deutschland
Objects. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is used in patients with hematologic malignant diseases. After a
high-dose chemotherapy patients receive stem cells from a histocompatible donor to replace the malignant hematopoietic system. Treatment
related side-effects and complications like fatigue and loss of physical
performance affect patients’ quality of life negatively. These side-effects
even occur before transplantation. A theoretical model tries to explain
the complex and multidimensional relationship between the multifactorial fatigue symptom and a possible modulation via exercise. It shows
that hypothetical causes including biological (e.g. loss of muscle mass
and anemia), functional (e.g. loss of functional capacity), and psychobehavioral (e.g. distress und sleep disturbances) can possibly be influenced by exercise [1].
Results. To investigate a possible modulation we used data from our randomized controlled trial [2]. N=96 patients prior to allo-HSCT could be
included in this analysis. Patients were between 18 and 71 years old (median age 49 years), 68% of the population was male and 32% female. 74%
of all patients reported mild to strong fatigue already before allo-HSCT.
General fatigue was significantly correlated with physical functioning
(r=−0.69), pain (r=0.48), insomnia (r=0.41), distress (r=0.49), endurance capacity (r=−0.36) and muscle strength (r=−0.26) (all p<0.01). When
performing a regression analysis, physical functioning, distress and depression could explain 58% of the variance of general fatigue (p<0.001).
Further, endurance capacity, pain, insomnia and hemoglobin level
could explain 54% of the variance of physical functioning (p<0.001).
However, anxiety and muscle strength seemed to have no direct influence on physical functioning, despite a significant medium range correlation between muscle strength and physical functioning (r=0.41) and
muscle strength and endurance capacity (r=0.52).
Conclusion. This data shows that already before transplantation patients
suffer from fatigue, which might be an indication for exercise training
prior to allo-HSCT. Our results suggest that fatigue could be influenced
indirectly by exercise by improving physical functioning and related
parameters.
1. Al-Majid S, Gray D (2009) A biobehavioral model for the study of exercise
interventions in cancer-related fatigue. Biol Res Nurs 10:381–91
2. Wiskemann J et al (2011) Effects of a partly self-administered exercise
program before, during and after allogeneic stem cell transplantation. Blood
117:2604–13
0417
High serum-free light chain levels correlate with the poor prognostic cytogenetic aberration del(17)(p13) in multiple myeloma
patients
*S. Janjetovic1, E.M. Murga Penas1, P. Behrmann1, C. Bokemeyer1, G. Schilling1
1
Universitätsklinikum Eppendorf, Hämatologie-Onkologie, Hamburg,
Deutschland
Multiple myeloma (MM) is a monoclonal B-cell malignancy characterized by terminally differentiated plasma cells and monoclonal
immunoglobulin secretion in the majority of cases. Cytogenetics is
an important tool to estimate prognosis in this disease. Recently developed serum-free light chain (SFLC) assay has proved invaluable in
case of light-chain-secreting MM and in a proportion of patients with
non-secretory disease. It has been previously demonstrated that high
serum-free light chain levels define an aggressive MM subtype with
poor prognosis and are associated with higher levels of LDH and β2 microglobulin, as well as higher plasma cell bone marrow infiltration (van
Rhee et al. 2007).
In order to investigate whether cytogenetic changes correlate with SFLC
levels in patients with newly diagnosed MM, we compared the SFLC
levels of 35 patients with their cytogenetic findings done by fluorescence
in situ hybridization (FISH).
The cut off value for “high” SFLC levels was fixed at 75 mg/dL, as previously described (van Rhee et al. 2007). We identified a SFLC baseline
level higher than 75 mg/dL in 12 out of 35 patients (34%), with the highest
level being 2741,7 mg/dL. The remaining 23 patients showed SFLC levels
between 60 and 0.1 mg/dl and, therefore, constituted our control group
with low SFLC.
The most common cytogenetic aberration in both groups was 13q14 deletion, found in 17 out of 35 analyzed patients (49%). Six deletions were
found in group with high SFLC (50%) and 11 deletions in lower SFLC
group (48%). Interestingly, we detected deletion 17p13 (TP53) in 2 patients both of them showing SFLC level higher than 75 mg/dL (2741.7
and 402.2 mg/dL respectively), but none in patients in “low level” group.
TP53 deletion is known to be an adverse prognostic factor in MM associated with a poor prognosis and refractoriness to conventional
chemotherapy, allogenic stem cell transplantation, and, so called, new
substances.
In this study we found that only patients with SFLC levels higher than
75 mg/dL exhibit the negative prognostic deletion of 17p13, whereas the
neutral deletion 13q14 was detected in both groups with the same frequency.
Our results point to a correlation between the negative prognostic deletion of the tumour suppressor gene TP53 and high SFLC levels. Further
investigations on larger patient cohorts are needed to confirm our interesting findings.
0476
Survival of Non-Hodgkin’s lymphoma patients in Germany
D. Pulte1,2, *L. Jansen1, A. Gondos1, B. Holleczek3, A. Katalinic4, H. Brenner1,5
1
Deutsches Krebsforschungszentrum (dkfz), Klinische Epidemiologie und
Alternsforschung, Heidelberg, Deutschland, 2Thomas Jefferson University, Division of Hematology, Philadelphia, Deutschland, 3Krebsregister
Saarland, Saarbrücken, Deutschland, 4Krebsregister Schleswig-Holstein,
Lübeck, Deutschland, 5GEKID Cancer Survival Working Group, Deutschland
Background. Non-Hodgkin’s lymphoma (NHL) is the most common hematologic cancer in adults. Recent advances in treatment of NHL have
led to improved survival both in clinical trials and on the population
level. Previously, in Germany data on population-level changes in survival was restricted to data from the Saarland cancer registry. Our study is
based on survival data provided by 11 population-based German cancer
registries covering 33 million people (40% of the population). This data
set allowed a detailed analysis of survival of German NHL patients by
major age groups and sex.
Methods. Patients diagnosed with NHL (ICD-10: C82–C85) in 1997–
2006 were included in the analysis. Period analysis was used to calculate
5-year relative survival estimates overall and by sex and age at diagnosis
(15–49, 50–54, 55–59, 60–64, 65–69, 70–74, 75+ years) for the time period 2002–2006. Trends in relative survival between 2002 and 2006 were
estimated by model-based period analysis. Relative survival estimates
for Germany and the United States (US) were compared using the Surveillance, Epidemiology, and End Results (SEER13) database.
Results. Overall age-standardized 5-year relative survival for NHL patients in Germany in 2002–2006 was 62.8%. Survival decreased strongly
with age from 81.7% at age 15–49 to 46.5% at age 75+. Women had a better
prognosis overall and in each age group. Survival significantly increased between 2002 and 2006 by 5.3 percent units (% units). This increase
can mainly be attributed to improvements in survival for patients aged
60–74 years. No increase was observed for the age groups 15–49 and 75+.
In the US, overall age-standardized 5-year relative survival was slightly
higher (65.1%) as a result of better survival of patients aged 65+ in the US
(+4.4 to +6.1% units). Patients aged 50–64 had comparable prognosis in
the US and in Germany, whereas patients aged 15–49 had a 6.6 % units
higher 5-year relative survival in Germany.
Conclusion. Our results show that age-standardized 5-year relative survival of NHL patients in Germany and in the US is comparable. However, patients aged 65+ had lower survival rates in Germany than in the
US. While the difference for patients aged 65–74 may decrease over time
as the prognosis of patients in this age group improved strongly between 2002 and 2006, no improvement was observed for patients aged
75+. These results suggest that greater focus on treatment of NHL in the
oldest patient group in Germany may be needed.
0015
Breast self-examination (BSE) in post treatment surveillance
after breast cancer: a prospective study
*J. Johannsen-Wrana1, H.J. Hamm1,2
Allg. med. Praxis Bachmann, Sylt OT Westerland, Deutschland, 2UK-SH,
Campus Kiel, medizinische Fakultät, Kiel, Deutschland
1
Introduction. Breast cancer is the most frequent tumor among women
in Germany, accounting for about 28% of all female cancer cases. Breast
self-examination (BSE) is an important part of breast cancer detection.
Many patients after surgery are reluctant to practice BSE because of
personal, cognitive, emotional and health-care provider factors. This
prospective consecutive two-arm study was conducted to investigate
Abstracts
the performance of BSE in rehab patients with or without a targeted
education program.
Methods. 1521 patients between the age of 30 and 75 were included in
the study. From September 2009 to September 2010, they were asked to
fill out a standardized self-report questionnaire about their use of BSE
before diagnosis, at the beginning of rehabilitation, after rehabilitation
and six month after rehabilitation. The last questionnaire asked for any
profit of the BSE-training and if they practice BSE or not. Patients were
divided into three groups. Group I (n=487) performed a classical S3-guideline-breast cancer-rehab, group II (n=534) was additionally educated
in BSE in theory and was offered the possibility to practice BSE with
educated physiotherapists. Group III (n=500) received the normal rehab
program and served as a wash-out-group between study groups.
Results. At the end of rehab in group I 61.3% reported to perform BSE regularly, 24.7% sometimes and 13.9% never. In group II 69.9% reported to
perform BSE regularly, 21.5% sometimes and 8.6% never. A questionnaire six month after rehab was answered by 789 patients (77.30% response
rate, 789/1021). Group I reported to perform BSE 55.8% regularly, 29.7%
sometimes and 14.5% never. Group II reported to perform BSE 53.8%
regularly, 35.5% sometimes and 10.8% never. 84.4% of group II reported
a profit regarding BSE while 41.1% did so in group I.
Conclusion. In this study, patients after breast cancer therapy reported a
significant profit after an education-program for BSE during rehabilitation in comparison to a control group undergoing a standard rehab program. However, the program promoted the performance of BSE only to
a small extent. We speculate that the questionnaire itself may have had
a positive impact on BSE performance. Further research is needed to
evaluate the quality of BSE after our program and the long-term adherence of the women to the procedure. Additionally, it would be of interest
to show if such a program would have an impact on morbidity and/or
mortality of breast cancer patients.
0024
The ProBone study: influence of zoledronic acid on bone mineral
density in premenopausal women with breast cancer and neoadjuvant or adjuvant chemotherapy and/or endocrine treatment
*P. Hadji , A. Kauka , T. Bauer , M. Kalder , U.-S. Albert , K. Birkholz , M. Baier ,
M. Muth2, M. Ziller1
1
Philipps-University of Marburg, Department of Gynecology, Endocrinology and Oncology, Marburg, Deutschland, 2Novartis Pharma GmbH, BU
Oncology, Nürnberg, Deutschland
1
1
1
1
1
2
2
Background. Based on baseline bone mineral density (BMD), adjuvant
chemotherapy (CT) or endocrine therapy (ET) for early breast cancer
(BC) patients (pts) can lead to substantially increased osteoporotic
fracture risk. After 2 years of CT and/or ET, a significant decrease of
BMD has been reported. In recent studies (e. g. ABCSG-12, Z-FAST,
ZO-FAST), the treatment of pts with zoledronic acid (ZOL) led to an
increase in BMD in premenopausal and postmenopausal pts with BC.
In addition, a significant increase in disease-free survival (DFS) with
ZOL versus no ZOL was observed in most of these studies.
Methods. The aim of 2 single-center, placebo-controlled, randomized
studies – Probone I and II – was to investigate the effect of adjuvant
treatment with ZOL on BMD in premenopausal women with early BC
treated with CT and/or ET. Pts with hormone-receptor-negative (HR-)
BC (ProBone I) were treated with (neo)adjuvant CT; pts with hormonereceptor-positive (HR+) BC (ProBone II) were treated with adjuvant ET
alone or in combination with (neo) adjuvant CT. Pts received ZOL 4 mg
or placebo IV every 3 months for 24 months. The primary objective was
the change in BMD at the lumbar spine between baseline and month
24 (measured by DXA). Secondary objectives included metastasis-free
survival; BMD at total hip; QUS at os calcis and phalanges; markers of
bone turnover (e.g. CTX and P1NP); endocrine hormones (e.g. FSH, estradiol, testosterone, SHBG, PTH, vitamin D, AMH, inhibin A/B, etc.);
pathologic fractures; safety and tolerability.
Results. 71 HR+ and 11 HR-BC pts have been enrolled into the studies at
1 site. The last patient will have been treated for 24 months by the end of
June 2011. The results of the primary and secondary endpoints will be
presented at the meeting.
Conclusion. The results of the ProBONE studies will provide information regarding the efficacy of ZOL in the prevention of bone loss in premenopausal women under CT or ET. Furthermore, the analysis of bone
markers will provide insights in bone metabolism and the evaluation
of several endocrine hormones could contribute important findings on
the relationship between the hormone status and the course of bone
markers with or without ZOL. Therefore, important findings could be
obtained for the growing number of young BC survivors who will enter
menopause early and experience a prolonged period of estrogen deficiency and an increased long-term fracture risk due to cancer treatment.
0026
Reduced HFSR incidence observed in a randomized phase II study in advanced breast cancer patients treated with sorafenib and
paclitaxel by initial ramp-up dose escalation (PASO)
*F. Overkamp1, C.-C. Steffens2, W. Abenhardt3, C. Lerchenmüller4, A. Nusch5,
T. Göhler6, M. Groschek7, S. Hegewisch-Becker8, N. Marschner9, S.B. Rösel10,
C. Salat11, T. Decker12
1
Oncologianova GmbH, Recklinghausen, Deutschland, 2Schwerpunktpraxis
Hämatologie/Onkologie, Stade, Deutschland, 3Münchner Onkologische
Praxis, München, Deutschland, 4Hämatologisch-Onkologische Gemeinschaftspraxis, Münster, Deutschland, 5Praxis für Hämatologie und internistische Onkologie, Velbert, Deutschland, 6Onkologische Gemeinschaftspraxis, Dresden, Deutschland, 7Onkologische Gemeinschaftspraxis, Würselen,
Deutschland, 8Onkologische Schwerpunktpraxis, Hamburg, Deutschland,
9
Praxis für interdisziplinäre Onkologie & Hämatologie, Freiburg i. Br.,
Deutschland, 10Onkodok, Gütersloh, Deutschland, 11Gemeinschaftspraxis f.
Innere Medizin, Hämatologie und Int. Onkologie, München, Deutschland,
12
Onkologie Ravensburg, Ravensburg, Deutschland
Introduction. Breast cancer is the most common malignancy among
women in Germany and despite some therapeutic progress still challenging in the metastatic stage. The importance of the VEGF pathway
was recently discovered and clinically verified in terms of prognosis.
Sorafenib (Sor) is a multi-targeted inhibitor for several tyrosine and serine/threonine protein kinases including VEGF, PDGF, cKIT and Raf.
Sor showed a considerable efficacy in three phase II trials in advanced
breast cancer (aBC) in combination with paclitaxel (pac), capecitabine
(cap) and gemcitabine (gem). The side effect profile seems manageable
and clinically safe but an improvement in terms of hand foot skin reaction (HFSR) remains desirable. A phase II trial was planned by the
AIO study group sponsored by GMIHO to investigate a combination
of sor with pac vs. pac monotherapy including an initial ramp-up dose
escalation in patients with aBC.
Patients and methods. The study will recruit 140 pts with aBC due for
second or third line cytostatic treatment in 30 AIO centers. The pts
are randomized to weekly 80 mg/m2 pac in combination with 400 mg
sor bid in treatment cycles of 4 weeks or applied as monotherapy until
progression or intolerable side effects. Dose modifications or temporary discontinuation are carried out in case of severe side effects for sor
and pac according to protocol. A ramp-up dose escalation scheme is
implemented starting with 400 mg/day for the first, 600 mg/day for the
second cycle and 800 mg/day as a continuous treatment starting with
the third cycle.
Results. The first safety analysis after 20 pts treated for at least two cycles
in June 2011 showed a side effect profile comparable with known data
from pac and sor. The overall incidence of HFSR in the sor+pac group
was found as previously published with 5/10 pts showing a HFSR of any
CTCAE grade but the incidence of grade 3 HFSR was surprisingly low
with only 2/10 pts (20%).
Conclusions. The incidence of grade 3 HFSR seems to be remarkably low
despite the early stage of our trial comparing our results with data for
sor + cap (Baselga et al., ESMO 2009; 89% all grade and 45% grade 3), for
sor + pac (Gradishar et al., SABCS 2009; 55% all grade and 30% grade 3)
and for sor + gem (Hurdis et al., ASCO 2011, 39% grade 3). The used
ramp-up dose escalation for sor seems promising. The study will be
continued as planned to confirm the reduction in HFSR using the new
dose scheme and determine the efficacy for the sor + pac combination
in pts with aBC.
0039
Fibroblast growth factor receptor 4 gene (FGFR4) 388Arg allele
predicts prolonged survival and platinum sensitivity in advanced ovarian cancer
*F. Marmé1, T. Hielscher2, S. Hug1, S. Bondong3, R. Zeilinger4, D. CastilloTong4, J. Sehouli5, I. Braicu5, I. Vergote6, I. Cadron6, S. Mahner7, C. Sohn1,
A. Schneeweiss1, P. Altevogt3
1
Universitätsklinikum Heidelberg, Frauenklinik, Heidelberg, Deutschland,
2
Deutsches Krebsforschungszentrum (DKFZ), Biostatistik, Heidelberg,
Deutschland, 3Deutsches Krebsforschungszentrum (DKFZ), Translationale
Immunologie, Heidelberg, Deutschland, 4General Hospital of Vienna,
Ludwig Boltzmann Cluster Translational Oncology, Wien, Österreich, 5Universitätsmedizin Berlin, Charité Campus Virchow Klinikum, Department
of Gynecology, European Competence Center for Ovarian Cancer, Berlin,
Deutschland, 6Universitaire Ziekenhuizen Leuven, Katholieke Universiteit
Leuven, Division of Gynaecological Oncology, Department of Obstetrics
and Gynaecology, Belgium, Belgien, 7Universitätsklinik Hamburg Eppendorf, Gynäkologie und Geburtshilfe, Hamburg, Deutschland
Background. FGFR4 has been shown to play an important role in the
etiology and progression of solid tumors. A single nucleotide polymorphism (SNP) within the FGFR4 gene has previously been linked
to prognosis and response to chemotherapy in breast cancer and other
malignancies. This study evaluates the relevance of this SNP in advanced ovarian cancer.
Patients and methods. FGFR4-genotype was analyzed in 236 patients
recruited as part of the OVCAD project. Genotyping was performed on
germ-line DNA using a TaqMan based genotyping assay. Results were
correlated with clinicopathological variables and survival.
Results. The FGFR4 388Arg genotype was significantly associated with
prolonged progression-free and overall survival (univariate: HR 0.68,
p=0.017; HR 0.49, p=0.005; multivariate: HR 0.69, p=0.025; HR 0.49,
p=0.006) though the positive prognostic value was restricted to patients
without post-operative residual tumor. Indeed, there was a significant
interaction between FGFR4 genotype and tumor rest for overall survival. Furthermore, the FGFR4 388Arg genotype significantly correlated
with platinum sensitivity in the same subgroup (multivariate OR 3.81,
p=0.004).
Conclusion. FGFR4 Arg388Gly genotype is an independent and strong
context specific prognostic factor in patients with advanced ovarian
cancer and could be used to predict platinum-sensitivity.
0045
An epidemiological prospective cohort study with Fulvestrant
and Exemestane in postmenopausal patients with advanced
HR+ breast cancer under real-life conditions in Germany: The
ACT-FASTER study
*H. Tesch1, B. Bruno2, W. Greiner3, H. Ostermann4, K. Possinger5, S. Zaun6,
N. Maass2
1
Onkologische Gemeinschaftspraxis, Frankfurt, Deutschland, 2Universitäts-Frauenklinik, Aachen, Deutschland, 3Universität Bielefeld, Fakultät für
Gesundheitswissenschaften, Bielefeld, Deutschland, 4Klinikum Großhadern
der Ludwig-Maximilians-Universität, Medizinische Klinik und Poliklinik III,
München, Deutschland, 5Charité, Medizinische Klinik mit Schwerpunkt
Onkologie und Hämatologie, Berlin, Deutschland, 6AstraZeneca, Medizin,
Wedel, Deutschland
Introduction. With the introduction of aromatase inhibitors followed
by fulvestrant as endocrine treatments for ER+ postmenopausal (PMP)
women with advanced breast cancer (ABC), sequential endocrine treatment has become the clinical standard of care in this setting (unless
disease is acutely life threatening; see AGO guidelines). Fulvestrant
500 mg (2×250 mg i.m. days 0, 14, 28, then monthly) was approved in
March 2010 for ER+ ABC in PMP patients, and both fulvestrant and
exemestane are approved post antiestrogen treatment in this setting.
ACT-FASTER aims to generate data on the use of fulvestrant 500 mg
and exemestane under real-life conditions with a focus on the use of
fulvestrant in different treatment lines.
Methods. ACT-FASTER is a prospective non-interventional cohort study sponsored by AstraZeneca Germany (ClinTrials ID: NCT01171417).
It is planned to enrole 660 PMP women with ER+ ABC at approx.
40 breast clinics and 100 office-based gynaecologists/oncologists. Data
on clinical characteristics, clinical outcome, epidemiological and pharmacoeconomic parameters of treatment with fulvestrant 500 mg or exemestane under real-life conditions in Germany will be collected. The
two co-primary objectives are, firstly, for patients receiving fulvestrant,
to compare the time to progression (TTP) as a function of the line of
treatment (i.e. 1st- vs. 2nd- vs. 3rd-line), and secondly, for all patients, to
collect and explore real-life data on the epidemiology and management
of patients receiving fulvestrant or exemestane for ER+ ABC, including
tumour characteristics, data on co-morbidities and treatments received. Secondary endpoints are effectiveness endpoints, pharmacoeconomic data (resource use, etc.) and data on health related quality of life.
Results. Recruitment started in August 2010. By July 2011, approx.
230 patients have been recruited. Study rationale, design and an update
on the recruitment will be presented.
Conclusion. ACT-FASTER aims to generate real-life information on the
endocrine treatment of PMP patients with ER+ ABC with a focus on the
effectiveness of fulvestrant 500 mg in different treatment lines. Patient
management in clinical practice, quality of life and pharmacoeconomics will also be explored. As such, ACT-FASTER constitutes an important project of outcomes research in this patient setting.
Abstracts
0046
Final results from PACT (Patient’s Anastrozole Compliance to
Therapy Programme), a non-interventional study evaluating the
influence of a standardized information service on compliance in
postmenopausal women with early breast cancer
*M. Blettner , P. Hadji , N. Harbeck , C. Jackisch , H.-J. Lück , S. Zaun ,
C. Windemuth-Kieselbach7, R. Haidinger8, A. Rexrodt von Fircks9, R. Kreienberg10
1
Gutenberg-Universität Mainz, Institut für medizinische Biometrie, Epidemiologie und Informatik, Mainz, Deutschland, 2Klinikum der PhilippsUniversität, Klinik für Gynäkologie, gyn. Endokrinologie und Onkologie,
Marburg, Deutschland, 3Klinik und Poliklinik für Frauenheilkunde und
Geburtshilfe, Brustzentrum Köln/Frechen, Köln, Deutschland, 4Städtisches
Klinikum, Frauenklinik, Offenbach, Deutschland, 5Gyn. Onkologische Praxis,
Hannover, Deutschland, 6AstraZeneca, Medizin, Wedel, Deutschland, 7Alcedis GmbH, Giessen, Deutschland, 8Brustkrebs Deutschland e.V., München,
Deutschland, 9Selbstständig, Autorin, Ratingen, Deutschland, 10Frauenuniversitätsklinik, Ulm, Deutschland
1
2
3
4
5
6
Introduction. In clinical trials, compliance to adjuvant endocrine therapy for hormone-receptor positive (HR+) early breast cancer (EBC) is
generally high (>80%), yet, retrospective data from non-study settings
shows that compliance may drop below 70% after one year and to only
50% by year 4. PACT aimed to generate data from routine clinical practice on treatment compliance in postmenopausal women taking an adjuvant aromatase inhibitor and to increase treatment adherence via a
standardized information service (educational arm).
Methods. PACT was a prospective, randomised, two-arm parallel-group
study in Germany (sponsor AstraZeneca; NCT00555867). Postmenopausal women on anastrozole for HR+ EBC were randomized to routine clinical care alone or to receive additional standardized information
(educational arm) over the first year of adjuvant therapy. Primary endpoints were compliance and persistence rates in the educational versus
routine arm after 12 months. Secondary endpoints included longer follow-up, reasons for non-compliance, influence of baseline characteristics, and clinical outcome parameters. Compliance was evaluated via
patient questionnaires, prescription data and physician recall. Per protocol compliance was analysed only for patients with full baseline documentation both by patients and physicians. Persistence was defined as
the duration of time from initiation to discontinuation of therapy and
measured by prescription data. Regression analysis was performed to
investigate variables influencing compliance or persistence rate.
Results. 4923 patients were enrolled at 109 breast centres and 1361 specialist practices. 4397 patients were evaluable for baseline characteristics,
and 2707 patients for the primary endpoint. No difference in compliance was shown between the standard (88.2%) and the educational arm
(88.3%) at 12 months (p=0.92, Fisher’s exact test). Persistence rates were
40.3% for the standard and 43.0% for the educational arm, respectively
(p=0.17, Fisher’s exact test). At 24 months, data from 1539 patients was
available for compliance per protocol. Compliance rates were 88.7%
(educational arm) and 87% (standard arm; p=0.29), persistence 41.1%
and 42.1% (p=0.68). Variables influencing compliance were regular
attendance to follow-up visits, participation in a cancer rehabilitation
program, number of co-morbidities and current employment status.
Persistence was influenced by factors such as tumour stage, joint pain
and cancer rehab program participation.
Conclusion. The addition of standardized information materials to standard clinical care did not increase the compliance or persistence rates.
This result led to closing the study after the 24 months follow-up (planned 60 months). However, PACT represents the largest prospective study to evaluate compliance and persistence to adjuvant endocrine therapy in postmenopausal patients with HR+ EBC and provides valuable
data on clinical practice and treatment adherence in Germany.
0060
COMPliance and Arthralgias in Clinical Therapy (COMPACT):
Assessment of the incidence of arthralgia, therapy costs and
compliance within the first year of adjuvant anastrozole therapy
*H.-J. Hindenburg1, M. Blettner2, W.W. Bolten3, P. Hadji4, N. Harbeck5,
C. Jackisch6, R. Kreienberg7, W. Rief8, D. Wallwiener9, S. Zaun10, P. Klein11,
K. König12
1
BNGO e.V., Berlin, Deutschland, 2Universität Mainz, Institut für medizinische Biometrie, Epidemiologie und Informatik, Mainz, Deutschland,
3
Klaus-Miehlke-Klinik für Rheumatologie, Wiesbaden, Deutschland, 4Phillips-Universität Marburg, Schwerpunkt für Gynäkologische Endokrinologie,
Reproduktionsmedizin und Osteologie, Marburg, Deutschland, 5Unifrauenklinik, Brustzentrum, Köln, Deutschland, 6Klinikum Offenbach, Klinik für Gynäkologie und Geburtshilfe, Offenbach, Deutschland, 7Universitätsfrauenklinik, Ulm, Deutschland, 8Philipps-Universität, Psychotherapie-Ambulanz,
Marburg, Deutschland, 9Universitätsfrauenklinik, Tübingen, Deutschland,
10
AstraZeneca, Medizin, Wedel, Deutschland, 11d.s.h. statistical services
GmbH, Rohrbach, Deutschland, 12Berufsverband der Frauenärzte e.V.,
Steinbach/Ts, Deutschland
Objective. Aromatase inhibitors (AI) are well established as adjuvant
endocrine treatment for postmenopausal women with hormone receptor-positive (HR+) early breast cancer (EBC). However, clinical trials
have shown for AI to be significantly more frequently associated with
arthralgia than tamoxifen. As arthralgia may be a determining factor
in influencing compliance to adjuvant endocrine therapy, we designed a
prospective trial to collect real world data on the effects of AI-associated
arthralgia on patient compliance, patient outcomes as well as treatment
costs of arthralgia.
Materials and methods. COMPACT is an open, prospective, non-interventional study assessing the incidence of arthralgia, therapy costs,
and compliance within the first year of adjuvant anastrozole therapy
in postmenopausal patients with HR+ EBC. The study is sponsored
by AstraZeneca and supported by German health insurance funds
(GWQ ServicePlus AG, DAK, TK). Patients on adjuvant anastrozole for
3–6 months were enrolled and stratified by initial adjuvant anastrozole or switch from tamoxifen. All patients receive regular standardized
information about breast cancer from baseline to week 20 after study
start to support treatment compliance. Data on demographics, arthralgias, therapy of arthralgia and quality of life are collected at baseline, 3,
6 and 9 months. Primary endpoints are scaled data on arthralgia and
compliance within the first year of anastrozole therapy. Secondary endpoints include the incidence of arthralgias, therapy costs, reasons for
non-compliance, and influence of arthralgias on clinical outcome. For a
subgroup of patients data on arthralgia therapy and compliance will be
validated with corresponding accounting data of participating health
insurance funds.
Results. From April 2009 to March 2011, 2313 patients were recruited,
2007 receiving upfront anastrozole and 306 patients on switch therapy. The mean age was 64.5 years, mean BMI 27.7. Only 16.8% of patients
had received HRT prior to their EBC. 41.5% of patients had concomitant
symptoms relating to skeleton or musculature, and 11.9% stated arthralgias existing prior to anastrozole treatment. 13.1% reported a worsening
of pre-existing arthralgias or new arthralgia after starting anastrozole.
All patients will be followed for arthralgia, treatment thereof, and compliance to therapy.
Conclusion. COMPACT aims to provide valid data on AI-associated arthralgias, treatment, therapy compliance and treatment costs. This may
help to better inform patients and health care providers about these clinically important issues with the aim to improve adherence to anastrozole treatment, breast cancer outcomes, and therapy costs.
0061
Vandetanib and Pegylated Liposomal Doxorubicin (PLD) in recurrent ovarian cancer: a phase I trail of the AGO Study Group
*F. Hilpert1, A. du Bois2, J. Sehouli3, P. Wimberger4, J. Rau5, C. Kurzeder2,
G. Elser6, S. Zaun7, P. Harter2
1
Universitätsklinikum Schleswig-Holstein Campus Kiel, Klinik für Gynäkologie und Geburtshilfe, Kiel, Deutschland, 2Kliniken Essen-Mitte, Gynäkologie
und Gynäkologische Onkologie, Essen, Deutschland, 3Charité Campus Virchow, Klinik für Gynäkologie, Berlin, Deutschland, 4Unirversitätsklinikum,
Klinik für Frauenheilkunde und Geburtshilfe, Essen, Deutschland, 5Philipps
Universität, Koordinierungszentrums für Klinische Studien, Marburg,
Deutschland, 6AGO Studiengruppe, Wiesbaden, Deutschland, 7Astra Zeneca, Wedel, Deutschland
Background. PLD is a standard treatment in patients with recurrent
platinum-resistant or refractory ovarian cancer. Vandetanib is an oral
once daily inhibitor of VEGFR-, EGFR- and RET-signalling with activity in combination with chemotherapy in some other solid tumours.
Therefore, we aimed to establish a feasible combination therapy of PLD
and vandetanib.
Methods. Eligible patients were treated with PLD 50 mg/m2 q28 and
vandetanib 100 mg/d po. It was planned to recruit at least 10 patients
evaluable for toxicity over 2 treatment cycles. Primary endpoints were
tolerability and safety; secondary endpoint was efficacy.
Results. Fourteen of 15 registered patients started treatment and were
evaluable for toxicity. Three patients (21%) stopped after first cycle (PD,
withdrawal of consent, nausea/vomiting). The remaining 11 patients
were treated for at least 2 cycles. Dose reductions of PLD and vandetanib were indicated in 4 (29%) and 5 patients (36%), respectively. The
following G3/4 toxicities occurred per patient: 3 (21%) elevated liver enzymes G3, 2 (14%) neutropenia G3/4, 5 (36%) PPE G3/4, 2 (14%) mucositis
G3. Tyrosine kinase inhibitor attributed side effects like hypertension or
bowel perforations were not reported. Toxicity led to end of treatment
in 4 patients (29%). Ten patients were evaluable for response: PR 1, SD 4.
The median PFS was 6.7 months and median OS was 11.1 months.
Conclusions. The combination of PLD and vandetanib is feasible, but
shows considerable toxicity. Efficacy has to be proven in subsequent
phase II trials.
This study was sponsored by AstraZeneca GmbH.
0074
Survival of metastatic breast cancer (MBC): Is there a survival
benefit over time?
*M.-P. Ufen1, B. Rosien1, T. Hammer1, U. Schubert1, E. Malik2, *C.-H. Köhne1
1
Klinikum Oldenburg, Hämatologie Onkologie, Oldenburg, Deutschland,
2
Klinikum Oldenburg, Gynäkologie, Oldenburg, Deutschland
Background. Whether survival of patients with MBC is improved over
time remains controversial. Randomised clinical trials demonstrated
if at all a small benefit between different therapies and a meaningful
translation into clinical practice is doubtful.
Methods. Excluding patients with local recurrence only, we analysed
839 patients, treated at our institution from 1985–2009, according to
date of primary diagnosis or date of first metastasis. The influence of
hormonal receptor status (HR+, HR−), metastasis free intervall (MFI)
(<24 months up to >60 months) and diagnosis before or after 1996 (introduction of taxanes and aromatase inhibitors) was examined.
Results. Improvement of survival was observed, when the primary tumor was diagnosed later (intervals of 1985–1990, 1990–1994, 1995–1999,
2000–2004, 2005–2009; p=0.006) however, no survival effect was observed according to date of metastasis (p=0.11). Median survival of patients
with HR+ was 32.1 vs. 17.0 months for in HR− (p<0.0001). A shorter metastasis free interval was associated with a shorter OS (MFI <24 months:
22.0 mo, MFI 24–60 months: 31.1 mo, MFI >60 months: 36.0 mo;
p<0.0001). HR+ patients survived longer when metastasis occurred
in a later period (5 year intervals between 1985–1999 median approx.
32.0 months vs. 2000–2004 median approx. 38.0 months; p=0.02). No
significance for HR− patients. No survival difference before or after 1996
was observed for the total cohort (median 27.1 vs. 30.0 months (p=0.58),
HR+ patients (p=0.92) or HR− patients (p=0.93) and also not for patients
with metastasis free interval <24 months (19.1 vs. 22.0 months; p=0.86).
Conclusions. A survival difference is only seen for HR+ patients with
metastasis diagnosed after 2000. An influence of taxanes in aggressive
disease (metastasis free interval <24 months) is unlikely. Whether aromatase inhibitors have an influence on survival for the overall cohort
(HR+ and HR−) is unclear, but may explain the survival benefit seen
in HR+ patients. The tumor biology has probably a greater impact on
survival than any new antineoplastic agent.
0076
HER4 coexpression is associated with improved recurrence free
survival in HER2-positve, Herceptin-treated patients
*G. Brockhoff1, A. Machleidt1, G. Piendl1, S. Seegers2, A. Sassen2, S. Diermeier-Daucher1, S. Buchholz1, O. Ortmann1
1
Caritaskrankenhaus St. Josef, Universität Regensburg, Frauenheilkunde
und Geburtshilfe, Regensburg, Deutschland, 2Universität Regensburg,
Institut für Pathologie, Regensburg, Deutschland
Background. Individual therapy efficiency of HER2-positive metastatic
and pre-metastatic breast cancer patients varies significantly and spans
from effectual responsiveness over acquired insensitivity to complete
resistance from the outset. Thus no predictive information can be deduced from HER2 diagnostics so that molecular biomarkers indicative
for sensitivity/resistance to Herceptin are needed to be identified. The
HER2 related HER4-receptor has been shown to have ambivalent (proapoptotic or pro-proliferative) activity and consequently represents a
prime candidate to affect HER2 activity under Herceptin treatment. We
retrospectively analyzed potential her4 gene amplification and HER4
protein expression in HER2-positive, Herceptin treated patients. Patient’s overall and recurrence free survival was evaluated as a function
of HER2/HER4 expression.
Methods. Using dual color Fluorescence in-situ Hybridization (FISH
probes, Zytovision, Bremerhaven, Germany) and qPCR (LC480, Roche,
Penzberg, Germany) we quantitatively investigated primary breast cancer tissues from nearly 50 (FISH) and 160 (PCR) patients who received
Herceptin treatment. We quantified the her4 gene copy numbers and
evaluated the protein expression profile of all four known HER4 isotypes (JM-a/CYT1, JM-a/CYT2, JM-b/CYT1, JM-b/CYT2)
Results. FISH analysis revealed a positive and independent prognostic
marker in Herceptin treated breast cancer patients with respect to overall survival. Moreover by quantitative PCR analysis we found a significant variability of HER4 protein expression (JM-a/CYT1 and JM-a/
CYT2; no JM-b isotypes) in HER2 positive breast cancer tissues, whereas HER2/HER4 positive patients show a significant better recurrence
free survival compared to HER2 positive but HER4 negative patients
(p=0.003).
Conclusions. HER4 has been demonstrated to potentially exert tumor
suppressing activity and in turn to have a favourable impact on the
course of breast cancer disease. We show here that HER4 expression
prolongs in particular recurrence free survival of Herceptin treated patients which indicates a functional integration of HER4 into anti-HER2
targeting. Complementing functional studies allowing for isotype specific function of HER4 will elucidate the special role of this receptor
tyrosine kinase in the context of Herceptin treatment and might facilitate individualized anti-ErbB-receptor targeting with higher efficiency.
Abstracts
0080
Comparison of the HER2, estrogen and progesterone receptor
expression profile of metastases and circulating tumor cells in
metastatic breast cancer patients
*B. Aktas1, M. Tewes2, V. Müller3, S. Kasimir-Bauer1, T. Fehm4
1
Universitätsklinik, Gynäkologie und Geburtshilfe, Essen, Deutschland,
2
Universitätsklinik, Innere Tumorklinik, Essen, Deutschland, 3Universitätsklinik, Klinik und Poliklinik für Gynäkologie, Hamburg, Deutschland, 4Universitätsklinik, Gynäkologie und Geburtshilfe, Tübingen, Deutschland
Background. Several studies have indicated that the expression of predictive markers including HER2, the estrogen (ER) und progesterone
(PR) receptor can change during course of disease. Therefore, reassessment of the predictive markers at the time of disease progression might
help to optimize treatment decisions. In this context, characterization
of circulating tumor cells (CTCs) could be of relevance in the future,
since metastatic tissue may be difficult to obtain for repeated analysis.
Therefore, the purpose of the present study was to compare the hormone receptor status as well as HER2 expression profile of metastases with
the expression profile on CTCs.
Materials and methods. A total of 82 patients with metastatic breast cancer from eight German University Breast Cancer Centers were enrolled
in this study. Blood was obtained at the time of first diagnosis of metastatic disease or disease progression. HER2 status of CTCs was assessed
using the FDA-approved CellSearch® assay and the hormonal receptors
were analyzed by immunomagnetic enrichment using the AdnaTest
BreastCancerSelect™ (AdnaGen AG, Germany) followed by RNA isolation and subsequent gene expression analysis by reverse transcription
and Multiplex-PCR in separated tumor cells using the AdnaTest BreastCancerDetect. Expression of the ER and PR receptor was assessed in
an additional RT-PCR. The analysis of PCR products was performed by
capillary electrophoresis on the Agilent Bioanalyzer 2100.
Results. The overall detection rate for CTCs was 27 of 82 (33%) with the
expression rates of 33% for HER2, 10% for ER and 6% for PR, respectively. Comparisons of expression profiles on CTCs with those on metastases were only performed in CTC-positive patients. In 15 patients with
ER-positive metastases, only one patient had ER-positive CTCs. 11 patients with PR-positive metastases expressed PR on CTCs in also only one
case. The rate of breast cancer patients with HER2-positive metastases
and HER2-positive CTCs was 27%. Metastases and CTCs displayed a
concordant ER, PR and HER2 status in 21% (not significant), 42% (not
significant) and 52% (not significant) of cases, respectively.
Conclusion. The concordance between expression profile of CTCs and
corresponding metastatic disease is low. The consequences for palliative
treatment have to be determined by monitoring therapy response based
on each expression profile.
0082
Pertuzumab is superior to Trastuzumab in rescuing the HRGcaused reversion of Lapatinib’s inhibitory effect on breast cancer
cells
*S. Diermeier-Daucher1, S. Breindl1, S. Buchholz1, O. Ortmann1, G. Brockhoff1
Caritas Hospital St. Josef, Department of Gynecology and Obstetrics,
Regensburg, Deutschland
1
Background. Monoclonal antibodies and small molecule inhibitors
emerged as potent therapeutic agents in the treatment of HER2 overexpressing breast cancer. However, many patients do not adequately
respond to anti-EGFR/HER2 receptor targeting. In this study we investigated receptor- and growth-stimulating effects, which potentially
hamper anti-proliferative cell treatment.
Methods. BT474 and SK-BR-3 breast cancer cell lines were treated with
therapeutic monoclonal antibodies Trastuzumab and Pertuzumab and
with tyrosine kinase inhibitor Lapatinib alone and in different combinations. EGF or HRG were added to reveal potential growth factor-me-
diated compensatory effects. The treatment-specific activation status of
EGFR and HER2 receptors and intracellular signaling cascades were
correlated to cell cycle kinetics and apoptosis.
Results. The presence of EGF or HRG strongly impaired Lapatinib-caused growth inhibition. This compensatory effect caused by EGF, however, was reversed by additional cell treatment with either Trastuzumab
or Pertuzumab. In contrast, the compensatory effect caused by HRG
treatment was only reversed by Pertuzumab, but not by Trastuzumab.
These data suggest that Pertuzumab might be superior to Trastuzumab
in affecting a HRG-caused HER receptor interaction (activation) involved in compensation of Lapatinib-caused cell cycle exit.
Conclusions. Modular HER/ErbB receptor targeting with Lapatinib,
Trastuzumab and Pertuzumab more efficiently affects receptor function than single treatment. Growth inhibition by anti-cancer drugs targeted to HER/ErbB receptors, however, can be significantly undermined
in the presence of EGF and in particular by HRG treatment. This observation suggests that specific therapeutic growth factor sequestration
might further enhance anti-EGFR/HER2 targeting.
0083
Hyperthermia triggers down-regulation of Estrogen receptor
α isoforms and its co-activators DEAD-box5 and DEAD-box17 in
breast cancer cells
*M. Hirschfeld1, M. Jäger1, V. Neumann1, G. Gitsch1, E. Stickeler1
1
Gynecological Hospital of Freiburg University Medical Center, Molecular
Oncology, Freiburg, Deutschland
Background and aims. Recently, the clinical application of hyperthermal
therapy becomes more and more reintroduced and is used concomitant to chemotherapy or radiotherapy, that might improves the effect of
those classical anti-cancer treatments. RNA helicases p68 (DEAD-box5,
DDX5) and p72 (DEAD-box17, DDX17) act as transcriptional co-activators of several tumor-relevant genes, e.g. estrogen receptor α (ERα).
DDX17 is significantly associated to an increase in relapse-free and
overall survival in ERα-positive breast cancer, however inversely associated to Her2/neu expression. In contrast, DDX5 expression correlates
with elevated levels of Her2/neu and higher stages of tumor grading.
Both factors regulate ERα-activity in breast cancer. We investigated
potential regulatory effects of hyperthermia on the expression of these
breast cancer-related factors.
Methods. Various ERα-positive breast cancer cell lines (MCF-7, ZR-75-1,
T47D, BT-474) were cultured under hyperthermia (42°C, 2 h) followed
by maintenance under regular culture conditions (37°C, 4 h). As a negative control the same cell lines were cultivated under regular temperature conditions permanently. mRNA and protein expression levels of
ESRα isoforms, DDX5 and DDX17 were analyzed by RT-PCR, Western
blot and immunocytochemistry technique.
Results. The analyses revealed markedly decreased mRNA and protein
levels of ERα isoforms, as well as of DDX5 and DDX17 in cells exposed
to hyperthermia compared to cells cultured under regular conditions.
Our results clearly indicate a regulatory effect of hyperthermal treatment on both, the mRNA and protein expression of the breast cancerrelevant gene ERα and its co-activators DDX5 and DDX17.
Conclusion. According to our findings, hyperthermal treatment seems
to represent a method that may improve classical anti-cancer therapies
by down-regulating the activity of important factors in breast cancer
biology. We hypothesize that hyperthermia inhibits the expression of
ERα isoforms and its co-activators, thus probably leading to a suppression of tumor progression. However, the molecular background of signaling pathways that undergo hyperthermia-dependent alterations and
its concomitant effects on tumor biology still need to be investigated in
more detail.
0085
Quality of life (QoL) in patients with metastatic breast cancer
(MBC) treated with capecitabine – second interim analysis of the
German non-interventional study (NIS)
*C.-C. Steffens1
1
MVZ Hämatologie/Onkologie, Onkologie, Stade, Deutschland
Background. Capecitabine (CAPE) is a commonly used treatment option for MBC with proven efficacy. The aim of this study was to analyse
QoL.
Patients and methods. Patients with MBC, irrespective of HER2-status
are included in this NIS. To evaluate QoL the EORTC Quality of Life
questionnaire QLQ-C30 (v 3.0) was used. The presented data are part of
a pre-planned interim analysis with up to 12 documented cycles.
Results. Until 12/2010, 594 of 750 planned patients had been registered
and 447 of these were documented to have received at least one cycle of CAPE. The average age of the patients was 61.4 (±11) years. 45%
of patients received CAPE monotherapy (MT) and 55% combination
therapy (CT). 41% of patients were treated 1st line, 28% 2nd line and
the remaining in 3rd or higher lines. The most common combination
partners were bevacizumab (16%), lapatinib (13%), vinorelbine (10%) or
trastuzumab (9%). Clinical responses were displayed by 27.9% patients
for MT and 39.9% for CT, while clinical benefit was noted in 61% of patients irrespective of treatment modality. Data from up to 482 patients
were available for analyses of QoL. Patients with CT showed significantly better scores at baseline than MT patients for physical, role and
cognitive functioning as well as fatigue, pain and financial problems.
During the course of treatment global health, emotional and role functioning increased for CT patients, but only the rise in global health was
statistically significant. Irrespective of treatment, physical functioning
remained stable over the course of up to 12 treatment cycles. Social
functioning showed a decrease in the group treated with MT, but an
increase for the group treated with CT. Compliance rates were between
68% (cycle 12, n=31) and 87% (cycle 1, n=209) during the 12 cycles. Patient satisfaction regarding the information given on the overall cancer
treatment and side effects was high (mean ≥4 out of 5). At least half of
the patients evaluated their treatment, the treatment outcome and the
side-effects as or better than expected.
Conclusions. CAPE was most commonly used as 1st line treatment and
displayed better treatment outcome when given in combination. Overall, QoL did not decrease and was better for the combination therapy
group. However, further data, especially for the later cycles, need to be
acquired to verify these assumptions.
0090
Survival analysis of patients with primary breast cancer initially
treated at a certified academic breast unit
* J. Heil1,2, A. Gondos3; F. Marmé2,4, H. Brenner3, G. Rauch5, C. Sohn1,2, A.
Schneeweis1,2
1
Frauenklinik, Brustzentrum, Heidelberg, Deutschland, 2Nationales
Centrum für Tumorerkrankungen, Gynäkologische Onkologie, Heidelberg,
Deutschland, 3DKFZ, Division of Clinical Epidemiology and Aging Research,
Heidelberg, Deutschland, 4Frauenklinik, Brustzentrum, Heidelberg,
Deutschland, 5Institut für medizinische Biometrie, Heidelberg, Deutschland
Results. Of all patients, 368 (11.0%) had carcinoma in situ (CIS) and 197
(5.9%) had bilateral cancers., For the 2970 patients with invasive cancer,
of which 49 patients (1.7%) had metastastic disease at time of diagnosis,
DFS, LCR, DDFS, OOS and ROS at 5 years were 79.8%, 84.7%, 81.2%,
86.3%, and 89.8%, respectively. In multivariate analysis age, pT category,
nodal status, hormone receptor status and grading were identified as
independent prognostic factors for OS.
Conclusion. Compared with recent population based reports from Germany, more favourable patient characteristics and nominally higher
survival was found among this large cohort of patients with primary
breast cancer treated at a single certified breast unit.
0094
Sequential treatment with Epirubicin/Cyclophosphamide, followed by Docetaxel vs. FEC120 in the adjuvant treatment of breast
cancer patients with extensive lymph node involvement: final
survival analysis of the German ADEBAR phase III study
*W. Janni1, N. Harbeck2, H. Sommer3, B. Rack3, D. Augustin4, W. Simon5,
J. Jueckstock3, A. Wischnik6, K. Anneke7, K. Friese3, M. Kiechle7
1
HHU, Frauenklinik, Düsseldorf, Deutschland, 2Universitätsklinik Köln,
Brustzentrum Köln Frechen, Köln, Deutschland, 3LMU, Frauenklinik,
München, Deutschland, 4Klinikum, Brustzentrum Ostbayern, Deggendorf, Deutschland, 5Robert-Bosch-Krankenhaus, Frauenklinik, Stuttgart,
Deutschland, 6Zentralklinikum, Frauenklinik, Augsburg, Deutschland,
7
Technische Universität, Frauenklinik, München, Deutschland
Background. Based on meta-analytic evidence, taxane containing adjuvant chemotherapy has been established as standard treatment in
node-positive breast cancer. However, in the MA-21 study, adriamycincyclophosphamide, followed by paclitaxel (AC-P) was significantly inferior to the gold standard of anthracycline treatment, FEC120 (Burnell,
SABCS 2006). We prospectively compared a sequential epirubicin-docetaxel chemotherapy regimen to FEC120.
Patients and methods. The ADEBAR study was a multicenter phase III
trial (n=1502) to evaluate whether breast cancer (BC) pts with >3 axillary
lymph node metastases benefit from a sequential anthracycline-docetaxel regimen (E90C–D: 4 cycles epirubicin [E] 90 mg/m2 plus cyclophosphamide [C] 600 mg/m2 q21 days followed by 4 cycles docetaxel [D]
100 mg/m2 q21 days) compared to dose-intensive anthracycline-containing polychemotherapy (FE120C: 6 cycles E 60 mg/m2 d 1+8, 5-FU
500 mg/m2 d 1+8 and C 75 mg/m2 d 1–14, q4 weeks). The median followup time will be 60 months.
Results. Treatment was stopped prematurely in 3.7% of the pts in the
E90C–D arm and in 8.0% in the FE120C arm due to toxicity (p=0.0009).
Antibiotic treatment was given in 10.4% (E90C–D) vs. 19.7% (FE120C),
G-CSF support in 39.2% vs 61.4 % and erythropoietin stimulation in
8.7% vs. 20.0%, respectively. Mature final 5-year-survival data will be
presented at the SABCS meeting 2011.
Conclusion. Different toxicity profiles given, hematological toxicity in
the FE120C group was more severe than in the E90C–D. Mature survival data will be discussed in this context.
Aim. Outcome evaluation of patients with primary breast cancer treated
at a certified academic breast unit.
Methods. We prospectively collected data of 3338 patients, diagnosed
with primary breast cancer between 01.01.2003 and 31.12.2010 and treated at the Breast Unit Heidelberg in order to analyze outcome in clinical
practice. We evaluated local control rate (LCR), disease-free survival
(DFS), distant disease-free survival (DDFS), observed overall survival
(OOS) and age adjusted relative overall survival (ROS). In addition, the
impact of known prognostic factors on these outcome variables was examined in univariate and multivariate analyses.
Abstracts
0108
Trastuzumab treatment of early breast cancer patients receiving
no adjuvant chemotherapy
*P. Dall1, K. Friedrichs2, H. Timmer³, V. Petersen4, A. Hinke5, C. Brucker6,
A. Nacke7, P. Schmidt8, A. von der Assen9
Städt. Klinikum, Frauenklinik, Lüneburg, Deutschland, 2Krankenhaus
Jerusalem, Mammazentrum, Hamburg, Deutschland, ³Onkologische Gemeinschaftspraxis, Münster, Deutschland, 4Praxis, Heidenheim, Deutschland, 5WiSP, Biostatistik, Langenfeld, Deutschland, 6Klinikum Nürnberg,
Brustzentrum, Nürnberg, Deutschland, 7Praxis, Remagen, Deutschland,
8
Praxis, Neunkirchen, Deutschland, 9Franziskus-Hospital Harderberg,
Georgsmarienhütte, Deutschland
1
Background. Trastuzumab (T) is approved for the treatment of early,
HER2+ breast cancer (BC) in parallel or sequentially to adjuvant chemotherapy (CT). However, as in advanced disease, the antibody is obviously used without chemotherapy in a selected group of HER2+ patients
(pts). The analysis characterizes this subgroup and describes safety and
efficacy outcome parameters based on data from a large prospective observation trial.
Methods. 2870 pts have currently been enrolled and documented in
this ongoing non-interventional study from 270 German institutions.
At data lock for this evaluation, adequate documentation was available
from 2422 eligible pts.
Results. T was given to 180/2422 pts (7.4 %) without preceding or concomitant CT (noCT). In this subgroup pts typically were older (median
58 vs. 56 in the CT group, p=0.0026; ≥70 years: 18%/10%), had smaller
tumors (pT1 49%/43%, p=0.11), more favorable histology (G3 45%/53%,
p=0.045), a higher percentage of positive hormone receptor (67%/61%,
p=0.096) and less radiotherapy (64%/79%, p<0.0001). The strong association to additional irradiation probably reflects the overall risk profiling of the pts. In contrast, nodal involvement was not differing (pN0:
52%/51%; positive nodes: mean 2.5/2.4). In a multivariate logistic regression model (not including radiotherapy), hormone receptor status is not
predictive (p=0.41), while age ≥65 (p=0.0011), grade 1/2 (p=0.046) and
pT1 (p=0.089) independently retain at least borderline significance. The
average number of T administrations was 18 and median duration of T
therapy was 12 months, both in the noCT group and CT group. 57% of
noCT pts received adjuvant endocrine therapy. 81% of CT pts received
anthracyclines and 61% taxanes. No differences in relapse-free survival
could be detected (p=0.38), but the observation of only 13 events in the
noCT group is very limited as yet. Pathological cardiac findings in the
pts history were not predictive of treatment selection (6%/7%) and similarly distributed at termination of T therapy (7%/8%). Cardiac function
disorders of CTC grade 3/4 were reported in 1% of both groups, across all
grades the frequency was slightly smaller in the noCT pts (2.8%/4.0%).
Conclusions. In early HER2+ BC pts, a small, but distinct subgroup receives T without adjuvant CT. These pts are typified by higher age and
favorable primary tumor staging/grading, but not by cardiac comorbidities in their history.
0109
Expression of Her4-receptor splice variants in triple negative
breast cancer
A. Machleidt1, S. Diermeier-Daucher1, M. Mögele1, S. Seitz1, S. Buchholz1,
O. Ortmann1, *G. Brockhoff1
1
Caritaskrankenhaus St. Josef, Universität Regensburg, Frauenheilkunde
und Geburtshilfe, Regensburg, Deutschland
Background. Triple negative Breast cancer (TNBC) is associated with
younger patient age, poor prognosis and high grade tumor differentiation. TNBC do not express estrogen receptors (ER), progesterone receptors (PR) and lack overexpression of Her2-receptors. Therefore this type
of breast cancer does not respond to endocrine therapy or Trastuzumab
(Herceptin). Her4, a member of the Her-family of tyrosin-kinase-receptors may be a new target for patients with TNBC. The impact of Her4
on breast cancer progression and outcome still appears contradictory.
Targeting of Her4 receptor positive breast cancer cells in vitro by a monoclonal antibody (mAb1479) that selectively recognizes specific Her4JMa splice variant showed a suppression of breast cancer cell growth (1).
We analysed the expression of the four Her4-receptor splice variants in
TNBC tissues, which differ not only in structure but also in function.
Methods. We examined 90 primary breast cancer samples and non-malignant breast tissues for differential Her4 isoform expression. RNA was
extracted from paraffin embedded and kryo-preserved tissues and was
analysed by qRT-PCR (Light Cycler 480, Roche). We then compared the
data from PCR analysis with the clinical patient data (e.g. overall survival, recurrence free survival), which we obtain from the clinical registry
of the tumor center Regensburg.
Results. Only the Her4 juxtamembrane JM-a splice variant is present in
triple negative breast cancer samples and non-malignant tissues. JM-b
which is found in heart muscle tissue for example, has not been found.
The relative Her4-JM-a expression differs up to 2.5-fold in TNBC tissues
and 6-fold in non-malignant samples. Cyt1 and Cyt2 intracellular domains of Her4-receptor were found in JM-a expressing tissues and the
intensity varies in individual patients.
Conclusion and perspectives. We identified a substantial (40%) subgroup
of TNBC tissues expressing Her4-JMa. Further studies will show the
clinical impact of these findings.
1. Hollmen et al (2009) Suppression of breast cancer cell growth by a
monoclonal antibody targeting cleavable ErbB4 isoforms. Oncogene
0111
Expression of stem cell and epithelial-mesenchymal transition
markers in primary breast cancer patients with circulating tumor
cells
*S. Kasimir-Bauer1, O. Hoffmann1, R. Kimmig1, D. Wallwiener2, T. Fehm2
1
Universitätsklinikum Essen, Klinik für Frauenheilkunde und Geburtshilfe,
Essen, Deutschland, 2Universitätsklinikum Tübingen, Klinik für Frauenheilkunde und Geburtshilfe, Tübingen, Deutschland
Introduction. The presence of circulating tumor cells (CTC) in breast
cancer might be associated with stem cell like tumor cells which have
been suggested to be the active source of metastatic spread in primary
tumors. Furthermore, to be able to disseminate and metastasize, CTC
must be able to perform epithelial-mesenchymal transition (EMT). We
studied the expression of three EMT markers and the stem cell marker
ALDH1 in CTC from 502 primary breast cancer patients. Data were correlated with the presence of disseminated tumor cells (DTC) in the bone
marrow (BM) and clinicopathological data of the patients.
Methods. 2×5 ml blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1, HER2 and
beta-Actin transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [TWIST1, Akt2, PI3Kα] and separately for the tumor stem cell marker ALDH1. The identification of EMT
markers was considered positive if at least one marker was detected in
the sample. Two BM aspirates from all patients were analyzed for DTC
by immunocytochemistry using the pan-cytokeratin antibody A45-B/
B3.
Results. 97% of 30 healthy donor samples investigated were negative for
EMT and 95% for ALDH1 transcripts, respectively. CTCs were detected
in 97/502 (19%) patients. At least one of the EMT markers was expressed in 29% and ALDH1 was present in 14% of the samples, respectively.
Interestingly, 5% of the ALDH1-positive and 18% of the EMT-positive
patients were CTC-negative based on the cut-off level determined for
CTC-positivity applying the AdnaTest BreastCancer. DTC in the BM
were detected in 107/502 (21%) patients and no correlation was found
between BM status and CTC positivity (p=0.41). The presence of CTC,
EMT and ALDH1 expression was not correlated to any of the prognostic
clinical markers.
Conclusion. Our data indicate that (1) a subset of primary breast cancer
patients shows EMT and stem cell characteristics and (2) the currently
used detection methods for CTC are not efficient to identify a subtype
of CTC which underwent EMT. (3) The clinical relevance on prognosis
and therapy response has to be further evaluated in a prospective trial.
0114
The PACOVAR-trial: A phase I/II study of pazopanib (GW786034)
and metronomic cyclophosphamide in patients with platinumresistant recurrent, pre-treated ovarian cancer
*C. Mayer1, R. Eickhoff2, E. Bischofs1, G. Gebauer3, T. Fehm4, F. Lenz5,
H.-C. Fricke6, E.-F. Solomayer7, N. Fersis8, M. Schmidt9, M. Wallwiener1,
A. Schneeweiss1,10, C. Sohn1, M. Eichbaum1
1
Universitäts-Frauenklinik Heidelberg, Heidelberg, Deutschland, 2Alcedis
GmbH, Gießen, Deutschland, 3Marienkrankenhaus, Frauenklinik, Hamburg,
Deutschland, 4Universitäts-Frauenklinik Tübingen, Tübingen, Deutschland,
5
Krankenhaus Hetzelstift, Frauenklinik, Neustadt/Weinstraße, Deutschland,
6
Klinikum Konstanz Frauenklinik, Konstanz, Deutschland, 7Universitätsklinikum des Saarlandes, Frauenklinik, Homburg, Deutschland, 8Klinikum
Chemnitz gGmbH, Frauenklinik, Chemnitz, Deutschland, 9UniversitätsFrauenklinik Mainz, Mainz, Deutschland, 10Nationales Centrum für Tumorerkrankungen, Gynäkologische Onkologie, Heidelberg, Deutschland
Background. The prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard
treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination
with the metronomic application of low dose chemotherapy. The novel,
investigational oral antiangiogenic agent pazopanib targeting vascular
endothelial growth factor receptor (VEGFR), platelet-derived growth
factor receptor (PDGFR) and c-kit is currently being studied in different
tumour types and is already used as first line therapy in recurrent renal
cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment
option to patients with recurrent, pretreated EOC.
Methods and design. This study is designed as a multicenter phase I/
II trial evaluating the optimal dose for pazopanib (phase I) as well as
activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of
patients with recurrent, platinum-resistant, pre-treated ovarian cancer
(phase II). The patient population includes patients with histologically
or cytologically confirmed diagnosis of EOC which is platinum resistant or refractory, cancer of the fallopian tube or peritoneal cancer. Patients must have measurable disease according to RECIST criteria and
must have failed available standard chemotherapy.
Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria
(phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13
cycles up to 52 weeks per subject). Enrollment has started in November
2010 in 5 sites experienced in the conducture of clinical trials. Three patients have completed first eight weeks of treatment without DLT so far.
Discussion. The current phase I/II trial shall clarify the potential of the
multitargeting antiangiogenic tyrosinkinaseinhibitor GW 786034 (pazopanib) in combination with oral cyclophosphamide as salvage treatment in patients with recurrent, pretreated ovarian cancer. Preliminary
safety results will be presented.
0115
Bevacizumab (rhuMAB VEGF) in combination with metronomic
cyclophosphamide in advanced gynecological cancers resistant
to standard treatment
*K. Smetanay, J. Aigner1, F. Marmé1, M. Eichbaum1, C. Sohn1, A. Schneeweis1
1
Universitätsklinikum Heidelberg, Frauenklinik/NCT Gynäkologische Onkologie, Heidelberg, Deutschland
Introduction. Patients with heavily pretreated gynecological cancers
(ovarian cancer, adenocarcinoma of the cervix uteri and endometrial
cancer) have limited treatment options. Vascular endothelial growth
factor (VEGF) is the best characterized angiogenic factor and is regarded as a promising therapeutic target at least in patients with ovarian
cancer. In addition to bevacizumab, the monoclonal antibody against
VEGF, low dose metronomic cyclophosphamide has shown some antiangiogenic properties. Here we report results of a retrospective analysis
of our patients with heavily pretreated gynecological cancers who received bevacizumab in combination with low dose cyclophosphamide
at our institution since 2008. In addition we present an overview of the
recent literature published in PubMed-, MEDLINE and EMBASE-database.
Patients and methods. Five patients with heavily pretreated (at least four
lines of chemotherapy) platin-resistent gynecological carcinomas received intravenous bevacizumab 10 m/kg every two weeks in combination
with oral cyclophosphamide 50 mg per day. Endpoints were time to progression and toxicity according to Common Terminology Criteria of
Adverse Events Version 3.0 (CTCAEv3.0).
Results. All patients showed a rapid improvement of tumour symptoms.
Median time to progression was 10 months (range: 6–33). One patient
with an adenocarcinoma of the cervix is still in remission for 7 months.
Bevacizumab related toxicities comprised deep vein thrombosis grade III in one patient and arterial hypertension grade II in 3 patients,
which were well manageable by standard treatment. We experienced no
proteinuria >grade 1 as assessed by urine dipsticks before each administration of bevacizumab. Although data to endometrial and cervical
cancers are very rare a comprehensive literature review supports our
experience and will be presented at the meeting.
Conclusion. Bevacizumab in combination with oral metronomic cyclophosphamide is well tolerated and has significant activity as palliative
therapy of heavily pretreated patients with platin-resistent gynecological cancers. Translational research to define predictors of response e.g.
anti-angiogenesis gene polymorphisms and severe side effects e.g. gastro-intestinal perforation to further improve the therapeutic index are
eagerly needed.
0124
LOH at chromosomal band 6q and 10q in fractionated circulating
DNA of ovarian cancer patients is predictive for tumor cell spread
and reduced disease-free and overall survival
*P. Wimberger1, J.D. Kuhlmann1, H. Schwarzenbach2, M. Heubner1, M. Poetsch3, R. Kimmig1, S. Kasimir-Bauer1
1
Universität Duisburg-Essen, Klinik für Gynäkologie und Geburtshilfe,
Essen, Deutschland, 2Universität Hamburg-Eppendorf, Institut für Tumorbiologie, Hamburg, Deutschland, 3Universität Duisburg-Essen, Institut für
Forensische Medizin, Essen, Deutschland
Background. We recently showed that LOH proximal to M6P/IGF2R locus (D6S1581) in ovarian tumors is predictive for tumor cell spread to
the bone marrow (BM). For therapy-monitoring, it would be desirable
to establish a blood-based biomarker. Therefore, we quantified circulating DNA (cirDNA) in sera of 63 ovarian cancer patients before surgery
and after chemotherapy, measured incidence of LOH at four cancer-relevant chromosomal loci, correlated LOH with tumor cell spread to the
BM and evaluated prognostic significance of LOH.
Abstracts
Methods. cirDNA was fractionated into high- and low molecularweight fraction (HMWF, LMWF) for LOH-profiling, utilizing PCRbased fluorescence microsatellite analysis. BM aspirates were analyzed
for DTC by immunocytochemistry using the pan-cytokeratin antibody
A45-B/B3.
Results. cirDNA levels in the HMWF before surgery were predictive for
residual tumor load (p=0.017). After chemotherapy, we observed a decline of cirDNA in the LMWF (p=0.0001) but not in the HMWF. LOH
was prevalently detected in the LMWF with an overall frequency of 67
%, only moderately ablating after chemotherapy (45%). Before surgery,
LOH in the LMWF at marker D10S1765, D13S218 and D6S1581 significantly correlated with tumor grading, FIGO stage and disease-free
survival (p=0.004, p=0.033, p=0.032, respectively). In both combined
fractions, LOH at D6S1581 additionally associated with overall survival
(p=0.030). Moreover, solely LOH at D10S1765 in LMWF after therapy
correlated with DTC in BM after therapy (p=0.017).
Conclusion. We demonstrate the necessity of DNA-fractionation for
LOH analysis on cirDNA and identified LOH at D10S1765 and D6S1581
as blood-based biomarkers for ovarian cancer, being relevant for treatment-monitoring.
0127
Implementation of the national S3 guideline recommendations
for primary surgery of breast cancer patients in different regions
of Germany: a population-based evaluation
*S. Schrodi1, A. Tillack2, A. Naas2, A. Niedostatek3, C. Werner3, B. Holleczek4,
C. Stegmaier4, G. Schubert-Fritschle1, J. Engel1
1
Deutschland, 2Tumorzentrum Land Brandenburg, Frankfurt (Oder),
Deutschland, 3Regionales Klinisches Krebsregister Dresden, Dresden,
Deutschland, 4Epidemiologisches Krebsregister Saarland, Saarbrücken,
Deutschland
Purpose. In 2004, the first national S3 guideline for the diagnosis, therapy and aftercare of breast cancer patients was implemented in Germany,
and the first update was released in 2008. One aim of the study was to
evaluate guideline adherence for primary surgery of breast cancer and
possible influences on survival in four different regions of Germany.
Methods. Data from 69,587 cases of operated breast cancer patients,
diagnosed between 1999 and 2010 was obtained from cancer registries
in the regions of Brandenburg (n=18,928), Dresden (n=9607), Munich
(n=33,496) and Saarland (n=7556). Guideline adherence was examined
first by means of annual percentages of the quality indicators breast
conserving surgery (BCS) and sentinel lymph node biopsy (SLNB), and
subsequently with multiple logistic models for three time periods. For
the interpretation of outcome quality (survival), cox regression models
were additionally calculated.
Results. Although regional differences in the frequency and speed of
realization of the quality care procedures BCS and SLNB were observed, both procedures were already conducted in all four regions before
the implementation of the S3 guidelines. Regarding the different distribution of prognostic factors, patients with small (pT1/2) tumours had
a 2.6-fold higher chance for BCS in the western regions compared to
the eastern regions during the period from 1999 to 2003. This difference
declined to an odds ratio (OR) of 1.2 in the period 2008 to 2010. While
SLNB has been known to be effective for the definition of nodal status
since 2003, it was not recommended in German guidelines for clinical
routine until 2008. Nevertheless, SLNB rates rose rapidly in all regions
starting in 2003, although faster rates were observed in the western regions than in the eastern regions. Between 2003 and 2007, the chance
of receiving SLNB was 3.2-fold higher in the west than in the east, but
these rates converged in 2008–2010 (OR 1.3). Such regional differences
in procedural quality could not be observed in the quality of outcome.
The better 10-year overall survival in Munich can largely be described
by different distributions of prognostic factors.
Conclusion. Concerning BCS and SLNB, guideline recommendations
were already practiced in all four German regions before their implementation. The East-West differences in the proportions of these procedures declined over the years and the speed of realisation seems not to
have had any impact on survival.
0128
Population-based consequences of mammography screening for
therapy of breast cancer patients. An analysis of Bavarian cancer
registry data
*S. Schrodi1, U. Braisch2, G. Schenkirsch3, T. Maisel4, S. Petsch5, M. Klinkhammer-Schalke6, D. Hölzel1, U. Mäder7, S.H. Heywang-Köbrunner8, M. Meyer2,
J. Engel1
1
Deutschland, 2Bevölkerungsbezogenes Krebsregister Bayern, Registerstelle, Erlangen, Deutschland, 3Tumorzentrum Augsburg, Augsburg, Deutschland, 4Klinikregister Bayreuth, Bayreuth, Deutschland, 5Tumorzentrum der
Universität Erlangen-Nürnberg, Erlangen, Deutschland, 6Tumorzentrum
Regensburg, Regensburg, Deutschland, 7Tumorzentrum Würzburg,
Würzburg, Deutschland, 8Referenzzentrum Mammographie München,
München, Deutschland
Purpose. A quality controlled mammography screening program was
initiated at the end of 2003 in Bavaria, a region with 12.5 million inhabitants, and transferred over to the national screening program at
the end of 2006. The purpose of this study was to evaluate immediate
population-based consequences of mammography screening on breast
cancer therapy.
Methods. Data from 75,475 breast cancer cases, diagnosed between 2000
and 2008 and registered in one of the six Bavarian clinical cancer registries were analysed. 51.4% of these patients were between 50 and 69 years of age and therefore the target population for screening. Trends of
prognostic factors and standard therapies were calculated for three age
groups (≤49 years, 50–69 years, ≥70 years) by means of annual percentages as well as 95%-confidence intervals for the percent difference between 2000 and 2008 (year of diagnosis). For interpretation of therapy
trends, logistic regression models were calculated.
Results. Therapy trends showed that the increasingly favourable stage
distribution may have resulted in the reduction of more radical surgical methods such as mastectomy (2000: 32.6%; 2008: 19.6%) or axillary
dissection (89.0% vs. 37.0%). An increase of radiation therapies (59.7%
vs. 66.6%) can be explained to some extent by the increase in breast conserving surgeries. The shift to more favourable prognostic factors led,
in accordance with the guidelines, to an increase of the proportion of
singular endocrine therapies (28.5% vs. 40.7%), a decrease of chemotherapies (20.4% vs. 13.1%) and therefore to more gentle systemic therapies
overall. These trends strengthened in the years following the introduction of screening, with a simultaneous rise of screening participants in
the target population.
Conclusion. The introduction of mammography screening in Bavaria
already shows the expected trend towards more favourable prognostic
factors. Among other things, this could be a reason for the increasing
use of more gentle therapies. Whether the screening in Bavaria leads
to a mortality reduction, has to be analysed on the basis of an initial
comparison of participation status followed by the trends in mortality
thereafter.
0139
Pegylated liposomal doxorubicin (PLD) and carboplatin in
malignant mixed epithelial mesenchymal and mesenchymal
gynecologic tumors. A meta-analysis of three prospective AGO
Study Group trials
*P. Harter1, A. Reuss2, L. C. Hanker3, J. Sehouli4, K. Baumann5, W. Meier6, P.
Wimberger7, W. Schröder8, A. Burges9, A. du Bois1
1
Kliniken Essen Mitte, Gynäkologie & Gynäkologische Onkologie, Essen,
Deutschland, 2Universitätsklinikum Gießen und Marburg, KKS, Marburg, Deutschland, 3Johann Wolfgang Goethe Universität, Frauenklinik,
Frankfurt, Deutschland, 4Charite Campus Virchow, Frauenklinik, Berlin,
Deutschland, 5Universitätsklinikum Gießen und Marburg, Frauenklinik,
Marburg, Deutschland, 6Evangelisches Krankenhaus, Frauenklinik, Düsseldorf, Deutschland, 7Universitätsklinik, Frauenklinik, Essen, Deutschland,
8
GYNAEKOLOGICUM, Bremen, Deutschland, 9Uniklinikum Großhadern,
Frauenklinik, München, Deutschland
Background. After conduction of a pure gynecologic sarcoma trial
(AGO-GYN7), showing promising activity of PLD and carboplatin, we
decided to perform a meta-analysis including two other trials in whom
patients with gynecologic sarcoma treated with the same regimen were
included.
Methods. Patients of the AGO-GYN 2, AGO-GYN 3, and AGO-GYN 7
trial with advanced or recurrent gynecologic sarcoma or carcinosarcoma were included. AGO-GYN 2 was a dose finding phase I/II trial (PLD
20 to 50 mg and carboplatin AUC 6). The 2 other trials investigated PLD
40 mg/m2 and carboplatin AUC 6, q28.
Results. 59 patients were included in this analysis: 30 pts with carcinosarcoma, 20 pts with leiomyosarcoma, and 9 pts with endometrial stromal sarcoma. 93% of the patients had first diagnosis. 91.5% of the pts
were treated with PLD 40 mg/m2 and carboplatin AUC 6, q28d. The
incidence of grade 3/4 hematologic toxicities was: anemia 17.0%, neutropenia 52.6%, and thrombocytopenia 23.8%. There was one febrile
neutropenia. Main grade 3/4 non-hematologic toxicities were: PPE 5.1%,
and constipation 3.4%. The rate of CR/PR was 31.6%, CR/PR/SD 68.4%
(58.8% in carcinosarcoma, 80% in leiomyosarcoma, 66.7% in endometrial stromal sarcoma). 12 months PFS and OS was 38.1% and 74.6%,
respectively. 12 months PFS and OS in carcinosarcoma was 37.6% and
71.3%, and in leiomyosarcoma and endometrial stromal sarcoma 37.9%
and 78.6%.
Conclusions. The combination of PLD and carboplatin is active in this
indication. The safety profile seems to be favourable compared to other
widely used combination therapies for these diseases.
0144
Review of screening mammograms from interval cancers – First
results of the pilot study of mammography screening in Lower
Saxony
*I. Urbschat1, G. Hecht2, J. Kieschke1
Epidemiologisches Krebsregister Niedersachsen (EKN), Registerstelle,
Oldenburg, Deutschland, 2Referenzzentrum Mammographie Nord, Oldenburg, Deutschland
1
Aim. Interval cancers (IV-Ca) are breast cancers which appear between
two screening examinations. The detection of IV-Ca is of crucial importance for the quality of any screening program and is a key parameter defined in the EU Guidelines. The goal of the quality assurance of
IV-Ca is to categorize them into five categories (“true interval cancer”,
“minimal sign”, “false-negatives”, “radiological occult”, “unclassifiable”) and to guarantee an optimisation of the quality of the screening
(§ 23 Abs. 10 Krebsfrüherkennungs-Richtlinie vom 15.10.09). The pilot
study in Lower Saxony will provide the opportunity to gain experiences with the different review processes of IV-Ca in Germany.
Methods. In June 2010, IV-Ca were identified by record linkage of data
from the population-based epidemiological cancer registry in Lower
Saxony (EKN) with the data of 25,000 women, who attended the 2006
mammography screening in one screening unit of Lower Saxony. The
classification of “false-negative” cases initially had to take place only
with the retrospective reviewing of the screening mammograms of the
IV-Ca without diagnostic mammograms (provisional classification).
Afterwards, the review will be repeated with medical tumour data
from EKN (ICD-10 code, side, localisation, tumour size). Lastly and
according to the EU Guidelines, radiologists should compare the screening mammograms with diagnostic mammograms to categorize them
into five categories (definitive classification).
Results. 65 IV-Ca were identified in the EKN; 22 of them were diagnosed in the first year after screening, 43 in the second year. First results
of the “provisional classification” will be shown.
Discussion: For optimisation of the quality of the mammography screening program, the results of the first review process (provisional classification) would be reported to the radiologists of the screening unit.
Actually, there are no possibilities to make a “definitive classification”
of all IV-Ca, because diagnostic mammograms are not available for
all patients. Without “definitive classification” there are no comparable results of IV-Ca-rates and frequencies of false-negative diagnoses.
In contrast to the Scandinavian and some other European countries,
in Germany the diagnostic records and mammograms can only be
accessed with the consent of the patient; this will be difficult for the
screening program. Alternatively, the government can enact laws to
facilitate the transfer of the diagnostic mammograms.
0146
Mammakarzinom und Adipositas – was zeigen die deutschen
BRENDA-Daten?
*L. Schwentner1, R. Wolters2, M. Wischnewsky2, C. Kurzeder3, R. Kreienberg1, A. Wöckel1
1
Universität Ulm, Gynäkologie und Geburtshilfe, Ulm, Deutschland, 2Universität Bremen, E-science, Bremen, Deutschland, 3Klinikum Essen Mitte,
Gynäkologische Onkologie, Essen, Deutschland
Einleitung. BRENDA („Breast Cancer Care under evidence-based-guidelines“) ist eine multizentrische Versorgungsforschungsstudie von
Patientinnen mit primärem Mammakarzinom. Ziel dieser KohortenStudie war die Untersuchung einer Korrelation zwischen Body-MassIndex (BMI) und dem Endpunkt RFS unter Berücksichtigung der adjuvanten Therapie.
Methoden. In einer Subgruppenanalyse des BRENDA-Kollektives
wurden retrospektiv die Daten von 4912 Patientinnen in multivariaten
Analysen untersucht.
Ergebnisse. Insgesamt lag bei 3992 (81,3%) Patientinnen ein BMI <30
und bei 929 (18,7%) ein BMI >30 vor. In der Gruppe der östrogenrezeptorpositiven Mammakarzinome zeigte sich ein signifikanter Überlebensvorteil für Patientinnen mit einem BMI <30 (RFS: p=0.001;
HR=1.46 (95%CI: 1.17–1.81). Bei rezeptornegativen Patientinnen zeigte sich kein Unterschied (p=0,84). Hinsichtlich des Menopausenstatus zeigte sich ein Trend für ein höheres RFS in der Gruppe der
prämenopausalen Patientinnen (p=0,15) beim Vergleich der normgewichtigen und adipösen Patientinnen, und ein signifikanter Überlebensvorteil bei den postmenopausalen Patientinnen zugunsten eines
BMI <30 (p<0,001). Patientinnen, die eine endokrine Therapie oder
eine Chemo- gefolgt von einer endokrinen Therapie erhalten hatten,
profitierten ebenfalls signifikant von einem BMI <30. Im Falle einer
endokrinen Therapie zeigte sich in der Gruppe der postmenopausalen
Patientinnen ein Überlebensvorteil für Aromatasehemmer bei normgewichtigen Patientinnen, während Adipöse eher von der Einnahme
von Tamoxifen profitierten.
Diskussion. Auch das BRENDA-Kollektiv zeigt die hohe prognostische
Bedeutung eines hohen BMI bei Patientinnen mit primärem MamJournal of Cancer Research and Clinical Oncology Suppl 1 · 2011 | 71
Abstracts
makarzinom. Weitere prospektive Studien müssen bestätigen, welche
Therapieformen bei hohem BMI das Outcome im adjuvanten Setting
günstig beeinflussen.
months for A arm and 13.21 (10.612–16.000) months for P arm; HR=1.099
(0.919–1.315); p=0.301.
Conclusion. Treatment with A did not translate into a prolonged PFS.
0160
Abagovomab maintenance therapy in patients with ovarian cancer after complete response (CR) post-first-line chemotherapy:
Results of the randomized, double-blind, placebo-controlled,
multicenter AGO-OVAR 10 (MIMOSA) trial
0169
The adhesion molecule L1CAM as novel therapeutic target for
highly malignant pancreatic and ovarian carcinoma
*S. Mahner1, P. Harter2,3, J. Sehouli4, W. Meier5, P. Wimberger6, N. de
Gregorio7, A. Hasenburg8, K. Baumann9, B. Schmalfeldt10, L. Hanker11,
E. Solomayer12,13, A. Staehle14, M. Beckmann15, U. Canzler16, A. Burges17,
K. Wollschlaeger18, P. Hillemanns19, C. Jackisch20, F. Hilpert21, G. Emons22,
W. Schröder23, A. Belau24, B. Richter25, J. Pfisterer26, AGO Study Group and
Mimosa Investigators27
1
Universitätsklinikum Hamburg-Eppendorf, Gynäkologie, Hamburg,
Deutschland, 2Kliniken Essen-Mitte, Klinik für Gynäkologie und Gynäkologische Onkologie, Essen, Deutschland, 3HSK, Klinik für Gynäkologie und
Gynäkologische Onkologie, Wiesbaden, Deutschland, 4Charite Campus
Virchow Klinikum, Frauenklinik, Berlin, Deutschland, 5Evangelisches
Krankenhaus Düsseldorf, Klinik für Gynäkologie, Düsseldorf, Deutschland,
6
Universitätsklinik Essen, Frauenklinik, Essen, Deutschland, 7Universitätsklinik Ulm, Frauenklinik, Ulm, Deutschland, 8Universität Freiburg,
Frauenklinik, Freiburg, Deutschland, 9Universität Marburg, Frauenklinik,
Marburg, Deutschland, 10Klinikum Rechts der Isar, Frauenklinik, München,
Deutschland, 11Universität Frankfurt, Frauenklinik, Frankfurt, Deutschland,
12
Universität Tübingen, Frauenklinik, Tübingen, Deutschland, 13Universität
des Saarlandes, Frauenklinik, Homburg, Deutschland, 14Klinikum Karlsruhe,
Frauenklinik, Karlsruhe, Deutschland, 15Universität Erlangen, Frauenklinik,
Erlangen, Deutschland, 16Universität Dresden, Frauenklinik, Dresden,
Deutschland, 17Klinikum Großhadern, Frauenklinik, München, Deutschland,
18
Universität Magdeburg, Frauenklinik, Magdeburg, Deutschland, 19Medizinische Hochschule Hannover, Frauenklinik, Hannover, Deutschland,
20
Klinikum Offenbach, Frauenklinik, Offenbach, Deutschland, 21Universität
Kiel, Frauenklinik, Kiel, Deutschland, 22Universität Göttingen, Frauenklinik,
Göttingen, Deutschland, 23Klinikum Bremen-Mitte, Frauenklinik, Bremen,
Deutschland, 24Universität Greifswald, Frauenklinik, Greifswald, Deutschland, 25Klinikum Radebeul, Frauenklinik, Radebeul, Deutschland, 26Klinikum
Solingen, Frauenklinik, Solingen, Deutschland, 27AGO Study Group, Mimosa
Investigators, Deutschland
Background. Abagovomab (A), a murine monoclonal anti-idiotypic
antibody directed against CA125, has been shown to induce an active
immune response against CA125 tumor-associated antigen in advanced
ovarian cancer patients.
Methods. A has been tested in a randomized (2:1) double-blind, placebo
(P) controlled, multicenter phase III trial in patients with FIGO stage
III/IV ovarian cancer after complete response to platinum-taxane firstline chemotherapy. A (2 mg/1 ml) or P was given subcutaneously every
2 weeks for 6 weeks (induction phase); then every 4 weeks (maintenance
phase) until recurrence, or up to 21 months after the last patient had
been randomized. Primary endpoint is progression-free survival (PFS);
secondary endpoints are OS and immunological response. An estimated 870 patients, with a mean follow-up of 18 months, were needed to
observe at least 535 recurrences, which provides a power >90% in rejecting the null hypothesis of equality between A and P on PFS according
to an HR (hazard ratio) of 1.33. Primary analysis was run on PFS in the
ITT population.
Results. 888 patients were enrolled by December 2008, 593 in A arm
and 295 in P arm. The median follow-up was 28.1 months and the mean
number treatment administrations was 18. Baseline characteristics
were balanced between arms. Overall tolerability profile was consistent
with previous A studies. Median (95% CI) PFS was 13.24 (10.612–13.602)
C. Dieckmann1, O. Korniienko2, G. Moldenhauer3, A. Krüger4, P. Altevogt3,
H. Schäfer1, *S. Sebens5
1
Department of Internal Medicine I, Laboratory for Molecular Gastroenterology & Hepatology, Kiel, Deutschland, 2Institute for Experimental
Cancer Research, Molecular Oncology, Kiel, Deutschland, 3German Cancer
Research Center, Translational Immunology D015, Heidelberg, Deutschland,
4
Technische Universität München, Institute of Experimental Oncology and
Therapy Research, München, Deutschland, 5Department of Internal Medicine I, Institute for Experimental Medicine, Kiel, Deutschland
Background. The adhesion molecule L1CAM (CD171) accounts for enhanced motility, invasiveness and chemoresistance of tumor cells and
thus represents a promising therapeutic target structure for various tumor entities. In pancreatic ductal adenocarcinoma (PDAC) and ovarian
carcinoma elevated L1CAM expression has been detected being associated with an advanced tumor stage and poor prognosis.
Aim. The present study intended to evaluate the therapeutic potential
of combined treatment with L1CAM antibodies and chemotherapeutic
drugs in PDAC and ovarian carcinoma model systems in vivo.
Methods and results. Two L1CAM-specific antibodies showing strong
binding to the L1CAM expressing PDAC cell line Colo357 and the ovarian carcinoma cell line SKOV3ip were used for treatment regimens.
Combined therapy of SCID mice with either L1CAM antibody and gemcitabine and paclitaxel, respectively, reduced the growth of Colo357 or
SKOV3ip tumors more efficiently than the treatment with the cytostatic
drug alone or in combination with control IgG. The improved therapeutic response was accompanied by an increased number of apoptotic
tumor cells, whereas proliferation of the tumor cells was not affected by
combined treatment. Furthermore, a lowered activation of NF-kB along
with a reduced expression of VEGF and a diminished number of CD31positive blood vessels were observed in tumors after combined therapy
compared to control treatments, while the infiltration of macrophages
was enhanced.
Conclusion. Overall, these data support the suitability of L1CAM as therapeutic target and of L1CAM-interfering antibodies as an appropriate
tool for an improved therapy of PDAC and ovarian carcinoma.
0181
Patient’s Perception and possibilities of optimization of clinical
trials in gynaecological oncology
*S.-M. Knetzger1, T. Hildebrandt1, M. Bani1, C. Bayer1, A. Hein1, L. Kahmann1,
C. Löhberg1, S. Jud1, M. Schauder1, F. C. Thiel1, P. Fasching1, M. Beckmann1,
M. P. Lux1
1
Frauenklinik, Universitätsklinikum Erlangen, Universitäts-Brustzentrum
Franken, Erlangen, Deutschland
Introduction. Clinical trials are becoming more and more important to
optimize prevention, diagnosis and therapy. They contribute towards
transferring the latest knowledge to daily clinical life. Moreover, the option of participating in trials is a criterion of quality – certified centres
are obliged to offer trials as well as to fulfil trial-quotes. On the other
hand, trials are highly dependent on the cooperation of patients. Therefore the perception of clinical studies and the possibilities to optimize
the offers from the patient’s point of view is very important.
Material and methods. 2500 women are surveyed on the topics of perception and optimization of clinical trials by 24 specific questions. The
results are compared relating to disease entity and other anamnestic
factors.
Results. 1029 patients could be evaluated (24.0% senological, 8.1% gynaecologic-oncological, 29.3% obstetrical, 7.5% with endometriosis, 2.0%
with desire of children, 21.9% others and 6.6% with missing categorization). Knowledge about clinical trials turned out to be very heterogeneous; e.g. only 18.5% of the participants know the term “randomisation”. 91.9% consider clinical trials as useful (0.7% not useful, 7.4% do not
know). In contrast, only 54.2% would participate in a clinical trial, 18.0%
reject this and 27.8% are undecided. 69.9% support the participation in
surveys and 64.4% would take part in trials to improve diagnosis. Only
13.0% agree with drug testing trials. Regarding the treatment in clinical
trials, 24.2% judge the quality of care better and 20.6% worse than treatment outside of trials (55.2% do not know). But 49.6% of the patients believe that they will get the best possible treatment within clinical trials.
While financial compensation would only influence the willingness to
participate of 11.8%, 33.4% of the patients think that a recommendation
of the German Cancer Society would be a positive factor for participation. 82.7% mention the medical specialist as the most important source
of information about clinical trials. Significant differences were found
in the sub-groups, which will be presented in detail.
Summary. Generally a high percentage of patients consider clinical trials
as important, though trials for drug testing are still seen most critically.
Knowledge about trails is very heterogeneous. More educational work
seems to be necessary, whereby patients have clear wishes and suggestions.
0182
Implementierung genexpressionsanalytischer Verfahren zur
Bestimmung des individuellen Mammakarzinomrückfallrisikos
in die klinische Praxis – Implementation of gene array methods
to determine the risk of recurrence in breast cancer in clinical
routine
*S. Paepke1, P. Völkel1, H. Bronger1, J. Ettl1, M. Kiechle1
1
Technische Universität München, Klinikum rechts der Isar, Frauenklinik,
Introduction. The biomarkers used so far to asses prediction and prognosis of early breast cancer are unreliable to a certain extent; grading
shows a high intraobserver variability, Ki67 is not validated enough to
differentiate between intermediate and highly proliferative disease, and
lymph node status is subordinated to tumor biology. Genomic arrays
(70- and 21-gene array) are available and partly used internationally in
clinical decision making, in Germany, however, only in clinical trials or
in individual cases.
Material and methods. At the IBZ (interdisciplinary breast center) of the
Technische Universität München an algorithm was developed for the
use of the 21-gene array in routine diagnostics, which leads to a therapy
decision change in 60% of the cases tested. The MammaPrint® test is a
DNA-micro array based diagnostic, multivariate in-vitro-Index-Assay
(IVDMIA) and measures the activity of 70 genes to determine the probability of recurrent disease (as low or high risk group). MammaPrint®
is used in both ER positive and ER negative stage I and II breast cancer
with up to three positive lymph nodes.
Concept. In a cohort study 15 cases in which the MammaPrint® assay
was used were compared to the standard collective. We expect that between 30% and 50% less cases will include chemotherapy in their therapy
recommendations. The actual therapy changes and the cost-benefit ratio are analysed as these will be relevant for an implementation of the
test in clinical routine.
Outlook. The feasibility of MammaPrint® in clinical routine has been
confirmed in several trials; an implementation in routine diagnostics
must be critically discussed on the basis of prospectively collected data
relevant to the German health care system. The results from the IBZ of
the TU München are be presented.
0191
BKM120 in advanced endometrial cancer: an update on clinical
trials
*J. Sehouli1, B. Gerber2, L. Trandafir3, C. Massacesi3, N. Fretault3, J. Stieglmaier4, M. Potzner4, W. Lichtenegger5
1
Charité Berlin, Europäisches Kompetenzzentrum für Eierstockkrebs, Berlin,
Deutschland, 2Klinikum Südstadt, Universitätsfrauenklinik und Poliklinik,
Rostock, Deutschland, 3Novartis Pharma, S.A.S., Rueil-Malmaison, Frankreich, 4Novartis Pharma, OCF, Nürnberg, Deutschland, 5Charité Berlin, Klinik
für Frauenheilkunde und Geburtshilfe, Berlin, Deutschland
Background. BKM120 is an oral pan-class I PI3K inhibitor targeting the
PI3K/AKT/mTOR pathway which is commonly deregulated in cancer.
The PI3K pathway is a key signal transduction system linking multiple
oncogenes, tumor suppressors and receptor classes to essential cellular
functions e.g. cell growth. Alterations of key components, like activating mutations of PIK3CA (the gene encoding the PI3K catalytic subunit) and loss of PTEN (phosphatase and the tensin homolog), trigger
aberrant activation of the pathway signaling, leading to a modulation
of different cell processes. BKM120 is an oral agent that showed potent
antitumor activity in preclinical research and has demonstrated antiproliferative effects in endometrial carcinoma (EC) cell-lines and xenograft models.
Current development. Most ECs showed dependency on PI3K pathway
activation. Both PIK3CA and PTEN alterations are observed. Mutations in both genes lead to an activation of the PI3K pathway signaling
in 26–36% and 26–59% of endometrioid EC, respectively, and in 5–21%
and 0–11% of non-endometrioid EC. Thus, efficacy of BKM120 is currently investigated in a prospective multi-center, open-label, single arm,
phase II study in patients with advanced, metastatic endometrial cancer. Adult patients with ECs whose disease progressed while on or after
first-line antineoplastic treatment for advanced EC who have not been
treated with any PI3K inhibitor are enrolled. After enrollment, PI3Kpathway activation status will be assessed, and defined as: PIK3CA mutation and/or PTEN mutation and/or PTEN-negative expression (<10%
staining by immunohistochemistry). The primary endpoint is overall
response rate per RECIST in all patients and in patients with PI3K pathway activation. Secondary endpoints include PFS, ORR in patients
with non-activated PI3K-pathway tumors, duration of response, overall
survival, safety and tolerability.
Conclusion. In context of large phase II programs first trials in ECs are
currently enrolling patients. This study will provide clinical data on the
relevance of PI3K-pathway inhibition in patients with advanced EC who
failed chemotherapy.
0199
Axillary lymph node dissection (ALND) in patients with sentinel
node metastasis has impact on treatment recommendations of
an interdisciplinary tumor board (ITB)
*J. Aigner1, K. Smetanay1, H.P. Sinn2, H. Hof3, C. Sohn1, A. Schneeweiss1,
F. Marme1
1
Universitätsklinik Heidelberg, Frauenklinik/NCT Gyn Onko, Heidelberg,
Djibouti, 2Universität Heidelberg, Pathologie, Heidelberg, Deutschland,
3
Universität Heidelberg, Radioonkologie, Heidelberg, Deutschland
Objective. Some studies have shown that ALND can be omitted without
adversely affecting prognosis in patients with cT1-2 cN0 primary breast
cancer (PBC) who showed one or two sentinel node metastasis [pN(1-2+
sn)] and underwent breast conserving surgery with postoperative whole
breast irradiation (BET). In those patients within our registry we investigated retrospectively the impact of ALND following one or two positive sentinel nodes on the recommendation of an ITB regarding adjuvant
chemotherapy und loco-regional irradiation.
Material and methods. We re-evaluated all patients with cT1-2 cN0 pN(1–
2+ sn) PBC who were consecutively diagnosed and treated with BET in
Abstracts
our breast unit since 2003. For each patient an ITB gave two treatment
recommendations: The first recommendation based on the results available from the sentinel node biopsy (ITB I). The second recommendation based on the results of the secondary axillary dissection (ITB II).
We evaluated differences regarding the indication of chemotherapy (yes
versus no), the type of adjuvant chemotherapy (conventional scheduled
versus dose dense regimes) and the type of radiotherapy (whole breast
irradiation with or without irradiation of regional lymph nodes).
Results. 170 patients were enrolled. 133 had one and 28 had two tumor
involved sentinel nodes. Comparing the two ITB recommendations for
each patient we could demonstrate an overall difference in 33 (20%) patients. In 29 (17%) patients ITB II recommended a more intensive treatment i.e. dose dense chemotherapy and/or additional irradiation of the
lymph nodes. In 4 patients (2.4%) a chemotherapy was recommended by
ITB I but not by ITB II.
Conclusion. Our results showed that a secondary ALND might have
a strong impact on treatment recommendations of an ITB favouring
more intensive adjuvant chemotherapy and/or irradiation.
0200
Carboplatin plus weekly Paclitaxel as an effective, non-anthracyclin-containing preoperative chemotherapy in triple negative
breast cancer (TNBC)
*L. Kahmann1, C.R. Löhberg1, M.G. Schrauder1, M.R. Bani1, C.M. Bayer1,
O. Strahl1, A. Hartmann2, R. Schulz-Wendtlandt3, E. Wenkel3, P.A. Fasching1,
M.W. Beckmann1, M.P. Lux1
1
Frauenklinik des Universitätsklinikums Erlangen, Universitätsstraße 21-23,
Deutschland, 2Pathologisches Institut des Universitätsklinikums Erlangen,
Erlangen, Deutschland, 3Institut für diagnostische Radiologie des Universitätsklinikums Erlangen, Erlangen, Deutschland
Objective. Despite substantial progresses in breast cancer therapy, patients with TNBC still remain a challenge. Pathological complete response (pCR) is one of the most important prognostic markers in preoperative setting of breast cancer treatment. Platinum-containing regimens
have been included as a possible preoperative option for patients with
TNBC into the recommendations of the AGO in 2011, due to increasing
data showing a high degree of effectiveness. The aim of this retrospective analysis is to evaluate the pCR rate after preoperative chemotherapy
with Carboplatin and Paclitaxel in the treatment patients with TNBC.
Methods. 20 patients with TNBC received preoperative chemotherapy
with six cycles of carboplatin (AUC 5), d1, in combination with paclitaxel (80 mg/m2), d1, 8, 15, q21d. Evaluation of clinical response was done
after cycle three and six by palpation and mammography/ ultrasound.
pCR was defined as no invasive cancer in the breast and axillary specimen after breast-conserving therapy/ breast ablation plus axillary dissection (pT0/pTis and pN0).
Results. 15 of 20 patients received surgery (breast-conserving therapy/
breast ablation plus axillary dissection). Clinical (cCR) and pCR were
seen in 46% (n=7/15) and 60% (n=9/15), respectively. Histological assessment showed a general response of minimum SINN grade 2.The
combination of carboplatin and paclitaxel was well tolerated except one
peripheral polyneuropathy grade 3 (NCI-CTC).
Conclusion. The combination of carboplatin (AUC 5), d1, and paclitaxel
(80 mg/m2), d1, 8, 15, q21d, in the preoperative setting is a highly effective and well tolerated option for patients with TNBC. Final results are
expected for December 2011 and will be demonstrated. Results of this
retrospective analysis should be proofed in major prospective, randomised trials.
0201
Whole gene expression profiling in patients with primary breast
cancer
*J. Aigner1, K. Smetanay1, M. Zapatka2, B. Burwinkel1, H. Junkermann1,
F. Marme1, H.P. Sinn1, P. Lichter2, C. Sohn1, A. Schneeweiss1
1
Universitätsklinik Heidelberg, Frauenklinik/NCT Gyn Onko, Heidelberg,
Deutschland, 2Universität Heidelberg DKFZ, Biologie, Heidelberg, Deutschland
Objective. Breast cancer is a heterogeneous disease in terms of therapeutic response and patients’ outcome. Gene expression analysis provides
new classification systems on the molecular level which might be used
to determine prognosis of outcome and prediction of response to specific therapies leading to a more individualized treatment for each patient.
The aim of our program is to validate prospectively four gene expression
signatures on our own platform which were either already commercially available or have been extensively tested within clinical trials.
Material and methods. Since 11/2010 patients with primary invasive breast cancer received one additional core biopsy at diagnosis to perform
a whole gene expression profiling and read out the expression of genes
belonging to the signatures Intrinsic Signature (IS), Genomic Grade Index (GGI), Recurrence Score (RS) and Amsterdam Signature (AS). In a
second step subtypes according to IS (luminal A, luminal B, HER2-enriched, basal-like), GGI (low, high), RS (low risk, intermediate risk, high
risk) and AS (low risk, high risk) were correlated with the immunohistochemical determined subtypes according to the expression of estrogen receptor (ER), progesterone receptor (PgR), HER2 and Ki-67 (luminal A-like: ER and PgR positive (+), HER2 negative (−), Ki-67 <14%;
luminal B-like: ER+ and either PgR− or HER2+ or Ki-67 >14%; HER2like: ER and PgR−, HER2+; triple negative: ER and PgR and HER-) and
the histological grade (G1–2, G3).
Results. Until June 2011, 94 patients have been enrolled. 18 patients had
to be excluded. 23 (30%) had tumor involved lymph nodes. Histological
grade I, II and III was reported in 8 (11%), 41 (54%) and 27 (36%) patients. 63 (83%) patients had a ER/PgR positive and 69 (91%) patients a
HER2 negative breast cancer. 51 patients showed a Ki-67>14%. The concordance between subgroups according to immunohistochemistry and
IS or GGI was 16% and 70%. Most G2 patients showed a low risk GGI.
A validation of RS and AS with the commercial available tests is still in
process.
Conclusion. In our cohort of primary breast cancer, thus far, there is
only partial overlap of subtypes according to immunohistochemistry
and gene expression analyses. Gene expression signatures as prognostic
or predictive markers have to be validated prospectively before they are
used outside of clinical trials. Updated results will be presented at the
meeting.
0203
A consecutive series of 12 heavily obese endometrial cancer
patients treated by robotic laparoscopic surgery
*Z. Maden1, P. Kannisto1, P. Harter1, A. du Bois1
1
Kliniken-Essen-Mitte, Gynäkologische Onkologie, Essen, Deutschland
Objective. The robotic technique was introduced in February 2011 in
our centre. We report here the first 12 consecutive cases of endometrial
cancer.
Methods. Surgery was performed by the SE da Vinci system without
uterine manipulator but with four robot arms. All patients got perioperative antibiotics as well as low molecular heparin.
Results. The mean BMI value was 40.6 and 33% of the patients had at
least one former abdominal surgery. Mean blood loss for the robot procedures was 140 ml. The average skin-to-skin time was 222 minutes.
The pressure controlled ventilation was used during anesthesia and the
PEEP values were kept 5–7 mmHg. There was a preparedness for early
intervention with cathecholamines. Ventilation was controlled by tran-
cutaneous CO2 monitoring, which has previously been shown to reduce
the risk of respiratory acidosis significantly. The conversion rate to laparatomy was 8.3% (1/12 pts) due to multiple adhesions and intestinal injury. The only severe complication was observed in a patient with BMI 70.
She had double dose heparine and experienced a heavy bleeding from
vaginal cuff 16 days after da Vinci surgery. A laparatomy was performed
and she suffered thereafter from a wound infection.
Conclusion. Robotic assisted hysterectomy is a safe procedure and showed a considerably low rate of major complications in this morbidly
obese group of endometrial cancer patients.
0205
Quality of life and therapy expectations of patients with recurrent platinum-sensitive ovarian cancer – a German substudy of
the Calypso/AGO-Ovar 2.9 trial
*K.H. Baumann1, J. Sehouli2, A. du Bois3, D. Lubbe4, P. Wimberger5,
M.W. Beckmann6, F. Hilpert7, L.C. Hanker8, A. Hasenburg9, B. Richter10,
S. Mahner11, A. Burges11,12, E. Pujade-Lauraine13, U. Wagner1
1
Universitätsklinikum Gießen und Marburg, Standort Marburg, Gynäkologie, Gyn. Endokrinologie und Onkologie, Marburg, Deutschland, 2Charite
– University Medicine of Berlin, Gynecology, Berlin, Deutschland, 3Hospital
Essen Mitte, Gynecology, Essen, Deutschland, 4University of Marburg, 4Coordinating Centre for Clinical Trials Marburg, Marburg, Deutschland, 5University of Duisburg-Essen, Gynecology and Obstetrics, Essen, Deutschland,
6
University of Erlangen, Gynecology and Obstetrics, Erlangen, Deutschland,
7
University Hospital of Kiel, Gynecology and Obstetrics, Kiel, Deutschland, 8University of Frankfurt, Gynecology and Obstetrics, Frankfurt am
Main, Deutschland, 9University of Freiburg, Gynecology and Obstetrics,
Freiburg, Deutschland, 10Elblandklinikum, Gynecology and Obstetrics,
Radebeul, Deutschland, 11University Medical Center Hamburg-Eppendorf,
Gynecology, Hamburg, Deutschland, 12Ludwig-Maximilians-University,
Gynecology and Obstetrics, München, Deutschland, 13Hopital Hotel Dieu,
Paris, Frankreich
Background. In patients receiving radiotherapy, correlations between
patients’ expectation regarding healing at start of therapy and quality
of life (QoL) have been reported. So far, in recurrent platinum-sensitive
ovarian cancer little is known about patients’ expectation undergoing
reinduction chemotherapy.
Objective. In this German substudy of the international CALYPSO/
AGO-Ovar 2.9 trial (JCO 28, 3323-9) patients’ subjective assessments of
success of therapy, and the relationship to QoL were evaluated. In the
CALYPSO/AGO-Ovar 2.9 trial patients with recurrent platinum sensitive ovarian cancer were randomized to receive carboplatin-paclitaxel
or carboplatin-pegylated liposomal doxorubicin chemotherapy. Systemic treatment consisted of 6–9 cycles carboplatin and paclitaxel (TC)
or carboplatin and pegylated liposomal doxorubicin (CD). At baseline
registration before randomization and at the end of therapy patients
completed the QoL questionaires (FACT-O, EORTC QLQ C-30 and
OV-28) and an expectations checklist (J Royal Soc Med 93, 621–8) with
the scores: “healing expectation”; “tumor and symptom control”; “pain
and emotional control”.
Results. Of 299 patients enrolled in Germany, 97 patients completed the
expectation checklist (50 in the TC arm; 47 in the CD arm). At baseline,
44 (TC) and 45 (CD) patients stated a positive “healing expectation”.
The subjective assessment of the patients at the end of therapy showed,
that 29 (CD) and 37 (TC) patients found their healing expectations fulfilled. Only one of the scales of the expectations checklist (“pain and
emotional control”) revealed a significant correlation with the QoL
questionnaires. Results of the QoL questionnaires and the expectations
checklist did not differ significantly between the treatment groups.
Conclusion. “Healing” was stated most frequently as expectation and assessment of success in patients with recurrent ovarian cancer, followed
by the other categories. QoL did not differ significantly between treat-
ment groups and patients with or without healing expectations, only
the expectation category “pain and emotional control” revealed some
correlation with the QoL questionnaires.
0224
Superparamagnetic nanoparticles for magnetic particle imaging
in breast cancer sentinel lymph node detection
*D. Finas1, K. Baumann1, B. Ruhland1, K. Heinrich1, K. Lüdtke-Buzug1, K. Diedrich1, T. Buzug1
1
Universität zu Lübeck, Klinik für Frauenheilkunde und Geburtshilfe,
Lübeck, Deutschland
Introduction. Radical axillary lymphonodectomy is associated with
high morbidity and significant loss of QoL. But, the exploration of the
axillary lymph nodes is part of the surgical staging in breast cancer.
The adverse effects decreased since the introduction of the sentinel lymphonodectomy (SNLB), were dyes and radio nuclides are injected. Super
paramagnetic iron oxide nano particles (SPIOs) could replace these
marker substances. Through the magnetic particle imaging (MPI), a
3D-imaging and distinct localization of SPIOs can be achieved in SNLB.
Qualitative and quantitative enrichment of SPIOs in the axillary lymphatic tissue is unexplored until now.
Methods. Within a healthy mouse model and than in a tumor bearing
mouse model with metastatic axillary lymph nodes we prove the principle of SNLB by MPI. Axillary and environmental tissues are analyzed
with different techniques: histology, Prussian blue staining, electron
microscopy, atomic absorption spectrometry and MPI spectrometry.
Nanoparticles are widely discussed as environmental toxins. Therefore,
we will extract the inoculated SPIOs from all organs and explore them
whether there are any SPIOs.
Results. We aim to show that SPIOs and the MPI technique are effective
to be used as SNLB tracer and finder as a new SNLB technique. This will
be less complex and incriminating for the patient and the staff. A new
MPI hand probe with unilateral solenoid arrangement designed for use
in the operating theater is under construction. Therewith the sentinel
lymph node detection can be easily performed after intra operative tracer application.
Conclusion. Intra operative 3D-imaging with the MPI hand probe facilitates the axillary SNL detection and moreover makes it more precise.
Through the avoidance of intensive surgical exploration of the axilla the
morbidity will be dramatically reduced. The tracer for MPI is easy to
obtain. This makes the method accessible to all patients. The concept of
SNLB by MPI can be applied in principle in all solid tumors.
Supported by the German Federal Ministry of Education and Research
(BMBF Grant number 01EZ0912). Part of the University Research Program Imaging of Disease Processes, University of Lübeck.
Abstract withdrawn
0228
Staging accuracy of gynaecological cancers with endorectal coil
MRI
*K. Brocker1, C. Alt1, C. Sohn1, M. Eichbaum1, P. Hallscheidt1
1
Universität Heidelberg, Frauenklinik, Heidelberg, Deutschland
Objective. Endometrial, cervical and vulvar cancer are frequent gynaecological cancers. The aim was to evaluate staging accuracy of MRI in
patients with primary endometrial, cervical or vulvar cancer using MRI
with an endorectal coil.
Material and methods. Patients with histologically proven cancers received 1.5T MRI with endorectal surface coil (eMRI) before surgery.
Performed sequences: sagittal, axial and coronal T2w turbo spin echo
(TSE), axial T1 incoherent gradient echo (gradient spoiled) 2D fat saturated (fs), sagittal T1 incoherent gradient echo (gradient spoiled) 3D
Abstracts
with/without contrast enhancement (CE), axial T1 TSE fs CE. eMRI staging was compared to histopathological results.
Results. 19 patients with vulvar cancer, 15/19 had primary surgery. 10 of
15 patients (pts) underwent eMRI, 5 underwent MRI without (w/o) endorectal surface coil due to eMRI contraindications. Histopathological
result was: 2 pts with stage T1a, 8 pts T1b, 4 pts T2 and one patient with
stage T3. Overall MRI accuracy was 53% (8/15), eMRI was 60% (6/10) and
MRI w/o endorectal coil was 40% (2/5). The urethra was histologically
affected in 5 cases, vagina in 3 cases, perineum and anus in 2 cases each.
Overall agreement of invasion of surrounding structures was 75% (9/12).
Histological proven lymph node (LN) affection in 7 of 15 pts, correctly
diagnosed with eMRI in 71% (5/7). If LNs were not affected, MRI staged
correctly N0. 33 pts with endometrial cancer, 21/33 with primary surgery. 8 pts had histological stage T1a, 10 pts T1b, 2 pts T2b, one patient T3a.
Overall eMRI staging accuracy of local tumor spread was 71% (15/21). In
lower tumor stage eMRI correctly diagnosed stage T1a in 6 of 8 pts and
T1b in 8 of 10 pts. In 2 cases eMRI overstaged, in 2 cases eMRI understaged. In only one patient LN were positive; correctly diagnosed by eMRI.
44 patients with cervical cancer received primary surgery of which 2
were inoperable. Histological results were 8/44 Cis, 3/44 T1a1, 2/44 T1a2,
15/44 T1b1, 1/44 T1b2, 0/44 T2a, 12/44 T2b, 0/44 T3 and 1/44 with T4 stage.
In 43% eMRI staged correctly, clinical examination staged correct in
47.6%. eMRI sensitivity of deciding between tumours up to T2a or a size
beyond was 92.3%, in clinical examination 38.5%. Uterine infiltration
was detected in 100% by eMRI.
Conclusion. eMRI presented high staging accuracy in lower endometrial tumour stage. In cervical cancer eMRI proved a reliable tool for tumours greater FIGO IIa improving the assessment of surround tumour
infiltration. In lower staged cases more practice and technical development is needed. In vulvar cancer eMRI is helpful for pretherapeutic
planning, especially for urethral involvement and lymph node affection. eMRI is a useful supplement in clinical gynaecological oncology
treatment planning.
0236
Targeting triple negative breast cancer through the luteinizing
hormone-releasing hormone receptor
*S. Seitz1,2, A.V. Schally2, A. Treszl2, F. Weber3, M. Mögele1, A. Machleidt1,
O. Ortmann1, S. Buchholz1,2
1
Universität Regensburg, Frauenheilkunde, Regensburg, Deutschland,
2
University of Miami, endocrine, polypeptide and cancer institute, Miami,
Deutschland, 3Universität, Pathologie, Regensburg, Deutschland
Introduction. Receptors for luteinizing hormone-releasing hormone receptor (LHRH-R) are expressed in >50% of human breast cancers. For
our knowledge to date the expression of LHRH-R in the distinct subtype of triple negative breast cancer (TNBC) was not evaluated. Systemic
treatment options for TNBC are limited to chemotherapy. New structures for targeted therapy would be very favourable. AN-152 [AEZS-108] is
a LHRH-analog conjugated to doxorubicin. AN-152 is targeted through
the peptide moiety to the LHRH-R. In this study we investigated the
expression of the LHRH-R on TNBC samples and the effect of AN-152
on tumor growth inhibition of AN-152 in an in vivo model.
Material and method. For the in vivo model we used the TNBC cell lines
MDA-MB-231 and HCC 1806. The cell lines were checked for LHRHreceptor expression by RT-PCR. Tumors grown from these cell lines
were xenotransplanted into nude mice subcutaneously. Animals were
randomised into three groups receiving solvent only (control), AN-152
(2.5 µmol/kg d 1, 7, 14 i.v.) or Doxorubicin (2.5 µmol/kg d 1, 7, 14 i.v.).
The experiment ended on day 28. The expression of LHRH-R on tumor
samples form patients with TNBC (n=69) was evaluated by immunhistochemistry.
Results. The LHRH-R was expressed in both cell lines on mRNA level.
In the animal experiment with the cell line MDA-MB-231 animals treated with AN-152 showed a significant (p<0.05) tumor growth inhibi-
tion compared to control and the doxorubicin group on day 14 which
lasted until the end of the experiment. Final tumor growth: control
1299% ±107; doxorubicin 1123% ±170; AN-152 620% ±160. In the animal
experiment with the cell line HCC 1806 animals treated with AN-152
showed also a significant tumor growth inhibition compared to control
and the doxorubicin group on day 14 in both cell lines which lasted until
the end of the study. Final tumor growth: control 2735% ±890; doxorubicin 2062% ±441; AN-152 1060% ±236. The samples from patients with
TNBC (n=69) showed in 49% positive staining for the LHRH-R by immunhistochemistry. There was no difference in grading, tumorsize or
nodal status between LHRH-R positive and negative cases.
Conclusion. The results showed an effective tumor growth inhibition
of TNBC treated with AN-152. This supports the concept of targeted
cytotoxic therapy. The LHRH-R was identified as a potential target
for the treatment of TNBC with the cytotoxic compound AN-152. The
LHRH-R has no influence on grading, tumorsize or nodal status.
0239
The antiapoptotic role of LFG in the carcinogenesis of human
breast cancer
*V. Bucan1, K. Reimers1, A. Lazaridis1, P.M. Vogt1
1
Medizinische Hochschule Hannover, Plastische Hand- und Wiederherstellung Chirurgie, Hannover, Deutschland
Background. Lifeguard (LFG) is an antiapoptotic protein that inhibits
death mediated by Fas in tumour cells. The molecular function of human LFG in the carcinogenesis of human breast cells, however, is uncertain. Here we studied the expression and function of endogenous LFG
in breast cancer cell line and in normal and tumour breast tissues.
Methods. Molecular (Western blot and RT-PCR) and immunohistochemical techniques were used to investigate LFG expression. To investigate the activation of caspase-3/7 in the breast cancer cells we using the
Apo-One Homogeneous Caspase-3/7 Assay. The possible association of
Fas with LFG was analyzed by immunofluorescence microscopy.
Results. In this study we provided convincing evidence that LFG is
overexpressed in several human breast cancer cell lines. Moreover, the
overexpression of LFG correlated with tumour grade. Our results therefore identify LFG as a target of the Akt/LEF-1 pathway in MDA-MB-231
breast tumour cells, a regulation which could play a key role in breast
tumour progression. Decreased LFG expression leads to an enhanced
sensitivity against treatment with agonistic Fas antibody or treatment
with perifosine.
Conclusion. Taken together, our findings underline the role of LFG as
an anti-apoptotic protein and give a further basis to investigate the
potential of LFG as a target for the development of novel therapeutic
strategies.
0241
Chloroquine and RAD001 lead to reduced mammary tumor
growth via inhibition of the PI3K/Akt/mTOR signaling cascade
*C.R. Loehberg1, P. Strissel1, R. Dittrich1, R. Strick1, J. Dittmer2, A. Dittmer2,
B. Fabry3, T. Koch3, W.A. Kalender3, D.L. Wachter4, A. Polier1, N. Groh1,
I. Brandt1, L. Lotz1, I. Hoffmann1, S. Oeser1, F. Koppitz1, A. Mueller1, P.A. Fasching1, M.P. Lux1, M.W. Beckmann1, M.G. Schrauder1
1
University Hospital of Erlangen, Dept. of OB/Gyn, Erlangen, Deutschland,
2
University Hospital of Halle, Dept. of OB/Gyn, Halle, Deutschland, 3University of Erlangen, Center for Medical Physics and Technology, Erlangen,
Deutschland, 4University Hospital of Erlangen, Dept. of Pathology, Erlangen, Deutschland
The PI3K/Akt/mTOR signaling cascade is frequently deregulated in
tumors, including breast cancer. Therapeutic modifications of this pathway exert anti-tumor effects. There is growing evidence that cytoplas-
matic and nuclear compartmentalization of the oncogene Akt and the
tumor suppressor mTOR are integrated in negative regulatory feedback
loops. The macrolide derivative of rapamycin RAD001 (everolimus) is
an inhibitor of the serine-threonine kinase mTOR, and was developed
as an anti-proliferative and anticancer agent. However, inhibition of
mTOR signaling by RAD001 leads to increased Akt activation through
phosphorylation. Akt activation abrogates RAD001-induced antiproliferative effects and results in RAD001 resistance.
Chloroquine is a 4-alkylamino substituted quinoline, an effective chemosensitizer when used in combination with PI3K/Akt inhibitors and
mediated breast cancer protective effects. Using MCF7 breast cancer
cells our aim was to test if Chloroquine could inhibit tumor growth
through PI3K signaling and overcome RAD001-induced Akt activation. Chloroquine and RAD001 inhibited phospho-mTOR and its
downstream target gene S6K1, especially in the nucleus. Importantly,
Chloroquine blocked the RAD001-induced phosphorylation of nuclear
phospho-Akt. Additionally, Chloroquine and RAD001 induced G1 cell
cycle arrest, reduced MCF7 breast cancer cell proliferation on a collagen matrix and disturbed formation of mammospheres. Furthermore,
Chloroquine and RAD001 together significantly reduced mammary
tumor growth in a murine xenograft model.
Our data show that Chloroquine exerts its anti-cancer effects through
modifications of the PI3K/Akt/mTOR pathway involving the nucleus
where cellular compartmentalization of Akt and mTOR might play a
crucial role. Treatment of breast cancer patients with Chloroquine in
combination with RAD001 may be important for overcoming RAD001
resistance.
0243
Prognostic role of lymph-node metastases in vulvar cancer and
implications for adjuvant radiotherapy
*L. Woelber1, C. Eulenburg2, M. Choschzick3, D. Rohsbach1, F. Gieseking1,
A. Kruell4, C. Petersen4, F. Jaenicke1, S. Mahner1
1
University Medical Center Hamburg-Eppendorf, Department of Gynecology, Hamburg, Deutschland, 2University Medical Center Hamburg-Eppendorf, Department of Medical Biometry and Epidemiology, Hamburg,
Deutschland, 3University Medical Center Hamburg-Eppendorf, Institute of
Pathology, Hamburg, Deutschland, 4University Medical Center HamburgEppendorf, Department of Radiotherapy and Radio-Oncology, Hamburg,
Deutschland
Background. Lymph-node metastases are the most important prognostic factor for recurrence and survival in vulvar cancer. However, conclusions regarding the impact of the number of positive nodes on survival
are inconsistent and so are recommendations when to apply adjuvant
radiotherapy to the groins/pelvis.
Methods. One-hundred-and-fifty-seven consecutive patients with primary squamous cell cancer of the vulva treated at our center were analyzed. All patients underwent primary surgery by triple incision resulting in complete tumor resection.
Results. Median age was 61 years; 49 patients (31%) had lymph-node metastases; 21 patients had 1, 13 had 2 and 15 had >2 positive lymph-nodes.
The risk of lymph-node metastases increased with age, greater tumor
size, deeper invasion and higher tumor grade. 32% of the patients received adjuvant radiotherapy. Median follow-up was 36 months; 23 patients (14.6%) developed disease-recurrence (61% vulva, 35% groins and
4% both). Compared to node-negative patients, survival in all nodepositive patients was significantly impaired with no evidence of disease
after 2 years in 88% of node negative patients and 60%, 43% and 29% in
patients with one, 2 and >2 affected nodes, respectively, p<0.001. No significant difference between the different node positive subgroups could
be demonstrated. In multivariate analysis lymph-node status remained
the most important prognostic factor regarding disease-free survival,
but the effect of positive nodes differed significantly dependent on adjuvant treatment (p=0.001): In patients without adjuvant radiotherapy
to the groins/pelvis the number of affected nodes was highly relevant
for prognosis (HR 1.752, p<0.001), whereas this effect disappeared in patients that were treated with adjuvant radiotherapy (HR 0.972, p=0.828).
Conclusions. The negative prognostic impact of lymph-node metastases is already evident in patients with only one affected lymph-node. If
patients receive adjuvant radiotherapy to the groins/pelvis the negative
effect of additional lymph-node metastases appears to be reduced and
adjuvant treatment might therefore already be beneficial in patients
with only one positive node.
0246
Communicating side effects by informing about possible benefits and harms: Effects on breast cancer patients’ satisfaction,
knowledge and expectations
*Y. Nestoriuc1, E. Kluge1, F. Schuricht1, P. von Blanckenburg1, W. Rief1,
U.S. Albert1
1
Philipps Universität Marburg, Klinische Psychologie, Marburg, Deutschland
Objective. Meeting breast cancer patients’ informational needs concerning endocrine therapy is important both for treatment satisfaction and
adherence. Decision aids contribute to a more patient-centered approach and engage patients in decisions about their treatment. Yet, the type
of information patients receive about side effects might influence risk
perception, actual development of side effects and, eventually, the drug
response. This study investigates the effects of a structured patient education focussing on the side effects of endocrine therapy.
Methods. In a prospective design, 58 postoperative breast cancer patients (age 26 to 77, mean: 56) were investigated before and after receiving
a structured patient education that was added to the standard hospital procedures. Side effect information was given in written and verbal form by psycho-oncologists and framed in the context of possible
treatment benefits and harms. Baseline and post-information measures
included knowledge about tumor status, satisfaction with information
about treatment and expectation to experience side effects from endocrine therapy. Expectations were rated on visual analogue scales for 45
prominent side effects, including those specific for endocrine treatment.
Results. The percentage of patients knowing their tumor receptor status increased from 23% to 58% after standard hospital information
and, furthermore, to 90% after the additional side effect education. The
structured side effect education significantly raised patients’ satisfaction with information about their treatment [t(57) 09.21, p<0.001]. Patients’ overall expectations about side effects decreased after the side
effect education [t(57)=2.73, p<0.01]. Particularly, the expected intensity
of unspecific adverse symptoms such as headache and abdominal discomfort was reduced [t(57)=3.41, p<0.001], while the expected intensity
of most side effects specific to endocrine treatment such as joint pain
and hot flashes remained stable.
Discussion. Educating breast cancer patients about the side effects of endocrine treatment increases patients’ knowledge and satisfaction with
treatment information. Furthermore, specific side effect information,
when framed in the context of possible benefits and harms of endocrine
therapy, reduces perceived health risk by decreasing patients’ expectations of treatment unspecific side effects.
Abstracts
0247
Prognostic impact of circulating tumor cells and their HER2
status assessed with two detection methods in patients with
metastatic breast cancer
*T. Fehm1, B. Rack2, S. Riethdorf3, W. Janni4, P. Fasching5, E. Solomayer6,
B. Aktas7, S. Kasimir-Bauer7, K. Pantel3, V. Müller8
1
Universitätsklinikum, Frauenklinik, Tübingen, Deutschland, 2Ludwig-Maximilians-Universität, Frauenklinik, München, Deutschland, 3Universitätsklinikum Eppendorf, Institut für Tumorbiologie, Hamburg, Deutschland,
4
Heinrich-Heine-Universität, Frauenklinik, Düsseldorf, Deutschland,
5
Universitätsklinikum, Frauenklinik, Erlangen, Deutschland, 6Universitätsklinikum, Frauenklinik, Homburg/Saar, Deutschland, 7Universitätsklinikum,
Frauenklinik, Essen, Deutschland, 8Universitätsklinikum Hamburg-Eppendorf, Klinik für Gynäkologie, Hamburg, Deutschland
Purpose. Circulating tumor cells (CTC) can be detected in the peripheral blood of 30–60% of metastatic breast cancer patients. However, the
optimal method for CTC detection is not clear so far. Therefore, we examined the prognostic impact of two methods for CTC detection in a
prospective multicenter study.
Methods. A total of 254 patients with metastatic breast cancer from nine
German breast centers were enrolled in this study. CTC detection and
HER2 status on CTC was examined at the time of tumor progression
using both the FDA-approved CellSearch® assay based on immunocytochemistry and the RNA-based AdnaTest Breast CancerTM.
Results. Using the CellSearch assay, 122 of 245 (50%) patients had ≥5
CTC, and HER2-positive CTC were observed in 50 (41%) of these patients. Ninety of 229 (39%) patients were CTC positive using AdnaTest,
and HER2 positivity rate was 47% (42 of 90). The rate of breast cancer patients with HER2-negative primary tumors but HER2-positive
CTC was 32% (25 of 78) and 49% (28 of 57) using the CellSearch assay
and AdnaTest, respectively. Detection of CTC was not correlated with
progression free survival for both methods. Patients with positive CTC
detected by Cell Search Assay showed shorter overall survival (14.6 mo.
versus 20.1 mo.; p<0.01), while no prognostic impact was observed for
the AdnaTest. HER2 status of CTC showed no prognostic impact.
Conclusions. HER2-positive CTC can be detected in a relevant number
of patients with HER2-negative primary tumors but HER2-positivity in
this cohort has no prognostic relevance. Only the detection of CTC with
the CellSearch assay showed prognostic relevance. In the upcoming trial DETECT III, we will examine the predictive impact of HER2-positive
CTC for treatment with Lapatinib in patients with HER2-negative primary tumor or metastasis.
0265
Cytotoxicity of the new antimetabolite-bisphosphonate (5-FdUalendronate) in comparison to standard therapeutics on breast
and ovarian cancer cell lines
*S. Schott1, M. Wallwiener1, B. Kootz2, H. Seeger2, T. Fehm2, H. Neubauer2
1
Universitätsklinikum Heidelberg, Universitätsfrauenklinik, Nationales
Centrum für Tumorerkrankungen, Heidelberg, Deutschland, 2Universität
Tübingen, Universitätsfrauenklinik, Tübingen, Deutschland
Background. By the chemical linkage of amino-bisphosphonate via the
nucleobase of cytostatic nucleoside-analogues new antimetabolite-bisphosphonate analogues can be obtained. The in vitro cytostatic activity
of 5-FdU-alendronate (5-FdU-ale), a representative of the new antimetabolites bisphosphonate, was comparably evaluated in breast and ovarian
tumour-cell lines in respect to 5-FdU, 5-FU, alendronate and zoledronate.
Methods. MCF-7, MDA-MB 231 breast and OvCa-29, OvCa-3 ovarian
cancer cell lines were cultured. The luminometric measuring of the ATP
tumour chemosensitivity assay was used to assess the in vitro activity. To
allow comparison between samples and different regimen the percenta-
ge of growth inhibition at different test drug concentrations and IndexSUM based on the percentage tumour cell growth inhibition at each test
drug concentration were determined.
Results. 5-FdU-ale was differently sensitive to breast and ovarian cancer
cell lines. For reaching 50% tumour cell growth inhibition (IC50) µM
drug concentrations are necessary. The cytostatic effect of 5-FdU-ale
corresponds more or less to that of alendronate, 5-FdU and 5-FU but was
lower in respect to zoledronate. IndexSum values for the broad range
efficacy were nearly corresponding for all drugs in each breast cancer
cell line. In the ovarian cancer cell lines OvCa-29 zoledronate was significantly more active in respect to the other drugs. The ovarian cancer
cell line OvCa-3 was insensible against 5-FdU-ale. 5-FU and zoledronate
show in this cell line the highest cytostatic effect in comparison to all
other tested cell lines.
Conclusion. The new antimetabolite-bisphophonates were designed for
bone-targeting of therapeutic antimetabolites. New therapeutic options
of these standard therapeutics have been developed, that could be effective against bone metastases or bone derived disease.
0272
CerbB2 status, HER3/4 of primary breast cancer and CNS metastases in primary breast cancer
*C. Bachmann1, *D. Schmidt1, E.-M. Grischke1, E. Solomayer2, D. Wallwiener1
1
Universitätsfrauenklinik, Gynäkologie/Geburtshilfe, Tübingen, Deutschland, 2Universitätsfrauenklinik, Gynäkologie/Geburtshilfe, Homburg/Saar,
Deutschland
Introduction. HER2 overexpression is a prognostic and predictive factor
for development of CNS metastases. Several previous studies have shown
that the immunophenotype of distant breast cancer metastases may be
different from that of primary tumour, leading to inappropriate choice of
systemic treatment. Further HER targeting agents are HER3/4. Although
a number of studies have demonstrated that HER3 overexpression is associated with poor prognosis in patients with breast cancer. HER3 may
provide a route for resistance to agents targeting EGFR or HER2. HER4
is more related with a favourable prognosis in breast cancer.
Aim. Aim is to study receptor conversion for ER/ PR status and HER2
status in a group of 21 patients with CNS metastases of breast cancer by
restaining all primary tumors and metastases with immunohistochemical and in situ hybridization methods on full sections. Additionally
investigations of HER3 and HER4 status in primary tumour and CNS
metastases were done.
Methods. A total of 21 consecutive patients with surgical resected CNS
metastases of breast cancer were IHC stained for ER, PR and HER2, and
expression was compared to that of the primary tumor. All patients were
treated with primary breast cancer at the university hospital Tübingen,
Departement of Gynecology and obstetrics and first diagnosis between
2001 and 2008. HER2 in situ hybridization was done in cases of IHC
conversion or when primary tumors or metastases showed an IHC 2+
result. All patients who occurred CNS metastases were included and got
a follow-up.
Results. Intervall first diagnosis of breast cancer – CNS metastases:
35 months (7–85 months). Almost 100% coincidence of cerbB2 status in
CNS metastases and breast cancer. In almost all cases the ER/PR status
showed loss of receptor positivity. cerbB2+ breast cancer showed higher
risk for CNS metastases and earlier development of CNS metastases than
cerbB2 negative tumours. Impact of HER3/4
Conclusion. CerbB2 positive breast cancer showed higher risk for CNS
metastases and earlier development of CNS metastases than cerbB2 negative tumours. The systemic treatment of CNS metastases is complicated by the blood-brain barrier and future therapies had to pass this
barrier. In the future, novel therapies may additionally improve survival
in these patients. The impact of HER3/4 expression on prognosis has to
be investigated in larger studies. Therefore, definite conclusions that may
change clinical practice could not yet be drawn.
0273
Resection of hepatic metastases from breast cancer imbedded
in a multimodal treatment concept – can it improve prognosis? A
systematic review of the literature
*K. Smetanay1, J. Bodem1, P. Schemmer2, K. Jensen3, J. Rom1, A. Schneeweiss1,
C. Sohn1, M. Eichbaum1
1
Universitätsklinikum Heidelberg, Frauenklinik/NCT Gynäkologische Onkologie, Heidelberg, Deutschland, 2Universitätsklinikum Heidelberg, Klinik für
Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Deutschland, 3Universitätsklinikum Heidelberg, Institut für Medizinische Biometrie
und Informatik, Heidelberg, Deutschland
Introduction. For many patients suffering from metastatic breast cancer
(MBC), surgical treatment of liver metastases is limited or not beneficial due to the systemic, multitopic character of the disease. Instead, for
patients with isolated hepatic metastases from colorectal cancer, liver
resection is a common procedure with a 5-year-survival of around 40%.
Previous retrospective studies, however, demonstrated that liver resection for selected patients with MBC limited to the liver could prolong the
survival rate to a greater extent than only systemic treatment. A 5-yearsurvival for resectable patients ranged from 18 to 59 %. The aim of this
systematic overview is to clarify the survival and morbidity of patients
with an additional surgical treatment within a multimodal concept.
Methods. We performed a systematic overview of all peer-reviewed published trials and studies documented in the PubMed-, MEDLINE and
EMBASE-database. Furthermore, a detailed search within published
trials in the Cochrane Library was undertaken. Included were all retrospective and prospective clinical trials published on patients with MBC
treated with surgery due to liver metastases. Primary endpoint of this
systematic review was overall survival (OS). Secondary endpoint was
peri- and postoperative morbidity.
Results. We analyzed 36 studies which were published between 1991 and
2010. From all included trials n=1428 patients had liver metastases from
breast cancer and n=803 patients were treated by surgery. In most of the
cases a major resection of the liver (3 or more than 3 segments) was performed. The mean disease-free interval comprised 44 months (range:
34–70 months). After surgery, patients with a R0-resection showed a median survival of 44 months (range: 27–73 month). The median OS after
5 years was described by n=393 patients with 40%. Complications were
reported on 95 patients. The most common local complications included
infected edema (n=12) and biliary leckage (n=12), while pleural effusion
(n=8) was the main systemic complication. The mean hospitalization
time was 9 days.
Conclusion. This systematic overview should help to advise patients with
hepatic MBC. Considering selected patients, the surgical treatment is an
additional option within a multimodal concept as it can prolong survival
with a relatively low morbidity. The aim of further studies should be to
identify prognostic factors for a more individual risk-benefit-profile of
each patient.
0280
Survial analyses in triple negative breast cancer patients: a
comparison between neoadjuvant and adjuvant chemotherapy
strategies
*G. Pfeiler1, C. Staudigl1, A. Brunner2, C. Singer1, R. Königsberg3
1
Medical University of Vienna, Department of Gynecology and Gynecologic
Oncology, Vienna, Österreich, 2Landesklinikum Thermenregion Mödling,
Department of Obstetrics and Gynaecology, Mödling, Österreich, 3Applied
Cancer Research – Institution for Translational Research Vienna (ACR-ITR
VIEnna)/CEADDP, Vienna, Österreich
Background. The primary goal of neoadjuvant treatment in breast cancer is to downstage breast cancer tumor size thereby increasing the breast conserving operation rate. Regarding triple negative breast cancer
(TNBC), there is a lack of evidence describing and comparing survival
parameters of neoadjuvant and adjuvant treated TNBC patients.
Methods. Between 1998 and 2006 pathologic and clinical data of 220
TNBC patients were retrospectively analysed of whom Eighty-two
were matched regarding neoadjuvant and adjuvant treatment. Baseline demographic and tumor characteristics were compared between the
two matched TNBC patient cohorts using a Students-t test for means
and χ2-test for frequencies.Kaplan-Meier plots for disease free survival
(DFS), distant disease free survival (DDFS), loco-regional disease free
(LDFS) and overall survival (OS) were used for each comparison. All
p values are two sided and a value of <0.05 was considered statistically
significant.
Results. Demographics and tumor characteristics as well as chemotherapy schemes of 40 adjuvant and 42 neoadjuvant treated patients with
triple negative breast cancer were well balanced. Breast conserving operation rate did not differ between adjuvant and neoadjuvant treated patients (70% and 69%, respectively, p=0.815). Neoadjuvant chemotherapy
lead to a significant worse DFS and DDFS (p=0.034 and p=0.041, respectively) compared to adjuvant chemotherapy. OS was tendetially worse
in the group of neoadjuvant treated patients (p=0.086). No difference in
LDFS could be detected.
Conclusion. This retrospective hypothesis generating observation claims
to further investigate efficacy endpoints of neoadjuvant versus adjuvant
treatment in TNBC patients.
0282
Therapeutic properties of a rat monoclonal antibody against
bone sialoprotein in MDA-MB-231 breast cancer cells
*M. Zepp1, F.-P. Armbruster2, M.R. Berger1
1
Deutsches Krebsforschungszentrum Heidelberg, Chemotherapie und
Toxikologie – G401, Heidelberg, Deutschland, 2Immundiagnostik AG, Bensheim, Deutschland
Bone sialoprotein (BSPII) is a member of the small integrin binding
ligand N-linked glycoprotein family, which has been described as a
prognostic serum marker in breast cancer patients with skeletal metastasis. This protein is recognized by a rat monoclonal antibody. In
an attempt to characterize the therapeutic potential of this antibody,
MDA-MB 231 cells were used to evaluate its anti-proliferative, antimigratory and anti-metastatic properties. As determinated by MTTassay, there was no convincing anti-proliferative activity following exposure to the antibody in the range of 100–800 mg/ml. Similarly, there
was no observable anti-migratory effect, as determined in the range of
100–200 mg/ml. However in an in vivo model of lytic skeletal metastasis the antibody showed remarkable activity. In the preventive arm of
this study, rats were pre-treated with the antibody (0 and 10 mg/kg). In
parallel, MDA-MB-231 cells were exposed to the antibody for 1 week
(0 and 0.5 mg/ml). Following inoculation of 1×105 MDA-MB-231 cells
into the femoral artery of 6 male nude rats, respectively, the appearance of lesions in the respective hind leg was monitored by photon emission, mediated by the metabolism of luciferin. In the treatment arm of
this study, the antibody administration (10 mg/kg/week) started when
tumor bearing rats had shown stable tumor growth. Experimental
groups of rats received the first treatment either at 4 (late onset; n=8)
or at 2 (early onset; n=6) weeks after tumor cell implantation. Tumor
bearing animals were (sham-) treated and followed for up to 6 weeks.
All 6 control rats of the preventive arm showed steady tumor growth.
In variance, the rats receiving MDA-MB-231 cells that had been pre-exposed to the antibody and those rats, which had been pre-treated with
the antibody showed significantly reduced light emission, as indicator
of reduced tumor growth. In the treatment arm, all but 1 untreated tumor bearing rats showed rapid tumor growth accompanied with lytic
destruction of femur and tibia of the respective hind leg (18/19; tumor
take rate 95%). In contrast, rats treated with the anti-BSPII antibody
did not show a significant increase in light emission nor a clinical deteJournal of Cancer Research and Clinical Oncology Suppl 1 · 2011 | 79
Abstracts
rioration. In conclusion, the monoclonal rat antibody directed against
BSPII is a powerful tool in treating experimental skeletal metastasis
and warrants further development.
0287
Efficacy of platinum/taxane-based chemotherapy in elderly with
advanced ovarian cancer: explorative analysis of three phase III
trials from the AGO Study Group
*A.M. Hempel , P. Harter , A. Strauss , J. Hedderich , E. Pujade-Lauraine ,
A. du Bois2, J. Pfisterer5, F. Hilpert1
1
Universitätsklinikum Schleswig-Holstein Campus Kiel, Klinik für Gynäkologie und Geburtshilfe, Kiel, Deutschland, 2Kliniken Essen-Mitte, Gynäkologie
und Gynäkologische Onkologie, Essen, Deutschland, 3Universitätsklinikum
Schleswig-Holstein Campus Kiel, Institut für Medizinische Informatik und
Statistik, Kiel, Deutschland, 4Hôpital Hôtel-Dieu, Oncology, Paris, Frankreich, 5Städtisches Klinikum Solingen, Gynäkologie und Gynäkologische
Onkologie, Solingen, Deutschland
1
2
1
3
4
Background. Age is a negative prognostic factor for survival in ovarian
cancer (OC). We analysed efficacy and prognostic factors in patients
≥70 years of age treated with platinum-based 1st-line chemotherapy.
Methods. Exploratory analysis of 3 prospective randomized trials
(AGO-OVAR 3, 5, 7) investigating platinum/taxane-based chemotherapy in OC FIGO IIb–IV conducted between 1995 and 2002. Datasets
from each trial were merged into a combined meta-dataset. Patients
≥70 years of age at randomization who had received at least one cycle
of the assigned treatment were analysed for progression-free (PFS) and
overall survival (OAS) by Kaplan Meier method and prognostic factors
by cox regression analysis.
Results. Out of 3333 patients 359 (10.8%) were ≥70 years of age and eligible. Age was an independent prognostic factor for survival: Median PFS
was 23.8 and 18.4 months (p<0.001) in the age group < and ≥70 years,
median OAS was 45.9 and 29.6 (p<0.001) months, respectively. In optimally treated elderly patients (≥5 cycles, no residual tumor) PFS and
OAS was 33.3 and 58.7 months, respectively. Independent prognostic
factors for survival were FIGO-stage, residual tumor, number of cycles,
mucinous histology and body mass but not dose reductions, cycle delay
or ECOG.
Conclusion. Optimal therapy can contribute to a meaningful prolongation of survival in elderly. Since the number of cycles but not cycle delay
or dose reductions had prognostic impact, the use of treatment modifications within the specifications of a study protocol might improve
cycle delivery and outcome.
0316
VEGF induces ascites in ovarian cancer patients via increasing
peritoneal permeability by downregulation of Claudin 5
*D. Herr1, A. Sallmann1, R. Konrad1, I. Holzheu1, R. Kreienberg1, C. Wulff1
1
Universitätsklinik Ulm, Frauenklinik, Prittwitzstr. 43, Deutschland
We evaluated the role of VEGF-dependent Claudin 5 production for
the development of ascites via influencing endothelial permeability in
peritoneal tissue of ovarian cancer patients. This study investigates the
mechanisms of formation of ascites in ovarian cancer patients performing RT-PCR, VEGF-ELISA and immunohistochemical dual staining
for CD31 and Claudin 5. In addition, in order to analyse the connectivity
of VEGF, Claudin 5, an endothelial cell/ovarian cancer cell-co-culture
system was established and evaluated using Western blot analysis and
a permeability assay. Firstly, VEGF-gene expression was demonstrated
for all ovarian cancer and peritoneal biopsies. In addition, quantification of VEGF in the serum and ascites of ovarian cancer patients revealed significantly increased values. We subsequently demonstrated
Claudin 5 production in the peritoneal vessels, which was weaker as in
the vessels of the controls. Evaluation of endothelial permeability finally
showed a VEGF-dependent regulation via Claudin 5. Taken together,
since our results indicate an important role of VEGF as regulator of
endothelial permeability via Claudin 5, our data suggest a new pathophysiological model, explaining the molecular connectivity of the development of ascites in ovarian cancer patients.
0319
The WSG ADAPT (adjuvant dynamic marker-adjusted personalized therapy) trial – a new concept for optimizing risk assessment and therapy response prediction in primary breast cancer
*U. Nitz1,2, O. Gluz1, C. Bühne1, C. Liedtke1,3, H. Kreipe4, N. Harbeck5
1
Westdeutsche Studiengruppe, Mönchengladbach, Deutschland, 2EVK
Bethesda, Mönchengladbach, Deutschland, 3Uniklinik Münster, Münster,
Deutschland, 4MHH Hannover, Hannover, Deutschland, 5Uniklinik Köln,
Köln, Deutschland
In primary breast cancer, the most important adjuvant therapy questions are: Who can safely be spared chemotherapy and who benefits
most from chemo-, endocrine, anti-HER2-therapy? Validated prognostic tests identify low-risk patients with a low enough chemotherapy
benefit to justify its omission. Results of the respective trials (TailorX,
MINDACT, NNBC-3, WSG planB) are pending. Regarding therapy
benefit prediction, the clinically most relevant predictors are hormone
receptor expression for endocrine and HER2-status for anti-HER2 therapy. Adjuvant (chemo)therapy indications today are mainly based on
the individual prognostic profile, i.e. clinical-pathological factors, gene
signatures, uPA/PAI-1, but not on actual therapy response. For endocrine therapy, response to short course endocrine treatment (decrease
in tumor proliferation), correlates strongly with outcome. For chemotherapy, neoadjuvant pathologic complete remission is an excellent predictor of outcome, particularly in HER2+ and TN disease. In ADAPT,
prognosis (static) and early prediction (dynamic) are combined for clinical decision making: The prognostic profile is evaluated in initial core
biopsies. A sequential biopsy for proliferation/apoptosis markers is performed after 3-weeks of pre-operative specific therapy. Since evidence is
strongest for hormone sensitive disease, Ki-67 is used to early identify
responders in intermediate risk patients, who are then considered sufficiently treated by endocrine therapy alone. Low responders and patients
initially identified as high-risk for recurrence are randomized into a
chemotherapy protocol. Adjuvant chemotherapy will thus be spared in
low-risk patients and intermediate risk ones with early therapy response. The ADAPT HER2+ and TN subprotocols correlate the early 3-week
results with pCR in a 12-week neoadjuvant concept. ADAPT primary
endpoints are optimization of the dynamic test system as well as patient
outcome. Central pathology will be performed. ADAPT aims at early
therapy individualization by integration of early dynamic response data
into clinical management. This early enrichment strategy aims to spare
unnecessary toxic therapies and costs without compromising outcome.
In a second step, results may help to early identify alternative therapeutic strategies in patients who do benefit from standard treatment. The
trial (n=4940) is scheduled to start in fall of 2011. First feasibility results
will be presented.
0329
PRÄFERENZ STUDY – Patients’ individual choice for oral vs.
intravenous Treosulfan in elderly patients with ovarian cancer:
analysis of tolerability – for the North-Eastern German Society of
Gynecological Oncology (NOGGO) study group
*S. Mahner1, P. Harter2, S. Fuxius3, L.C. Hanker4, L. Müller4,5, P. Klare6, E. Heidrich-Lorsbach7, J. Sehouli8
1
Universitätsklinikum HH-Eppendorf, Gynäkologie, Hamburg, Deutschland,
2
Kliniken Essen-Mitte, Essen, Deutschland, 3Onkologische Schwerpunktpraxis Heidelberg, Heidelberg, Deutschland, 4University Cancer Center Frankfurt, Frankfurt, Deutschland, 5Onkologische Schwerpunktpraxis Leer, Leer,
Deutschland, 6Praxisklinik Krebsheilkunde für Frauen, Berlin, Deutschland,
7
Alcedis GmbH, Gießen, Deutschland, 8Charite University Medicine Campus
Virchow, Gynecology and Gynecologic Oncology, Berlin, Deutschland
Background and aims. There is an increasing interest in oral drug administration in oncology. Treosulfan is effective as oral (p.o.) and intravenous (i.v.) formulation for recurrent ovarian carcinoma. Primary
aim of this study was to explore individual preference and compliance
of elderly patients (≥65 years) for p.o. or i.v.-treosulfan. Secondary aims
were to evaluate toxicity, response and survival. We present an interim
analysis of patient’s characteristics and treatment choice, compliance of
the treatment and toxicities for 102 included patients.
Methods. Patients with platinum resistant or refractory ovarian cancer
had free choice of treosulfan i.v. (7000 mg/m2 d1, qd29) or p.o. (600 mg/
m2 d1-28, qd56) for a maximum of 12 cycles (i.v.) or 12 months (p.o.).
Indecisive patients were randomized. Toxicity was evaluated according
to the NCI-CTC version 2.0.
Results. 102 recruited patients completed therapy at the time of this analysis (median age 72 years, range 65–87). 84 patients chose i.v. and 14
p.o., 3 were randomized to i.v and 1 to p.o. Median ECOG was 1 (n=0–2),
and median number of prior chemotherapy-regimens was 3 (n=1–6). In
total, 351 cycles of chemotherapy (n=1–12, median: 3) were administered.
Most common hematological toxicites (grade 3/4) were thrombopenia
(12.7%), leukopenia (11.8%) and anemia (3.9%). Most frequent non-hematological toxicities (grade 3/4) were fatigue (4.9%) and constipation
(6.9%).
Conclusions. Treosulfan therapy was generally well tolerated despite
heavy pretreatment in most patients. As nearly 82% of patients at this
interim analysis chose i.v.-treosulfan there seems to be an individual
preference for i.v.-administrations in elderly patients with recurrent
ovarian cancer.
0330
Quality of life and sexuality in patients with borderline tumors of
the ovary (a substudy of the ROBOT-Study of the AGO-Ovar)
*A. Hasenburg1, J. Farthmann1, M. Weil1, C. Fotopoulou2, N. Ewald-Riegler3,
O. du Bois3, F. Trillsch4, S. Mahner4, H.-G. Strauß5, P. Wimberger6, A. du Bois7
1
Universitätsklinik, Frauenklinik, Freiburg, Deutschland, 2Charité, Frauenklinik, Berlin, Deutschland, 3Horst-Schmidt-Kliniken, Frauenklinik, Wiesbaden,
Deutschland, 4Universitätsklinik, Frauenklinik, Hamburg, Deutschland,
5
Universitätsklinik, Frauenklinik, Halle/ Saale, Deutschland, 6Universitätsklinik, Frauenklinik, Essen, Deutschland, 7Kliniken Essen Mitte, Frauenklinik,
Essen, Deutschland
Background and aims. Being sexually active may be an important aspect
of quality of life (QoL). Both diagnosis itself and therapy of borderline
tumors of the ovary (BOT) including surgical bilateral salpingo-oophorectomy could have an impact on quality of life (QoL) and sexual
function. Therefore, we evaluated the influence of disease and surgical
treatment on QoL including sexuality. Treatment impact on QoL and
sexuality of patients with borderline tumors were evaluated with questionnaires.
Methods. The presented study is a substudy of the ROBOT-study of the
AGO Study Group. ROBOT is a pattern of care study, in which 1237 patients diagnosed with BOT between 1998 and 2008 in 27 institutions were
included. 111 patients from 7 gyneco-oncological centres in Germany
were evaluated with three different questionnaires (EORTC QoL-C30
and SAQ, as well as a self-made questionnaire designed for this purpose). With these tools the impact of the different therapeutic strategies on
QoL and sexual function and pleasure was evaluated.
Results. Of the 111 patients (mean age 53 years) 55 were sexually active
(mean age 44 years), whereas 51 were not (mean age 62 years). 5 patients
did not answer this question. The mean value of the overall quality of
life was 5.42 (0 meaning low quality, 7 high QoL). Asked about the subjective state of health, the mean score was 5.19 (0 meaning impaired status of health, 7 high status of health). Those patients (n=55) who were
sexually active had a mean score of pleasure of 7.34 (ranging from 0 to
18, a low score representing low pleasure). 28 patients were able to have
an orgasm always with every intercourse or almost always without greater difficulty, 24 patients had small or moderate problems to obtain an
orgasm, 5 patients almost never or never reached an orgasm.
Conclusions. Overall sexual function and QoL were quite high, but only
about half of the patients were sexually active at the time of our survey.
Those patients who were sexually active were younger than those who
were not. As patients with BOT have a very good overall survival, the
long-term impact on QoL and sexual function needs special attention.
0343
Therapeutic genes delivered by targeted AAV9-vectors inhibit
tumor growth in breast cancer in vivo
*S. Michelfelder1, A. Hunger1, E. Koziolek2, M. Kaul2, J. Kleinschmidt3,
M. Trepel1
1
Universitätsklinikum Hamburg Eppendorf, Hubertus Wald Tumorzentrum
und Abteilung für Hämatologie und Onkologie, Hamburg, Djibouti, 2Universitätsklinikum Hamburg Eppendorf, Klinik und Poliklinik für Diagnostische und Interventionelle Radiologie, Hamburg, Deutschland, 3Deutsches
Krebsforschungszentrum, Heidelberg, Deutschland
Introduction. Targeted gene therapy is a potential means to systemically
treat cancer. Vectors derived from adeno-associated virus serotype-9
(AAV9) are particularly attractive due to their high transduction efficiency and their excellent safety profile, but their tropism is unspecific. Here, we report a combined approach to target therapeutic genes to
disseminated tumors by incorporation of tumor specific peptides into
the viral capsid and microRNA (miR)-regulated gene expression in a
mouse model for multifocal breast cancer.
Methods. Targeted AAV9 vectors harbouring a mir1-d binding domain and luciferase or an HSV-tk gene (SR39) displaying a breast cancer-targeted peptide selected from random AAV display libraries were
established. Vectors were applied intravenously to PymT mice bearing
palpable breast tumors. In vivo transduction of rAAV-luciferase was
determined by bioluminescence imaging (BLI) and single organ transduction was analyzed by luminometry. Gancyclovir (GCV) treatment
was initiated four days after application of SR39 vectors. Therapeutic efficiency and possible side effects of suicide gene therapy was assessed by
tumor growth, histology and magnetic resonance tomography (MRT)
analysis.
Results. After systemic vector injection, AAV-ESG-mir1-d luciferase
vectors mediated strong gene expression in tumor tissue while, compared to wild type vectors, expression decreased in almost all control
tissues including heart and liver. Suicide gene treatment significantly
inhibited tumor growth after one single vector administration and eight
cycles of GCV treatment [tumor volume 0.51±0.12 ×1000 mm3 treated
(n=8) vs. 3.4±0.81 ×1000 mm3 control group (n=10)]. Treatment response was further validated by MRT.
Conclusions. Tumor-specific gene delivery can be realized by insertion
of targeting peptides into putative receptor-binding capsid regions of
Abstracts
AAV9 and microRNA-regulated transgene expression. Systemic HSVtk suicide gene transfer inhibits progression of growth of multifocal
tumors in vivo, while apparent side effects do not occur. This demonstrates the feasibility of targeted AAV vectors as promising candidate
for therapeutic application in disseminated cancer.
0358
Radiation-related quality of life parameters after targeted
intraoperative radiotherapy versus whole breast radiotherapy
in patients with breast cancer: Results from the randomized
phase III trial TARGIT-A
*G. Welzel1, A. Boch1, E. Blank1, U. Kraus-Tiefenbacher1, A. Keller1, B. Hermann2, M. Sütterlin3, F. Wenz1
1
Universitätsmedizin Mannheim, Universität Heidelberg, Klinik für
Strahlentherapie und Radioonkologie, Mannheim, Deutschland, 2Klinikum
Hanau GmbH, Klinik für Radioonkologie und Strahlentherapie, Hanau,
Deutschland, 3Universitätsmedizin Mannheim, Universität Heidelberg, Universitäts-Frauenklinik, Mannheim, Deutschland
Purpose. In the multicenter phase III trial TARGIT-A women with early
breast cancer were randomly treated either with targeted intraoperative
radiotherapy (IORT, 20 Gy) during breast-conserving surgery or whole
breast radiotherapy (WBRT, 56 Gy). In presence of risk factors, postoperative WBRT (46–50/2 Gy) was added after IORT. Initial results show
non-inferiority of IORT and WBRT in terms of local recurrence and
toxicity (Vaidya et al. Lancet 2010; 376: 91–102). Here, we assess radiation-related quality of life parameters from 123 women of a single centre
from the phase III trial TARGIT-A.
Patients and methods. Radiation-related quality of life was collected
using two validated questionnaires of the EORTC (QLQ-C30, QLQBR23). In addition, fatigue, anxiety, depression, self-esteem and body
image parameters were controlled. The response rate was 72% (n=88).
Forty-six patients were randomized to IORT. Of them, 16 patients were
postoperatively treated with additional WBRT, 5 patients did not receive
IORT due to technical problems: 4 patients were treated with WBRT, 1
patient refused WBRT. The median age at the time of TARGIT-A entry
was 65 years (range: 47–84). With a median follow-up time of 25 months
(range: 9–94), all patients were disease-free at the time of the survey.
Results. IORT patients reported less pain, breast and arm symptoms and
better role functioning as compared to WBRT patients (mean ± standard deviation: 21.3±33.2 versus 40.9±32.3 points, p=0.007; 7.0±14.0 versus 19.0±20.0 points, p=0.001; 15.1±22.2 versus 32.8±28.6 points, p=0.009;
and 78.7±35.2 versus 61.8±28.3 points, p=0.007). IORT + WBRT patients
reported significantly more pain (mean ± standard deviation: 43.8±32.1
points), breast (mean ± standard deviation: 29.7±22.8 points) and arm
symptoms (mean ± standard deviation: 32.6±25.8 points) compared to
patients with IORT alone (p-values: 0.018 for pain, <0.001 for breast
symptoms, and 0.011 for arm symptoms).
Conclusion. At a median follow-up of 2 years, important radiation-related quality of life parameters after IORT are superior to WBRT.
0363
Overall survival of patients with primary hormone-receptor-positive breast cancer registered in the Tumorcenter Regensburg
depending on endocrine treatment
*R. Görse1, G. Kiesilewicz1, M. Gerstenhauer2, M. Klinkhammer-Schalke2,
F. Hofstädter3, O. Ortmann1
1
University, Departement of Gynecolgoy and Obstetrics, Regensburg,
Deutschland, 2Tumorcenter, Regensburg, Deutschland, 3Institute of Pathology, Regensburg, Deutschland
Introduction. Breast cancer is the most frequent diagnosed malignancy
in women. Most breast tumors show positive estrogen and progesterone
receptors. In these hormon-receptor- positive cases endocrine therapy
is the most important treatment in the adjuvant situation. Since 2002
the standard therapy after surgery consists of aromatase inhibitors beside tamoxifen. This trial is an analysis of overall survival comparing
patients with hormone-receptor-positive breast cancer treated endocrine and patients with hormone-receptor-positive breast cancer without
endocrine treatment.
Methods. The Tumorcenter Regensburg is an institution of 50 Hospitals
of Oberpfalz and Niederbayern, the University Hospital of Regensburg
and 1100 physicans. The region Oberpfalz and Niederbayern consists of
2.3 million of inhabitants. Until now, over 200,000 courses of tumorpatients are reported in the register of the Tumorcenter Regensburg. This
trial is a retrospective analysis of patients with primary breast cancer in
the years 1998 to 2010. The dates of 9236 patients with hormonsensible
breast cancer undergo special analysis.
Results. In 1995 premenopausal cases 74.4% showed poitive estrogen and
progesterone receptor, in 7241 postmenopausal cases 79.6% were hormone-receptor-positive. Both pre- and postmenopausal patients received in 82% an endocrine therapy. In most cases endocrine therapy consisted of tamoxifen. 57% of the premenopausal patients and 66% of the
postmenopausal patients were treated with tamoxifen. 34% of postmenopausal patients were treated with aromatase inhibitors. The analysis
of the overall survival from 1998 to 2010 shows a significant advantage
for patients with hormone-receptor-positive breast cancer when they
receive endocrine therapy.
Conclusion. The overall survival of patients with endocrine therapy is
significantly better than without endocrine therapy. This analysis of health care research shows the reality of treatment of patients with primary hormone-receptor-positive breast cancer.
0380
Prognostic value of intercellular adhesion molecule (ICAM)-1
expression in breast cancer
*C. Schroeder1, I. Witzel1, V. Müller1, R. Wirtz1, U. Schumacher1, K. MildeLangosch1
1
Universitätsklinikum Hamburg-Eppendorf, Institut für Anatomie und
Experimentelle Morphologie, Hamburg, Deutschland
Purpose. The intercellular adhesion molecule (ICAM)-1 is expressed
on many cell types including endothelial cells and different cancer cell
entities. Experimental data strongly indicate that ICAM-1 can activate
intracellular signalling pathways in cancer cells leading to enhanced
cell motility, invasion and metastasis. Yet, little is known about the role
of ICAM-1 expression during malignant progression in breast cancer
patients.
Methods. We investigated ICAM-1 protein and mRNA expression in
two overlapping cohorts of breast cancer patients. ICAM-1 protein was
detected by western blot analysis in 104 cases and verified by immunohistochemistry. Additionally, ICAM-1 mRNA microarray data from 169
tumours were analysed.
Results. With both methods, high ICAM-1 expression was significantly
associated with a poorly differentiated phenotype, a negative estrogen
receptor status and positive lymph node involvement. In addition, there
was a significant prognostic impact of ICAM-1 protein overexpression
on recurrence-free survival (HR=2.82, p=0.023), which was most pronounced in ER-negative tumours. ICAM-1 mRNA overexpression was
associated with high uPA and PAI-1 protein and mRNA levels as well as
high Ki67 and VEGF expression.
Conclusions. Because of its association with malignant progression,
ICAM-1 might represent a therapeutic target particularly for ER-negative breast cancer patients, which still lack therapeutic options.
0387
ID4 and WISP-2: potential role as tumorsuppressor in ovarian
cancer?
0396
Kisspeptin-10 reduces tumor growth and metastasis in a breast
cancer model in vivo
*K. Bräutigam1, Y.-N. Maché1, D.O. Bauerschlag1, I. Meinhold-Heerlein1,
N. Maass1
1
Uniklinikum Aachen, Klinik für Gynäkologie und Geburtshilfe, Aachen,
Deutschland
*E. Ziegler1, G. Emons1, C. Gründker1
1
Universitätsmedizin Göttingen, Frauenklinik, Göttingen, Deutschland
Objective. Ovarian cancer stands for the most fatal disease among gynecological malignancies. Late stage-diagnosis and high recurrence rate
as reason for poor prognosis stimulate the detection of new prognostic
marker and the development of targeted therapies. Thus, the aim of this
study was to characterize the role of ID4 and WISP-2 in ovarian cancer
by expression analyses in ovarian cancer cell lines, in primary cultured
cells derived from tumor-tissue and ascites and in tissues of malignant,
benign and normal origin.
Methods. To characterize the role of ID4 and WISP-2 oligonucleotide
and methylation array analyses, qRT-PCR experiments, immunoblotting and immunhistochemistry analyses were performed.
Results. The microarray analyses showed higher expression of ID4
in low malignant potential (LMP) tumors versus high grade (G2/G3)
tumors. Expression analyses of mRNA and protein level displayed a
downregulation of ID4 in malignant tumors compared to normal and
benign cases. Interestingly, strong ID4 expression could be examined
in primary culture originated from metastasis or ascites. WISP-2 was
shown to be hypermethylated while mRNA and protein expression was
strongly repressed in malignant ovarian cancer compared to normal
ovarian tissue samples. In benign cases the expression of WISP-2 was
diverse.
Conclusion. While ID4 seems to have a dual role in ovarian cancer progression and may be used as prognostic marker, the protective effect of
WISP-2 in ovarian cancer progression may have important therapeutic
implications.
0394
Radical vaginal trachelectomy with laparoscopic pelvic lymphonodectomy in a pregnant patient with cervical cancer
*K. Abel1, E.-F. Solomayer1, I. Juhasz-Böss1
1
Universitätsklinik Homburg, Frauenklinik, Homburg, Deutschland
Kisspeptin-10 (KP-10) belongs to a group of peptides derived from
KISS1, a gene identified as metastasis suppressor. The antimetastatic effect of the kisspeptins was shown in mice having less metastasis after injection of melanoma and breast cancer cells transfected with KISS1. Peripherally administered kisspeptins also inhibited metastasis in mouse
models with melanoma and prostate cancer cells. In vitro, kisspeptins
showed an inhibitory effect on cell migration and invasion in addition.
The aim of this study was to show the effect of KP-10 on breast cancer
growth and metastasis in vivo.
As xenograft CD-1 nude female mice were chosen. Tumor cells of two
human breast cancer cell lines HCC 1806 and MDA-MB-435 were injected orthotopically. Mice were treated daily with KP-10 by intraperitoneal injection and tumor growth was measured. Metastasis was quantified after the end of the study as amount of human DNA in murine
organs by real-time PCR.
An increasing tumor growth could be detected. The treated groups
bore smaller tumors compared to the untreated groups. Metastasis
was measured in lung showing a decreased amount of human DNA in
the groups treated with KP-10. To verify the inhibitory effect on tumor
growth, KP-10 was tested for antiproliferative capacities in a viability
assay. No difference between treated and untreated samples could be
detected in vitro.
The results in vivo demonstrate an inhibitory effect of KP-10 on breast
cancer growth and metastasis. An antiproliferative effect of KP-10 could
not be confirmed in cell culture assays. This may be based on the used
experimental conditions. Furthermore, reduced proliferation caused
by kisspeptins is controversially described in literature. The observed
inhibition of tumor growth may also be mediated by an antiangiogenic
effect of KP-10.
According to the decreased amount of metastasis found in the treated
group of mice, this effect could be caused by the lower tumor growth.
But on the opposite, KP-10 also showed antiinvasive properties in vitro.
Thus, KP-10 can be described having antimetastatic properties within
the treatment of breast cancer in vivo.
Malignancies occurring during pregnancy are always a challenge both
from the oncologic and the obstetric point of view. Despite a generally
declining incidence in western countries cervical cancer is still one of
the most frequent malignant diseases in pregnant patients. So far different therapeutic strategies have been described depending on the stage
of the disease, gestational age at diagnosis as on whether the patient wishes to continue her pregnancy: Postponing surgery after delivery, neoadjuvant chemotherapy, fertility-sparing operation during pregnancy
or determination of pregnancy by radical hysterectomy.
We report on a 30 years old primigravida who presented with a FIGO
Ib1 cervical cancer and a tumor size of 25 mm at 11 weeks gestation.
Radical vaginal trachelectomy combined with laparoscopic pelvic lymphonodectomy was performed without any complications. After close
monitoring during pregnancy a planned caesarean section followed by
a radical hysterectomy was performed at 35 weeks gestation. After one
year of follow-up both mother and child are doing well without any evidence of recurrent disease.
Abstracts
0397
Treatment of ovarian cancer by combining rapamycin and cytostatic drugs under hypoxic conditions
*K. Bräutigam1, L. Schacht1, D.O. Bauerschlag1, I. Meinhold-Heerlein1,
N. Maass1
1
Uniklinikum Aachen, Klinik für Gynäkologie und Geburtshilfe, Aachen,
Deutschland
Objective. Malignant tumors usually involve a relatively hypoxic state,
which induces overexpression of hypoxia-inducible factor-1alpha (HIF1alpha) to satisfactorily enable the tumor to survive. And inhibition
of the mammalian target of rapamycin (mTOR) pathway including
HIF-1alpha is expected to play a major role in suppression of tumor cell
growth. Thus the aim of this study was to assess the potential to use
rapamycin and currently applied anticancer agents in combination in
ovarian cancer under normoxic and hypoxic conditions.
Methods. The chemosensitive ovarian cancer cell line HEY was utilized
to induce resistance against cisplatin, etoposide, doce- and paclitaxel.
Besides these four chemoresistant subclones and the parental HEY cell
line, IGROV-1 and SKOV-3, two resistant ovarian cancer cell lines were
treated with either rapamycin or one of the four cytostatic drugs alone
and also with the combination of rapamycin with each of the drugs.
Cell viability and the expression of proteins in apoptotic pathways and
molecules downstream of the mTOR signaling pathways were assessed
by chrystal violet assay and immunoblotting.
Results. Synergistic effects could be observed in all cell lines from the
combination of rapamycin with either cisplatin or etoposide. Rapamycin enhanced induction of apoptosis and inhibition of proliferation by
influencing the AKT pathway. Comparison of incubation under hypoxic or normoxic conditions led to no significant difference.
Conclusion. The combination of the chemotherapeutic drugs cisplatin
and etoposide with rapamycin could be worth exploring as a treatment
modality for epithelial ovarian cancer.
0403
Reverse phase protein microarrays for protein profiling in breast
cancer tumor samples
*J. Sonntag1, S. von der Heyde2, T. Beissbarth2, S. Wiemann1, H.-P. Sinn3,
A. Schneeweiss4, U. Korf1
1
DKFZ, Division of Molecular Genome Analysis, Heidelberg, Deutschland,
2
University Medical Center Göttingen, Department of Medical Statistics,
Göttingen, Deutschland, 3University Hospital of Heidelberg, Department of
Pathology, Heidelberg, Deutschland, 4National Center for Tumor Diseases,
Department of Gynecology and Obstetrics, Heidelberg, Deutschland
Introduction. Breast cancer is nowadays recognized as a heterogeneous
disease. With the knowledge of the histopathological as well as molecular heterogeneity in mind and following the hypotheses that intrinsic
biologic features of breast tumors affect the response to different therapies, we want to further elucidate the underlying molecular mechanisms on the proteome level using reverse phase protein microarrays
(RPPA, [1]).
Method. RPPA allow the quantitative analysis of target protein expression and posttranslational modifications in large sample sets. The method, in principle, is a miniaturized dot blot immunoassay. Tissue lysates
of 140 fresh-frozen breast cancer tumor samples (80% ERa positive, 5%
HER2 positive, 13% triple negative) were spotted with a highly accurate
contact printer on numerous nitrocellulose coated glass slides. Each replicate array of tumor samples was probed with one of over 100 targetspecific antibodies. A secondary antibody coupled to a near-infrared
dye was used for detection of the primary antibody. Data analysis was
done with the RPPanalyzer [2].
Results. As proof of principle, RPPA data for ERa and HER2 were compared with the routine classification of the respective targets as obtained by immunohistochemical (IHC) staining. RPPA data significantly
separated the IHC ERa positive from the ERa negative as well as the
IHC HER2 positive from the HER2 negative group of patients (p<0.001,
respectively). In addition, we could show that an over-expression of
EGFR was associated with the triple negative subtype, and high Ki67
expression was correlated with high grade tumors.
Outlook. Quantitative data on protein expression as well as protein
phosphorylation obtained for over 100 targets using RPPA is used for
pathway activation profiling of the breast cancer tumor samples. Such
pathway activation patterns could possibly be translated into defining
pathway-specific and patient-tailored therapy options.
1. Löbke C et al (2007). Proteomics 7:558–564
2. Mannsperger HA et al (2010). Bioinformatics 26:2202–2203
0423
Prognostic significance of HPV vaccine protein L1 detection with
Cytoactiv®
*G. Mehlhorn1, M. Koch1, M.W. Beckmann1, L. Bubendorf2, E. Obermann2,
H. Griesser3, A. Weiss3, G. Negri4, H. Sander5, M. Lütge6, R. Hilfrich7
1
Fraunklinik/Universität, Onkologie, Erlangen, Deutschland, 2Universität,
Pathologie, Basel, Schweiz, 3Labor, Zentrum für Pathologie, Köln, Deutschland, 4Labor, Pathologie, Italien/Bolzano, Italien, 5Labor, Zytologie, Einbeck,
Deutschland, 6Labor, Zytologie, Salzgitter Bad, Deutschland, 7Labor,
Cytoimmun Diagnostics, Pirmasens, Deutschland
Background. Cervical cancer screening programs for the detection of
precancerous cervical neoplasia are highly effective and caused a decline in the incidence of invasive cervical carcinomas. Consequently, dysplastic epithelial lesions are being diagnosed frequently. We and others
have shown that HPV-L1 capsid protein detection results with Cytoactiv
predict spontaneous remission or progression to histologically confirmed CIN3 for such precancerous lesions associated with high risk HPV
high infection.
Objective. The aims of this prospective, randomized study are: 1.) to validate the prognostic relevance of HPV-L1 capsid protein detection for
early dysplastic lesions, 2.) to evaluate the impact of different preparation techniques (conventional Pap smear versus LBC) on the sensitivity
of L1 detection and its prognostic significance.
Material and methods. Beginning in 2007, follow up until June 2011,
HIV negative, non-pregnant, non HPV-L1 vaccinated women reported
as LSIL (internationally) or (Germany) as group IIID with subclassification into mild (LSIL) or moderate (HSIL) dysplasia were included.
Results and conclusion. 53–85% of the LSIL and 23–50% of the HSIL cases were positive for L1 capsid protein immune staining. After 53 month
follow up records of 642 cases are completed and available. Only 16%
of 349 L1 positive, but 63.4% of the 293 L1 negative precancerous lesions
showed a progression to histologically confirmed CIN3. A spontaneous
remission was observed in 53.3% of the L1 positive, but only 4.8% of the
L1 negative cases. A stable disease was reported in 30% of the L1 positive
and L1 negative cases. L1 positive mild and moderate dysplasias, reflecting productive HPV infection, had low malignant potential, justifying
a watch and wait strategy to prevent overtreatment especially in women
of child-bearing age. L1 negative early dysplastic lesions, as non-productive infections or precancerous lesions, have a considerable malignant
potential and close follow up with colposcopy and histological evaluation is advised.
0428
HPV16-L1-specific antibody rapidtest improves the prognostic
significance of Cytoactiv®
0434
Quality of care for premenopausal patients with early-onset
breast cancer in Germany
G. Mehlhorn1, *S. Hautmann1, M.W. Beckmann1, R. Hilfrich2
1
Fraunklinik/Universität, Onkologie, Erlangen, Deutschland, 2Labor, Cytoimmun Diagnostics, Pirmasens, Deutschland
*D. Fischer1, M. Hedderich1, A. Heinrichs1, M. Thill1, C. Dittmer1, B. Wedel1,
C. Banz1
1
Unversitätsklinikum SH, Campus Lübeck, Frauenklinik, Lübeck, Deutschland
Background. Immunochemical detection of the HPV-L1 capsid-protein
with Cytoactiv is used as a prognostic marker to predict remission and
progression of HPV High risk (HR) associated LSIL/HSIL. In the presence of the HPV-L1 capsid-protein an activation of the immune system
is expected and a spontaneous remission is observed. In a minor proportion of cases (20%) the immune system fails to clear the dysplasia,
and a progression of HPV-L1 capsid-protein positive cells occur.
Objective. The aims of this study were 1.) to validate the use of an HPV16
L1-specific antibody rapidtest as a marker for the L1-specific activation
of the immune system and 2.) to validate if this test could improve the
prognostic significance of Cytoactiv for HPV HR+ LSIL/HSIL.
Material and methods. 84 patients showing HPV HR+ LSIL/HSIL were
recruted for this study. Immunochemical detection of the HPV-L1 capsid-protein was carried out with Cytoactiv®. All serum samples were
tested with an HPV16 L1-specific antibody rapidtest (HPVix-Cytoimmun diagnostics). HCII was used to confirm HPV HR positivity. Serum
samples of 50 Pap-negative, HCII positive women served as control.
Results and Conclusion. 22 (26%) patients of the study groupe but only 2
(4%) women of the control groupe showed an HPV16 L1-specific antibody response. A combined analysis of Cytoactiv and HPVix showed
no progression for 11, L1 capsid-protein and L1-antibody, double positive
women. Seven women showed a progression to CIN3 within the L1 single positive or double negative women. The observed 6.5-fold increase of
the antibody response for women showing an HPV HR+ LSIL/HSIL is
indicative for an L1-specific activation of the immune response. Since
no progression was observed for L1 double positive women, the rapidtest could be a promissing tool to improve risk assesement of HPV HR+
LSIL/HSIL.
0429
miRNAs as a prognostic marker/marker for circulating tumour
cells in metastatic breast cancer
*D. Madhavan, M. Wallwiener, K. Cuk, C. Modugno, I. Baccelli, M. Zucknick, A. Trumpp, S. Riethdorf, P. Sinn, C. Sohn, K. Pantel, A. Schneeweiss,
B. Burwinkel
Circulating tumour cells (CTCs) have been shown to be an independent
prognostic factor in metastatic breast, prostate and colorectal cancer.
Based on these evidences, the FDA has approved the use of CTCs counted by the Veridex Cell Search system, as an index to monitor therapy
and assess outcome. However, there are few logistical challenges, technical difficulties and discrepancies in the detection of CTCs. Therefore,
an easier and more robust method committed to an equal or even better
prognostic value is strongly appreciated. We exploited the potential of
circulating miRNAs in plasma to distinguish CTC positive from CTC
negative patients. By array based analysis of 667 miRNAs in plasma of
11 CTC positive and 9 CTC negative patient samples and further verification via TaqMan realtime PCR of the identified hits in 60 CTC
positive and 60 CTC negative samples, we identified a set of miRNAs
capable of reliably distinguishing CTC positive from CTC negative patients as well as from normal control individuals. These data show that
circulating miRNAs are suitable prognostic marker in metastatic breast
cancer.
Background and objective. The objective of the study is to evaluate how
young breast cancer patients are treated adjuvantly and whether treatment adheres to the guidelines. The distinction between this cohort and
a normally distributed cohort was verified.
Materials and methods. The study evaluates the data from a total of
1100 patients who were treated adjuvantly in the period from 2006 until
now and participated in a resident mother-child program. To date, the
data of 535 patients have been analyzed. The data includes TNM-stage,
the biology of tumor, therapies and their guideline-adherence. In addition the amount of participation in studies was evaluated. All data was
compared to an age-heterogeneous cohort from the state of SchleswigHolstein and the DMP report of the state of North Rhine-Westphalia.
Results. Of the patients that have been evaluated so far, 46% were diagnosed with stage pT1, 38% pT2, 7% pT3 and 2% pT4. 5% had merely
DCIS. 49% of the patients were pN0, 31% pN1 and 20% had a more intense infestation of lymph nodes. 44% of the tumors showed G3, 34% were
ER negative, 36% PR negative and 73% HER2 negative. 21% of the examined probands showed a triple negative carcinoma. 58% of the patients
with stage pT1 underwent breast-conserving surgery, 54% with stage T2
and 25% with stage pT3. Overall 15% of the women received mastectomy with subsequent reconstruction. 73% of the patients received axillary dissection, 90% received chemotherapy. Overall 21% were treated
within studies. 61% of the patients with antihormonal therapy received
GnRH-analoga. An additional analysis of data, the examination with
regard to the conformity with guidelines and the comparison with a
normally distributed age group has not been completed yet.
Conclusion. Young breast cancer patients provide a special challenge for
the therapists because their prognosis is often worse, frequently the tumor has developed to a worse stage, and carcinomas are more aggressive. Furthermore we have to view the kind of surgery in this age group in
a more differentiated way. It remains unclear to what extent guidelines
adherence improves overall survival and disease free survival.
0437
Prognostic value of CA 27.29 trend during adjuvant chemotherapy and two years thereafter in patients with primary breast
cancer
*J. Neugebauer1, B. Rack1, P. Hepp2, U. Andergassen1, J. Salmen2, G. Heinrich3, J. Schreier4, A. Hönig5, D. Finas6, T. Zwingers7, R. Kreienberg8,
M.W. Beckmann9, W. Lichtenegger10, K. Friese1, W. Janni2
1
Klinikum der LMU München – Innenstadt, Frauenklinik, München,
Deutschland, 2Universitätsfrauenklinik, Düsseldorf, Deutschland, 3Praxis
Dr. Heinrich, Fürstenwalde, Deutschland, 4DRK-Kliniken, Berlin Köpenick,
Deutschland, 5Universitätsfrauenklinik, Würzburg, Deutschland, 6Frauenklinik, Universität zu Lübeck, Deutschland, 7estimate GmbH, Augsburg,
Deutschland, 8Universitätsfrauenklinik, Ulm, Deutschland, 9Universitätsfrauenklinik, Erlangen, Deutschland, 10Charité, Berlin, Deutschland
Background. Emerging data show that the use of tumor markers (TM)
can lead to an early diagnosis of tumor recurrence in breast cancer. TM
are therefore frequently used in routine clinical patient care. But it is
still under investigation whether early treatment induction can improve
the prognosis of breast cancer patients with recurrence of their disease.
Methods. The SUCCESS Trial compares adjuvant FEC-Docetaxel (Doc)
vs. FEC-Doc-Gemcitabine (Doc-G) regime and two vs. five year treatment with Zoledronate in nodal positive or high risk nodal negative paJournal of Cancer Research and Clinical Oncology Suppl 1 · 2011 | 85
Abstracts
tients with primary breast cancer. CA27.29 was measured prior to and
immediately after chemotherapy (CHT), as well as 2 years thereafter
with the ST AIA-PACK Ca27.29 reagent using MUC-1 for AIA-600II
(Tosoh Bioscience, Tessenderlo, Belgium). For this analysis, the change
of Ca27.29 from pre-chemotherapy baseline to 2 years was evaluated.
Results. CA27.29 data was available of 3202 patients before and 2015 patients 2 years after chemotherapy. 20.2% of patients showed increasing
(≥1 U/ml) CA27.29 levels from before CHT to 2 years thereafter. 59.7%
of patients had decreasing and 20.1% had stable CA27.29 levels from baseline to 2 years. Patients with increasing CA27.29 levels from before
CHT to 2 years after CHT had a significant worse disease-free survival
(DFS) (HR 1.016; [95% CI 1.011–1.021] p=5 U/ml had a 81% increased risk
for recurrence (HR 1.81; [CI: 1.111–2.948]). Between those patients with
stable and decreasing levels there was no significant difference in terms
of prognosis. In the multivariate analysis taking into account tumor
size, nodal status, grading, age, hormonal and Her2/neu receptor status
increasing CA27.29 levels were an independent prognostic marker with
respect to poor DFS and OS.
Conclusion. A small increase of the tumor marker Ca27.29 compared to
pre-chemotherapy level was associated with a worse prognosis. Therefore, individual changes in tumor marker values compared the patient’s
baseline could lead to a more accurate and clinically relevant interpretation of tumor markers.
0442
Primary colorectal adenocarcinoma metastatic to the breast:
case Report and review of the literature
*J. Radosa1,, R. Mayroya1, A. Leingartner1, I. Juhasz-Böss1, E.-F. Solomayer1,
S. Baum1
1
Universitätsklinikum des Saarlandes, Frauenklinik, Homburg/Saar,
Deutschland
Introduction. Metastases to the breast from extramammarian carcinomas are extremely rare and account for 1–6% of all breast malgnancies.
Mostly gastric and lung carcinomas, lymphoma and malignant melanoma are the most freuquently nonmammary metastases. Colorectal
carcinoma as a metasis in the breast are very uncommon. We presented
a case of poorly differentiated colon cancer metastatic to the breast.
Case presentation. A 79-year-old caucasian woman who was diagnosed
with primary colon adenocarcinoma stage Duke C in 2010 and treated with right hemycolectomy and chemotherapy (Folfox 10 cycles). Six
month after chemotherapy a tumor in the right upper quadrant of the
breast was discovered incidentally during re-staging. Patients received
segment resection of the right breast, sentinel node biopsy and intraoperative radiation. Postoperative pathology results showed an undifferentiated adenocarcinoma which could be identified as a metastasis
from the primary colorectal carcinoma.
Conclusion. Colorectal metastases in the breast are extremely seldom
and there is no general therapy standard. Very important in the management of this occurrence is a multidisciplinary approach to provide
best treatment for the patient.
0448
Clinical value of circulating tumour cells (CTC) in metastatic breast cancer (MBC) as prognostic and predictive factors
*M. Wallwiener1,2, C. Modugno2, I. Baccelli3, M. Sprick3, B. Schoenfisch4,
S. Riethdorf5, S. Schott1,2, C. Domschke1,2, C. Pantel5, F. Marmé1,2, C. Sohn1,
A. Trumpp3, A. Schneeweiss2
1
Universitäts-Frauenklinik, Onkologie, Heidelberg, Deutschland, 2NCT,
National Center for Tumor Diseases, Heidelberg, Deutschland, 3HI-STEM,
DKFZ, German Cancer Research Center, Heidelberg, Deutschland, 4University of Tübingen, Department of Obstetrics and Gynaecology, Tübingen,
Deutschland, 5University Medical Center Hamburg-Eppendorf, Institute of
Tumour Biology, Hamburg, Deutschland
Background. CTC (≥5/7.5 ml blood) are prognostic of worse progressionfree survival (PFS) and overall survival (OS) in MBC. We aimed to correlate CTC kinetics during first cycle of treatment and CTC phenotype
to response.
Methods. Patients (pts) with progressive MBC had 7.5 ml blood samples taken at baseline and after completing the first cycle of a new line
of systemic therapy. CTC changes from baseline (BL) to first cycle (C1)
(CTCBL+ → CTCC1−/ CTCBL+ → CTCC1+) were correlated with Radiological Response Evaluation Criteria in Solid Tumors (RECIST). Changes
from CTCBL → CTCC1 were grouped as increasing (>25%), decreasing
(>25%),) or constant (<25%) and compared to response. Samples were
also analysed for intact (CTCint) and apoptotic (CTCapop) CTC (CellSearch™ System (Veridex). Primary tumour and CTC were compared for
HER2 receptor expression.
Results. From 03/2010 to 07/2011 219 pts were included. 75/219 pts (34%)
had ≥5 CTCs/7.5 ml blood (CTCBL+) before treatment started (median 18, range 5–200,000 CTC). Patient and tumour characteristics
were as follows (CTCBL+/CTCBL−, n): median age 55/61 years; line of
therapy (1st/2nd/≥3rd, n) 28/49 18/30 28/64; 26 of 50 (52%) CTCBL+
pts were CTCC1+ and 24 (48%) were CTCC1−. For 171 patients follow-up
data are available with a median follow-up (FU) of 6.7 months. 85/171
(50%) pts showed so far progressive disease (PD), thereof CTCBL+ 30/56
(54%); CTCBL− 55/115 (48%). 33 pts responded to treatment [response
rate (PR)]: CTCBL+: 4%, CTCBL−: 11%). PFS and OS were decreased for
CTCBL+ patients (p=0.002 resp. p<0.001). Respective responses rates
(PR) (CTCBL →CTCC1) for initially 10 pts with at least 25% increasing
CTCC1, 28 pts with at least 25% decreasing CTCC1 and 11 pts with constant CTCC1 were PD 5/11/2, SD 5/16/5, PR 5/13/2. Respective median PFS
was 3.2/5.3/4.6 months (PFS p=0.28).
44 patients with CTCapop both positive (at baseline and after cycle 1) responded
after cycle 1 with PD 13 (30%), SD 14 (32%), PR 3 (7%) vs. 14 patients with
CTCapop both negative with PD 3 (21%), SD 4 (28%), PR 2 (14%). Median
PFS was 4.7/4.6 months. Analysis of HER2 expression in the PT and
CTCs was concordant in 87/105 (83%) and discordant in 18/105 (17%) patients (20%); thereof 12 (11%) patients changing from positive to negative
and 6 (6%) changing from negative to positive.
Conclusions. Interim analysis of these prospective data showed that detection of ≥5 CTCs/7.5 ml is prognostically relevant in MBC pts with
decreased PFS and OS. HER2 expression by the PT and CTCs is discordant in up to 8% of cases. Further data will be collected to evaluate if
CTC monitoring can be a versatile tool for predicting response to treatment in MBC.
0451
Epithelial cell adhesion molecule (EpCAM) is associated with a
favorable prognosis in epithelial ovarian cancer patients
*H. Woopen1, K. Pietzner1, R. Richter1, C. Fotopoulou1, T. Joens1, E. Braicu1,
J. Shetje2, H. Mellstedt2, S. Darb-Esfahani3, C. Denkert3, J. Sehouli1
1
Charité – Universitätsmedizin Berlin, Department of Gynecology, Berlin,
Deutschland, 2Cancer Center Karolinska, Department of Oncology, Karolinska, Schweden, 3Charité – Universitätsmedizin Berlin, Department of
Pathology, Berlin, Deutschland
Background. EpCAM, a well known cancer antigene is currently experiencing a renaissance in its use as a binding site for targeted oncologic
therapy and prognostic marker in various epithelial carcinomas such as
breast cancer or carcinomas of the oral cavity. Goal of this retrospective
study was to identify EpCAM as a potential prognostic marker for patients with primary epithelial ovarian cancer (EOC).
Methods. EpCAM Expression was assessed in tumor tissue by immunohistochemistry using the Avidin-Biotin-Complex method on paraffinembedded ovarian cancer tissue samples. EpCAM overexpression was
defined as an expression of EpCAM as high as 76–100%. Clinical data
as well as tumor tissue samples were collected within the “Tumorbank
Ovarian Cancer” network.
Results. Seventy-four patients with the primary diagnosis of EOC between 01/1994 and 12/2009 were included in this study. Median age at
diagnosis was 56 years. The vast majority of the patients (75.4%) presented an advanced stage disease (FIGO III/IV). Forty-one (55.4%) patients
were diagnosed with a serous, 19 (25.6%) a endometrioid and 14 (19%) a
mucinous histology. EpCAM was overexpressed in 87.7% of the patients.
Serous tumors expressed EpCAM significantly higher than mucinous
tumors (p=0.045). There was no significant difference in the expression
of EpCAM between the other histological subgroups. EpCam overexpression correlated in univariate analysis with a significantly better
overall survival. When classifying EpCAM expression into two groups,
namely ≤50% and 76–100%, in a Log Rank (Mantel Cox), it was proved
that EpCAM overexpression of higher than 76% was found to be associated with a significantly better survival compared to a lower EpCAM
expression of ≤50% (p=0.008).
Discussion. EpCam overexpression in EOC appears to be significantly associated with significantly higher overall survival rates. Larger,
prospective multicenter studies are warranted to further evaluate and
confirm these novel findings and possibly establish EpCAM as a potent
therapeutic target in EOC.
0452
Breast density and breast cancer characteristics
*K. Heusinger1, S.M. Jud1, C.R. Loehberg1, C. Hack1, M. Bani1, M.P. Lux1,
M.G. Schrauder1, R. Schulz-Wendtland2, B. Adamietz2, M. Meier-Meitinger2,
M.W. Beckmann1, P.A. Fasching1
1
University Hospital Erlangen, Dept. of OB/Gyn, Erlangen, Deutschland,
2
University Hospital Erlangen, Dept. of Radiology, Erlangen, Deutschland
Background. Breast cancer risk factors are increasingly linked with breast cancer molecular subtypes. For example family history might be linked to triple negative breast cancer and hormone replacement therapy
is supposed to increase the risk for hormone receptor positive breast
cancer. Aim of our study was to associate mammographic density with
the tumor characteristics of invasive breast cancers.
Methods. In a case only design 1974 invasive breast cancers with available information about age at diagnosis, BMI and parity on the one
hand and tumor characteristics like quantitative ER and PR status, were
analyzed concerning their association with mammographic density.
Mammographic density was obtained with the MADENA. For the association of the continuous variable mammographic density with the
other factors an unconditional linear regression model was built.
Results. Mammographic density was strongly associated with age, BMI
and parity. Concerning tumor characteristics mammographic density
was negatively correlated with tumor stage and progesterone receptor
status and negatively correlated with estrogen receptors status. After adjusting for the influence of BMI, age and parity, the negative association
with the estrogen receptor status and the positive association with the
progesterone receptor status remained statistically significant.
Conclusions. There seems to be a positive correlation between mammographic density and the progesterone receptor status, and a negative correlation of the estrogen receptor status of the breast tumor with
the mammographic density of the breast, implying a possible balanced
interaction between both sex hormones in the pathogenesis of breast
tumors.
0455
Prognostic relevance of circulating tumor cells in the peripheral
blood of primary breast cancer patients
*B. Rack1, C. Schindlbeck2, U. Andergassen1, R. Lorenz1,3, T. Zwingers1,3,4,
A. Schneeweiss1,3,4,5, W. Lichtenegger1,3,4,5,6, M.W. Beckmann1,3,4,5,6,7, H. Sommer1, K. Pantel1,8, K. Friese1,8, W. Janni1,8,9
1
LMU, Gynäkologie, München, Deutschland, 2Klinikum Traunstein, Traunstein, Deutschland, 3Gemeinschaftspraxis Dr. Lorenz/Hecker/Wesche,
Braunschweig, Deutschland, 4estimate GmbH, Augsburg, Deutschland,
5
Universität Heidelberg, Heidelberg, Deutschland, 6Charite Universitätsmedizin, Berlin, Deutschland, 7Universitätsfrauenklinik, Erlangen, Deutschland, 8Institut für Tumorbiologie, Hamburg, Deutschland, 9Heinrich-HeineUniversität, Düsseldorf, Deutschland
Background. Circulating tumor cells (CTC) in blood have been shown
as predictor of shortened survival in metastatic disease. We evaluated
whether the presence of CTC before the start of systemic adjuvant treatment increases the risk of subsequent relapse and death.
Patients and methods. The SUCCESS A -Study compares disease-free
survival in patients treated with 3 cycles of FEC (100/500/100), followed
by 3 cycles of Docetaxel (100) versus 3 cycles of FEC, followed by 3 cycles of Gemcitabine (1000 mg/m2 d1,8)-Docetaxel (75). In 2026 patients
CTC were analyzed using the CellSearchSystem (Veridex, USA). 23 ml
of peripheral blood were drawn before the start of adjuvant systemic
treatment. After immunomagnetic enrichment with an anti-Epcamantibody, cells were labelled with anti-Ck8/18/19 and anti-CD45 antibodies. Patients were followed for a median of 35 months. Patients with
evidence of at least 1 CTC were counted as positive.
Results. In 21.5% of patients (n=435) CTC were detected before the start
of systemic treatment (median 1.3, range 1–827). Patients with CTC before treatment were more frequently node-positive (p<0.001), but no
correlation to tumor size, grading and HR-Status could be found. 114
recurrences occurred and 66 patients died of their disease. The presence of CTC before systemic treatment predicted poor disease-free
(p<0.0001), distant disease-free survival (p<0.001) and overall survival
(p=0.0002). In multivariate analysis, detection of CTC before treatment
was confirmed as independent predictor for both disease-free (HR 1.88)
and overall survival (HR 1.91) next to tumor size, grading, lymph node
involvement and hormone receptor status (p for all <0.05). Outcome of
patients was correlated to the number of CTC. Prognosis was worst in
patients with 5 CTC or more with a four-fold increased risk for recurrence and and a three-fold increased risk for death (HR 4.04 for DFS
and 3.05 for OAS; p<0.05).
Conclusions. This is the first study to prospectively demonstrate the
prognostic relevance of CTC in peripheral blood of early breast cancer
patients before the start of systemic treatment in a large patient cohort.
CTC detection could serve as clinically useful prognostic marker and
treatment monitoring tool.
Abstracts
0459
Impact of the ratio of positive to resected nodes on prognosis of
advanced epithelial ovarian cancer
*C. Bachmann1, *S. Bachmann1, E. Grischke1, E. Solomayer2, T. Fehm1,
D. Wallwiener1
1
Universitätsfrauenklinik, Gynäkologie/Geburtshilfe, Tübingen, Deutschland, 2Universitätsfrauenklinik, Gynäkologie/Geburtshilfe, Homburg/ Saar,
Deutschland
Introduction. The objective of this study was to assess the value of metastatic lymph node ratio (positive to resected nodes) in predicting
prognosis of patients with stage IIIc ovarian cancer. 5-year survival
rate is about 25% for advanced ovarian cancer with worst prognosis in
FIGO IIIc. The most important prognostic factor is radical surgery without residual tumour. Additionally according to the FIGO classification IIIc can present abdominal tumour lesions >2 cm and/ or positive
retroperitoneal or inguinal nodes. Known is the increasing node positivity in advanced ovarian cancer; with about 40% of node positivity
in patients with advanced ovarian cancer. Prognostic impact of node
status or node ratio in advanced ovarian cancer is still unknown and is
examined in studies. In other tumor entities a node ratio (e.g. colon cancer) already showed a unique significant prognostic value. So far there
is very little data about node ratio in ovarian cancer. Possibly the node
ratio is a way to assess the prognosis for initial diagnosis in stage IIIc
ovarian cancer patients.
Methods. Therefore, 261 consecutive patients with primary ovarian cancer underwent surgery between 2000 and 2007 at the Department of
Gynecology at the University Hospital, Tübingen, Germany. Every patient underwent surgical staging or tumour debulking as clinically indicated and adjuvant standard platinum- based chemotherapy. Patients
with residual tumour mass>2cm or reduced general health got no lymphadenectomy. Tumour stage was classified according to FIGO classification. Data of all patients with primary advanced ovarian cancer and
FIGO IIIc were evaluated (133 patients). The ratio of positive to resected
lymph nodes was stratified into the following groups: 1 (LNR=0); 2 (>0–
<LNR– ≤0.5); 3 (0.5– <LNR– ≤1; LNR: lymph node ratio).
Results. 112 patients with primary FIGO IIIc ovarian cancer were evaluated, 91 got pelvic/paraaortic, 21 patients got pelvic and 21 patients got
no lymphadenectomy. Patients with node ratio >0–0.5 had significant
best OS in FIGO IIIc (p=0.037; 53.42 months). Node negative (node ratio =0) and high node positive patients (node ratio >0.5) had similar OS
(34.7 vs. 32.6 months). No significant impact on PFS was seen with the
node ration in the three groups. In other tumor entities a node ratio (e.g.
colon cancer) already showed a unique significant prognostic value. So
far there is very little data about node ratio in ovarian cancer.
Conclusion. So far there are very few studies on the importance of the
node ratio in ovarian cancer. Our results show that node ratio can estimate prognosis in FIGO IIIc ovarian cancer for OS, but had no significant impact on PFS. Best OS have patients with node ratio >0–<0.5, but
it is possible that these patients have no residual tumour mass in FIGO
IIIC. Further prospective studies had to investigate the impact of node
ratio also in correlation with residual tumour.
0460
Maxillary and upper jaw malignancies – a review over 40 years
M. Böhm1, M. Kappler1, M.H.W. Lautner1, J. Schubert1, H. Taubert1,
*A.W. Eckert1
1
Martin-Luther-Universität Halle-Wittenberg, MKG-Chirurgie, Halle(Saale),
Deutschland
Introduction. Carcinoma of the upper jaw and the maxillary sinus are
rare events. Most of the published papers consider only between 30 and
50 cases. Therefore, it was the aim of the investigation to analyse all cases with the diagnosis upper jaw malignoma to give an overview about
treatment modalities.
Materials und methods. We analyzed all patients with a retrospective monocentric study with a diagnosed malignoma of the upper jaw
between 1969 and 2011. Clinical and histological parameters (kind of
tumor, TNM, grading) were summarized to a data bank SPSS 17.5. Statistical analyses were performed using Anova-t-test, log-rank test and
Cox’s regression hazard analysis.
Results. A total of 185 patients were analyzed. There were 102 men and
83 women with an age range between 28 and 95 years (average age 62 years). Squamous cell carcinomas (SCC) dominated. We found 108 SCC,
26 adenoid-cystic carcinoma and 48 other malignancies. Among the
group of SCC there were 15 T1-, 12 T2-, 9 T3- and 40 T4-tumors (undefined nine cases). The N-status was as follows: 22× N0, 13× N1, 6× N2,
5× N3 and 39× Nx, respectively. The five-year survival of all SCC’s was
more than 60%. A local reccurence had a 4.9-fold increased risk of tumor-related death with marginal significance (p=0.086). Interestingly,
the strongest predictor for overall survival was the N-status. Patients,
whose tumors had lymph node metastases had an 11-fold increased risk
of tumor related death in comparision to N0-necks (Cox’s regression;
p=0.004).
Summary: tvvvTo our knowledge, this is one of the largest analyses of maxillary and upper jaw malignancies in Europe. SCC is the predominant
kind of tumor, followed by adenoid-cystic carcinoma and other salivary
gland tumors. The surgical treatment of upper jaw carcinomas led to
good results. Only 22% of all SCC cases had, also in advanced cases,
lymph node metastases. Therefore, we do not suggest an elective neck
dissection in general.
0479
Enhanced antineoplastic properties of a genetically engineered
oncolytic measles vaccine virus armed with the prodrug-converting enzyme cytosine-deaminase to treat ovarian cancer
*A. Hartkopf1, J. Lampe2, S. Berchtold2, I. Smirnow2, M. Zimmermann2,
S. Bossow3, W. Neubert4, D. Wallwiener1, T. Fehm1, U.M. Lauer2
1
Universität Tübingen, Frauenklinik, Tübingen, Deutschland, 2Universität
Tübingen, Innere Medizin I, Tübingen, Deutschland, 3Nationales Centrum
für Tumorerkrankungen, Heidelberg, Deutschland, 4Max-Planck-Institut für
Biochemie, Martinsried, Deutschland
Background. Oncolytic viruses (OVs) effectively invade, replicate in and
kill cancer cells. Moreover, infection with OVs leads to the release of
progeny virions that can spread throughout the tumor. A promising
candidate to treat ovarian cancer is the oncolytic measles vaccine virus (MeV). Although wild-type measles virus causes serious disease the
vaccine strain has been safely administered to millions of people. In a
recent phase I trial intraperitoneal delivery of MeV to treat recurrent
ovarian cancer was well tolerated and resulted in promising clinical
activity. To enhance their antineoplastic properties many OVs can be
armed with therapeutic transgenes, e.g. suicide-genes.
Methods. The prodrug-converting enzyme cytosine-deaminase (CD)
converts non-toxic 5-fluorcytosine (5-FC) into cytotoxic 5-fluouracil
(5-FU). We generated a CD-carrying MeV (MeV ld-SCD). The ability
of MeV ld-SCD to infect, kill and replicate in ovarian cancer cell-lines
(SKOV3, OAW-42) as well as treatment of infected cells with the prodrug 5-FC was analyzed.
Results. MeV ld-SCD was highly cytotoxic to ovarian carcinoma cell-lines. This cytotoxic effect was significantly enhanced (p<0.001) when the
prodrug 5-FC was added. As expected, 5-FC was not toxic to uninfected
cell-lines. Moreover high titers of progeny virions were produced upon
infection.
Conclusion. MeV ld-SCD is a promising candidate to target ovarian cancer and specifically hit tumor cells with (1) a highly oncolytic but safe
virus and (2) a potent and well characterized cytotoxic drug.
0485
Variations in VEGF- and TIMP2-expression during therapy seem
to predict the response to platinum-based chemotherapy in
patients with primary cervical-cancer (CC)
*E.I. Braicu1, C. Fotopoulou1, R. Chekerov1, R. Richter1, J.-U. Blohmer2, C. Pop1,
M. Mentze1, S. Kümmel3, W. Lichtenegger1, J. Sehouli1
1
Charité, Virchow Klinikum, Frauenklinik, Berlin, Deutschland, 2Sankt Gertrauden-Krankenhaus, Frauenheilkunde und Geburtshilfe, Berlin, Deutschland, 3Kliniken Essen Mitte, Brustzentrum, Essen, Deutschland
Objective. The aim of this study was to analyze the type of variations
in expression-profile of MMP2, MMP9, TIMP2, and VEGF before and
after chemotherapy in patients with advanced FIGO stage Ib–IIb CC.
Therefore we analysed the impact of changes in expression on platinum
response.
Methods. Serum from 72 CC patients treated within a phase-III trial
with either simultaneous radiochemotherapy with cisplatin S-RC or
systemic paclitaxel and carboplatin followed by percutaneous radiation
PC-R was analyzed by ELISA. Sera were obtained during surgery and
after end of the adjuvant treatment. Statistical analysis was performed
using SPSS and following standard procedures.
Results. The median age at time of diagnosis was 46 years (range 30–
71 years). Most of the patients presented a squamous cell- (73.6%) followed by adenocarcinomas (25%). 35 (48.6%) patients received surgery
followed by S-RC and 37 (51.4%) patients were treated with PC-R. Five
patients developed recurrence within 6 months after end of chemotherapy. VEGF levels were increased in platinum non-responders (mean
difference: 150 pg/ml) and decreased in platinum-responder patients
(mean difference: −233 pg/ml). This difference reached no statistical significance (p=0.144). The TIMP2 expression was not significantly increased in platinum-sensitive patients compared to platinum-resistant ones
(p=0.112). An increase of more than 500 pg/ml VEGF and a decrease
of more than 9% of the pre-therapeutically value of TIMP2 were significantly associated with a higher risk of platinum resistance (RR=8.5,
95% CI=1.8–39.8 and RR=11.0, 95% CI=2.5–48.2, respectively).
Conclusions. Our results indicate that VEGF and TIMP2 might predict
the platinum-response in patients with advanced primary CC.
0491
Zoledronic acid has antitumor activity in primary breast cancer
cells as determined by the ATP tumor chemosensitivity assay
*T. Fehm1, H. Seeger1, M. Zwirner1, D. Wallwiener1, H. Neubauer1
1
Eberhard-Karls-University Tübingen, Department of Obstetrics and Gynecology, Tübingen, Deutschland
Introduction. The NeoAzure study has demonstrated that the use of the
bisphosphonate zole-dronate increases the rate of complete response in
primary breast cancer and therefore indicates direct antitumor activity. The aim of this study was to compare the antitumor effect of zolendronic acid with standard chemotherapy in primary breast cancer cells
using ATP-tumor chemosensitivity assay (ATP-TCA).
Material and methods. Tumor specimens were obtained from patients
with breast cancer who underwent primary breast cancer surgery at the
Department of Obstetrics and Gynecology, Tübingen, Germany, between 2006 through 2009. Antitumor effects of zoledronic acid (Zol),
TAC (Docetaxel, Adriamycin, Cyclophosphamide) and FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) were tested in 116 fresh human
primary breast cancer specimens using ATP-TCA. ATP-TCA results
were analyzed with different cut-off levels for the half maximal inhibitory concentration (IC50) and for IC90 or a defined sensitivity index
(IndexSUM). Each single agent or combination was tested at six doubling dilutions from 6.25, 12.5, 25, 50, 100, and 200% of test drug concentrations (TDC) derived from the plasma peak concentrations determined by pharmacokinetic and clinical information. The assay was carried
out in duplicate wells with positive and negative controls.
Results. For Zol the median IndexSUM value was 36.8% and 12.9% lower than for FEC and TAC, respectively, indicating increased antitumor activity in primary breast cancer cells. The difference between Zol
and FEC was significant (p<0.05). The median IC50 value for Zol (8.03%
TDC) was significantly lower than the IC50 values for FEC (33.5% TDC)
and TAC (19.3% TDC) treatment (p<0.05). However, the median IC90
value for Zol (152.5% TDC) was significantly higher than the IC90 value
obtained with TAC (49.5% TDC; p<0.05), but similar to the IC90 value
for FEC (180.9% TDC).
Conclusion. Zoledronic acid has a strong antitumor effect on primary
breast cancer cells in vitro which is equal or superior to commonly used
chemotherapeutic regimens for treating breast cancer.
0494
1H NMR and LC-MS Metabolomics Study of Response to preoperative Chemotherapy of Breast Cancer
*H. Neubauer1, S. Wei2,L. Liu3, J. Zhang2, S. Murthy4, N. Gowda2, D. Raftery2,
U. Vogel5, H. Seeger1, T. Fehm1
1
Eberhard-Karls-University Tübingen, Department of Obstetrics and
Gynecology, Tübingen, Deutschland, 2Purdue University, Department of
Chemistry, West Lafayette, USA, 3Purdue University, Weldon School of
Biomedical Engineering, West Lafayette, USA, 4MatrixBio Inc.,West Lafayette, USA, 5Eberhard-Karls-University Tübingen, Institute of Pathology,
Tübingen, Deutschland
Objectives. Predicting response for preoperative chemotherapy will
save patients’ time and money, will reduce exposure to toxic drugs, and
will help to optimize treatment. The aim of this project was to apply metabolomics or metabolite profiling to identify serum markers to predict
response to preoperative chemotherapy.
Materials and Methods. Serum was obtained before the start of the chemotherapy (“baseline sample”) from 30 patients who were indicated to
neoadjuvant chemotherapy because of histopathologically verified lesions of locally advanced breast cancer (T2–4, N0–1, M0). All patients
consented to neoadjuvant chemotherapy. They were treated with 4
three-weekly cycles of epirubicin plus cyclophosphamide (EC) followed
by docetaxel fourtimes in three weekly intervals. Patients with Her2/neu
positive tumors also reveived Trastuzumab every three weeks, starting
with on day 1 of the first EC cycle. Response was determined by histopathology. Serum samples were analyzed by combining nuclear magnetic
resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Data analysis was done with Matlab software (Mathworks) installed with the PLS toolbox (Eigenvector Research, Inc.,
version 4.0) for partial least squares (PLS) analysis. The same software
was also used for partial least squares discriminant analysis (PLS-DA)
modeling. Leave-one-patient-out CV was chosen, and latent variables
were selected according to the root mean square error of CV procedure.
The R statistical package (version 2.8.0) was used to generate receiver
operating characteristics (ROC) curves and Box-whisker plots.
Results. We identified 27 NMR and 10 LC-MS metabolites which are differentially represented between responders and non responders: 3 metabolites (threonine, glutamine and linolenic acid) from NMR and linolenic acid from LC-MS spectra are significantly differentially expressed
(p<0.05 and p<0.03). PLS-DA and Leave-one-out cross validation provide AUROC for responder and non responder of 0.95, a sensitivity of 1
and a specificity of 0.78 when combining NMR and LC-MS metabolites.
Discussion. Metabolic profiling combining NMR and LC-MS is an effective way to separate patients’ response differently to chemotherapy.
We identified 4 metabolites in blood taken before starting preoperative
chemotherapy which in combination can identify 90% of the patients
that will not benefit from preoperative chemotherapy. Further validation will be done based on a large sample set.
Abstracts
0496
Expression of embryonic stem cell factor Sox2 in serous ovarian
carcinomas
*T. Fehm1, D. Pham2, V. Scheible2, C. Lengerke3, S. Perner2, H. Neubauer1,
A. Staebler2
1
Gynecology, Tübingen, Deutschland, 2Eberhard-Karls-University Tübingen,
Department of Pathology, Tübingen, Deutschland, 3Eberhard-Karls-University Tübingen, Department of Internal Medicine, Tübingen, Deutschland
Background. The transcription factor Sox2 is involved in the maintenance of embryonic stem cell pluripotency and is expressed in several
carcinoma types such as adenocacinoma of the lung and squamous cell
carcinomas (SCC) of various origins. The gene SOX2 is located at chromosome 3q26, a region that is a frequently amplified in serous ovarian
carcinoma. Therefore, the aim of this study was to explore the potential
role of Sox2 in ovarian carcinogenesis by correlating Sox2 protein expression in 167 serous ovarian carcinomas with clinical outcome.
Methods. 167 consecutive cases of serous ovarian carcinoma were analyzed by immunohistochemistry and in a tissue microarray for nuclear
expression of Sox2. The cut-off level for Sox2 positity was>0% stained
cells (Lengerke et al. BMC 2010). Correlation with clinicopathological
factors were determined by chi-squared test. Recurrence-free and overall survival was compared by the logrank-test.
Results. 57% of all 167 serous ovarian carcinomas showed detectable
Sox2 positive cells. Sox2 expression was associated with grade 3 tumors
(p<0.05). No correlation could be observed with FIGO stage (p=0.15)
or nodal status (p=0.81). Sox2 had a significant impact on survival
in patients with serous ovarian cancer (excluding G1 and FIGO I tumors). The median recurrence-free survival was 29.2 months (95% CI:
19.9–38.5 months) in the Sox2 negative group compared to 43.2 months
(95% CI: 33.6–52.8 months) in the Sox2 positive group (p<0.05).The overall survival was also shorter in the Sox2 negative group (40.3 months
(95% CI: 29.1–51.5 months) versus 52.5 months (95% CI: 43.6–61.3 months)
but did not reach statistical significance (p=0.06).
Conclusions. Sox2-positive cells can be detected by immunohistochemistry in a majority of serous ovarian carcinomas. Interestingly, Sox2
expression is associated with a significantly better prognosis, suggesting that in this specific tumor entity activation of certain stemnesspathways may unexpectedly predict favourable outcome which may be
related to increased platin sensitivity.
0500
Bisphosphonates may improve survival of breast cancer patients
with disseminated tumor cells in bone marrow
E.-F. Solomayer1, *M. Banys2, N. Krawczyk3, G. Gebauer2, D. Wallwiener4,
P. Hirnle5, W. Janni6, H.-J. Lück7, S. Becker4, J. Huober8, B. Kraemer4, B. Wackwitz9, T. Fehm4
1
Universitäts-Frauenklinik, Gyn/OB, Homburg, Deutschland,
2
Marienkrankenhaus Hamburg, Frauenklinik, Hamburg, Deutschland,
3
Klinikum Bremen-Mitte, Frauenklinik, Bremen, Deutschland, 4Universitaets-Frauenklinik, Gyn/OB, Tübingen, Deutschland, 5Central Academic
Hospital, Department of Radiation Oncology, Bielefeld, Deutschland,
6
Heinrich-Heine University, Gyn/OB, Düsseldorf, Deutschland, 7Hannover
Medical School, Gyn/OB, Hannover, Deutschland, 8Breast Center Kantonsspital, Gyn/OB, St. Gallen, Schweiz, 9Novartis Oncology, Novartis, Nürnberg,
Deutschland
Introduction. The presence of disseminated tumor cells (DTC) in bone
marrow (BM) is an independent prognostic factor in breast cancer. In
addition, tumor cells are able to survive chemotherapy and their persistence is strongly associated with poor outcome. Bisphosphonates have
been previously reported to improve survival in nonmetastatic breast
cancer. The purpose of this study was to investigate the impact of zoledronic acid (ZOL) on DTC persistence and patients’ survival.
Material and methods. In total, 96 DTC positive breast cancer patients
were included into this prospective open-label parallel-group study between 2002 and 2004. Patients were randomized 1:1 to adjuvant therapy
alone (control) or with intravenous ZOL q4w for 24 months. In 71 and 59
cases an additional BM biopsy was conducted 12 months and 24 months
after diagnosis, respectively.
Results. An adequate follow-up of at least 8 months was available for
86 patients (ZOL group: 40 pts, controls: 46 pts; median follow-up
88 months, range: 8–108 months). Patients in the control group were
more likely to die than those in ZOL group (11% vs. 2%, p=0.106). In
addition 15% of patients in the control group presented with relapse
whereas only 8% of ZOL group patients developed metastatic or recurrent disease during follow-up (p=0.205). These differences did not reach
statistic significance due to small sample size. However, a trend toward
shorter overall and disease-free survival in the control group was observed. Patients treated with ZOL became DTC negative after 24 months of
treatment. DTC persistence was associated with shorter overall survival
(p=0.011).
Discussion. Intravenous zoledronic acid may help to eradicate DTC
from bone marrow. Our data support the possible protective effect of
bisphosphonates in DTC positive patients.
0018
Strong negative feedback from Erk to Raf confers robustness to
MAPK signalling and impaired the efficiency of small-molecule
inhibitors
*R. Fritsche1, F. Witzel1, A. Sieber1, R. Herr1, N. Schmidt1, S. Braun1, T. Brummer1, C. Sers1, N. Blüthgen1
1
Charité – Universitätsmedizin Berlin, Pathologie CCM, Berlin, Deutschland
Aim. It is known, that protein levels within signal transduction pathways vary strongly from cell to cell. This problem lead to several questions: How the signalling network can deal with uncertainty and the
noise inherent to biochemical processes? How signalling pathways can
still process information quantitatively despite strong heterogeneity in
protein levels? How robust cells are due to perturbations in one central
signalling pathway?
Methods and results. We combined an experimental and theoretical
approach to analyses how the activity of the MAPK signal transduction pathway is influenced by changes in protein level. A kinetic model
suggested that Erk would be linearly dependent on the concentration
of the kinase. In stark contrast, we found experimentally that the phosphorylated form is only weakly dependent on the protein concentration. We found that the steady-state phosphorylation of Erk is very
robust against perturbations of Erk protein level, suggesting that there
are mechanisms that provide robustness to the pathway against protein fluctuations. Using mathematical modelling, we identified three
potential mechanisms: kinetic effects, transcriptional or post-translational negative feedbacks. By experimental analysis we could exclude
kinetic effects and transcriptional negative feedback as mechanisms of
robustness. Detailed molecular analysis of the system shows that a single post-translational feedback to Raf mediates robustness. By analysing
a panel of cell lines we found that cells are robust as long as the signal
passes through Raf-1. In contrast, cells where the pathway is activated
by a mutation in B-Raf loose robustness. Therefore, once the feedback
is broken, the system loses robustness and can be readily modulated by
low concentrations of targeted inhibitors. In contrast, if the feedback is
intact, inhibition of the pathway is inefficient.
Conclusion. This finding explains why Mek inhibition has shown little
success in the past in cancer treatment. However, it also shows that a
subgroup of patients with B-Raf mutation will likely benefit, and that
due to the robustness of the healthy cells that have no B-Raf mutation
side effects might be minimal. We believe that analysing robustness of
other signalling pathways in a similar way will be the key to devise efficient targeted interventions for these, and will unveil which mutations
in the pathway will break robustness and thereby open the door for efficient intervention.
0034
Mutual regulation of Bcl-2 proteins independent of the BH3
domain as shown by the BH3-lacking protein Bcl-xAK
*M. Plötz1, A. M. Hossini1, B. Gillissen2, P. T. Daniel2, E. Stockfleth1, J. Eberle1
1
Charité, Department of Dermatology and Allergy, Skin Cancer Center,
Berlin, Deutschland, 2Charité, Department of Hematology, Oncology and
Tumor Immunology, Berlin, Deutschland
Introduction. The BH3 domain of Bcl-2 proteins was regarded as indispensable for mutual regulation of pro- and antiapoptotic family
members as well as for apoptosis induction. We have recently described
Bcl-xAK, a proapoptotic splice product of the bcl-x gene, which lacks
BH3 but encloses BH2, BH4 and a transmembrane domain. It remained
however unclear, how Bcl-xAK may trigger apoptosis.
Materials and methods. For its efficient overexpression, Bcl-xAK was
subcloned in an adenoviral vector under Tet-OFF control.
Results. Strong induction of apoptosis was seen in melanoma and nonmelanoma cell lines in a time-dependent manner, reaching up to 50%
of apoptotic cells at 72 h. Interestingly, Bcl-xAK shared typical characteristics with other proapoptotic Bcl-2 proteins, namely mitochondrial
translocation, disruption of mitochondrial membrane potential and
cytochrome c release, clearly indicating its regulation of the mitochondrial apoptosis pathway. Importantly, Bcl-xAK activity was critically
dependent on the expression of either Bax or Bak, as shown in genetic
models, and apoptosis was abrogated in Bax/Bak double knockout cells
as well by overexpression of antiapoptotic Bcl-2 proteins as Bcl-2 or BclxL. A direct interaction with Bcl-2 or Bax was however ruled out by
immunoprecipitation.
Conclusion. Bcl-xAK proves the existence of an additional level of mutual regulation of Bcl-2 proteins that is independent of the described BH3mediated interaction between family members. Therein, mitochondrial
translocation appears as a critical step, and this type of regulation may
also play a role for other proapoptotic family members. New pathways
may be used for overcoming therapy resistance frequently determined
by Bcl-2 protein of cancer cells.
0035
SEC62: A new oncogene bridging the gap from 3q amplification
to molecular cell biology in non-small cell lung cancer
*J. Linxweiler1, M. Linxweiler1, M. Greiner1, M. Barth1, V. Jung2, R. Grobholz3,
Y.-J. Kim4, R.M. Bohle4, R. Zimmermann1
1
Universität des Saarlandes, medizinische Fakultät, Institut für medizinische Biochemie und Molekularbiologie, AG Zimmermann, Homburg/ Saar,
Deutschland, 2Universitätsklinikum des Saarlandes, Klinik für Urologie
und Kinderurologie, Homburg/Saar, Deutschland, 3Kantonsspital Aarau,
Institut für Pathologie, Aarau/Schweiz, Schweiz, 4Universitätsklinikum des
Saarlandes, Institut für allgemeine und spezielle Pathologie, Homburg/
Saar, Deutschland
We previously reported a markedly increased Sec62-protein level in
lung and thyroid cancer tissue samples compared to respective tumor
free tissue using a multi-tumor-tissue-microarray. Keeping in mind the
SEC62-gene locus at 3q26.2 and with respect to 3q-amplification having
repeatedly been reported as the most common genetic alteration in
non-small cell lung cancer (NSCLC) with emphasis on squamous-cell
carcinoma (SCC) we wanted to elucidate a possible oncogenic function
of SEC62 in lung cancer.
Therefore, we analyzed the SEC62-mRNA and protein level in freshfrozen tissue samples from 70 lung cancer patients (35 SCC, 35 adenocarcinoma (AC)) by quantitative real time PCR (qPCR), Western Blot
(WB) as well as immunhistochemistry (IHC) and found a significantly
increased SEC62-mRNA (p<0.05) and protein-content (p<0.0001) in tumor- compared to tumor-free tissue samples of the same patients. Thereby, fitting well with genetic data, SEC62-mRNA and protein content
was elevated in >80% of the examined SCC cases and about 35% of the
AC cases. Correlation analyses revealed a significantly higher Sec62-level in tumors with lymph node metastases compared to tumors having
not metastasized (p<0.05) as well as in low- compared to middle-differentiated tumors (p<0.005). Experiments on 10 cases of thyroid cancer
using the same approaches on FFPE-tissue led to consistent results. As
Sec62 is an endoplasmic reticulum (ER) transmembrane protein to test
whether the increase in Sec62 protein content in tumor tissue is a specific phenomenon or is due to a global ER-expansion in cancer cells we
carried out qPCR, WB and IHC experiments and could clearly show
that this increase is specific for Sec62 whereas the amount of other ER
membrane proteins like e.g. Sec61a is not increased. Based on these promising data, we examined the role of Sec62 in cancer cell biology in vitro. Cell-migration assays showed a distinct stimulation of migration in
SEC62-overexpressing and a selective inhibition of migration after siRNA-mediated Sec62-depletion in lung and thyroid cancer cells. Moreover, we found that a SEC62-silencing sensitized the cells to thapsigargin
induced ER-stress as well as constrained the cells ability to initiate an
effective unfolded protein response (UPR) whose crucial role in cancer
biology could be ascertained over the last years.
So we could show that SEC62 represents an oncogene in the amplified
3q-region in NSCLC and harbours various functions in cancer cell biology.
0036
Alteration des Glykosemetabolismus im Magenkarzinom induziert Dissemination
*D. Zieker1
1
Uni Tübingen, Allgemeine Chirurgie, Tübingen, Deutschland
Hintergrund. Metastasen und Peritonealkarzinose sind die wesentlichen
limitierenden Prognosefaktoren beim Magenkarzinom. Dabei scheint
die Überexpression des glykolytischen Enzyms PGK1 eine Schlüsselrolle zu spielen.
Methodik. In einem orthotopen humanen Magenkarzinomtumormodell der Nacktmaus, wurde humanes Magenkarzinomgewebe mit
und ohne Überexpression von PGK1 in die Magenserosa implantiert.
Die Tumorentwicklung, Metastasierung und peritoneale Aussaat wurden in vivo mittels PET-MRT und anschließend durch Sektion korreliert. Des Weiteren wurde bei einer humanen Magenkarzinomzelllinie
in vitro eine PGK1-Hemmung mittels shRNA erzielt, um das Invasionsverhalten der Zellen im Excellegence zu untersuchen.
Ergebnisse. Die PGK1-überexprimierten humanen Karzinome zeigten
eine signifikant gesteigerte Metastasierung und Peritonealkarzinose so
dass dieses Tumormodel die klinische Situation im Humanen sehr gut
abbildet. Die in vivo gewonnenen Ergebnisse des PET-MRTs korrelierten sehr gut mit den Sektionsergebnissen hinsichtlich Tumormasse und
Metastasierung. Bei der Hemmung des PGK1 Enzyms in vitro konnte
die Invasion der Zellen im Vergleich zu den Kontrollen verhindert werden.
Zusammenfassung. Die Überexpression von PGK1 beim metastasierten
Magenkarzinom deutet darauf hin, dass dieses Molekül relevant für die
Dissemination maligner Zellen sein kann. Somit kann vor allem PGK1
in Zukunft als prognostischer Marker Verwendung finden und/oder
als therapeutisches Kandidatengen zur Verhinderung einer malignen
Streuung bei Magenkarzinomen dienen.
Abstracts
0040
Impact of polymorphisms in genes regulating apoptosis on further course of disease in patients with prostate cancer
*A. Meyer1, S. Janssen1, N. Bogdanova1,2, F. Imkamp3, C. von Klot3, J.H. Karstens1, J. Serth3, T. Dörk-Bousset2
1
Medizinische Hochschule Hannover, Klinik für Strahlentherapie und
spezielle Onkologie, Hannover, Deutschland, 2Medizinische Hochschule Hannover, Klinik für Frauenheilkunde und Geburtshilfe, Hannover,
Deutschland, 3Medizinische Hochschule Hannover, Klinik für Urologie und
Urologische Onkologie, Hannover, Deutschland
Purpose. Ionising irradiation leads to changes of the DNA with activation of cellular mechanisms responsible for the detection and repair of
DNA double strand breaks or induction of apoptosis. Aim of this evaluation is the possible impact of polymorphisms in genes responsible for
apoptosis on further course of disease in patients with low-risk prostate
cancer for individualization of the therapy.
Methods. 139 patients with low-risk prostate cancer treated with LDR
brachytherapy between 11/2000 and 10/2004 at Hannover Medical
School were included. The minimum follow-up was >12 months in all
these patients. After extraction of the genomic DNA a screening for
certain polymorphisms in 10 candidate genes with a key function in
apoptosis was carried out: ATM (Ser49Cys), BID (Ser56Cys), CASP8
(Asp302His), CASP10 (Val410Ile), LGALS3 (Pro64His), RASSF1
(Ser133Ala), TP53 (Arg72Pro), TP53AIP1 (Ala7Val), BCL2 (-938C/A) and
HDM2 (SNP309).
Results. The median age of the patients at the implantation was 66.8 years, the mean Gleason score was 6, the mean PSA level before implantation was 7.2 ng/dl, the mean follow-up was 62,4 months. The overall
survival after 2 and 5 years was 100% and 99%, the biochemical disease-free survival according to the ASTRO definition 90% and 84% and
according to the Phoenix definition 97% and 91%. After correlation with
the underlying polymorphisms only for BID (Ser56Cys) a statistical significant impact for biochemical disease-free survival according to the
ASTRO definition could be detected (p=0.010). A biochemical recurrence could be seen in 2 of 4 carrier (50%) vs. 20 of 135 non-carrier (15%)
though the small number of events and carrier has to be considered.
Conclusions. In our analysis no clear correlation between polymorphisms in genes regulating the apoptosis and further course of disease
could be detected that could lead to an individualization of the therapeutic options.
0042
Heat-shock protein 27 (HSP27) levels define the efficacy of HSP90
inhibitors in cancer therapy
H. Nagata1, T.Y. Tsui1, *O. Stöltzing2,1
1
Universitätsklinikum Hamburg-Eppendorf, Hepatobiliäre Chirurgie, Hamburg, Deutschland, 2HELIOS Klinikum Berlin-Buch, Allgemein-, Viszeralund Onkologische Chirurgie, Berlin, Deutschland
Heat-shock protein 90 (Hsp90) inhibitors have gained great interest for
therapy of gastrointestinal cancers. Although Hsp90 inhibitors harbor
the potential to impair multiple oncogenic signaling pathways in cancer cells, they also lead to induction of certain transcription factors and
heat-shock proteins, such as Hsp27. Initially we sought to improve the
anti-neoplastic efficacy of mTOR inhibitors in therapy of cholangiocarcinomas by combining them with Hsp90 antagonists in order to overcome the mTOR-inhibitor induced oncogenic Akt/Erk feed-back loop
activation. However, we observed that dual-targeting mTOR/Hsp90
displayed variable efficacy on cancer cells, which was paralleled by differences in an Hsp90-inhibitor-mediated Hsp27 induction. We therefore hypothesized that Hsp27 levels may modulate the efficacy of Hsp90
inhibitors.
Human cholangiocarcinoma and colon cancer cell lines were used for
experiments. Hsp27 expression levels were additionally investigated on
human colon cancer liver metastases. The results showed that low Hsp27
expressing cancer cells were substantially less sensitive to Hsp90 inhibitors (17DMAG), as determined in proliferation assays and by Western
blotting. Knock-down of Hsp27 (shRNA) in high-Hsp27-expressing
cancer cells significantly reduced their response to Hsp90 inhibition
(p<0.05). Similarly, re-expression of Hsp27 (full-length overexpression
plasmid) in low-Hsp27-expressing cancer cells significantly improved
their susceptibility towards 17DMAG (p<0.05). Interestingly, only 55%
of human colorectal liver metastases showed a high Hsp27 expression,
as determined by Western blotting.
In conclusion, Hsp27 expression levels critically define the efficacy of
Hsp90 inhibitors on cancer cells. Therefore, similarly to determining
KRAS mutations in colon cancer, screening for Hsp27 expression may
be valuable when considering therapy with Hsp90 antagonists.
0055
Targeted alpha-irradiation using Bi-213 overcomes DNA-repair
NHEJ, playing critical role in radioresistance and deficient caspases activation in cancer cells
*C. Friesen1, I. Hormann1, M. Roscher1, O. Leib2, S. Marx2, J. Moreno2, E. Miltner1
1
Institute of Legal Medicine, University Ulm, Ulm, Deutschland, 2Isotope
Technologies Garching GmbH, ITG, Garching, Deutschland
Aim. One of the primary causes for therapeutic failure in anticancer therapy are resistances to radiation and chemotherapy. Deregulation of the
DNA-repair mechanism and/or deficient caspases activation can lead to
apoptosis-resistance. DNA-PKcs (DNA-PK) and LigaseIV (LigIV) are
key enzymes in the Non-Homolog-End-Joining-pathway (NHEJ), the
predominant pathway to repair DNA-double-strand breaks (DSBs) in
mammalian cells. We examined different sources of radiation in induction of DNA-damage and cell death and in activation of caspases and
apoptosis pathways in DNA-repair proficient and deficient cancer cells.
Materials and methods. Pre-B-leukemia cells [Nalm6 LigIV (+/+)
(NHEJ-DNA-repair proficient) or LigIV (−/−) (NHEJ-DNA-repair-deficient)) and glioblastoma cells (DNA-PK(+/+) (NHEJ-DNA-repair-proficient) or DNA-PK(−/−) (NHEJ-DNA-repair-deficient)] were treated
with the alpha-emitter [Bi-213], the beta-emitter [Y-90] and the gammaemitter [Co-60]. DNA strand breaks were analyzed by alkaline Comet
assay. Induction of cell death was measured by flowcytometry at different time points. Involvement of apoptotic pathways was assessed by
Western blot analyses.
Results. Treatment of LigIV (+/+) and LigIV (−/−) cells with [Y-90] or
[Co-60] led to damages in the chromosomal DNA. In DNA-PK (−/−)
and LigIV (−/−) cells, these lesions were left unrepaired in contrast to
those in DNA-PK (+/+) and LigIV (+/+) cells. [Y-90] or [Co-60] could
not induce apoptosis in DNA-PK (+/+) and LigIV (+/+) cells. Only in
DNA-repair deficient DNA-PK (−/−) and LigIV (−/−) cells apoptosis
were induced and apoptotic pathways were activated by [Y-90] or [Co60]. In contrast to these results, [Bi-213] induced apoptosis and activated
apoptosis pathways in LigIV (−/−) as well as in LigIV (+/+). The alphaemitter overcomes DNA-repair and restored apoptosis induction and
deficient activation of caspases in radioresistant cells.
Conclusion. Our findings demonstrate that DNA-PK and LigIV are
involved in resistance to beta- and gamma-irradiation. Only in LigIV (−/−) and DNA-PK (−/−) cells apoptosis can be induced and caspases can be activated. Alpha-radiation induces DNA damages which
cannot be repaired by LigIV or DNA-PK and their cytotoxic potential
are independent of NHEJ-DNA-repair. In contrast to the beta-emitter
or the gamma-emitter, only the alpha-emitter has the potential to overcome DNA-repair in cancer cells. Inhibition or defects in NHEJ sensitize cancer cells for conventional radiotherapy.
0064
Fatty acid synthase (FAS-272) expression increases with rise of
WHO-grade of human gliomas and can be blocked by specific
inhibitors
*P. Dünisch1, J. Walter1, S. Grube1, R. Kalff1, A. Waschke1, R. Bauer2, C. Ewald1
1
Universitätsklinikum Jena, Neurochirurgie, Jena, Deutschland, 2FriedrichSchiller-Universität, Molekulare Zellbiologie, Jena, Deutschland
Purpose. Fatty acid synthase is a multifunctional polypeptid which
plays an essential role in cell metabolism. High expression levels of fatty
acid synthase (FAS) have been reported in hormone receptor-positive
tumors. In our current study we investigate the expression of FAS in
gliomas of different WHO-Grades as a possible new target for anti tumor therapy.
Material and methods. First 80 tumor samples of human brain tumors,
were immunohistochemically evaluated via densitometric analysis.
The FAS-mRNA concentration in fresh glioma tissue, removed during
surgery, was analysed using Real-time PCR. We measured the effect
of known FAS Inhibitors like Cerulenin, Orlistat, and C75 on glioma
cell viability, cell proliferation and cell migration in the glioma cell line
A-172 with the MTT assay and the xCELLigenceTM System. Cell apoptosis was visualizes via a nuclear fragmentation assay with the fluorescence dye Hoechst 33258 (Invitrogen).
Results. Densitometric measurement revealed a significant increase of
FAS expression in high grade gliomas. The incubation of the glioma cell
line A172 with the FAS inhibitors Cerulenin, C75 and Orlistat leads to
a time and dose dependent proliferations stop and induced cell death.
This apoptotic cell death was confirmed by the nuclear fragmentation
assay and Western blotting.
Conclusion. With our study we could underline the essential role of
FAS in the biology of human gliomas on protein and mRNA level. And
our findings suggest that FAS might be a possible target for antiglioma
therapy. Further studys in animal models are nessecary to confirm our
findings in vivo.
0081
New molecular and imaging tools to detect and follow up extraadrenal phaeochromocytoma
*D. Barski1, V. Müller-Mattheis1, S. Ezziddin2, S. Heikaus3, H. Neumann4,
P. Albers1
1
Universitätsklinik Düsseldorf, Urologie, Düsseldorf, Deutschland, 2Universität, Nuklearmedizin, Bonn, Deutschland, 3Universitätsklinik Düsseldorf,
Pathologie, Düsseldorf, Deutschland, 4Universität, Nephrologie, Freiburg,
Deutschland
Background. The prevalence of phaeochromocytoma in patients with
hypertonia is 0.1–0.6% and about 15% of phaeochromocytoma are detected in extraadrenal tissue. The diagnosis and therapy of this rare disease
detected as a retroperitoneal tumor mass can be difficult for clinicians.
Objective. The publication aims to highlight the importance of standardised management and new genetic tools for the outcome and prognosis.
Evidence acquisition. A literature review of the recent peer-reviewed
articles was performed. Additionally we report on a 50-yr-old man presenting in our clinic with unclear retroperitoneal tumor mass, detected
as extraadrenal phaeochromocytoma with SDHB mutation.
Evidence synthesis. MRI is a first choice imaging for phaeochromocytoma, showing a hyperintense mass in T2-phase. Alternatively a CT
scan can be done with nearly the same sensitivity (90–100%). For the
validation of the diagnosis or follow up the functional imaging with
radioactive tracers as 131I, 123I-metaiodobenzylguanidine (MIBG) or
Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission
tomography (excellent specificity and sensitivity of 90–100% in detection of small tumors >1–2cm) are used. Laparoscopic surgery with
complete resection is safe and a first choice approach. The conversion
(about 5%) or direct open operation was needed for large lesions (>8 cm)
with the suspicion of malignancy. Currently there are no histological
criteria for distinguishing benign and malignant tumors. The genetic
testing (PCR, DNA sequencing) for hereditary syndromes (MEN, von
Hippel-Lindau, neurofibromatosis, etc.) is a new crucial tool for prediction of malignancy and recurrence. All patients should get genetic
analysis and consultation including family members. First, the rate of
malignancy in phaeochromocytoma is about 5% but the prevalence of
malignant disease is about 33% for extraadrenal phaeochromocytomas
and even higher in patients with specific familial mutations (e.g. SDHB,
NF1, VHL, MEN2). In patients with proven germline mutations, multiple phaeochromocytomas and recurrences are likely. A stringent lifelong
clinical follow-up is recommended in these cases. Second, the patients
with syndromic hereditary forms should be screened for the often associated other neoplasms.
Conclusion. Genetic analysis provides an important and good tool for
the prognosis of phaechromocytoma.
0105
The influence of combined treatment with 13-cis retinoic acid
and Thalidomide on the growth of U251 glioblastoma xenografts
*D. Milanovic1, A.L. Grosu1, G. Niedermann1
1
Universitätsklinikum Freiburg, Strahlenheilkunde, Freiburg, Deutschland
Objective. 13-cis retinoic acid (RA) and Thalidomide (THAL) show
some clinical effects in Glioblastoma (GBM) patients as sole agents or
in combination with other chemotherapeuticals. RA is a differentiation
agent acting on cell cycle regulation and on EGFR-mediated growth
stimulation. However, RA may induce expression of homeobox (HOX)
genes, i.e., of developmental regulators during embryogenesis that are
normally inactive in adults but may become active during carcinogenesis. RA-induced HOXB7 may in turn induce bFGF, which is a potent
angiogenic and mitogenic factor, and this might limit the usefulness of
RA in the treatment of GBM. THAL has immunomodulatory and antiangiogenic effects and can downregulate bFGF. In our previous work
we showed that in vitro THAL inhibits RA stimulation of homeobox B7
gene expression in human GBM cells. The purpose of the present study
was to test the influence of RA and THAL, as sole agents and in combination, on the growth of U251 glioblastoma xenografts.
Materials and methods. 1.5×106 U251 cells were inoculated s.c. into the
right hind limb of NMRI-Foxn1nu athymic female nude mice. Animals
were randomly assigned in 4 groups (7–11 animals/group) for treatment:
control, RA, THAL and RA + THAL. The animals were treated daily (Monday-Friday) via intragastric tube with RA (30 mg/kg), THAL
(30 mg/kg), or RA (30 mg/kg) plus THAL (30 mg/kg). Xenografts from
sacrifed animals were used for hematoxylin and eosin staining.
Results. The treatment was tolerated excellently; no side effects were observed. RA and THAL as sole agents did not affect the tumor growth in
comparison to untreated controls. However, combined treatment caused a significant decrease in tumor volume. The final tumor volumes
were: control = 1.37±0.2 cm3, RA = 1.38±0.23 cm3, THAL = 1.43±0.5 cm3,
RA + THAL =0.69±0.075 cm3. Hematoxylin and eosin staining of xenografts showed marked hypocellularity in the case of combined treatment.
Conclusions. Additive growth inhibition by RA and THAL can be achieved in U251 glioblastoma xenografts. These results support our prevoious findings from in vitro experiments. Because RA and THAL are well
tolerated in patients, these data encourage further clinical studies on
combinations of these compounds. Molecular-biological analysis of xenografts is underway and will be presented at the meeting.
Abstracts
0136
The membrane transport protein Na+K+ATPase and intracellular
ATP are involved in the selective inhibition of tumor stem cells by
salinomycin
*H. Bühler1, A. Kochanneck1, B. Priesch1, K. Polz2, R. Galalae2, I. Adamietz2
1
Marienhospital, Klinikum der Ruhr-Universität Bochum, Institut für Molekulare Onkologie, Strahlenbiologie und Experimentelle Strahlentherapie,
Herne, Deutschland, 2Marienhospital, Klinikum der Ruhr-Universität, Klinik
für Strahlentherapie und Radio-Onkologie, Herne, Deutschland
Background. In 2009 Gupta et al. did show that some ionophores for
monovalent kations could inhibit cancer stem cells (CSCs) at significantly lower doses than epithelial cancer cells, however the mechanism
remained unclear. The antibiotic salinomycin was identified as the
most effective substance. We checked this compound as to its inhibitory potency in CSCs isolated from a breast cancer cell line and tried to
clarify the underlying mechanism. An obvious candidate is the membrane transporter Na+K+ATPase since this enzyme is responsible for
the maintenance of the important Na+/K+ gradient over the cellular
membrane.
Methods. CSCs were isolated from MDA-MB 231 breast cancer cells via
spheroids. An epithelial counterpart was obtained by transfection of keratin 18 into MDA 231 wt cells. Salinomycin was added in concentrations from 10−7 to 5×10−5 M. Cellular viability with and without inhibitor
was measured by a MTS-test. In addition, Na+K+ATPase was partially
inhibited by 2.5×10−8 M hellebrin. Intracellular ATP was measured by
chemiluminescence. Na+K+ATPase was quantified by qRT-PCR.
Results. In our model system we could show a selective reduction of
tumor stem cells viability in response to salinomycin, comparable to
the published data. The isolated stem cell fraction was compromised
at significantly lower doses than the epithelial subclone (IC50 10−6 vs.
2×10−5 M). First approaches revealed that the Na+K+ATPase might play
a role in this selective effect: the dose dependent inhibition of stem cells
by salinomycin was approximated in epithelial cells, if additionally the
Na+K+ATPase inhibitor hellebrin was added in low doses. However,
qRT-PCR did not reveal any difference in the expression of the enzyme
on the transcriptional level but a significantly lower content of free ATP
was observed in stem cells.
Conclusion. The selective inhibition of cancer stem cells by salinomycin might be caused by a disturbed Na+/K+ gradient originating more
likely from energy deficiency than from a less active Na+K+ATPase in
these cells.
0143
Radiotherapy combined with immune therapeutic approaches is
capable to induce immunogenic tumor cells leading to anti-tumor immunity
B. Frey1, Y. Rubner1, E.-M. Weiss1, R. Fietkau1, *U. Gaipl1
1
Strahlenklinik Erlangen, Strahlen-Immunbiologie, Erlangen, Deutschland
Combination of classical tumor therapies like radiotherapy with immune therapy has been considered, for a long time, to be counterproductive.
Nowadays it is well accepted that specific immune responses contribute
to the eradication of smaller tumor masses, recurrent tumors and metastases. To find the optimal combination and chronological sequence of
radiotherapy, chemotherapy and immune therapy will be a great future
challenge of scientists and clinicians. We present how tumor cells can
be rendered immunogenic by ionising radiation (X-ray) alone and most
importantly by combination with further immune stimuli like quality controlled hyperthermia (41.5°C for 1 h) or the naturally occurring
adjuvant AnnexinA5. The latter is a ligand for phosphatidylserine that
gets exposed on tumor cells after irradiation. X-ray plus heat led to the
release of the immune activating danger signals high-mobility group
box 1 protein (HMGB1) and heat shock protein 70 by tumor cells and
subsequent activation of dendritic cells (DC). In addition, AnnexinA5
shifted the uptake of tumor cells from macrophages to DC. The latter
are key players in starting a tumor specific adaptive immune response.
In vivo syngeneic mice experiments with radiation procedures closely
resembling the human situation give first hints that AnnexinA5 further
retards tumor growth when combined with X-ray. We conclude that radiotherapy alone or especially in combination with additional immune
activatory stimuli like heat or AnnexinA5 is capable to induce an immune activatory tumour microenvironment that triggers anti-tumour
immunity via activation of DC.
This work is supported by the German Research Foundation (GA 1507/1-1 and
GK1660) and by the Bundesministerium fuer Bildung und Forschung (BMBF;
01EX1021R).
0148
Hyperthermia induces increased Estrogen Sulfotransferase
SULT1E1 gene expression in vitro
*M. Jäger1, M. Hirschfeld1, G. Gitsch1, E. Stickeler1
1
Universitäts-Frauenklinik, Molekulare Onkologie, Freiburg, Deutschland
Background and aims. The clinical application of hyperthermal therapy
is gaining more importance, by its beneficial co-application in combination with chemotherapy or radiotherapy in malignant disease management. This approach might improve the therapeutical effect of these
classical anti-cancer treatment strategies in certain circumstances. The
SULT1E1 is a member of the Sulfotransferase family. Sulfotransferases
are responsible for the sulfate conjugation of various hormones, drugs
and xenobiotics. SULT1E1 is capable to inactivate estrogen by adding a
sulfate group to the estrogen molecule.
Methods. We investigated the potential regulatory effects of hyperthermia on the expression of SULT1E1. Several gynecological and breast
cancer cell lines were cultured under hyperthermia (42°C, 2 h) followed
by maintenance under regular culture conditions (37°C, 4 h). As a negative control, these cell lines were also permanently cultivated under
regular temperature conditions. Transcript and protein expression levels of SULT1E1 were investigated by RT-PCR and Western Blot, respectively.
Results. The analyses revealed an increase in mRNA and protein level
of SULT1E1 under hyperthermia. Our results demonstrate a regulatory effect of hyperthermal treatment on the Estrogen Sulfotransferase
SULT1E1
Conclusion. We therefore hypothesize that hyperthermia can induce the
expression of SULT1E1, thereby creating suppressive effects on tumorigenesis. The regulatory effect of hyperthermia on Estrogen receptor
expression was described by our group previously. Our findings support
the theory that hyperthermal treatment might represent a method that
may improve classical anti-cancer therapies by a direct influence on the
regulation of gene expression of important factors in cancer biology.
0165
Differential regulation of p53 isoforms in clear cell renal cell
carcinomas
*S. Heikaus1, L. van den Berg1, H.E. Gabbert1, C. Mahotka1
1
Universitätsklinikum Düsseldorf, Institut für Pathologie, Düsseldorf,
Deutschland
Aims. Renal cell carcinomas (RCCs) exhibit a marked resistance towards conventional chemotherapy, which is – at least in part – due to
functional suppression of p53. In contrast to many other tumours, however, this p53 suppression in RCCs is mediated by mechanisms other
than inactivating mutations. One of these mechanisms might be differential expression of p53 isoforms, which can influence the transcriptional activity of p53. Therefore, the aim of our study was to elucidate
the relevance of differential p53 isoform expression for carcinogenesis,
progression and therapy-resistance of RCCs.
Methods. Semiquantitative “Realtime PCR”, Western Blot and Caspaseassays.
Results. RCCs revealed a shift towards a more p53 activating isoform expression pattern during tumour initiation and progression, in vivo. In
vitro, two cell lines exhibiting a similar sensitivity towards Topotecaninduced cell death revealed a similar induction of p53 target genes by
Topotecan but differed in the extend of Topotecan-induced apoptosis.
Furthermore, they strongly differed in their basal expression patterns of
the p53 isoforms as well as in the differential regulation of p53 isoform
expression upon Topotecan-treatment.
Conclusions. p53 isoforms are strongly differentially regulated by chemotherapy in RCCs. However, p53 isoform expression and regulation
seems to be neither responsible for induction and progression of RCCs
in vivo, nor for regulation of p53 gene expression, sensitivity towards
chemotherapy and induction of apoptosis in vitro.
0167
Investigation of the postulated EGFR-pAkt- HIF1 alpha-survivin
pathway in tumor cell lines and the role of HIF1 alpha under
normoxic conditions
*M. Kappler1, S. Rot2, H. Taubert3, M. Bache2, D. Vordermark4, J. Schubert5,
A.W. Eckert5
1
Universitätsklinik und Poliklinik für Mund-, Kiefer- und Plastische Gesichtschirurgie, Molekulare Tumorbiologie, Halle(S), Deutschland, 2Universitätsklinik und Poliklinik für Strahlentherapie, Molekulare Strahlenbiologie,
Halle(S), Deutschland, 3Universitätsklinik und Poliklinik für Urologie,
Nikolaus-Fiebiger-Zentrum für Molekulare Biologie, Erlangen, Deutschland,
4
Universitätsklinik und Poliklinik für Strahlentherapie, Halle(S), Deutschland, 5Universitätsklinik und Poliklinik für Mund-, Kiefer- und Plastische
Gesichtschirurgie, Halle(S), Deutschland
Background. The tumorbiological importances of tyrosine kinases receptors (e.g., insulin and EGF receptor) for proliferation, apoptosis and
metabolism of tumor cells have already been shown. Both receptors
(insulin receptor and EGFR) activate the tumor-relevant PI3K/AKT
pathway. Recently, an EGFR- pAkt- HIF1α-survivin pathway was described, which activates the prognostic relevant inhibitor of apoptosis
protein survivin in breast cancer cell lines under normoxic conditions
(Peng et al. 2006).
Methods. Accordingly to the study published by Peng et al. we treated
two breast cancer cell lines (MDA-MB-231, MCF-7) with 100 ng/ml EGF,
0.65 µg /ml insulin or with 50 nM of a PI3-K-Inhibitor Ly294006 under
serum free conditions. The protein expression of pAkt, survivin and
HIF1α was analyzed by western blot analysis. Furthermore, a cell cycle
analysis was performed.
Results. In accordance to the results of Peng et al, the cell line MCF-7
showed an increase in survivin expression using EGF/insulin-stimulation in vitro. However, that pathway is detectable only under none
physiological conditions (without serum). The cell cycle analysis demonstrated a G1-cell cycle arrest caused by serum deprivation, which
is associated with a low protein expression of the IAP survivin. Insulin
or EGF application induced an increase of G2/M-cell cycle cells and an
increase of the expression of the G2/M marker protein survivin. In opposite to the MCF-7 cell line in the cell line MDA-MB231 the G1-cell
cycle arrest caused by the serum deprivation is not influenced by EGF/
insulin-stimulation. The IAP survivin is slightly induced by insulin
application. Moreover, the HIF1α expression is not directly induced by
signal transduction caused by an insulin or EGF induction, but by metabolic processes under normoxia.
Conclusion. We found that the postulated EGFR- pAkt- HIF1 alpha-survivin pathway is unverifiable in the same cell lines used by Peng et al.
We propose that the postulated activation of the protein survivin by
EGF or insulin application is caused by a simple change in the distribution of cells in different cell cycle phases. Moreover, and in accordance
to our results, the cell line MDA-MB231 was described by other aut-
hor as insensible to an EGF-like stimulus (Takabatake et al. 2007). The
accumulation of HIF1 alpha under normoxia seems to be induced by
metabolic processes. We assume that the pathway postulated by Peng et
al. is an artificial pathway.
0172
Decreased cell proliferation and induced apoptosis in CTCL cells
lines by non-steroidal anti-inflammatory drugs (NSAIDs)
*F. Braun1, M. Plötz1, N. Al-Yacoub1, M. Möbs1, W. Sterry1, J. Eberle1
1
Charité – Universitätsmedizin Berlin, Klinik für Dermatologie, Venerologie
und Allergologie, Berlin, Deutschland
Cutaneous T cell lymphomas (CTCL) form a heterogeneous group of
non-Hodgkin lymphomas with primary involvement of the skin. Even
though early stages of CTCL are often indolent over long periods of
time, advanced stages are refractory and difficult to treat. Death ligands
(CD95L and TRAIL) critically contribute to lymphocyte homeostasis
due to induction of apoptosis and may further represent safeguard mechanisms to prevent lymphoma development. In previous studies, we
characterized CTCL cell lines as resistant to TRAIL-mediated apoptosis
which was correlated to high c-FLIP expression. In the present study,
we investigated the effects of non-steroidal anti-inflammatory drugs
(NSAIDs) as acetylsalicylic acid, sodium salicylate and diclofenac in
CTCL cell lines (HH and MyLa) as well as in tumor T cells from SzS patients. NSAIDs decreased cell proliferation and induced apoptosis, associated by caspase-3 processing. Decreased mitochondrial membrane
potential and cytochrome c release were indicative for an involvement
of intrinsic pathways. Furthermore, downregulation of c-FLIP and caspase-8 processing clearly indicated an activation of extrinsic pathways.
Finally, NSAIDs sensitized CTCL cells for TRAIL-induced apoptosis.
In conclusion, the study provides a rational for the use of NSAIDs as
a potentially new therapeutic option for cutaneous T cell lymphomas.
0197
Conditional RNAi-mediated knockdown of osteopontin in
MDA-MB-231 breast cancer subclones in vitro
*M. Kovacheva1, S. Berger2, M. Berger1
1
DKFZ, Toxikologie and Chemotherapie, Heidelberg, Deutschland,
2
Zentralinstitut für Seelische Gesundheit, Molekularbiologie, Mannheim,
Deutschland
Breast cancer is the second most common cause of cancer-related death
in women. This is due to metastasis which renders breast cancer virtually incurable. In breast cancer progression, high levels of osteopontin
(OPN) correlate with poor prognosis. As a member of the SIBLING
(small integrin-binding ligand N-linked glycoprotein) family of glycoproteins, OPN has a pivotal role in the processes of migration and
invasion, which are essential for metastasis formation.
The combination of RNA interference (RNAi) with the tetracyclinecontrolled transcription activation (tet) system is a powerful method
for conditional gene inactivation in cultured cells. Here, we aimed to
investigate, whether the conditional RNAi-mediated knockdown of
OPN would impair the metastatic properties of invasive breast cancer
cells. Therefore, two MDA-MB-231 subclones (OPN clones 1 and 2) were
generated, in which the tetracycline-dependent transactivator tTA controls the simultaneous expression of the red fluorescent protein mCherry, firefly luciferase and a highly efficient and specific miRNA targeting
OPN mRNA.
Knockdown efficiency was determined by quantifying OPN mRNA
and protein concentrations after cultivating respective cell clones for
either 3 or 6 days with or without doxycycline in the medium. Here,
OPN mRNA concentration was reduced by 62–96% after 3 days and
85–98% after 6 days respectively. However, a decrease in OPN protein
was only observed after 6 days. The decrease in OPN expression led to
Abstracts
a reduction in colony formation by 55–60 % and to a similar inhibition
of spontaneous migration, determined 9 days after initiation of OPN
miRNA expression. However, there was no significant influence on proliferation as assessed by MTT assay after cultivating the respective cell
clones for 3 and 6 days in the same media.
In conclusion, the conditional knockdown of OPN in breast cancer subclones resulted in a distinct reduction of OPN mRNA and protein concentrations. This effect was associated with significantly reduced migration and colony formation, but there was no effect on cell proliferation.
0202
TPX2 as potential target in breast cancer treatment
*C. Wilde1, S. Berger2, M. Berger1
1
DKFZ, Chemotherapie und Toxikologie, Heidelberg, Deutschland, 2ZIMannheim, Mannheim, Deutschland
The microtubule-associated protein TPX2, a key component in mitotic cell division and cell cycle progression, is discussed as a potential
therapeutic target in different types of human cancer. Several studies
implicated that there is a TPX2 over-expression in tumor cells, which
is considered to be important for the maintenance of the tumorigenic
state. Our intention was to evaluate the expression and role of TPX2 as
a target for new anti-mitotic therapies in breast cancer.
TPX2 expression was compared in cell lines including the non-tumorigenic cell line MCF-10A and in various breast cancer cell lines as well
as in primary patient samples. The expression was determined at the
protein (Western Blot) and mRNA (real-time PCT) levels. There was
only a marginal TPX2 expression in MCF-10A cells, whereas the various
breast cancer cell lines showed a significant up-regulation of TPX2 expression both at RNA and protein levels. In contrast, Western blot and
real-time PCR analysis from fresh frozen tissue samples of breast cancer
patients showed low TPX2 levels.
To investigate the functional role of TPX2 in breast cancer cells, two
MDA-MB-231 cell lines with a conditional TPX-knockdown were generated. In these cell lines TPX2 production can be inhibited by a TPX2specific miRNA under the transcriptional control of the TetOff system.
The efficiency of the knockdown was also determined by real-time PCR
and Western Blot.
In the absence of doxycycline an almost complete knockdown could be
seen both at RNA and protein levels. TPX2 expression was suppressed
up to 97% in MDA-MB-231-TPX-54-1.1 and up to 99% in MDA-MB-231TPX-23-25. This effective inhibition of TPX2 production led to an increased number of apoptotic cells as identified by life cell imaging. In
addition, MTT assay showed a significantly reduced cell proliferation of
34% (MDA-MB-231-TPX-54-1.1) and 19% (MDA-MB-231-TPX-23-25) at
three days after induction of the knockdown.
In conclusion TPX2 knockdown causes apoptosis and has an anti-proliferative effect. TPX2 expression was more pronounced in breast cancer
cell lines than in primary tissues from breast cancer patients. The value
of TPX2 as potential target for breast cancer treatment needs further
consideration.
0204
Estrogen receptor β agonists reduce invasiveness of triple-negative human breast cancer cell lines
*C. Lattrich1, J. Häring1, R. Meier1, S. Schüler1, A. Stegerer1, O. Treeck1, O. Ortmann1
1
University Medical Center Regensburg, Department of Obstetrics and
Gynecology, Regensburg, Deutschland
Objective. Estrogen receptor β (ERβ) is expressed in the majority of triple-negative breast cancer cases. In this study, we tested to what extent
treatment of triple-negative breast cancer cell lines with two highly specific ERβ agonists would affect their invasiveness and motility.
Methods. Cellular invasion was assessed by means of a modified Boyden
chamber with a membrane pore size of 8 µm coated with a soluble basement membrane extract. Migration was measured using the same model system without ECM. Relative cell numbers were assessed by means
of the fluorimetric Cell Titer Blue Assay (Promega). Gene expression
was examined by RT-qPCR using a Light Cycler 2.0 device (Roche) and
by Western Blot analysis.
Results. Selective ERβ agonist ERB-041 significantly reduced invasiveness of the triple negative breast cancer cell lines MDA-MB-231 and
HS578T in vitro in a dose-dependent manner. ERB-041 inhibited invasion of MDA-MB-231 cells down to 70.7% (p<0.01) and of HS578T cells
down to 65% (p<0.01). The second highly specific ERβ agonist tested,
Liquiritigenin, inhibited invasion of MDA-MB-231 cancer cells down
to 70.2% (100 nM; p<0.05), whereas HS578T cells were not affected. In
contrast to ERB-041, Liquiritigenin also inhibited migration of MDAMB-231 cells in a Boyden chamber assay. The inhibitory effects of ERB041 and liquiritigenin on invasiveness of triple-negative breast cancer
cells were accompanied by a strong decrease of Stromelysin 3 (MMP-11)
gene expression by about 50% and by upregulation of ERb2 mRNA levels
by 77.5% (p<0.01). Expression of other MMPs tested (MMP-1, MMP-2,
MMP-9, MMP-13, MMP-14, MMP-18), of Cathepsin L, ERβ1 and ERβ5
was not or only slightly affected by treatment with the ERβ agonists.
Conclusions. We demonstrated that highly specific ERβ agonists were
able to significantly reduce invasiveness of triple negative breast cancer
cells in vitro. Our data suggest that this effect was mediated by downregulation of Stromelysin 3 (MMP-11) expression. Whether ERβ agonists
might be useful drugs in the treatment of triple-negative breast cancer
has to be evaluated in further animal and clinical studies.
0227
Dysegulation of Sox9-dependent gene expression leads to enhancement of angiogenesis and metastases in pancreatic cancer
*P. Camaj1, I. Ischenko1, S. Krebs2, K.-W. Jauch1, C.J. Bruns1
1
Klinikum Großhadern, Exp. Forschung: Chirurgie, München, Deutschland, 2Laboratory for Functional Genome Analysis, Genomics, München,
Deutschland
Background. The aim of this study is to analyse the regulation of differentially expressed genes in highly proangiogenic and prometastatic
(L3.6pl) compared to low metastatic and low angiogenic pancreatic cancer cells (FG).
Materials and methods. The transcriptome of the low metastatic pancreatic cancer cell line and its highly angiogenic and metastatic derivate
L3.6pl have been compared under the normoxic and hypoxic conditions
using gene arrays. Affymetrix data have been validated via qRT-PCR
and ELISA. Differentially expressed genes from relevant pathways were
investigated as target of Sox9-regulation. Binding of the transcription
factors on the promoter was confirmed via ChIP. Proteins were assayed using western blotting. Effect of Sox9 was analysed on stable Sox9shRNA transfectants. Effect of promoter-methylation was studied using
2 different inhibitors of methylation.
Results. The Affymetrix analysis revealed clusters of differentially regulated genes with regard to the cell line and the oxygen level. While
VEGF expression was upregulated in FG cells under hypoxic condition,
it was constitutively fully upregulated already under normoxic conditions in aggressive L3.6pl cells. This regulation pattern was similar in a
cluster of genes that share a promoter sequence coding for a binding site
for the transcription factor Sox9. Sox9 itself shows a similar regulation.
ChIP results demonstrated binding of Sox9 on promoters of regulated
genes. Refined analysis revealed differential Sox9 promoter methylation as reason for observed HIF1α-independent phenomenon. We have
demonstrated that in majority of the patient’s cancer tissue samples is
Sox9 upregulated in comparison to the normal tissue. In vitro experiments (Boyden chamber assay, apoptosis assay) as well as animal expe-
riment demonstrated that overexpression of Sox9 gene supports tumor
growth and metastasing.
Conclusions. Proangiogenic genes such as VEGF are upregulated in
the more aggressive cell line L3.6pl, compared to FG. We identified a
gene cluster that is constitutively upregulated in L3.6pl, independent
of hypoxia. These genes are controlled by the transcription factor Sox9
physically binding on their promoters. A Sox9 promoter differential
methylation may be the reason for the escape from hypoxic regulation
in L3.6pl cells and thus may contribute to the higher angiogenic and
metastatic potential.
0231
Cancer initiating cells in colon and pancreatic cancer are resistant to nutrient stress – a characteristic for tumor growth?
*T. Grimmig1, J. Schmitt1, N. Matthes1, M. Faber1, C.-T. Germer2, M. Gasser2,
A.M. Waaga-Gasser1
1
Background. Recent findings suggest that conditions of ischemia and
low nutrient tumor microenvironment stimulate tumor growth and
involve survival advantage of pluripotent and resistant tumor cells. The
aim of this study was to determine the presence of different Toll-like
receptors (TLR), heat shock proteins (Hsp), and markers for putative
tumor initiating cells (CD133 and multidrug resistance proteins ABCB1
and ABCB5) in colon and pancreatic cancer cells suffering from nutrient stress.
Methods. To mimic pathophysiological nutrient stress in the tumor microenvironment human colon and pancreatic cancer cell lines (HT-29
and PANC1, MIA PaCa-2) were cultured using different media providing varying conditions of nutrient stress (basic culture medium containing 10% FCS or 10% FCS and 2.5% HS basic culture medium without
serum and PFHM-II protein-free hybridoma medium). Cells were kept
in each medium for 24, 48, and 72 hours before harvesting and protein
(Western Blot) and gene analysis (RT-qPCR) were performed for their
TLR 1-10, Hsp70, Hsp90, ABCB1 and ABCB5, and CD133 profiles.
Results. Compared to normal nutrient cell conditions TLRs were found
at higher protein and gene expression levels in cells exposed to starvation. Upregulated CD133, ABCB1 and ABCB5 levels were observed as well
as rising levels of Hsp70 and Hsp90. Expression levels varied between
both cell lines and were dependant on the duration of nutrient stress.
Conclusions. TLR, Hsp70 and Hsp90, as well as CD133, ABCB1 and
ABCB5 expression characterizes surviving cells that are relatively unsusceptible to starvation. This indicates that a minor population of cells
within a tumor is comparably resistant to nutrient stress through specific repair mechanisms compared to the bulk of differentiated tumor
cells. Thus through this survival advantage this cell population may
contribute to further metastatic growth in vivo.
0249
Estrogen receptor targeting by raloxifene potently inhibits
human pancreatic adenocarcinoma growth
*H. Seeliger1, N. Seel1, P. Camaj1, I. Ischenko1, K.-W. Jauch1, C.J. Bruns1
1
Klinikum der Universität München, Chirurgische Klinik und Poliklinik,
Background. The role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we demonstrated that expression of
the isoform ER beta correlates with an adverse prognosis in patients
with pancreatic cancer. Here, we show that raloxifene, a specific estrogen receptor modulator (SERM), suppresses in vitro and in vivo tumor
growth by interfering with ER beta signaling in human pancreatic adenocarcinoma.
Methods. The human pancreatic adenocarcinoma cell line L3.6pl was
cultured and exposed to raloxifene in vitro, and cell proliferation was
determined by the BrdU assay. To analyze the specificity of raloxifene
induced effects, ER knockdown was performed using siRNA specific
for ER alpha and ER beta. In an in vivo model of orthotopic tumor xenografts in nude mice, raloxifene was administered daily, and tumor
growth was monitored. Expression of ER beta and the proliferation
marker Ki-67 were determined by immunohistochemistry.
Results. Raloxifene treatment resulted in a potent, dose dependent reduction of proliferation in vitro over a nanomolar dose range. This effect was completely reversed by siRNA knockdown of ER beta, but not
ER alpha, indicating an ER isotype specific signaling. In vivo, orthotopic tumor growth, as well as lymph node and liver metastases, was
significantly suppressed in raloxifene treated mice. Analogous to the in
vitro data, Ki-67 expression in vivo was significantly reduced in raloxifene treated mice, while ER beta expression was not changed in vivo.
Conclusions. Inhibition of ER beta signaling by raloxifene results in a
potent reduction of human pancreatic adenocarcinoma growth in vitro
and in vivo. Treatment with SERMs may be an attractive therapeutic
option in subjects expressing the ER beta isotype.
0261
shRNA mediated knock down of S100A4 in colorectal carcinoma
reduces metastasis formation in vivo
*M. Dahlmann1, U. Sack2, P. Herrmann1, M. Lemm3, I. Fichtner3, P.M. Schlag4,
U. Stein2,1
1
Charité Universitätsklinikum, Chirurgische Onkologie, Berlin, Deutschland,
2
MDC-Berlin, Chirurgische Onkologie, Berlin, Deutschland, 3MDC-Berlin,
Experimentelle Pharmakologie, Berlin, Deutschland, 4Charité Universitätsklinikum, Comprehensive Cancer Center, Berlin, Deutschland
Colon carcinoma, due to its metastases, is still a major cause of death
even after the excision of the primary tumor. The small calcium binding
protein S100A4 was found to be an indicator for metachronous metastasis formation. Its expression level positively correlates to the metastatic
potential of human colon cancer, where it promotes cell motility and
invasion, and negatively affects the survival of colon cancer patients. A
therapeutic decrease of S100A4 expression in patients could therefore
result in less metastasis formation and increased survival rates. In the
present study, we used shRNA expressing plasmids to inhibit S100A4
expression in the colorectal carcinoma cell line HCT116 and observed
a clear reduction of cellular migration and invasion in vitro to about
45% and 55%, respectively, while proliferation of the cell lines was not
affected. Intrasplenical transplantation of either S100A4 knock down or
control cells in mice reduced the formation of liver metastases in correlation with reduced S100A4 expression.
We also evaluated the therapeutic potential of systemically applied
shRNA expressing plasmids via repeated hydrodynamics-based tail
vein injection of plasmid DNA, expressing either specific S100A4shRNA or unspecific control shRNA. Mice with intrasplenically transplanted HCT116-LUC cells showed a 3-fold decrease in metastasis formation in the liver, when treated with S100A4-shRNA plasmids. The
average tumor size of treatment and control group was comparable,
but showed a decrease of S100A4 and MMP-9 expression levels to 60%
and 20%, respectively, when treated with S100A4-shRNA plasmids. The
developed liver metastases showed a similar reduction in S100A4 expression, while the decrease in MMP-9 expression was less pronounced
(50% and 60%, respectively). In summary, the knockdown of S100A4 via
systemic application of plasmid DNA, expressing gene specific shRNA,
resulted in a decrease of metastasis formation in a xenograft mouse model of colon cancer.
Abstracts
0286
Cancer-retina antigens in pancreatic adenocarcionoma: impact
of guanylyl cyclase 1
S. Karakhanova1, J. Werner1, *A. Bazhin1
1
Uniklinikum Heidelberg, Chirurgische Klinik, Heidelberg, Deutschland
Background and aims. Recently, we have shown that the key photoreceptor proteins, that are normally restricted to retinal cells, function in
cancer cells as cancer-retina antigens (CRA). The aim of the work was
to investigate the phenomenon of CRA in pancreatic carcinoma cells
with a focus on function of guanylyl cyclase 1 (GC1) in the tumor cells.
Methods. shRNA plasmids were used to knock-down the GC1 expression. RT-PCR, Western blotting, cyto/histoimmunochemistry, Ca2+
and cGMP measurement and FACS analysis were applied for in vitro
experiments. An orthotopic mouse model of pancreatic carcinoma was
used for in vivo experiments.
Results. We showed that CRA are expressed in pancreatic carcinoma
cell lines and tumors. Moreover, GC1, phosphodiesterase 6 and transducin are expressed in pancreatic cancer at a high frequency. Expression
of these antigens leads to autoantibody production in the pancreatic
cancer patients. Besides, we found that GC 1 is functional in pancreatic
carcinoma cells, and this enzyme is involved in cGMP metabolism and
Ca2+ accumulation in the tumor cell lines. Knocking-down of the enzyme affect viability, proliferation, radiosensitivity, migration and invasion of pancreatic carcinoma cell in vitro. The GC 1 knocking-down
reduces the tumor volume, appearance of peritoneal carcinosis and metastases, and has a tendency to prolong a survival of the tumor-bearing
mice in an orthotopic model of pancreatic cancer. Moreover, inhibition
of GC1 leads to better activation of CD4+ T cells by tumor cells.
Conclusions. We suggest that the aberrant expression of GC1 in pancreatic carcinoma cells is important for the tumor biology. Establishing of
new methods for an in vivo knocking-down of GC1 and searching a
down-stream molecular partner of GC1 could be important for the pancreatic carcinoma treatment.
0296
Cell-in-cell structures in tumours
*L. Distel1, M. Büttner2, M. Schwegler1, F. Putz1
1
Strahlenklinik, Strahlenbiologie, Erlangen, Deutschland, 2Universität Erlangen, Pathologie, Erlangen, Deutschland
Objective. Cell-in-cell structure means the entire internalisation of a
cell by another cell. This phenomenon is mainly found in tumour cells,
especially in malignant exudate cells and sporadic in tumour tissue
specimen. Entosis was recently identified to be a mechanism for the
generation of cell-in-cell structures. This process is regarded as a nonapoptotic cell death. Some studies exist, describing cell-in-cell structures generated by in vitro experiments. Additionally, there are several
case reports on cell-in-cell structures in tumour tissues. To study the
appearance of cell-in-cell structures we have scanned tumour tissue
sections. Cell-in-cell positive tumours were stained for apoptosis and
cell adhesion molecules.
Methods. Tumour tissue sections (2 µm thickness) of three individuals
were stained immunohistochemical for cleaved caspase-3, β-Catenin
and E-Cadherin. The total tissue sections were scanned with high resolution (Mirax Scan, Zeiss, Germany) and the corresponding tumour
regions with different stainings were analysed and compared to each
other.
Results. Two renal carcinoma and one metastasis of an unknown primary cancer were identified harbouring numerous cell-in-cell structures. Cell-in-cell structures were clustered in special regions of the tissue
specimens with a frequency of up to one cell-in-cell per ten cells. Some
cell-in-cells were very complex with more than one cell internalised in
another cell and cells with an internalised cell having internalised another cell. The apoptotic rates in the three tumours were 5%, 4% and 1%,
however only very small numbers of cell-in-cells were involved in apoptotic events. Regularly the internalised cells were non apoptotic. The regional distribution of cell-in-cell structures hints on special alterations
of the cells in these regions. Therefore the tissue specimen were stained
for adhesion molecules. In all three tumour types cells were positive for
β-Catenin and E-Cadherin. Cells with cell-in-cell had no different staining for β-Catenin and E-Cadherin compared to non cell-in-cell cells.
Conclusion. Entosis or cell-in-cell may be a cell death modality occurring in tumour cells as frequently, or even more frequently than apoptosis. A simultaneous apoptotic event in the internalised cell seems to
be a very rare event.
0303
Retinoid receptors in pancreatic cancer: Differential expression
in malignant and healthy pancreatic cells and link to the epithelial-mesenchymal transition
*T. Bleul1, J. Werner1, A. Bazhin1
1
Universitätsklinikum Heidelberg, Chirurgie, Heidelberg, Deutschland
Background and aims. Pancreatic adenocarcinoma is a cancer with
extremely poor prognosis and limited therapeutic options. Although
preclinical experiments with retinoids showed beneficial effects of retinoid treatment, clinical studies had disappointing results. However,
little quantitative data is available concerning retinoid receptor expression in healthy pancreas compared to pancreatic carcinoma. The main
aim of this work was to study comprehensively the retinoid receptor
expression in order to evaluate their role in pancreatic cancer and try to
find reasons for the negative clinical results.
Methods. Nine human pancreatic carcinoma cell lines and one healthy cell line were used. Expression of the retinoic acid receptor (RAR)
and retinoic X receptor (RXR) subtypes (α, β, γ) was quantified on RNA
level in all cell lines as well as in the murine pancreatic carcinoma samples using quantitative real-time PCR. On protein level the expression
of RAR and RXR subtypes was studied with immunocytochemistry in
all cell lines. As differentiation markers cytoceratin 7 and carbonic anhydrase II were analyzed by immunocytochemistry. To determine epithelial-mesenchymal transition vimentin expression was assessed with
immunocytochemistry. Cytotoxicity of retinoic acid was tested with the
MTT assay and the effects on proliferation with the BRDU assay.
Results. On protein level RAR α and β is significantly lower expressed in
seven out of nine pancreatic tumor cell lines compared to healthy cells.
No difference in the expression occurred between primary tumor and
metastatic cell lines on RNA and protein level. Retinoic acid treatment
of pancreatic cancer cell lines with high and low expression of RAR showed neither cytotoxic, nor antiproliferative, nor differentiating effects.
A negative correlation between vimentin expression and RAR α and β
expression was found. In the orthologous system of murine pancreatic
cancer RAR α and β as well as RXR α and β is significantly lower expressed in tumor samples compared to healthy pancreas at RNA level.
Conclusions. Our results show that malignant transformed pancreatic
cells express less retinoid receptors than their healthy counterparts.
Mesenchymal transition leads to decreased RAR α and β expression. It
is tempting to speculate that the decreased retinoid receptor expression
could play an important role in pancreatic cancer and it would be a reason for the negative clinical results of pancreatic carcinoma treatment
with retinoids.
0328
Differential Daxx isoform expression in renal cell and colorectal
carcinoma
*S. Funke1, N. Wethkamp1, S. Heikaus1, K.-L. Schäfer1, H.E. Gabbert1,
C. Mahotka1
1
Deutschland
Aims. Death associated protein (Daxx) is an important transcriptional
co-repressor for a large number of genes, mostly related to apoptosis.
Daxx interacts with p53 and represses its transcriptional activity. Alternative splicing of the Daxx results in the generation of a c-terminally
truncated and modified isoform termed Daxx-β. According to the new
C-terminus, Daxx-β shows a markedly reduced affinity to PML and p53.
Consequently, in contrast to Daxx, Daxx-β is unable to repress transcriptional activity of p53. As deregulation of p53 is closely related to
carcinogenesis, alternative splicing of Daxx may also participate in tumour development and progression.
Methods. Here, we examined the in vivo splicing pattern of Daxx and
Daxx-β during renal cell and colon carcinoma progression using kinetic
RT-PCR.
Results. Both Daxx transcripts are expressed in epithelia from kidney
and colon, in non-neoplastic as well as in tumour tissue. Interestingly,
in renal cell carcinoma a significant reduction of both isoforms was notable whereas in colorectal carcinoma a different Daxx splicing pattern
was evident with only Daxx-β being transcriptionally reduced. In both
tumour types, these alterations could be found already at early stages
(pT1/2) and did not further change in late stages (pT3/4).
Conclusion. Therefore, our results indicate for the first time that differential Daxx isoform expression is associated with tumourigenesis of
renal cell and colorectal carcinoma and may serve as a novel biomarker
on mRNA level.
0336
Inhibition of FGFR impairs angiogenic signaling in human HCC
cell lines and stromal cells
*T.P. Scheller1, C. Moser1, M. Mycielska1, C. Hellerbrand2, A.A. Schnitzbauer1,
E.K. Geissler1, H.-J. Schlitt1, S.A. Lang1
1
Universität Regensburg, Chirurgie, Regensburg, Deutschland, 2Universität
Regensburg, Innere Medizin I, Regensburg, Deutschland
Background. Expression of receptors for fibroblast growth factors
(FGFR) and their corresponding ligands have been associated with tumor growth in human hepatocellular carcinoma (HCC). Furthermore,
hypervascularisation is a typical characteristic of HCC and activation
of the FGF/FGFR system is a crucial event in tumor angiogenesis via
effects on both, tumor cells and stromal cells. Therefore, we sought to
evaluate the effects FGFR inhibition on cancer cells and stromal cells in
a model of HCC.
Methods. For the experiments HCC cell lines (Huh-7, HepG2), stromal
cells (endothelial cells (EC), vascular smooth muscle cells (VSMC), hepatic stellate cells (HSC)) and the FGFR inhibitor BGJ398 (Novartis Oncology, Basel) were used. Effects of targeting FGFR on growth of cells
were determined by MTT assays. Inhibition of constitutive and growth
factor induced cell motility was investigated using modified Boyden
Chamber assays. Activation of signaling pathways and expression of
trasncription factors upon FGFR inhibition was assessed by Western
Blot analyses. Effects on expression of vascular endothelial growth factor-A (VEGF-A) and FGFs were determined by RT-RCP and ELISA,
respectively.
Results. Targeting FGFR system with BGJ398 impaired growth of tumor
cells and ECs in dose-dependent manner, whereas only minor effects
were observed on VSMC and HSCs as determined by MTT assays. In
addition, motility of tumor cells and stromal cells was significantly reduced (p<0.05 for all). Moreover, treatment with BGJ398 led to inhibi-
tion of angiogenic pathways (Akt, ERK) in cancer cells, ECs and HSCs
even upon stimulation with bFGF. In contrast, minor effects were observed on VSMC signaling. Furthermore, expression of transcription
factor c-Myc was impaired upon treatment with FGFR inhibitor BGJ398
and expression of VEGF-A was significantly reduced upon hypoxic
condition.
Conclusion. Inhibition of FGFR system diminishes tumor cell motility
and angiogenic signaling in cancer cells and stromal cells in vitro. Hence, targeting FGFR might be an interesting approach for anti-neoplastic
treatment protocols in human HCC.
0338
Migration signalling in Panc-1 ductal pancreatic adenocarcinoma cells: Synergistic interaction between the TGF-beta type I
receptor ALK5 and PAR2
*F. Gieseler1, S. Stölting1, T. Gädeken1, T. Bartscht1, H. Ungefroren1
1
Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck,
Deutschland
Background. Cellular migration is an early and essential feature of metastatic tumor cells and is induced by TGF-beta1 through activation of
the TGF-beta type I receptor activin receptor-like kinase 5 (ALK5) in
several types of epithelial cells. Another class of receptors that control
proliferation and migration of tumor cells are the protease-activated
receptors (PARs). These receptors are activated by cleavage of part of
their extracellular domain by serine proteases. PAR2 can be activated in
vivo by trypsin and coagulation active serine proteases such as Tissue
Factor/Factor Xa/Factor VIIa complexes. Thus, the initiation of PARs
can be a consequence of the frequently activated coagulation system in
cancer patients.
Methods. The continuous ductal adenocarcinoma cell line Panc-1 is
known to express ALK5, PAR1 and PAR2. Migration of these cells under
various conditions has been examined in a real-time based cell migration assay (RTCA assay) using the xCELLigence system from Roche.
TGF-beta1 has been used for activation of ALK5 and the specific peptide
agonists SFLLRN and SLIGKV for PAR1 and PAR2 activation, respectively.
Results. TGF-beta1 (at 5 ng/ml) induced a time-dependent induction
of cell migration with peak values after 14–20 h (123±4.95% of medium
control). PAR1 activation by its specific agonist resulted in a weak and
non-significant induction of migration (103.56±9.33%) and the combination of both TGF-beta1 and PAR1 did not increase migration over the effect of TGF-beta1 alone. PAR2 activation by its specific agonist SLIGKV
induced a strong migration signal (136±3.73%). The combination of
TGF-beta1 and SLIGKV resulted in a synergistic effect of 165.24±6.79%
between 10–14 h, which is significantly more than both single effects.
Conclusions. It will be interesting to investigate the molecular mechanism of the observed combined TGF-beta1/SLIGKV effect. The process
of tumor cell migration in vivo, although not completely understood,
is nevertheless a potential target in cancer therapy. Further understanding of the molecular control of tumor cell dissemination and the development of more specific ALK5 inhibitors and coagulation inhibitors,
such as FXa inhibitors or the low molecular weight heparin tinzaparin
with high TFPI inducing capacity, will open the possibility to perform
clinical studies.
Supported by DFG.
Abstracts
0351
The pandeacetylase inhibitor panobinostat induces autophagy
related factors in liver cancer cells
*P. Di Fazio1, R. Montalbano1, S. Jabari2, K. Quint1,2, M. Ocker1
1
Philipps University of Marburg, Institute for Surgical Research, Marburg,
Deutschland, 2Universität Erlangen-Nürnberg, Institut für Anatomie, Erlangen, Deutschland
Background. Liver cancer, placed as the 5th common malignant tumor
entity, has rising incidence rates also in Western countries. Panobinostat (LBH589, Novartis Oncology), a pandeacetylase inhibitor, represents
a new agent with a promising future in liver cancer therapy. We have
previously demonstrated that panobinostat is able to induce cell death
through activation of ER stress related apoptotic pathways. Panobinostat also significantly reduced the growth of HepG2 xenografts in nude
mice (Cell Oncol 2010, 32:285–300). We, here, clarify the implication of
autophagy mechanisms into cell demise mediated by panobinostat.
Materials and methods. HepG2 (p53 wt) and Hep3B (p53 null) were
treated for 72 hours with panobinostat and cell death was quantified
through FACS with propidium iodide staining and CK18 fragmentation
staining. Impedance based real-time cell analysis (Xcelligence Roche)
was performed to monitor cell viability after panobinostat treatment.
The expression of autophagy related factors was analyzed through RTqPCR, western blot and immunofluorescence based cytochemistry;
transmission electron microscopy (T.E.M.) was performed to monitor
autophagosome formation.
Results. Panobinostat induced cell death in a dose and time dependent
manner. Autophagy related factors Atg5, Beclin and its activators Ambra, p62 and UVRAG were upregulated after 48 hours of treatment.
We also observed significant increase of p73 expression in Hep3B cells
after 24 hours of treatment. Immunofluorescence based cytochemistry
showed a modification of the ubiquitous cytosolic distribution of Beclin and LC3B in both cell lines to a defined spot formation after treatment with panobinostat, indicating a probable autophagosome formation. Western blot analysis also demonstrated an increase of Beclin
and LC3-I and LC3-II; no variations in the level of Apg12 were detected.
T.E.M. showed double-membrane cellular vescicles, after treatment
with panobinostat, which represent autophagosomes.
Conclusion. Panobinostat treatment determines the involvement of autophagy related mechanisms in an ER stress related apoptosis scenario.
The wide spectrum of mechanisms of action of panobinostat needs to
be further investigated.
0356
The pandeacetylase inhibitor panobinostat determines downregulation of oncogenic miRNAs in HCC cells
A. Henrici1, M. Ocker1, *P. Di Fazio1,2
1
Philipps University of Marburg, Institute for Surgical Research, Marburg,
Deutschland, 2Universität Erlangen-Nürnberg, Institut für Anatomie, Erlangen, Deutschland
Background. miRNAs represent new targets for future cancer therapy.
It has been shown that they possess tumorigenic and tumorsuppressor
activity. In particular, miR-19a, miR-19b and miR-30a promote tumor
progression by blocking the translation of proteins related to apoptotic
and autophagic cell death like APAF1, PAK6 and Beclin1 in many solid
tumors. We have previously shown that panobinostat, a potent pandeacetylase inhibitor, was able to promote the modulation of hsa-let7b and
its related target HMGA2 favouring the block of cellular proliferation
in liver cancer cells (HCC). Here we clarify, for the first time, that panobinostat is responsible for downregulating the above mentioned oncogenic miRNAs with subsequent modulation of their targets in HCC
cell lines.
Material and methods. HepG2 (TP53 wt) and Hep3B (TP53 null) liver
cancer cells were treated with 0.1 mM panobinostat for 6–48 hours.
Quantitative RT-PCR was used to determine the expression of miR-19a,
miR-19b, miR-30a, and their precursor transcripts; moreover their targets were also quantified.
Results. We demonstrate that panobinostat treatment causes a downregulation of miR-19a, miR-19b and their precursors. Panobinostat treatment determines also a downregulation of miR-30a while its precursor
is detectable neither in nuclear nor in cytosolic compartment. miRNAs
targets expression was differently affected in the two cell lines.
Conclusion. Panobinostat negatively regulate oncogenic miRNAs by favouring the expression of their targets. The modulation of these miRNAs has been shown for the first time in liver cancer cells and it needs to
be further investigated. Panobinostat represents a promising modulator
of miRNAs in a cancer related scenario.
0362
Overexpression of Hepatitis B virus envelope proteins induce
endoplasmic reticulum-mediated stress pathways in liver cancer
cell lines
*R. Montalbano1, P. Di Fazio1, D. Glebe2, M. Ocker1
1
University of Marburg, Institute for Surgical Research, Marburg, Deutschland, 2University of Gießen, Institute of Medical Virology, Gießen, Deutschland
Background. Hepatocellular carcinoma (HCC) is the 5th most common
malignancy worldwide. More than 90% of HCCs develop in cirrhotic
livers on a background of chronic liver disease, esp. infection with the
Hepatitis B virus (HBV). HBV represents the most common chronic
viral infection with about 370 million people being affected worldwide.
Although HBV has been documented to cause HCC, the exact role of
HBV in the development of HCC remains enigmatic. HBV is a hepatotropic virus with an outer lipoprotein envelope and an inner core bearing the viral genome. HBV envelope consists of 3 co-carboxyterminal
proteins, the small (SHBs), the middle (MHBs) and the large surface
protein (LHBs) that are cotranslationally inserted into the endoplasmic
reticulum (ER) as transmembrane (glycol-)proteins. When overexpressed, all three viral proteins are secreted as non-infectious subviral particles via the secretory pathway, while only virions containing the viral
core are secreted by multivesicular bodies (MVB). The LHBs cannot build viral particles by itself, but needs SHBs or MHBs for proper propagation. A massive storage of HBV envelope proteins was reported to lead
to cell stress causing cell death and sustained inflammatory responses.
Here we investigate if overexpression of L and S proteins in liver cancer
cells can induce ER-stress and trigger the expression of genes involved
in this pathway.
Methods. Human HCC cells HuH-7 was cultured under standard conditions and transfected with pSVL and pSVBX24H plasmids, overexpressing only LHBs and SHBs, respectively. Impedance based real-time
cell analysis was performed to continuously monitor cell viability. ERstress factors were evaluated by RT-PCR, FACS and IF analysis. ER-staining was performed by IF analysis.
Results. Cell based impedance analysis of HuH-7 cells showed that the
transfection with the plasmid encoding LHBs caused a reduction of cell
growth comparable with the effect of 10 nM thapsigargin, an ER-stress
inducer. Interestingly, the SHBs expression was cytostatic. The expression of both viral proteins induced an increase of BiP and CHOP mRNA
levels after 24–96 h of transfection, while the protein level was stable. ER
detection by IF revealed an increase of the selective fluorescent dye in
cells transfected with LHBs.
Conclusions. Overexpression of HBV envelope proteins LHBs and SHBs
activate ER-stress markers in HuH-7 cells. Further investigations are
needed to better clarify their mechanism of action.
0364
Formation and incidence of cell-in-cell structures in tumor and
normal tissue cells in vitro
*M. Schwegler1, B. Abendroth2, F. Putz2, L. Distel1
1
Universitätsklinikum Erlangen, Strahlenklinik, Erlangen, Deutschland,
2
Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Deutschland
Objective. Internalisation of cells is a phenomenon called cell cannibalism or entosis that has been recently described. These cell-in-cell structures (CIC) have been detected in tumor tissue sections and studied by
in vitro experiments. CIC structure has a characteristic appearance.
The cell is filled with a cell inside a vacuole that pushes the nucleus crescent shaped to one side. CIC is regarded to be one type of cell death
modality. Our question was whether CIC formation is common among
tumor cells and whether cells from normal tissue are able to form CIC.
Methods. The precondition for cell uptake is cell adhesion. For quantification of adhesion two samples of tumor cells were stained either with
the life cell dye CellTrace Oregon Green or CellTrace Far Red, mixed
and analyzed by flow cytometry before and after 90 minutes of coincubation. One of the so dyed samples was heat-treated (56°C, 45 min) to
stimulate incorporation. Microscopic analysis followed 4 hours of coincubation. This experiment was repeated 3 times with 5 tumor cell lines,
one primary tumor cell line, one lymphoblastoid cell line and 3 primary
skin fibroblasts cell lines. Additionally the process of incorporation was
imaged via life-cell microscopy.
Results. Flow cytometry analysis showed a significant increase of adhesion between untreated and heat-treated samples of all cell lines. All
cell lines were able to form CIC structures. Using an image, analysis
software CIC rates of 1000–2500 cells were quantified. Highest rates
were among the tumor cell lines (e.g. pancreatic carcinoma cell line
BxPC-3: 2.71%), lower rates in the fibroblasts (e.g. cell line GP: 2.17%) and
lowest in the lymphoblastoid cell line (0.66%). The number of cell-incell structures found via microscopy correlated with the degree of adhesion quantified via FACscan. We observed that 41.7% of viable green
cells adhered to necrotic red cells of the pancreatic carcinoma cell line
BxPC-3, 37.3% of the primary skin fibroblast cell line GP and only 9.4%
of the lymlphoblastoid cell line SBL-1. Engulfment of early necrotic cells
seems to be a membrane-dependent process whereas damaged cells
which had lost completely their shape and membrane integrity could
not be taken up.
Conclusion. Not only tumor cells but even normal tissue cells and lymphoblastoid cells are able to form CIC. CIC seems to be more frequent
in tumor cell lines but common to a variety of cell types and may be an
underestimated type of cell death.
0372
Activation of the human immune system via Toll-like receptors
by the oncolytic parvovirus H-1 and its combination with chemotherapeutic or targeted agents
*M. Sieben1, S. Roth1, F. Springsguth1, C. Dinsart2, P.R. Galle1, J. Rommelaere3,
M. Möhler1
1
Universitätsmedizin Mainz, I. Medizinische Klinik und Poliklinik, Mainz,
Deutschland, 2German Cancer Research Center, Infection and Cancer
Program, Department F010, Heidelberg, Deutschland, 3German Cancer
Research Center, Institut National de la Santé et de la Recherche Médicale
Unité 701, Heidelberg, Deutschland
Background. Promising new approaches to tumor-directed therapy include oncolytic parvoviruses since they also increase the host immune
response by priming effector immune cells against the tumors. During
the activation of dendritic cells (DC) by H-1PV-induced tumor cell lysates (TCL) the functional role of Toll-like receptors (TLR) and their
signaling pathways is yet unknown. Since H-1PV kills human cancer
cells using different pathways than other anticancer therapies, we eva-
luated the immunologic effects of H-1PV induced TCL for efficient human antitumor immune responses. Thus, we explored the molecular
interactions and synergistic effects between H-1PV, chemotherapeutic
agents and the targeted agent sunitinib as a typical molecule of the new
multi-tyrosine kinase inhibitors (TKI) for targeted therapy.
Methods. In view of the stimulatory capacity for DCs by H-1PV-infected
SK29Mel cell lysates, we stably transfected human HEK293 cells expressing single TLRs, analysed the expression and function of TLRs during
H-1PV infection and determine whether the parvovirus-induced immune stimulation is correlated with the Toll-like receptor (TLR) signaling pathways. In addition our human melanoma model enables to study immune responses in the context of corresponding HLA-restricted
human DCs. In this human tumor model, activation of tumor-specific
autologous CTL clones can also be analysed.
Results. In TLR-transfected HEK293 cells we identified TLR3 and 9
which were clearly activated by H-1PV. Furthermore, NFkB-expression
was increased after H-1PV infection. In addition, TLR expression profiles of DCs coincubated with H-1PV-infected SK29Mel cells was studied
and showed an increased TLR3 and 9 expression. DC co-cultures with
TCL incubated with H-1PV combined with chemotherapeutic agents or
sunitinib induced effective immune stimulation via a pronounced DC
maturation, significant better cytokine release and cytotoxic T-cell activation. Again, cytokine levels increased after coculture of autologous
CTLs with DCs stimulated by H-1PV-induced TCLs.
Conclusions. H-1PV induced tumor cell lysates stimulate human immature DCs and cytotoxic T-cells, at least in major parts by the TLR signaling pathway. Even more, combined treatment with chemotherapeutic
or targeted agents did not interfere with the pronounced immunomodulatory properties of H-1PV, but reinforced drug-induced tumor cell
killing. Thus, this very promising approach has also high immunotherapeutic potentials for tumor patients.
0374
Akt/mTORC1-signalling in human sarcoma cells under heatshock.
*E. Strozyk1, V. Sujeva1, E. Kampmann2, R. Issels2,1
1
Helmholtz Zentrum München, KKG Hyperthermie, München, Deutschland,
2
Universitätsklinikum Großhadern, Medizinische Klinik und Poliklinik III,
Introduction. The completed randomized phase III EORTC/ESHO
intergroup trial (NCT 0003052) showed that regional hyperthermia
(RHT) combined with neo-adjuvant chemotherapy (NAC) improves
response, tumor control and survival of patients with high-risk soft
tissue sarcomas (STS; Lancet Oncol 2010). Recently, the notion is that
grade 2 STS, which are thought to be less chemosensitive than grade 3,
predominantly benefit from the addition of RHT to NAC (ASCO 2011).
Because grading is mainly scored on mitotic index, we investigated the
Akt/mTORC1 pathway, which is involved in proliferation, survival and
protein synthesis, under heat-shock conditions.
Methods. Human sarcoma cell lines were exposed to heat-shock (41.8 or
43°C for 90 or 150 min) and treated with perifosine (0–15 µM) as inhibitor of Akt-phosphorylation or RAD001 (0.1–10,000 nM) as inhibitor of
mTORC1 kinase-activity. Induction of HSP70 and phosphorylation of
Akt and downstream proteins mTOR, p70S6K and S6 were detected by
immunoblotting. Cytotoxic effects were estimated by using the WST-1
assay, measuring clonogenic survival and recording colony diameters.
Results. Increased HSP70 expression and enhanced phosphorylation
of Akt, mTOR, p70S6K and S6 were immediately detected after heatshock. Both, inhibition of Akt-phosphorylation by perifosine and inhibition of mTORC1 kinase-activity by RAD001 led to reduced HSP70-induction. Perifosine reduced cellular viability dose-depently and yielded
enhanced cytotoxicity when combined with heat-shock. Combining
RAD001 and heat-shock did not enhance cytotoxicity. Chosen concen-
Abstracts
trations of RAD001 had only marginal effects on clonogenic survival
but reduced colony growth.
Conclusion. Activation of Akt/mTORC1 is important for HSP70-induction in response to heat-shock. Inhibition of Akt-phosphorylation but
unexpectedly not of mTORC1 kinase-activity reduced survival when
combined with heat-shock. Other targets of Akt besides mTOR might
be essential for surviving cellular stress and are investigated in ongoing
experiments.
0383
CTLA-4 antibodies Tremelimumab and Ipilimumab overcome
tumor-mediated immunsuppressive effects of CTLA-4 on human
dendritic cells
*K. Goepfert1, P. Schäfer1, B. Heinrich1, P. Galle1, M. Moehler1
1
Universitätsmedizin Mainz, I. Medizinische Klinik, Mainz, Deutschland
Introduction. Tumors have distinct mechanisms to circumvent the human immune system. Expression of CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) on tumors and regulatory T cells (Tregs) can
lead to suppression of immune defence mechanisms. However CTLA-4
mediated blockage of human dendritic cells (DCs) by CTLA-4 expressing tumors have not been analysed so far. As CTLA-4 receptors can be
blocked by new CTLA-4 antibodies tremelimumab or ipilimumab, we
analysed these antibodies in our ex vivo human melanoma model for
their effects on maturation of DCs and their role on Tregs.
Methods. Tregs and monocytes were isolated from human Buffy coats
from HLA-A2 restricted donors with magnetic beads. For differentiation of monocytes into DCs, monocytes were stimulated with IL-4 and
GM-CSF and maturation of iDCs was induced by a cytokine cocktail
(CC), containing 0.01 µg/ml TNFα, IL-6, IL-1β and 1 µg/ml PGE2 [Jonuleit et al. (1997), Eur J Immunolo 27(12):3135–42]. Parvovirus H1-infected
and uninfected Sk29Mel melanoma cells were cocultured with iDCs
with or without tremelimumab (10 µg/ml) and with or without ipilimumab (10 µg/ml) in a ratio of 1:3 for 3 days.
Results. Sk29Mel cells and some colon carcinoma cells (CaCo2) clearly
expressed CTLA-4 on the surface, measured by extra- and intracellular
FACScan analyses. Furthermore, tremelimumab and ipilimumab did
not disturb maturation of iDCs. In coculture, the oncolytic parvovirus
H1-infected (H1-PV) SK29Mel cell lysates induced maturation of iDCs
which was increased by the addition of tremelimumab and ipilimumab.
Using ELISA, a clear increase in IFNgamma and IL-6 was detected in
the supernatants of H-1PV infected SK29Mel cocultured with iDCs in
the presence of tremelimumab and ipilimumab. In further coculture
experiments the negative effect of Tregs on mDCs was partially restored
in the presence of tremelimumab and a decrease of IL-10 was detected in
the supernatant via ELISA. The further analysis of CTL activation and
DC cross presentation will be presented at the meeting.
Conclusion. To our knowledge this is the first direct analysis that tremelimumab and ipilimumab can overcome the negative feedback of
tumor cells expressed CTLA-4 on human DCs. These results clarify the
importance of CTLA-4 as therapeutical goal for treatment of human
tumours to overcome tumor-induced immune suppression.
0393
Radiation-induced damage of the rat intestine after external
beam irradiation of the liver
*S. Cameron1, A. Schwartz1, S. Sultan1, I.-M. Schaefer1, M. Rave-Fraenk1,
C.F. Hess1, H. Christiansen1, G. Ramadori1
1
UM Göttingen, Gastroenterologie und Endokrinologie, Göttingen,
Deutschland
Introduction. Ionizing radiation is routinely used in the treatment of
malign tumors. To date, no experimental setting exists for investigating out-of-field effects of the intestine, with a parenchymatous organ
as target.
Methods. A single dose of 25 Gray was administered percutaneously to
the liver of randomly paired male Wistar rats after a planning CT-scan.
Sham-irradiated animals served as controls. At 1, 6, 24, 96 hours (h),
and 1.5 and 3 months the duodenum, jejunum, ileum and distal colon
were removed, washed and frozen in liquid nitrogen or prepared for
paraffin staining.
Results. All animals survived the treatment. In the duodenum and jejunum, acute changes at 1 h resulted in epithelial cell damage. At 6 h, the
villus architecture was disrupted. In the submucosa, vessel congestion
was observed. Radiation mucositis with granulocyte (MP0+) infiltration was seen from 1 to 24 h in the duodenum and jejunum, when ED1+
macrophages, CD3+ T-lymphocytes, and CD34+ hematopoietic precursor cells were recruited. Duodenum and jejunum showed regeneration
of the crypt-villus axis at 1.5 and 3 months. In the ileum at 1 h after irradiation, only edema was observed. At 6 h, the ilial mucosa showed complete denudation of the villi and destruction of the crypt lining. In the
lamina propria, vessels were scarce with increased collagen deposition.
Early granulocyte infiltration was delayed but continued throughout
the observation time. Recruitment of macrophages and lymphocytes
was missing with a lack of induction of chemokines such as CCL2. Tissue regeneration in the ileum was deficient during the observation time.
In the colon, changes were minor and transient.
Conclusion. The ileum, even though it received only scattered irradiation, was most sensitive to radiation. This needs to be taken into account to prevent the clinically observed irradiation complications to the
ileum.
0404
Effect of Sox9 induced IFIT3 expression in pancreatic cancer
*R. Mair1, P. Camaj1, I. Ischenko1, A. Renner1, Q. Bao1, Y. Zhao1, K.-W. Jauch1,
C.J. Bruns1
1
Klinikum Großhadern, Experimentelle Forschung Chirurgie – AG Bruns,
Introduction. Pancreatic cancer is associated with a very poor overall
prognosis. To analyze the aggressive tumor biology of human pancreatic cancer, we genomically compared high-metastatic and non-metastatic human pancreatic cancer cell lines and analyzed the relevance of
differentially expressed IFIT3 gene in vivo and in vitro.
Methods. The transcriptomes of the non-metastatic FG and the highmetastatic L3.6pl human pancreatic cancer cell lines were compared
via Affymetrix analysis. The interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) gene was significantly over-expressed
in L3.6pl cells. The results were validated with RT-PCR and Westernblotting. Promoter sequence analysis was used to determine transcription factor binding sites. L3.6pl, FG, their IFIT3-transfectants and the
L3.6pl-Sox9shRNA-transfectant were examined in vitro with regard
to proliferation, apoptosis, angiogenesis, chemotherapy-resistance and
cytokine-production and orthotopically injected into nude mice. OneSTrEP-tag identified interacting proteins. Regulation of gene expression
was studied after treatment with IFN-alpha and/or inhibitors NFκB
(BAY-11-7082) and STAT1 (S-19).
Results. IFIT3 was significantly over-expressed in high metastatic L3.6pl
cells and inducible by IFN-alpha. The IFIT3-promoter presented a binding site for the transcription factor Sox9 which is constitutively upregulated in L3.6pl cells. Overexpression of the IFIT3 gene increased
tumor growth, angiogenesis and metastasis. In addition, it led to an
increased VEGF production, higher proliferation rate and decreased
apoptosis as well as resistance to chemotherapy. Furthermore, a significant increase in IL-6 production was detected, whereas IFIT3-downregulation via downregulation of its transcription factor Sox9 led to
a decreased IL-6 production. STAT1 and JNK were shown to be interacting partners. Inhibition of NFκB and STAT1 led to diminished IFIT3
expression, respectively.
Conclusion. Previous studies have shown an up-regulation of IFIT3 in
the context of inflammation. In our experiments IFIT3 led to an aggressive phenotype in pancreatic cancer. It is inducible by IFN-alpha. Sox9triggered over-expression of IFIT3 led to an increased IL-6 production
in tumor cells. Therefore, our results suggest that Sox9 triggered IFIT3
over-expression induces a pseudo-inflammatory environment, supporting tumor cell proliferation and metastasis, which is represented in the
phenotype of L3.6pl cells.
0421
A new in vitro model for cell-in-cell structure formation using the
pancreatic carcinoma cell line Bxpc-3
*F. Putz1, M. Schwegler1, R. Fietkau1, *L. Distel1
1
Strahlenklinik der Universität Erlangen-Nürnberg, Strahlenbiologie,
Objective. Pathologists have described cell-in-cell structures in malignant tumor samples for many years. This cell-in-cell phenomenon, also
referred to as “cell cannibalism”, consists of a tumor cell that has completely engulfed another tumor cell leading to a characteristic bird´s eye
appearance. Recently, a new mechanism, called entosis, was described,
which can partially explain cell-in-cell structure formation. Nevertheless, the mechanisms underlying the cell-in-cell phenomenon in tumors
still remain largely unknown. We have discovered a new in vitro model
using a mechanism different from entosis that allows the generation
of numerous cell-in-cell structures. As the uptake of apoptotic cells in
neighboring cells is well recognized in the literature, we investigated
whether the observed cell-in-cell structure formation was induced by
apoptosis.
Methods. Bxpc-3 cells were stained red and green with CellTrace Oregon Green and CellTrace Far Red, respectively. Red Bxpc-3 were heattreated (56°C, 45 min) with or without the caspase inhibitor ZVADFMK (0.5 h pretreated, 100 µM). Alternatively, red Bxpc-3 were treated
with 25% ethanol or 1 M sodium azide for 1 hour. After coincubation of
red and green cells in suspension for 3 hours, cells were fixed and examined under the fluorescence microscope. Red cells that were completely internalized into green cells were counted as cell-in-cell structures.
Furthermore, cells were immunostained for cleaved caspase-3.
Results. Bxpc-3 cells were present in small clusters. Numerous characteristic cell-in-cell structures were noted, irrespective of treatment.
Cell-in-cell structures consisted of a red Bxpc-3 cell that was completely
engulfed by a green cell with typical crescent-shaped nucleus. Treated
cells were negative for cleaved caspase-3. Using heat-treated cells we
observed 1.25% (39/3108) and 1.36% (41/3010) cell-in-cell structures with
and without caspase inhibition, respectively.
Conclusions. Engulfment of early necrotic cells by viable Bxpc-3 cells
can lead to characteristic cell-in-cell structures in vitro strongly resembling those frequently described in histological and cytological tumor
specimens. In conclusion, we present a new mechanism for cell-in-cell
structure formation between malignant cells that is different from entosis and apoptotic cell uptake.
0426
Conditional RNAi-mediated knockdown of TPX2 synergizes with
docetaxel cytotoxicity against HeLa cell sub-clones in vitro and
in vivo
*A.J. Allmendinger1, K. Schönig2, O. Gruss3, S. Berger2, M.R. Berger1
1
Deutsches Krebsforschungszentrum, AG Toxikologie und Chemotherapie, Heidelberg, Deutschland, 2Zentralinstitut für Seelische Gesundheit,
Mannheim, Deutschland, 3Zentrum für Molekulare Biologie, Heidelberg,
Deutschland
The microtubule-associated protein TPX2 could be a potent novel target
for anti-cancer therapy. Knockdown of TPX2 is highly effective in inhibiting tumor cell growth, both in vitro and in vivo. The combination
of TPX2-knockdown with docetaxel could further augment therapeutic
efficacy. To test this hypothesis, respective experiments were performed with a HeLa cell line in which the reverse tetracycline-dependent
transactivator rtTA2S-M2 drives the expression of eGFP and a miRNA,
inducing RNAi-dependent inhibition of TPX2 expression, from the bidirectional tet-regulated promoter (Hela EM2-11-TPX2). A similar cell
line (Hela EM2-11), in which the presence of the inducer doxycycline
(dox) activates expression of the genes mCherry and firefly luciferase,
served as a negative control.
First, the combined effect of TPX2-knockdown and docetaxel (DCX)
on in vitro proliferation was determined by MTT assay. Here, the respective cells were treated with either DCX (0.2–4.0 nmol/l) or dox
(0.5 μg/ml) or a combination of both and cell viability was assessed after
72 h. Treatment with DCX caused a concentration-dependent decrease
in proliferation in vitro, whereas dosages of dox, which were sufficient
to knock down TPX2 expression but not yet anti-proliferative, reduced
cell growth by 42%. The proliferation of HeLa EM2-11-TPX2 was synergistically reduced by the combination treatment compared to the single
agent exposures.
Next, the therapeutic potential of TPX2-knockdown alone or in combination with DCX was tested in a nude mouse xenograft model. Here,
the size of tumors growing in nude mice following s.c. implantation was
monitored over a period of 4-5 weeks. A control group received no treatment; a TPX2-knockdown group received treatment with dox (0.2 mg/
ml in drinking water), starting on day 14 after cell injection and being
continued for 18 days; a DCX group was given 22.3 mg/kg (applied twice,
on days 14 and 25); a fourth group received a combination treatment. In
nude mice, TPX2-knockdown alone caused a 52% reduction in tumor
growth and DCX a reduction by 25%. The combination of both treatments inhibited tumor growth synergistically by 87%.
In our experiments, knockdown of TPX2 alone was highly effective
against HeLa cell growth. The combination of TPX2-knockdown with
docetaxel showed a synergistic therapeutic effect, both in vitro and in
vivo. It is concluded that TPX2 is a valuable treatment target, which can
be successfully combined with other anti-mitotic agents.
0477
Preclinical evidence that CD47 is a common therapeutic antibody
target on human solid tumors
*S.B. Willingham1, J.-P. Volkmer2,1, H. Contreras-Trujillo1, R. Martin1, J.D. Cohen1, K. Weiskopf1, A.K. Volkmer1, P. Dalerba1, F.A. Scheeren1, I.L. Weissman1
1
Stanford University, Institute for Stem Cell Biology & Regenerative Medicine, Stanford, USA, 2Uniklinik Düsseldorf, Urologie, Düsseldorf, Deutschland
Background. CD47 is a ligand for SIRP-alpha, a protein expressed on
macrophages and dendritic cells. CD47 binding to SIRP-alpha transmits a “don’t eat me” signal that results in the inhibition of phagocytosis.
Blocking anti-CD47 monoclonal antibodies neutralize the CD47- SIRPalpha interaction, enabling macrophages to phagocytose leukemia and
lymphoma cells. We hypothesized that patient solid tumor cells express
CD47 to circumvent macrophage surveillance and that blocking anti-
Abstracts
CD47 antibodies would inhibit the growth and metastasis of solid tumors.
Methods. All experiments were performed with either primary or lowgeneration xenograft human tumors, including bladder, breast, colorectal, glioblastoma, hepatocellular carcinoma ovarian, prostate, and
head and neck squamous cell carcinoma samples. CD47 expression was
analyzed on solid tumor cells by flow cytometry or immunofluorescence. Patient gene expression and survival data were analyzed to evaluate
CD47 as a prognostic factor. CD47 was evaluated as a therapeutic antibody target using in vitro assays and orthotopic xenotransplantation
models established with patient solid tumor cells.
Results. Nearly all solid tumor cells express CD47. CD47 mRNA expression levels correlated with a decreased probability of survival. Blocking
anti-CD47 monoclonal antibodies enabled macrophages to phagocytose patient tumor cells in vitro, and in vivo inhibited tumor growth,
prevented metastases, and increased survival.
Conclusions. These results suggest that CD47 expression is a common
mechanism exploited by human solid tumor cells to evade phagocytosis
and establish CD47 as a potential therapeutic antibody target for solid
tumors.
0487
MMP11 expression increases during progression of breast cancer
*S. Schultz1, H. Bartsch2, B. Kootz1, K. Sotlar2, K. Petat-Dutter2, M. Bonin3,
S. Poths3, M. Walter3, O. Riess3, D. Wallwiener1, T. Fehm1, *H. Neubauer1
1
Eberhard-Karls-University Tübingen, Department of Obstetrics and Gynecology, Tübingen, Deutschland, 2Ludwig-Maximilians-University Munich,
Institute for Pathology, Munich, Deutschland, 3Eberhard-Karls-University
Tübingen, Microarray Facility Tübingen, Tübingen, Deutschland
Aims. The ductal carcinoma in situ (DCIS) of the breast is considered
to be the pre-invasive form of the invasive duct carcinoma (IDC). The
aim of this project is (1) the identification and validation of potential
progression markers and (2) to identify markers for high risk DCIS with
aggressive potential. MMP11 (matrix-metalloproteinase 11) is a marker
for the transition from DCIS to IDC. It is associated with tumour cell
invasion and a poor clinical outcome.
Material and methods. 14 formalin fixed and in paraffin embedded
(FFPE) tissue samples with a pure DCIS without IDC component
(patients were at least five years free of cancer), and 15 paraffin tissue
samples with DCIS/IDC tumours were selected. Tissue sections were
prepared, stained with hematoxylin-eosin and the epithelial cells were
isolated by laser capture microdissection (LCM). 200 ng RNA were extracted, hybridized to the Whole Genome DASL Array (Illumina) and
bioinformatically evaluated. The RNA was linear amplified using the
Ribo-SPIA® technology (WT-Ovation TM FFPE System, NuGenTM)
and the validation was done by qRT-PCR using the LightCycler® 480
System (Roche).
Results. We were able to identify 993 transcripts that are differentially
expressed between DCIS and IDC of the same tumor and 1138 transcripts which are differentially expressed between pure DCIS and DCIS/
IDC tumors. Differential expression was validated for 9 transcripts
using two sample sets, the technical validation sample set (15 DCIS/IDC
tumors, 14 pure DCIS) and an independent validation sample set (26
DCIS/IDC tumors, 17 pure DCIS). MMP11 is highly expressed in IDC
and moderately expressed in DCIS with IDC component. In pure DCIS
less or no expression of MMP11 was determined.
Conclusion. We identified progression-specific candidate transcripts
using LCM and microarray analysis from FFPE breast cancer tissues.
MMP11 is a progression marker which differentiates between high- and
low-risk DCIS.
0488
Analysis of single tumor cells by a one-step Multiplex-RT-PCR
*H. Schneck1, A. Tögl2, P. Hartmann2, C. Grimmel3, T. Biedermann3, T. Fehm1,
H. Neubauer1
1
Gynecology, Tübingen, Deutschland, 2Beckman Coulter Biomedical GmbH,
Munich, Deutschland, 3Eberhard-Karls-University Tübingen, Institute for
Dermatology, Tübingen, Deutschland
Objectives. Circulating tumor cells (CTC) are essential for establishing
metastasis and therefore their detection and molecular characterization
might help to optimize treatment decisions. By dint of a one-step Multiplex-RT-PCR approach on the breast cancer cell line MCF-7 the parallel analysis of tumor-related expression markers (e.g. CK19, EpCAM,
Muc1) was established and served as proof of principle for the molecular
characterization of CTC.
Material and methods. For analysis of single cells MCF-7 cells were spiked into blood of healthy donors or 7.5 ml of blood obtained by metastatic breast cancer patients was used. Patients’ blood was collected in
EDTA tubes (Monovette, Sarstedt) and CTC were either enriched using
a Percoll density gradient method or processing the blood samples with
the CellSearch® Profile Kit (Veridex, LLC). Single cell deposition happened in 1×PBS after staining against epithelial cell-specific markers
(EpCAM, MUC1; Beckman Coulter) by cell sorting (FACSAria, BD) or
micromanipulation onto the reaction sites of an AmpliGrid slide (Beckman Coulter). Multiplex-RT-PCR was performed using the Single Cell
One-Step RT-PCR Kit and primers for β2-microglobulin, calmodulin,
GAPDH, EpCAM, CK19 and Muc1 on the AmpliSpeed cycler (Beckman Coulter). Products were analysed with the Agilent DNA 1000 Kit
and the Agilent 2100 Analyzer.
Results. Single epithelial cells were successfully deposited on the reaction
sites of AmpliGrid slides with both cell sorting and micromanipulation.
For confirmation and in order to correlate RT-PCR results with template presence or absence, a visual quality control using a microscope
was performed. Furthermore, single-plex one-step RT-PCRs for three
housekeeping genes (β2-microglobulin, calmodulin and GAPDH) and
three epithelial markers (EpCAM, Muc1 and cytokeratin-19), as well as
the combination of all markers in a 6-Plex-RT-PCR could be achieved
on single cells.
Conclusion. A One-Step Multiplex-RT-PCR using the AmpliGrid system
can be applied for parallel analysis of multiple transcripts from single
epithelial cells isolated from peripheral blood of breast cancer patients.
0495
Combined transcriptome and methylation analyses to identify
new targets of cisplatin resistance in ovarian cancer patients
*T. Fehm1, J. Hoffmann2, M. Walter2, A. Staebler3, S. Poths2, O. Riess2, D. Wallwiener1, M. Bonin2, *H. Neubauer1
1
Gynecology, Tübingen, Deutschland, 2Eberhard-Karls-University Tübingen,
Microarray Facility, Tübingen, Deutschland, 3Eberhard-Karls-University
Tübingen, Institute for Pathology, Tübingen, Deutschland
Objectives. The standard therapy for Ovarian cancer consists of aggressive cytoreductive surgery followed by platinum-based chemotherapy.
However, intrinsic or acquired platinum resistance in the majority of
patients leads to high mortality rate. To gain new insights in resistance
mechanisms and modified pathways, we performed combined wholegenome expression and methylation studies using Illumina BeadArrays.
Material and methods. Eleven cryopreserved tissue samples from each
platinum resistant and platinum sensitive ovarian carcinomas were selected. From consecutive tissue sections RNA and DNA was extracted
and analysed for differences in gene expression and methylation pat-
terns by using Illumina BeadArray platforms. Results obtained were
confirmed using qRT-PCR and pyrosequencing.
Results. We assessed the DNA methylation profile of approx.
27,000 CpG sites (associated with approx. 14,000 transcripts) and found
613 differentially methylated promoter sites using M-value statistics. To
investigate the relationship between DNA methylation status and gene
expression, we measured levels of transcripts from the same set of genes
in the same samples. After normalization and biostatistical analysis we
detected 115 significantly differentially expressed transcripts with a fold
change >1.6 and a p-value <0.05. Promoter DNA methylation and levels
of the corresponding gene’s transcript have been found to be inversely
correlated in some cases. Overall, we were able to detect 14 negatively
correlated transcripts. Pathway and network analyses indicate a strong
enrichment of genes involved in cell differentiation and tumorigenesis
processes.
Conclusion. By combining whole-genome expression and methylation
analyses we reveal molecular changes in ovarian cancers which might
be involved in establishing platinum resistance. Functional verification
and pathway analysis is under way.
0497
Prognostic significance of apoptotic disseminated tumor cells in
primary breast cancer patients
*N. Krawczyk1, *M. Banys2, G. Milanova3, A. Hartkopf3, S. Becker3, D. Wallwiener3, T. Fehm3
1
Klinikum Bremen-Mitte, Gynäkologie, Bremen, Deutschland, 2Marienkrankenhaus Hamburg, Frauenklinik, Hamburg, Deutschland, 3Universität
Tübingen, Gynäkologie, Tübingen, Deutschland
Background. An imbalance between cell proliferation and programmed
cell death leads to tumour growth. Although most cytostatic agents
used in systemic therapy of breast cancer induce an apoptosis in tumour cells leading to their destruction, a high ratio of apoptotic cells in
primary breast cancer is correlated with poor prognosis. The purpose of
this study was to investigate (1) the incidence and (2) prognostic significance of apoptotic tumour cells in bone marrow (BM) of primary breast
cancer patients who underwent primary surgery or were treated with
neoadjuvant chemotherapy.
Methods. 261 primary breast cancer patients treated at the Department
of Gynecology and Obstetrics (University Hospital Tübingen, Germany) between 2003 and 2007 were included into our study. 186 underwent
primary breast surgery and 75 were treated with neoadjuvant chemotherapy. BM aspirates were analysed by immunocytochemistry (M30
antibody) using ACIS system (Chromavision) according to the ISHAGE
evaluation criteria. The survival data were evaluated after 25 months of
follow up.
Results. In 50 of 186 (27%) patients who underwent a primary surgery
and 34 of 75 (45%) patients treated with neoadjuvant systemic therapy
M30 positive disseminated tumour cells (DTC) could be detected. The
incidence of apoptotic cells was significantly higher in patients with
complete/partial remission compared to patients with stable/progressive disease (65% and 49% vs. 31% and 0%). In the group of neoadjuvant
treated patients M30-positive BM status was correlated with an improved disease-free survival (9% relapsed vs. 22% in M30-negative group).
Inversely, the detection of apoptotic DTC in patients with primary operated breast cancer was associated with poor prognosis [8/50 (16%) vs.
9/136 (7%) of the events].
Conclusion. 1.) Apoptotic DTC can be detected in breast cancer patients
before and after the systemic treatment 2.) The presence of apoptotic
DTC in BM of breast cancer patients can reflect the effects of neoadjuvant treatment. 3.) Spontaneous and chemotherapy-induced apoptosis
can possibly have different prognostic significance
0504
Recurrent GNAS mutations define an unexpected pathway for
pancreatic cyst development
*H. Matthaei1,2, J. Wu2, A. Maitra2, M. Dal Molin2, L.D. Wood2, J.R. Eshleman2, M.G. Goggins2, M.I. Canto2, R.D. Schulick2, B.H. Edil2, C.L. Wolfgang2,
A.P. Klein2, L.A. Diaz2, P.J. Allen3, M.C. Schmidt4, K.W. Kinzler2, N. Papadopoulos2, R.H. Hruban2, B. Vogelstein2
1
Rheinische Friedrich-Wilhelms-Universität, Klinik für Allgemein-, Viszeral-,
Thorax-, und Gefäßchirurgie, Bonn, Deutschland, 2Johns Hopkins University, Baltimore, USA, 3Memorian Sloan-Kettering Cancer Center, New York
City, USA, 4Indiana University, Indianapolis, USA
More than 2% of the adult U.S. population harbors a pancreatic cyst.
These often pose a difficult management Problem because conventional
criteria cannot always distinguish cysts with malignant potential from
those that are innocuous. One of the most common cystic neoplasms of
the pancreas, and a bona fide precursor to invasive adenocarcinoma, is
called intraductal papillary mucinous neoplasm (IPMN). To help reveal
the pathogenesis of these lesions, we purified the DNA from IPMN cyst
fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS
mutations, we identified recurrent mutationsat codon 201 of GNAS. A
larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found
that GNAS mutations were present in 66% of IPMNs and that either
KRAS or GNAS mutations could be identified in 96%. In eight cases, we
could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight
cases, the GNAS mutations present in the IPMNs were also found in the
invasive lesion. GNAS mutations were not found in other types of cystic
neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. In addition to defining a new pathway for pancreatic
neoplasia, these data suggest that GNAS mutations can inform the diagnosis andmanagement of patients with cystic pancreatic lesions.
0507
Fluorinated [1,2-diarylethylenediamine]platinum(II) complexes:
differences between in vivo and in vitro cytotoxicity
*A. Molchanov1, R. Gust2
1
Freie Universität Berlin, Institut für Pharmazie, Berlin, Deutschland, 2Universität Innsbruck, Institut für Pharmazie, Innsbruck, Österreich
Cisplatin is an established drug in the treatment of various types of human cancer (testicular, ovarian, bladder, head and neck [1, 2, 3], with
side-effects as nephrotoxicity, ototoxicity and neurotoxicity which limit
its therapeutical value. The second and the third generations of the platinum(II) complexes were developed to overcome resistance to cisplatin
and to minimize its side-effects. The current structure-activity relationship studies on fluorinated [1,2-diarylethylenediamine]platinum(II)
complexes continue the work of Spruß et al. [4] The IC50 values of 8
meso- and 10 d,l/R,R/S,S-configurated complexes were determined on
the hormone-dependent MCF-7 breast cancer cell line. Selected compounds were also tested against hormone-independent MDA-MB-231
breast cancer and HT-29 colon carcinoma cells. The results on MCF-7
cells indicated similar or superior activity of the majority of the complexes (IC50 in the range of 3.15–18.45 µM for meso- and 0.36–14.25 µM for
d,l/R,R/S,S-compounds) compared to cisplatin. The results on MDAMB-231 and HT-29 cancer cells are also discussed.
The results were tried to be correlated with in vivo data reported in the
literature for the testing of the corresponding substances on P388 leukemia of the CDF1 mice and MXT (M 3.2) OVEX mammary carcinoma
of B6D2F1 mice [4]. Unfortunately only the [d,l-1,2-bis(2,6-difluorophenyl)ethylenediamine]dichloroplatinum(II) complex and its meso-configurated counterpart possessed high activity. A possible explanation
might be the insufficient water solubility of the complexes resulting in
Abstracts
insufficient bioavailability when injected intraperitoneally or subcutaneously as a suspension in high concentration in in vivo tests.
1. O’Dwyer P, Stevenson J., Johnson SW (1999). In: Lippert B. (ed.), Cisplatin. Chemistry and Biochemistry of a Leading Anticancer Drug, WILEY-VCH, Weinheim,
pp 31 Fluorinated [1,2-diarylethylenediamine]platinum(II) complexes 72
2. Reedijk J (1999) Chem Rev 99:2499–2510
3. Boulikas T, Vougiouka M (2003) Oncol Rep 10:1663
4. Spruß T, Bernhardt G, Schickaneder E, Schönenberger HJ (1991) Cancer Res
Clin Oncol 117:435–443
Seltene Tumoren
0016
The oral cancer knowledge of dentists and physicians in Schleswig-Holstein
*K. Hertrampf1, H.-J. Wenz2, M. Koller3, N. Arpe4, J. Wiltfang1
1
Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für MKGChirurgie, Kiel, Deutschland, 2Universtitätsklinikum Schleswig-Holstein,
Campus Kiel, Klinik für Zahnärztliche Prothetik, Propädeutik und Werkstoffkunde, Kiel, Deutschland, 3Universitätsklinikum Regensburg, Zentrum
für Klinische Studien, Regensburg, Deutschland, 4Universtitätsklinikum
Schleswig-Holstein, Campus Kiel, Klinik für Strahlentherapie, Kiel, Deutschland
Objectives. Oral cancer is a considerable health problem with more than
10,000 new diagnosed cases each year in Germany. Comparable little is
known about the knowledge of dentists and physicians on oral cancer
with focus on diagnostic items. It was the aim of the project to evaluate
the level and determinants of knowledge about diagnostic factors of oral
cancer by means of a standardised questionnaire in the State of Schleswig-Holstein, Germany.
Material and methods. A self-administered survey was mailed together
with a business reply envelope to all dentists (n=2233) and the medical
disciplines involved in oral cancer diagnostics (Otolaryngology, dermatology, internal Medicine, general medicine; n=2575) in SchleswigHolstein. Three and six weeks after the initial mailing, a reminder was
sent to all possible participants. The survey was composed of 41 items.
Descriptive statistics of the sample and responses to the questionnaire
were reported by means of counts and percentages.
Results. 306 questionnaires of the dentists (14%) and 408 questionnaires of the physicians (17%) were returned and analysed. Around 90%
and more of the respondents knew that early detection improves the
5-year survival rate. Almost two-thirds of all respondents correctly recognized that the floor of the mouth is one of two most commonly affected sites. The knowledge that the tongue is the second of the two most
commonly affected sites was recognized 45–70%. Twenty-one percent to
60% of the respondents knew that early cancer lesions usually appear
as small, painless red areas. However, only 27–57% (except dermatology
with 82%) correctly recognized that patients in early stage of oral cancer
are asymptomatic. The oral cancer knowledge with regard to signs and
symptoms showed interesting differences among the different responder groups.
Conclusions. Appropriate knowledge about signs and symptoms of oral
cancer is not only essential for dentists but also for several medical disciplines. Although the knowledge of different diagnostic items was almost sufficient, the responders were surprisingly unaware about the fact
that the early stage of oral cancer is almost symptom-free and discrete
in appearance. These results underline the development and implementation of specific advanced educational programmes for dentists and
the several medical disciplines.
0019
Die Rhinobasisrekonstruktion durch vital-autologen lokalen
sowie distalen Gewebetransfer
*T. Hoffmann1, P. Schuler1, O. Müller2, R. Hierner1, M. Wagenmann3, G. Lehnerdt1, U. Sure2, S. Lang1, D. Hänggi4, I.E. Sandalcioglu2
1
Universitätsklinik Essen, Hals-Nasen-Ohrenklinik, Essen, Deutschland,
2
Universitätsklinik Essen, Neurochirurgie, Essen, Deutschland, 3Universitätsklinik Düsseldorf, HNO, Düsseldorf, Deutschland, 4Universitätsklinik
Düsseldorf, Neurochirurgie, Düsseldorf, Deutschland
Die nach Tumorchirurgie oder Trauma eröffnete Rhinobasis bedarf
eines suffizienten Abschlusses um Rhinoliquorrhoe u./o. Hirngewebeprolaps zu verhindern. Das alleinige Einbringen von avitalem autologen, allogenem sowie xenogenem Material ist oft unzureichend und
verlangt unter Umständen nach einer zuverlässigen Versorgung mit
Hilfe eines vaskularisierten lokalen oder distalen Gewebetransfers.
Rhinobasisdefekte von insgesamt 41 Patienten wurden interdisziplinär
mit Hilfe von autologem Gewebetransfer gedeckt. Kleinere, nach endoskopisch endonasaler Chirurgie entstandene Defekte (n=23, hierunter
Meningeome, spontane Liquorfisteln, Chordom, Chondroblastom, Metastase, nasale Fistel) wurden durch lokale gefäßgestielte (A. sphenopalatina) Schleimhautlappen aus der unteren Muschel (3) oder dem Septum (20) gedeckt. Bei größeren Defekten [n=14, hierunter Malignome
(10), Meningoencephalozelen (2), Aneurysmatische Knochenzyste (1)]
wurde die Rhinobasis mit Hilfe eines Calvarian-Split und eines GaleaPeriost-Lappens in einer „Sandwich-Technik“ verschlossen. In einem
Fall wurde der Defekt mit Hilfe eines M. temporalis Lappens gedeckt.
In 4 Fällen (Trauma, Adenokarzinom) wurden nach mehrfachen, auswärts durchgeführten und frustran verlaufenen Deckungsversuchen
die Rhinobasis mit einem freien, gefäßanastomisierten und desepithelisierten Unterarmlappen revidiert. Alle 41 Fälle wurden in Hinblick auf
die Prävention/Behandlung einer Rhinoliquorrhoe und/oder Hirngewebeprolaps erfolgreich abgeschlossen. Die suffiziente Revision komplexer Rhinobasisdefekte gelingt unter Verwendung eines autologen
lokalen und im Extremfall auch distalen Gewebetransfers und bedarf
einer engen Kooperation zwischen den in der Kopf-Hals-Chirurgie tätigen Fachdisziplinen.
0023
Vollhauttransplantate für die temporäre und definitive Defektabdeckung im Rahmen der mikroskopisch kontrollierten Chirurgie bei bösartigen Geschwülsten der Gesichtshaut
*L. Tischendorf1
Praxis MKG-Chirurgie, Praxis, Halle, Deutschland
1
Einleitung. Die tumorfreie Absetzungsgrenze (R0-Resektion) ist der
prognostisch bedeutsamste Faktor für den Behandlungserfolg bei bösartigen Geschwülsten de Gesichtshaut. Ihre Bewertung ist mit hoher
Präzision mit den Methoden der mikroskopisch kontrollierten Chirurgie möglich- allerdings nur mittels definitiver formalinfixierter
histologischer Schnitte vor allem im basalen Bereich. In den aktuellen
Leitlinien wird folglich eine verzögerte Defektabdeckung empfohlen –
nämlich dann, wenn Gewissheit darüber besteht, dass alle Schnittränder tumorfrei sind. Eine verzögerte also zweizeitige Defektabdeckung
ist eine langwierige und für den Patienten belastende Prozedur. Um
diesem aus dem Weg zu gehen rekonstruieren wir bis zu mittelgroße
Defekte sofort mit freien Vollhauttransplantaten. Dies erlaubt eine einfache Revision im Fall einer nachgewiesenen R1-Resektion. Wenn das
ästhetische Ergebnis befriedigt, handelt es sich dabei um die definitive
Rekonstruktion. Andernfalls kann eine Korrektur zum Zeitpunkt der
Wahl erfolgen.
Material und Methode. Von September 1993 bis zum April 2010 wurden
nach mikroskopisch kontrollierter Exzision von 265 bösartigen Tumoren der Gesichtshaut die Defekte durch infraklavikuläre Vollhauttransplantate versorgt.
Resultate. Die ursprünglich temporäre Defektabdeckung mit den infraklavikulären Vollhauttransplantaten nach Resektionen der bösartigen Tumoren der Gesichthaut führt in 262 von 265 (99%) Fällen zu derart guten ästhetischen Ergebnissen, dass die Patienten eine mögliche
sekundäre Korrektur durch Nahlappen nicht mehr wünschten. Nur in
wenigen Fällen war eine sekundäre Korrektur notwendig. In den sehr
seltenen Fällen einer primären R1-Resektion (4 Fälle = 1,5%) konnten wir
problemlos eine dreidimensional orientierte Nachexzision ohne Notwendigkeit einer aufwendigen sekundären plastischen Rekonstruktion
ausführen. Alle Operationen erfolgten unter ambulanten Bedingungen.
Schlussfolgerung. Die Anwendung von infraklavikulären Vollhautransplantaten zum sofortigen Defektverschluss nach Entfernung bösartigen
Geschwülste der Gesichtshaut erlaubt bei mittlerer Ausdehnung eine
onkologisch sichere, in ästhetischer Hinsicht in der überwiegenden
Anzahl der Fälle befriedigende und zeitsparende operative Behandlung
unter ambulanten Bedingungen ohne die Nachteile einer verzögerten
chirurgischen Rekonstruktion.
0025
Expression of activated EGF-receptor and k-ras mutations in
carcinomas of the salivary glands
T. Schneider1, A. Strehl2, A. Rosenwald2, A. Kübler1, *U. Müller-Richter1
1
Universitätsklinikum Würzburg, Mund-, Kiefer- und Plastische Gesichtschirurgie, Würzburg, Deutschland, 2Universität Würzburg, Institut für
Pathologie, Würzburg, Deutschland
Background. The activated EGF-receptor has been proved as a prognostic as a prognostic aid and therapeutic target in many different tumours.
In this context k-ras plays a crucial role. Autonomous activation of the
EGFR pathway by a mutated k-ras would preclude treatments with
EGFR-antibodies. Aim of this study is to analyze EGF-receptor and kras status in salivary gland carcinomas.
Methods. 43 patients with carcinomas of the salivary glands were selected (24 males, 19 females). The chosen tumours included 23 adenoidcystic carcinomas, 17 mucoepidermoid carcinomas and 3 adenocarcinomas not otherwise specified (NOS). First, a molecular examination
of mutations by PCR and sequencing of the codons 12 and 13 of the k-ras
gene were performed. Second, the activated EGF-receptor was detected
by immunohistochemistry. The results were statistically correlated with
clinical parameters.
Results. None of the tested carcinomas showed mutations in codon 12 or
13 of the k-ras gene. The activated EGF-receptor was present in 79% of
the tumours. Statistically significant correlations (p>0.05) were found
for age and lymph node metastasis. A correlation of tumour stage and
EGFR-status was not found.
Conclusions. As we did not find any k-ras mutation in the tested tumours we can rule out an important role of it in salivary gland tumours.
The percentage of activated EGF-receptor was high. Unfortunately this
finding did not correspond to many clinical parameters. Additionally,
the high percentage of activated EGF-receptor seemingly facilitates a
treatment with EGFR-antibodies. This is in contradiction with clinical
results that did not yield any good results in patients treated with such
target drugs. Therefore, the role of the activated EGF-receptor in salivary gland tumours remains unclear.
0029
An open-label multicenter phase II study of Imatinib mesylate
(Glivecâ) treatment of patients with malignant peripheral nerve
sheath tumors
*J. Panse1, V.-F. von Mautner2, P. Reichardt3, T. Brümmendorf1, M. de Wit4
1
Universitätsklinukum Aachen, Aachen, Deutschland, 2Universitätsklinikum, Hamburg Eppendorf, Deutschland, 3Helios Klinikum, Bad Saarow,
Deutschland, 4Vivantes Klinikum Neukölln, Berlin, Deutschland
Introduction. Malignant peripheral nerve sheath tumors (MPNSTs) are
malignancies with poor prognosis, arising sporadically or in patients
with neurofibromatosis type 1 (NF1). In adult NF1 patients MPNSTs are
the main cause for mortality and therapeutic options are unsatisfying.
The only curative treatment is complete surgical resection with a wide
tumor free margin. MPNSTs exhibit individual variability in chemotherapeutic sensitivity. Radiotherapy and chemotherapy rarely result in
local control of the MPNST; they do not have major impact on survival.
Immunohistochemistry showed that PDGFRalpha is highly expressed
in the majority of MPNSTs, while few cases showed focal c-Kit expression. Interestingly, MPNSTs with PDGFRA amplification generally
also showed KIT amplification. In-vitro Imatinib treatment (10 µM) of
a PDGFRalpha expressing MPNST cell cultures resulted in more than
50% reduced cell proliferation after 48 hours, indicating that MPNST
treatment with Imatinib warrants further investigation.
Methods. A multicenter, single-stage, open label phase II trial was conducted to determine the efficacy and safety of Imatinib in patients with
local recurrent or metastatic MPNST who already had undergone surgery and had no further surgical treatment options. Patients (pts.) were
included in two subgroups based on the assumption that pts. with NF1
associated or sporadic MPNST might respond differently to treatment.
Each subgroup was planned to include 16 patients. The primary objective was the number of patients showing response defined as at least once
stable disease (SD) within 36 weeks according to RECIST after treatment with 400 mg Imatinib daily.
Results. The STI571BDE57 trial was started in 2006. While 32 patients in
total were planned to be included only 10 patients have been recruited (4
male and 6 female; median age 34; range 20–51) until April2009; based
on the slow recruitment rate the study was terminate d in 2009. Six of
the ten patients enrolled in the study showed at least once stable disease
during the course of the study, with a 95% confidence interval of (29.6–
90.4). Only one patient showed stable disease after 24 weeks. All patients
discontinued treatment due to unsatisfactory results. Imatinib was safe
and well tolerated; however, one patient experienced a facial paresis.
Conclusion. While protein expression in MPNST suggested a potential
treatment benefit in selected MPNST patients, our results did not show
a significant clinical impact. However, given the low toxicity profile of
STI571BDE57 and the fact that 6/10 patients showed disease stabilization, imatinib therapy may still be considered in selected patients in addition to other treatment modalities or in combination with therapies
targeting other over expressed proteins such as somatostatin.
0038
The role of imaging in modern cancer research
*B. Walter1
1
LMU München, Institut für klinische Radiologie in der Chirurgischen Klinik,
Background. The modern pharmaceutical research mainly bases on the
development of substrates triggering special tissue structures by causing certain effects. The evaluation of efficacy and innocuousness occur
in several phases. Only a few active ingredients are finally suitable for
the marketing approval. Highest priority therefore has the establishment of new procedures to improve risk assessment and predictability.
Material. The integration of functional imaging in the early phases of
pharmaceutical development enables the application of radio-labelled
Abstracts
agents to show localization and distribution pattern of pharmaceutical
effects by computer-assisted analyses as well as the assessment of the
saturation levels of the target receptors
Results. The calculation of distribution and concentration of the substances used in correlation with measured metabolites and proper clinical parameters results into a standardized profile of dose and efficacy.
Risks and benefits can be more objectively evaluated so that the number
of probands and costs can be reduced significantly.
Conclusions. Until now preferentially nuclear medicine diagnostics
have been applied. Other radiologic procedures with tracer technique
are necessary to be established. The future way of pharmaceutical research continues to rest upon antibody applications and on concepts
named “personalized medicine”. The latter comprises recent therapeutic approaches by which individual cells are extracorporally treated and
reinfused. Illustrations in vivo of efficacy by imaging technique would
support these developments in marketing approval, and therapy-monitoring.
0056
Specific activity of substanceP radiolabeled with bismuth-213
plays a critical role in targeted alpha-therapy in the treatment of
glioblastoma
*C. Friesen1, I. Hormann1, M. Roscher1, O. Leib2, S. Marx2, J. Moreno2, E. Miltner1
1
Technologies Garching GmbH (ITG), Garching, Deutschland
Aim. Targeted alpha-therapy using substanceP radiolabeled with the
alpha-particle bismuth-213 ([Bi-213]SubP) is a promising treatment approach for glioblastoma. Different specific activities are used during
radioimmunotherapy of high risk leukemia and lymphoma. However,
the effect on cell killing using different specific activities at radiopeptidetherapy was not examined. In the present study we analyzed the effect
of different specific activities (MBq/µg substanceP) on cell death induction and activation of apoptosis pathways in glioblastoma cells using
[Bi-213]SubP.
Methods. The glioblastoma cell line T98G was treated with 2000, 1000
and 500 kBq/mL of [Bi-213]SubP using different specific activities (40,
20 and 5 MBq/µg substanceP). 24, 48, 72 and 96 h after treatment induction of cell death, induction of apoptosis, cell cycle, caspase activation
and activation of apoptosis pathways were determined using flowcytometry and Western Blot analyses.
Results. Our results demonstrate that specific activities of substanceP
radiolabeled with Bi-213 play a critical role in induction of cell death,
apoptosis and in activation of deficient apoptosis pathways in glioblastoma cells. The efficacy of cell death induction depends on both dose
and specific activity. At a specific activity of 40 MBq/µg substanceP, it
was possible to induce high rates of apoptotic cell death in glioblastoma
cells also at a very low activity concentration (500 kBq/mL) of [Bi-213]
SubP after 96 h. In addition, decreasing the specific activity of [Bi-213]
SubP to 5 MBq/µg substanceP only a low percentage of glioblastoma
cells could be killed. Similar results were also found after examination
of the effect of different specific activities of [Bi-213]SubP in activation
of apoptosis pathway at comparable concentrations. Only at a specific
activity of 40 MBq/µg and a specific activity of 20 MBq/µg substanceP
a strong activation of caspases and PARP cleavage were found. Reactivation of deficient apoptosis pathway was strongly decreased at lower
specific activities.
Conclusions. Our findings suggest that not only the activity concentrations of substanceP radiolabeled with Bi-213 play an important role in killing glioblastoma cells and in activation of apoptosis pathways but also
the specific activities meaning the amount of radionuclides per peptide
are crucial. These findings have important implications for glioblastoma therapies using radiolabeled substanceP with Bi-213 during targeted
alpha-therapy.
0057
Deficient apoptosis induction and caspases activation can be
reversed in glioblastoma-initiating stem cells as well as primary
human glioblastoma cells by targeted alpha-therapy using [Bi213]SubstanceP
*C. Friesen1, I. Hormann1, M. Roscher1, J. Moreno2, S. Marx2, O. Leib2, L. Nonnenmacher3, K.-M. Debatin3, E. Miltner1
1
Technologies Garching GmbH (ITG), Garching, Deutschland, 3Children‘s
Hospital, University Ulm, Ulm, Deutschland
Aim. Glioblastomas are the most malignant type of brain tumors. Because glioblastoma and in particular the high tumorigenic glioblastoma-initiating-stem cells are resistant to conventional therapies,
glioblastomas are untreatable. Novel strategies are needed to improve
therapeutic success. Targeted alpha-therapy using the alpha-emitter Bi213 seems to be a promising approach for killing tumor cells. Glioblastomas and glioblastoma-initiating-stem cells overexpress neurokinin-1receptors, the binding site for Bi-213 labelled substanceP ([Bi-213]SubP).
In our studies, we tested the cell death inducing potential of [Bi-213]
SubP and clarified the molecular pathways of apoptosis induction by
[Bi-213]SubP in primary glioblastoma cells and glioblastoma-initiating
stem cells.
Materials and methods. Primary human glioblastoma cells and glioblastoma-initiating-stem cells were treated with a range of activities (3000–
500 kBq/mL) [Bi-213]SubP. At different time points after irradiation cell
death induction was measured by flowcytometry. Involvement of apoptotic pathways was assessed by Western-Blot-analyses.
Results. We found that [Bi-213]SubP induced a strong apoptotic cell
death in primary glioblastoma cells as well as in the highly resistant
glioblastoma-initiating-stem cells overexpressing neurokinin-1-receptors. In the highly resistant glioblastoma-initiating-stem cells, [Bi-213]
SubP reversed deficient activation of caspases, cleavage of PARP and
restored activation of the apoptotic mitochondrial pathway. In addition,
downregulation of the death inhibitory protein Bcl-xL and the strong
caspase inhibitor XIAP, both contributing to glioblastomas’ resistance,
was provoked by [Bi-213]SubP in the highly resistant glioblastoma-initiating-stem cells comparable to primary glioblastoma cells.
Conclusions. Our findings demonstrate that [Bi-213]SubP is a promising
strategy to break radio-and chemoresistance in primary glioblastoma
cells and to kill the extremely resistant glioblastoma-initiating-stem
cells efficiently by reversing deficient activation of caspases and downregulation of XIAP and Bcl-xL. [Bi-213]SubP seems to improve therapeutic success in glioblastoma by targeting and killing glioblastomainitiating stem cells.
Supported by Deutsche Forschungsgemeinschaft (DFG).
0062
The prognostic value of molecules of the HIF 1 alpha – and
TGF beta 1 pathway crosstalk in patients with oral squamous cell
carcinoma
*C.K. Müller1, M. Mtsariashvilli1, S. Schultze-Mosgau1
1
Universitätsklinikum Jena, Klinik und Poliklinik für Mund-, Kiefer- und Gesichtschirurgie/Plastische Chirurgie, Jena, Deutschland
Background and aim. Despite improvements in diagnosis and treatment
of patients with oral squamous cell carcinoma survival rates have not
changed significantly over the past years. Molecular markers might
provide an additional tool for evaluation of the patients’ prognosis. Hypoxia Inducible Factor (HIF) 1 alpha as well as Transforming Growth
Factor (TGF) beta 1 were investigated extensively as prognostic markers
with conflicting results. Taking this into account the present study was
conducted to investigate a correlation between the activity of markers
at the HIF 1 alpha/ TGF beta 1 pathway crosstalk and tumor prognosis.
Materials and methods. Biopsies from the tumor margin were harvested
in 50 patients with histologically confirmed squamous cell carcinoma
of the oral cavity at the time of tumor resection. Biopsies were subjected
to immunohistochemical staining for TGF beta 1, HIF 1 alpha as well as
the transcription factor Sp1. Staining intensity was evaluated histomorphometrically. A multivariate statistical approach was chosen to verify
the correlation between marker expression and disease free survival.
Results. Median disease free survival was found to be 31 months. HIF1
alpha + (p=0.023), TGFbeta1 + (p=0,019) as well as Sp1 + (p=0.022) tumor patients showed significantly reduced disease free survival in the
bivariate testing. Using the multivariate approach only combined HIF1
alpha+, TGF beta 1+ and Sp1+ tumor patients showed significantly reduced disease free survival (p=0.043).
Conclusion. Patients with combined HIF 1 alpha+, TGF beta 1+ as well
as Sp1+ tumors showed significantly reduced disease free survival in
the investigated patients collective. Investigation of prognostic markers
located at molecular pathway crosstalks might improve sensitivity and
specifity of prognostic markers.
0063
D,L-Methadone sensitizes glioblastoma-initiating stem cells and
primary glioblastoma cells for doxorubicin treatment ex vivo
*C. Friesen1, I. Hormann1, M. Roscher1, L. Nonnenmacher2, K.-M. Debatin2,
E. Miltner1
1
Institute of Legal Medicine, University Ulm, Ulm, Deutschland, 2Childrens’
Hospital, University Ulm, Ulm, Deutschland
Aim. Glioblastomas are highly malignant primary brain tumors with one
of the worst survival rates among all human cancers, because glioblastoma cells are extremely resistant to conventional therapies. After surgery
or radiotherapy glioblastomas recur in focal masses. This recurrence is
linked to glioblastoma-initiating stem cells, a high tumorigenic subpopulation, which could not be killed. Thus, novel therapeutic strategies
are needed to break resistance by targeting glioblastoma cells as well as
glioblastoma-initiating stem. The synthetic opioid D,L-methadone is effectively used in substitution and pain therapy and it can kill leukemia
cells. In our studies, we analyzed the effect of D,L-methadone alone and
D,L-methadone in addition to doxorubicin on glioblastoma-initiating
stem cells in comparison to primary human glioblastoma cells.
Materials and methods. Primary glioblastoma cells isolated from human specimen and glioblastoma-initiating-stem cells were treated with
different therapeutic concentrations of D,L-methadone alone or in addition to therapeutic concentrations of doxorubicin using as Caelyx®
in glioblastoma treatment. After different time points, cell death was
measured by flowcytometry and activation of apoptosis pathways was
analyzed by Western Blot analyses.
Results. We found that D,L-methadone sensitizes primary glioblastoma cells as well as the highly resistant glioblastoma-initiating stem cells
for doxorubicin-induced cell death and reverses deficient activation of
apoptosis pathways. Therapeutic concentrations of D,L-methadone in
addition to doxorubicin induced a strong apoptotic cell death in primary glioblastoma cells as well as in the extremely resistant glioblastoma-initiating stem cells. In addition, D,L-methadone reversed deficient
caspases activation and cleavage of PARP by doxorubicin. The strong
inhibitor of apoptosis XIAP, playing a crucial role in glioblastomas’ resistance was inactivated by cotreatment with D,L-methadone and doxorubicin. Futhermore, D,L-methadone provoked downregulation of the
antiapoptotic protein Bcl-xL by doxorubicin in primary glioblastoma
cells and glioblastoma-initiating stem cells.
Conclusions. Our findings suggest that D,L-methadone in addition to
doxorubicin kills the highly resistant glioblastoma-initiating stem cells
similar to the primary glioblastoma cell. D,L-methadone seems to be a
promising strategy to enhance doxorubicin-sensitivity in glioblastoma
therapy.
Supported by Deutsche Krebshilfe.
0068
Group-specific therapy comparison of the quality of life in patients with head and neck cancer
*C. Zaldivar Wither1, K. Bikowski2, K. Freier1, C. Hofele1, J. Hoffmann1
1
Universitätsklinik Heidelberg, MKG-Chirurgie, Heidelberg, Deutschland,
2
Nationales Centrum für Tumorerkrankungen Heidelberg, Medizinische
Onkologie, Heidelberg, Deutschland
Background. Head and neck cancer treatment is associated with loss of
quality of life independent from treatment modality. We investigated
the influence of treatment surgical vs. conservative treatment (RC/Neoadjuvant/Adjuvant) in regard to quality of life of patients during different stages of therapy.
Method. In an observational study, 57 patients of the Clinic of Oral and
Maxillofacial Surgery Heidelberg of all stages were enrolled (2007–
2010). We evaluated the quality of life before treatment, immediately
after the primary therapy, after three, six and twelve months. The survey
of quality of life was established by the EORTC QLQ-C30 and EORTC
H&N35.
Results. “Global Health Status improved in both treatment arms
(p=0.038) from 3th month to one year after treatment. Physical functioning” was 3 months after primary treatment lower in the conservative
treatment group, but this changed completely after 12 months, the value
has deteriorated significantly in the surgical arm. Regarding the Pain,
surgical patients suffer significantly more after 3 months (34.4–28.07)
but from the 3rd month on they suffer less than other forms of therapy
(p=0.011). After 12 months we evaluated better quality of life in Swallowing, Speech and Felt ill in patients after surgery (p=0.011, p=0.021,
p=0.003 respectively). We found a pronounced deterioration in mouth
opening and dry mouth after conservative therapy, after 6 (p=0.007)
and 3 months (p=0.04).
Conclusions. The aspect of quality of life gains increasing attention in
addition to the quantity of life in the discussion about the treatment
of tumors in the head and neck region. Patients undergoing a primary
surgery suffer considerably loss-of-function after 6 months, but have
superior coping in the study period than other forms of therapy. In order to measure long-term results and to exclude acute adverse effects,
a study in the course of time points after 12 or 18 months is reasonable.
0069
TGFbeta activates NF-kappaB signaling through a TAK1-dependent mechanism in head and neck cancer
*C. Freudlsperger1,2, Y. Bian2, J. Hoffmann1, Z. Chen2, C. Van Waes2
1
Universitätsklinikum Heidelberg, Mund-. Kiefer- und Gesichtschirurgie,
Heidelberg, Deutschland, 2NIH, NIDCD, Bethesda, USA
TGFbeta signaling in epithelial malignancies, including head and
neck squamous cell carcinoma (HNSCC), is complex. Inactivation of
TGFbeta signaling promotes the de novo development of epithelial
cancer, while the activation of attenuated but residual TGFbeta signaling in established cancer clearly favors the progression to a more invasive and metastatic phenotype. The mechanism responsible for these
double-edged effects of TGFbeta signaling in oncogenesis is less well
characterized. Since aberrant activation of transcription factor Nuclear Factor-kappaB (NF-kappaB) promotes the malignant phenotype
similar to TGFbeta mediated effects in late staged tumors, we hypothesized that TGFbeta signaling in tumor promotion could be mediated
through the cross-activation of NF-kappaB pathway. Here, we show
that TGFbeta-1 treatment induced phosphorylation and activation
of IKK, leading to phosphorylation of IkappaBalpha, the inhibitor of
NF-kappaB, and subsequential NF-kappaB activation in HNSCC lines. TGFbeta-1 and TNFalpha induced NF-kappaB activation was
mediated through TGFbeta-activated kinase 1 (TAK1), since knocking
down of TAK1 using siRNA decreased both TGFbeta-1 and TNFalpha
induced NF-kappaB-dependent reporter gene activity. Furthermore,
Abstracts
TAK1 knockdown decreased degradation of IkappaBalpha and promoted nuclear translocation and binding activity of the transactivating NF-kappaB subunit p65 (RELA). Consequently, transcription of
NF-kappaB downstream genes was attenuated. Conversely, transient
overexpression of TAK1 increased basal, TGFbeta-1 and TNFalpha
induced NF-kappaB reporter gene activity. Futhermore, Celastrol, an
herb extract from Tripterygium wilfordii used in the traditional Chinese medicine for decades because of its immunosuppressive properties,
decreased TGFbeta-1 induced phosphorylation of TAK1 and p65, and
suppressed basal, TGFbeta-1 and TNFalpha induced NF-kappaB reporter gene activity. In addition, Celastrol reduced cell growth as measured
by XTT assay (IC50=1.2–1.3 µM) and increased sub-G0 DNA fragmentation indicating induction of apoptosis.
In conclusion, we identified a cross-talk between TGFbeta and NF-kappaB pathways, where TGFb signaling leads to NF-kappaB activation
through a sequential activation of TAK1 and IKK activities, and promotes malignant phenotype of HNSCC. With Celastrol being a potent suppressor of TAK1 mediated NF-kappaB activation; we present a potential
therapeutic strategy targeting this alternative TGFbeta pathway.
0087
The versatility of the antero-lateral thigh flap (ALT) in the reconstruction of oral and maxillofacial defects after ablative tumor
surgery
*K. Freier1, J. Bodem1, M. Engel1, J. Hoffmann1
1
Universitätsklinikum Heidelberg, Klinik und Poliklinik für Mund-, Kieferund Gesichtschirurgie, Heidelberg, Deutschland
The anterolateral thigh flap (ALT) is pedicled on septocutaneous or musculocutaneous perforators of the descending branch of the lateral circumflex femoral artery. Due to its extraordinary versatility and low donor site morbidity it has gained increasing popularity in the treatment
of oral and maxillo-facial defects after ablative tumor surgery in the last
decade. The anterolateral thigh flap allows the generation of subcutaneous, fasciocutaneous, myocutaneous, or adipofascial flap, which has
made it to a work-horse in reconstructive maxillo-facial surgery. The
aim of the present retrospective analyses of a collection of n=135 cases,
which were treated in two highly specialized institutions for craniomaxillo-facial surgery, was to illustrate the intriguing applications of
the ALT flap as well as the clinical robustness and excellent functional
outcome of this approach. The overall flap failure rate was low in this
patient series (13/135) and comparable to other free flaps utilized in the
head and neck area like the radial forearm flap. It was successfully used
for reconstruction in case of oral cavity, oropharynx, external skin and
maxilla defects after ablative tumor surgery. For more bulky reconstructions after total parotidectomy or skull base surgery, a muscle component was frequently harvested and transferred additionally. When
a thinner, more pliable flap was required for the reconstruction of the
floor of the mouth, suprafascial anterolateral thigh flaps were raised or
the flaps were thinned after harvesting. In conclusion, the anterolateral
thigh flap is a highly versatile and reliable flap for use in the reconstruction of various soft tissue defects of the head and neck area. This flap
has gained great popularity given its versatility, ability for a two-team
approach, and minimal donor site morbidity.
0112
The determination of urokinase plasminogen activator (uPA) and
plasminogen activator inhibitor 1 (PAI-1) based on immunohistochemistry and semiquantitative image analysis represent a
potential alternative to the quantitative ELISA method
*D.S. Lang1, U. Heilenkötter2, W. Schumm3, B. Lie4, O. Behrens5, R. Simon6,
E. Vollmer1, T. Goldmann1
1
Forschungszentrum Borstel, Klin. & Exp. Pathologie, Borstel, Deutschland, 2Klinikum Itzehoe, Frauenklinik, Itzehoe, Deutschland, 3Krankenhaus
Rendsburg, Pathologie, Rendsburg, Deutschland, 4Paracelsus Klinik Henstedt-Ulzburg, Frauenklinik, Henstedt-Ulzburg, Deutschland, 5Krankenhaus
Rendsburg, Frauenklinik, Rendsburg, Deutschland, 6UKE HH-Eppendorf,
Pathologie, Hamburg, Deutschland
Aim. During the last few years, the tumor associated proteolytic factors
urokinase Plasminogen-Activator (uPA) und plasminogen activator inhibitor 1 (PAI-1) have gained clinical significance as invasion markers
with both predictive and prognostic potential for individual treatment
regimens of patients with breast cancer. A commercially available ELISA test as the only validated method for routine determination is laborious with the need of considerable amounts of fresh, shock frozen material. Therefore, this study was aimed at the establishment of a reliable
alternative method suitable for routine procedures based on immunohistochemistry (IHC) and image analysis to overcome these drawbacks.
Materials and methods. Tissue samples of primary ductal invasive breast
cancer were treated with the alternative HOPE (Hepes-glutamic acid
buffer mediated Organic solvent Protection Effect) fixation and paraffin-embedding method that does not require antigen retrieval. For enhanced comparability, the specimens were arranged on tissue microarrays (TMA) and stained with the respective specific primary antibodies
(mouse anti-human uPA, DCS, Hamburg; goat anti-human PAI-1, Morphosys, Düsseldorf). The intensity of the cytoplasmic staining patterns
of both proteins was measured at the tumor front by adapted semiquantitative image analyzing.
Results. There was a statistically significant correlation between the semiquantitative data based on IHC for uPA and PAI-1 (uPA n=67; PAI-1
n=27) and the corresponding quantitative ELISA results with p=0.011
and p=0.029, respectively. Analogous to the ELISA method, a cut off
value of >115 was obtained for the semiquantitative uPA results (χ2-test,
two-tailed p=0.032).
Conclusion. These first results strongly suggest that an optimized IHC
protocol combined with a matched image analysis can provide a reliable alternative method for the commercial ELISA test. The validation
of these experimental results will be achieved by incorporating the relevant clinical data of the corresponding patients examined in this ongoing study conducted in collaboration with the Holsteinisches Brustzentrum.
0116
Classification of human mucosa by in-vivo hyperspectral imaging
*A. Gerstner1, W. Laffers1, R. Martin2, B. Thies2
1
Universitätsklinikum Bonn, Klinik für HNO-Heilkunde/Chirurgie, Bonn,
Deutschland, 2Universität Marburg, Geographische Fakultät, Marburg,
Deutschland
Aim. To give proof of principle for the applicability of hyperspectral
imaging for the analysis and classification of human mucosal surfaces
in vivo.
Material and methods. The larynx as a well-defined anatomical region
was chosen as a prototypical surgical test area. The standard intra-operative setting for microlaryngoscopies was modified by using a polychromatic light source and a synchronous triggered monochromatic
CCD-camera. Image stacks were analyzed by established software tools
for principal component analysis and unsupervised hyperspectral classification.
Results. Sequential illumination of the same field of view by stepwise
increasing wavelengths (390–680 nm, with 10 nm steps) yielded a hyperspectral image datacube of the mucosa. These lambda-image stacks
could be analyzed and classified by commercially available software. In
principal component analysis, images at 590–680 nm loaded most onto
the first principal component. Typically, the first principal component
contained 95% of the total information. Unsupervised hyperspectral
classification clustered the data thus highlighting areas of altered mucosa.
Conclusion. The technology of hyperspectral imaging can be applied to
mucosal surfaces. This approach opens the way to analyze spectral characteristics of histologically different lesions in order to build up a spectral library and to allow non-touch classification of mucosal changes.
0135
Paraoxonase-2 (PON-2) expression in four head and neck
carcinoma cell lines as potential predictor of resistance against
radiotherapy – a pilot study
*M. Krüger1, M. Moergel1, B. Al-Nawas1, S. Horke2
1
Universitätsmedizin Mainz, Klinik und Poliklinik für Mund- Kiefer- und
Gesichtschirurgie, Mainz, Deutschland, 2Universitätsmedizin Mainz, Institut
für Pharmakologie, Mainz, Deutschland
Background. Apoptosis induction is a key mechanism of radio- and
chemotherapy. Unfortunately, carcinomas often present altered protein expression which leads to upregulation of antiapoptotic proteins.
It is known, that changes in redox-potential of tumors have critical
influence on the intrinsic apoptotic pathway. Recent studies showed a
protective effect against ROS (reactive oxygen species) for cells of the
vascular system by Paraoxonase-2 (PON-2). In vascular cells PON-2 is
mainly localized to nuclear lamina, endoplasmatic reticulum (ER) and
mitochondria, with potential to prevent endothelial cells to undergo
mitochondrial induced apoptosis. Since irradiation typically induces
elevated levels of ROS and subsequent oxidative damage in nucleus,
mitochondria and ER, elevated expression of PON-2 could also protect
squamous cell carcinoma against oxidative stress. The present study is
the first to examine expression pattern and potential functional influence of PON-2 in squamous cell carcinoma of the head and neck.
Methods. Therefore, the basal PON-2 expression was determined in vitro in four squamous cell carcinoma cell lines by western blot analysis.
Further visualisation of PON-2 utilized immunfluorescence staining.
We also examined induction of PON-2 protein expression after singular
radiation with 7 Gray 24, 48 and 72 hours after irradiation. Simultaneously, activity of caspase 3/7 was examined for apoptosis detection.
Finally expression of PON-2 was tested in 5 patients with oral carcinoma within tumor tissue compared to normal mucosa.
Results. The present study revealed regular expression of PON-2 in
carcinoma of the head and neck region for the first time. Furthermore,
the basal PON-2 expression pattern varies in different individuals. We
found that irradiation leads to a general upregulation of PON-2 expression. Intriguingly, higher basal levels of PON-2 seem to protect cells
against radiation-induced apoptosis.
Discussion. The pilot study showed regular but variable expression of
PON-2 in head and neck carcinoma. Furthermore, the in vitro model
revealed elevated levels of PON-2 in head and neck carcinoma possibly
protect the tumor against radiation-induced apoptosis. Thus, characterization of PON-2 expression might serve as clinical prediction marker
for irradiation response and patient outcome. Since the distinct molecular mechanism remains still unclear, further experiments are needed
to unveil the biological role of PON-2 in squamous cell carcinoma of the
head and neck region.
0137
The migration of cultured glioblastoma cells is enhanced in
response to radio therapy
*T. Abeln1, A. Kochanneck1, K. Polz2, C. Demirel2, H. Bühler1, I. Adamietz2
1
Marienhospital, Klinikum der Ruhr-Universität Bochum, Institut für
Molekulare Onkologie, Strahlenbiologie und Experimentelle Strahlentherapie, Herne, Deutschland, 2Marienhospital, Klinikum der Ruhr-Universität Bochum, Klinik für Strahlentherapie und Radio-Onkologie, Herne,
Deutschland
Background. Glioblastoma multiforme is a very aggressive tumor with
an unfavorable prognosis for the patient. It is characterized by early recurrences frequently adjacent to the primary tumor. One reason, widely overlooked so far, might be based on the motility and migratory
potential of the tumor cells. Low dose radiation in the penumbra of an
irradiated volume might enhance the motility of the cells enabling them
to escape the ionizing radiation. We, therefore, have analyzed whether
or not low dose irradiation enhances the migration of cultivated glioblastoma cells.
Methods. U343 or U87 cells were irradiated with 1.7 MeV electrons or
with photons from a 15 MeV linear accelerator. For beta irradiation cells
were placed as central spot in a culture dish on a 32P-activated foil and
irradiated with 10×2 Gy. Subsequently the cells were stained with crystal
violet to evaluate number and distance of satellite colonies. Cells irradiated with 4×2 Gy photons were placed in an environmental chamber and observed by time laps videography over a period of 5 days. The
image stacks were analyzed with ImageJ as to distance and velocity of
the cells.
Results. In response to beta irradiation, the number of colonies increased from 33 (control) to 102 (irradiated). In addition the mean distance of the colonies to the central spot was significantly higher for the
irradiated cells. The videographic analysis of the cells irradiated with
photons revealed an increase in velocity that peaked at +80% 2 days after
irradiation.
Conclusion. The hypothesis of induced cellular migration in response
to therapeutic irradiation is supported by our data. This effect might
contribute to the poor prognosis of glioblastoma patients and has to be
elucidated in further studies. There might be promising implications for
new radio-chemotherapies e.g. with inhibitors of the focal adhesion kinase, a central point of cellular migration.
0156
A monocenter evaluation of the frequency of malignant tumours
in the head and neck area
*O. Thiele1, R. Seeberger1, J. Hoffmann1, K. Freier1
1
Universitätsklinik Heidelberg, Mund-, Kiefer-, Gesichtschirurgie, Heidelberg, Deutschland
Introduction. In this study, we analysed how many patients were diagnosed with a malignant tumour in the head and neck area in our
department of oral and maxillofacial surgery over a 20-year period
(1989–2008). The aim of this study was to evaluate the distribution and
frequency of different malignant diseases in our field.
Results. 2277 patients with a malignant tumour were included. We found
49 different histological diagnoses in this group. Overall, we found the
squamous cell carcinoma to be the most frequent histological diagnosis (n=1903). Salivary gland tumours were the second entity (n=121),
followed by basal cell carcinoma (n=117), sarcomas (n=62) and distant
metastases to the head and neck (n=55), respectively. These subgroups
consist of a broad variety of different histological entities. They must
be very well defined by the pathologist because treatment strategies are
different and depend upon the histological diagnosis. For example, the
subgroup of the distant metastases consisted of 10 different histologies,
the sarcoma subgroup consisted of 12 different histological entities. A
“top 10 list” of the histological diagnoses would include squamous cell
Abstracts
carcinoma, basal cell carcinoma, adenoid cystic carcinoma, malignant
lymphoma, malignant melanoma, mucoepidermoid carcinoma, adeno
carcinoma, osteosarcoma, rhabdomyosarcoma, cup- syndrome and
plasmocytoma (in descending order of frequency).
Conclusion. These results could be the basis for a standardised oncological training of young doctors and surgeons. Especially for the rare tumours, an interdisciplinary treatment is often necessary.
0162
Functional characterization connects individual patients’ mutations in ataxia telangiectasia mutated (ATM) with dysfunction of
specific DNA double-strand break repair signalling pathways
M. Keimling1, M. Volcic1, A. Csernok1, B. Wieland2, T. Dörk2, *L. Wiesmüller1
1
Universität Ulm, Universitätsfrauenklinik, Ulm, Deutschland, 2Medizinische
Hochschule Hannover, Frauenklinik im Forschungszentrum, Hannover,
Deutschland
ATM has multiple functions in homologous recombination (HR) and
non-homologous end-joining (NHEJ), which lead to conflicting data
regarding its DNA-double-strand-break-repair (DSBR) functions in
previous studies. To explore the effect of clinically relevant ATM mutations, we characterized DSBR between mutated EGFP genes and ATM
kinase signalling in 9 lymphoblastoid cell lines (LCLs) derived from
Ataxia telangiectasia (AT) patients with defined versus 3 control LCLs
without ATM mutations. Our study revealed that the DSBR phenotype in AT cells is not uniform, but appears to depend on the mutation
causing up to 32-fold increased or up to 3-fold decreased activities in
particular pathways. Comparison with a further 10 LCLs mutated in
downstream factors (BRCA1, BRCA2, Nibrin, Rad50, Chk2) showed
that the most diametrically opposed DSBR patterns in AT cells phenocopied NBN/RAD50 or BRCA1 mutations. Importantly, re-expressing
wild-type ATM reversed these defects by 2.3- to 3.5-fold. Our data suggest that ATM stimulates repair proteins like Nibrin, which execute HR,
single-strand annealing (SSA), and NHEJ. Concomitantly ATM minimizes error-prone repair (SSA, NHEJ) through activation of surveillance factors like BRCA1. Since the outcome of the individual defect can be
diametrically opposed, distinguishing repair patterns in patients with
ATM mutations may also be relevant regarding therapeutic responses.
0210
Targeting of cancer-associated fibroblasts for integrative tumor
therapy
*C. Monasterio1, D. Jäger1, C. Renner2, S. Bauer1, V. Teichgräber1
1
Nationales Centrum für Tumorerkrankungen, Medizinische Onkologie,
Heidelberg, Deutschland, 2Universitätsspital Zürich, Klinik und Poliklinik für
Onkologie, Zürich, Schweiz
Solid tumors modulate their environment to keep non-malignant stromal cells in a tumor-promoting state. Recent studies have revealed that
the extrinsic cues provided by these stromal cells are essential for tumor cells to even manifest a fully transformed phenotype, angiogenesis
and metastasis. Delineation of these cues and their underlying cellular
and molecular pathways offers the opportunity of a new era of integrative cancer therapy based on combinatorial drug regiments that act
synergistically to destroy the tumors by targeting both, the intrinsic
and extrinsic oncogenic pathways. The main cells in the stroma of epithelial derived tumors are cancer-associated fibroblasts (CAF) that are
critical to tumorigenesis and angiogenesis. CAFs also supply the tumor
cells with growth factors and extracellular matrix (ECM) degrading
enzymes. They are thus essential for tumor initiation as well as tumor
progression and metastasis, suggesting that they represent an ideal
cellular target of an integrative tumor therapy. Fibroblast activation
Protein (FAP) is a well defined marker, expressed at high levels at the
cell surface of CAFs. FAP, a constitutively active serine peptidase with
both dipeptidyl peptidase IV (DPIV) and collagenase activity, promotes malignant and invasive behaviour of epithelial cancers and stromal
expression levels correlate with worse prognosis. Normal adult tissue
lacks FAP expression. In our experiments, we aimed for a reduction of
the pro-tumorigenic activities of CAFs by downregulating FAP expression. The decrease of FAP at the CAF surface is achieved by two different
ways: FAP internalisation using a specific antibody or FAP gene silencing by transfecting CAFs with small interfering RNA (siRNA). The
anti-FAP IgG antibody ESC11 is cross-reactive for mouse and human
FAP and binds to FAP at low nanomolar affinities. Regarding migration
and invasion, the antibody converted a FAP-positive cellular phenotype
into a negative one. Hence, the antibody is capable of reversing the FAP
mediated migratory and invasive capacity. FAP RNA interference was
equally effective when compared to the antibody. Thus, targeting FAP
on CAF suppresses pro-tumorigenic activities and may result in a reduction of tumor progression and dissemination.
0213
Non-thermal irreversible electroporation (NTIRE): a novel cancer
therapy
*J.J. Wendler1, M. Porsch1, M. Pech2, M. Schostak1, J. Ricke2, U.-B. Liehr1
1
University of Magdeburg, Department of Urology and Paediatric Urology,
Magdeburg, Deutschland, 2University of Magdeburg, Department of
Radiology and Nuclear Medicine, Magdeburg, Deutschland
Purpose. Typical features, current experimental knowledge and first clinical results of non-thermal irreversible electroporation (NTIRE) as a
novel cancer therapy are presented. Future aspects of using NTIRE in
oncology are discussed.
Methods. NTIRE is a new localized soft-tissue ablation technology that
applies high-voltage and high-current electrical pulses on a microsecond timescale with inserted needle-like electrodes. NTIRE just alters
in vivo cells on a molecular level via induced high-electric field transmembrane voltage that causes an electrical breakdown of the dielectric
lipid bilayer. This leads to a generation of nanometer sized pores with
irreversible permeabilization of the cell membrane that ends in the loss
of cell homeostasis and a delayed apoptosis within approximately 4 (±3)
days. This new electrical, non-thermal technique does not alter the extracellular matrix and does not cause protein denaturation that is usually associated with other current ablation methods. Hence, anatomical
borders as well as the organ integrity in the NTIRE ablation zone are
safe. Since the 60s, NTIRE is used commercially as a bactericidal method in the food industry. Its use as an ablative method in the context of
medical applications was not studied until the early 2000s.
Results. Recent studies have shown the multidisciplinary potential in
oncologic therapy. Previous experimental studies in animal models
investigated the effect of NTIRE in liver, kidney, lung, prostate, heart,
pancreas, brain, dermis, breast and muscle. Hereby, it could be demonstrated that NTIRE leads to a localized complete decellularization whereby the tissue matrix stays unaltered. Moreover, in the ablation zone located structures such as blood vessels, nerves, exocrine glandular ducts,
urethra, ureter, renal calyxes and pelvis were spared out and showed
regeneration. Thus, the organ function can be preserved. The first clinical results of human phase-I studies showed the safety and the potential
of NTIRE in the ablation of renal cell cancer, hepatocellular cancer and
metastases from different entities.
Conclusions. NTIRE is a new soft-tissue ablation technology that offers
minimal-invasive, locally targeted cancer therapy. It seems to be superior to current thermal ablation techniques and is a therapeutic alternative in inoperable cases with curative treatment intention. Further
human studies are warranted to determine NTIRE ablation efficacy of
this novel technology in different cancers.
0235
Evaluation und Quantifizierung der Tumorperfusion von hyperarterialisierten Tumoren unter Nutzung der neuen computertomographischen 4D-Volumenperfusion(VPCT)-Technik
*M. Horger1, M. Schulze1
1
Eberhard-Karls-Universität Tübingen, Radiologie, Tübingen, Deutschland
Ziel. Vergleich von Perfusionsparametern folgender maligner Tumoren:
Sarkome, gastrointestinale Stroma-Tumoren (GIST), neuroendokrine
Tumoren (NET) und Nierenzellkarzinome (RCC) mithilfe der VPCT
zwecks Differenzierung und Charakterisierung (angiogenetische Signatur).
Material und Methodik. Alle Tumoren wurden histologisch gesichert und
keiner war bereits anbehandelt. Mittleres Patientenalter war 60 Jahre.
Es wurden 18 Sarkome, 6 NETs, 5 RCCs und 5 GISTs untersucht. Folgende Parameter wurden gemessen: Blutfluss (BF in ml/100 ml/min),
Blutvolumen (BV in ml/100 ml) und k-trans oder Gefäßwandpermeablitätskonstante (ml/100 ml/min) im Gesamttumor (avg) und in der
am stärksten vaskularisierten Tumorregion (max). Für die statistische
Analyse Mean-Werte wurden berechnet und die Ergebnisse als Means ± SD angegeben. Die Differenz zwischen den jeweiligen Gruppen
wurde mittels eines exakten „Wilcoxon signed-rank“-Test berechnet.
Statistische Analysen wurden durchgeführt mittels JMP 9.0 (Biostatistische Software -SAS Institute); p<0,05 wurde als statistisch signifikant
erachtet.
Ergebnisse. Sarkome: BF avg: 38,3±26,7; BV avg: 10,46±7,96; k-trans
avg: 22,37±16,43. BF max: 75,4±21,6; BV max: 19,1±12,1; k-trans max:
30,9±19,8. NET: BF avg: 59,0±33,0; BV avg: 21,28±16,2, k-trans avg:
27,1±14,1. BF max: 92,8±31,4; BV max: 24,5±18,6; k-trans max: 26,8±9,0.
RCC: BF avg: 85,4±13,0; BV avg: 25,4±11,4; k-trans avg: 35,7±23,2. BF max:
112,5±24,8; BV max: 21,8±4,0; k-trans max: 40,0±19,8. GIST: BF avg:
75,6±21,8; BV avg: 16,0±6,6; k-trans avg: 31,5±11,6. BF max: 101,5±28,7;
BVmax: 16,3±6,4; k-trans max: 35,2±14,3. BF(avg)-Wertunterschiede
zwischen Sarkomen, GISTs und RCCs erwiesen sich statistisch signifikant. BF(max)-Werte zwischen Sarkomen und RCCs erwiesen sich nur
marginal signifikant (p= 0.05).
Schlussfolgerung. VPCT ermöglicht eine zuverlässige volumetrische
Perfusionsbestimmung von hypervaskularisierten Tumoren. Die Tumorperfusionsparameter überlappen zwar z. T., die Mean-Werte von
BF unterschieden sich jedoch signifikant zwischen GIST and RCC. Viel
wichtiger: Perfusionsparameter sind Ausdruck der unverkennlichen Signatur eines jeden einzelnen Tumors.
0267
Reduction of pain in patients suffering from cancer-associated
fractures of vertebral bodies by combining kyphoplasty and
dorsal instrumentation
*A. Winkel1, A. Joist1
1
Prosperhospital Recklinghausen, Unfallchirurgie, Recklinghausen, Deutschland
Background. Within the last years, the probability of surviving cancer
rose due to the development of new pharmaceuticals. Because of this, the
number of patients with osseous metastases will increase continuously within the next years. Breast, prostate and lung cancer in particular
bear a high risk of evolving osseous metastases. Two thirds of these are
located in the spinal column. The spectrum of the treatment of spinal
pain induced by metastases ranges from medicamentous treatment over
radiation to surgery. Adequate planning of the therapy of osseous metastases found in the spinal column requires multidisciplinary strategies.
Nevertheless, until now no evidence-based class-1-studies exists on this
issue. The Tokukashi score table can give a first impression.
Aim. The combination of two well-established operative strategies in
trauma surgery (kyphoplasty and dorsal instrumentation) shall be a new
building stone in a multidisciplinary concept to relieve patients’ pain as
much as possible. The featured prospective study aims at proving the
superiority of the combination of both of the mentioned techniques over
the use of only one of them. Furthermore, it targets at developing criteria
for the individual planning of the therapy.
Methods. Patients with an indication to operative treatment of an unstable spinal column due to osseous metastases obtain a combination of
kyphoplasty and dorsal instrumentation. The patients measure the intensity of their pain by employing a visual analogue scale on an everyday
basis. Additionally, a multidisciplinary treatment of pain including medicamentous intervention and radiotherapy supplement the operative
strategies.
Results. The study including a small number of patients has so far shown
a reduction of pain with the score on the mentioned scale decreasing
from 9.5 points preoperative to 4.5 points postoperative. Complications
occurred neither during operation nor after.
Conclusion. The combination of kyphoplasty and dorsal instrumentation
can be an important building stone in a multidisciplinary concept to treat osseous metastases found in the spinal column.
0270
Image-guided hypofractionated re-irradiation as salvage
treatment in recurrent glioblastomas: a retrospective analysis of
23 patients
*J. Gerstein1, D. Steinmann1, B. Wiese2, A. Meyer1, M. Bremer1
1
Medizinische Hochschule Hannover, Klinik für Strahlentherapie und spezielle Onkologie, Hannover, Deutschland, 2DK Henriettenstiftung gGmbH,
Klinik für Neurologie und klinische Neurophysiologie, Hannover, Deutschland
Background. In multi-disciplinary treatment concept re-irradiation in
recurrent malignant gliomas is often used beyond re-resection and chemotherapy. However, clinical data are limited. We retrospectively assessed feasibility and outcome in patients treated at a single institution with
hypofractionated stereotactic re-irradiation (hfS-Re-RT).
Patient and methods. Between 09/2007 and 03/2011, 23 patients with recurrent glioblastma multiforma (recurrent GBM, n=20; GBM secondary
to WHO III° glioma, n=3) were treated with image-guided hypofractionated stereotactic re-irradiation (hfS-Re-RT). HfS-Re-RT was performed using a stereotactic mask fixation and an on-board cone-beam
CT. Median age was 53 years (range: 35–72 y.) and the median Karnofsky
performance score (KPS) was 70% (range: 50–90%). Radiotherapy was
performed to a median total dose of 30 Gy (range: 20–40 Gy) median
fraction size was 4 Gy (range: 3–5 Gy). The planning target volume (PTV)
encompassed the contrast-enhancing area with a 4 mm safety margin at
all dimensions. Median PTV was 60.54 ccm (range: 8.6–252 ccm). Median time interval between re-irradiation and primary radiotherapy was
25.8 months (range: 2.9–102.0 mo.). Prior to hfS-Re-RT, 15 patients (65.2%)
underwent re-resection and 22 patients (95.7%) salvage chemotherapy.
Results. Median overall survival (OS) after primary diagnosis and hfSRe-RT was 33.9 months (95% CI, 27.9–39.9 mo.) and 5.5 months (95% CI,
4.1–6.9 mo.), respectively. Tumor progression after hfS-Re-RT was found
in 17 patients after median 4.5 months (95% CI, 1.6–14.29 mo.). OS was
not significantly influenced by age (<50 vs. ≥50 years; p=0.479), KPS (<70
vs. ≥70%; p=0.269), salvage resection (p=0.183), PTV (<30 vs. ≥30 ccm;
p=0.410), total dose (<30 vs. ≥30 Gy; p=0.099) or time interval between
hfS-Re-RT and primary irradiation (<20 vs. ≥20 mo.; p=0.553). Despite
the relatively large median PTV hfS-Re-RT was well tolerated, no severe
treatment-related side effects were observed. 12 patients received corticosteroids during re-irradiation (median dose 2 mg). Radiation necrosis
was reported in 2 cases in follow-up MRI scans and in one case histologically.
Conclusion. In concordance with comparable data in the literature, hypofractionated re-irradiation appears a valuable treatment option for
selected patients with recurrence disease of glioblastoma and should be
considered in interdisciplinary decision making.
Abstracts
0277
The Sarcoma Treatment and Burden of Illness in North America
and Europe (SABINE) Study – Results from Germany
0320
CD90-positive perivascular cells as mediators of immunosuppression in human malignant glioma
*P. Reichardt1, S. Bauer2, A. Reichardt1, M. Hoiczyk2, M. Brunner3, P. Kaskel4,
L. Jönsson5, A. Musayev5, E. Landfeldt5, T. Burke6, C.-M. Wendtner3,7
1
HELIOS Klinikum Bad Saarow, Hämatologie, Onkologie und Palliativmedizin, Sarkomzentrum Berlin-Brandenburg, Bad Saarow, Deutschland, 2Universitätsklinikum Essen, Innere Klinik (Tumorforschung), Westdeutsches
Tumorzentrum, Essen, Deutschland, 3Universitätsklinikum Köln, Klinik I für
Innere Medizin, Centrum für Integrierte Onkologie Köln-Bonn, Köln am
Rhein, Deutschland, 4MSD SHARP & DOHME GMBH, Outcomes Research,
Haar, Deutschland, 5Optum Insight, Stockholm, Schweden, 6MERCK & CO.,
INC., Global Health Outcomes, Whitehouse Station, NJ, USA, 7Städtisches
Klinikum München GmbH, Klinikum Schwabing, Klinik für Hämatologie
und Onkologie, München, Deutschland
*K. Ochs1,2, F. Sahm3,4, C. Opitz1,2, U. Litzenburger1,2, A. von Deimling3,4,
W. Wick1,5, M. Platten1,2
1
Neurologische Klinik, Neuroonkologie, Heidelberg, Deutschland, 2Deutsches Krebsforschungszentrum, Experimentelle Neuroimmunologie,
Heidelberg, Deutschland, 3Pathologisches Institut, Neuropathologie, Heidelberg, Deutschland, 4Deutsches Krebsforschungszentrum, Klinische Kooperationseinheit Neuropathologie, Heidelberg, Deutschland, 5Deutsches
Krebsforschungszentrum, Klinische Kooperationseinheit Neuroonkologie,
Background. Data on treatment patterns in patients (pts) with metastatic soft tissue sarcoma (mSTS) in general, and Germany in particular,
are limited. The objective of this study was to describe chemotherapy
(CTX) treatment patterns after 1st attainment of favorable response
(FR) to CTX in pts with mSTS in 7 European and 2 North American
countries.
Methods. Data from medical records were collected from initiation of
1st line CTX to end of follow-up (EOFU) or death. Inclusion criteria
were: 1) Confirmed mSTS diagnosis; 2) FR (complete, partial, or stable
disease) after ≥4 cycles within any line of CTX; 3) Age ≥13 years. First
line CTX was to be initiated between Jan 2004 and Dec 2009.
Results. A total of 240 pts were enrolled at 25 sites, with 214 comprising
the evaluable patient set (n=14 from 3 German sites). In contrast to other
countries, German sites were allowed to recruit only non-deceased pts.
The mean age at diagnosis of mSTS pts was 54.8 years and 41.6% were
male (52.7 years and 28.6% male for German pts). The most common
pathologies were leiomyosarcoma (46.3%) and liposarcoma (26.2%). The
mean time from CTX initiation to EOFU or death was 27.2 months,
with 62.6% of pts dying during follow-up. A total of 585 lines of CTX
were used by 213 pts (mean = 2.7 lines). The most commonly used 1st
line CTX regimens were doxorubicin (36.6%), doxorubicin/ifosfamide
(19.2%), and gemcitabine/docetaxel (8.9%). FR to CTX was first observed
in 1st line (81.8%) or 2nd line plus (18.2%) CTX. The main reason for
CTX discontinuation in lines where FR was observed was a pre-defined number of CTX cycles given for 1st and 2nd lines of therapy (64.0%
and 34.3%, respectively), and disease progression for 3rd line (52.4%).
The median overall survival from first FR to CTX was 26.3 months (95%
CI: 21.8, 31.9). For German pts, undifferentiated pleomorphic sarcoma/
malignant fibrous histiocytoma and synovial sarcoma were the most
common STS pathologies. A total of 43 lines of CTX were used by 14 pts
(mean =3.1 lines) over 36.7 months of follow-up. FR was observed in 1st
line CTX for 71% of German patients. Ifosfamide/epirubicin was the
most commonly used 1st line CTX regimen (43%), while gemcitabine
(29%) and trofosfamide (29%) were the most commonly used regimens
in 2nd line.
Conclusions. Multiple lines of CTX are used to treat mSTS pts with FR
to CTX. The data will assist in service planning and evaluation of new
therapies for mSTS pts with FR to CTX in Germany.
Background. Malignant gliomas are primary brain tumors characterized by an extensive neoangiogenesis including the recruitment of endothelial cells and pericytes. Besides their role in vascular development,
perivascular cells have been discussed as a source of undifferentiated
mesenchymal stem cell-like cells. CD90-positive (CD90+) bone marrow-derived mesenchymal stem cells (MSC) exert immunosuppressive
properties. In the present study, we analyzed the immunomodulatory
effect of cerebral perivascular cells in human malignant glioma.
Methods. The influence of human cerebral CD90+ pericytes (HBVP)
on allogeneic or mitogen-activated T cell responses was assessed and
compared to the inhibitory capability of MSC. Using immunohistochemical stainings, the presence of CD90+ cells and blood vessel associated
leukocyte common antigen (LCA) expressing cells in human healthy
brain and glioma tissue was analyzed.
Results. Proliferation of peripheral blood mononuclear cells (PBMC)
was equally effective inhibited by HBVP than by MSC. HBVP-caused
immunosuppression was mediated by prostaglandin E2, nitric oxide,
soluble human leukocyte antigen-G, hepatocyte growth factor and
transforming growth factor-β. While in human healthy brain only neurons showed CD90 expression, in human glioblastoma tissue CD90+
cells were associated with tumor blood vessels. These CD90+ cells were
identified as platelet derived growth factor receptor-β expressing perivascular cells distinct from CD31 expressing endothelial cells. Analysis
of CD90 expression levels in glioma WHO grade II-IV demonstrated a
positive correlation between perivascular CD90 expression and glioma
malignancy and a negative correlation between perivascular CD90 expression and the presence of blood vessel associated leukocytes.
Summary. Human cerebral CD90+ perivascular cells possess a T cell
inhibitory capability comparable to the immunosuppressive phenotype
of human bone marrow-derived MSC. Presence of CD90+ perivascular
cells in malignant glioma is associated with a decreased perivascular
leukocyte infiltration. Thus, besides their critical role in tumor vascularization, perivascular cells may also promote glioma immunevasion.
0326
Prognosis and treatment variables in primary and secondary
angiosarcomas
*J. Hartmann1, V. Hanf2, D. Drücke3, E. Dehnke1, H. Kross1
1
Universitätsklinikum Schleswig-Holstein Kiel, Klinik für Innere Med. II, Hämatologie und Internische Onkologie, Kiel, Deutschland, 2Klinikum Fürth,
Frauenklinik, Fürth, Deutschland, 3Universitätsklinikum Schleswig-Holstein
Kiel, Plastische, Hand- und Mikrochirurgie, Kiel, Deutschland
Background. Angiosarcoma (AS) can be divided into primary (PAS) and
secondary angiosarcoma (SAS) the latter occurring after prior radiation
therapy. The objective was to compare clinicopathologic factors for both
groups.
Methods. AS cases of the Sarcoma Center North were identified. In a
retrospective analysis, patient characteristics, treatment modality, and
survival were determined and compared for both types of AS, PAS and
SAS.
Results. Fourty patients (pts) with PAS and 24 pts with SAS were identified, overall representing 5.7% of pts in the database. Patients with PAS
were younger at time of diagnosis than pts with SAS (median age: 52 years vs 65 years, respectively). The proportion of female patients was 57.5
% for PA, but 95.8 % for SA. The distribution of cancer types was uneven,
with AS of the breast accounting for 17.5% of PAS, but 87.5% of SAS. For
the majority of PAS (63.2%), tumor size was ≥5 cm, as opposed to only
8.3% of SAS with tumor size ≥5 cm. At the time of diagnosis of the angiosarcoma, 42.5% of PAS had metastasized, but only 8.3% of SAS. All
pts with SAS had previously received radiation therapy with a median
time from radiation to diagnosis of SAS of 6.9 years (range: 0.7–24.8).
The proportion of pts treated with surgery was the same for both groups
with 79%, however, more pts with PAS received chemotherapy. 35.5% of
PAS were treated with radiotherapy and 13.3% received radiochemotherapy. 23.5% of SAS pts received a second course of radiation as part of
their SAS treatment. While only half of the PAS relapses (53.6%) were
local, 88.9% of SAS developed a local relapse. Median PFS was 11 months
for PAS and 17 months for SAS (OR: 1.45; CI 95%, 0.71–2.96; p=0.31). Median overall survival (OS) was 18 months for PAS and 36 months for
SAS (OR: 1.74; CI 95%, 0.85–3.59; p=0.13). Both PFS and OS (n.s.) were
higher in pts with R0 compared to R1/2 resection, particularly for breast-AS (p=0.01). Metastases at time of diagnosis lowered PFS (n.s.) and
OS (p=0.02). Non-breast AS had a lower PFS (p=0.01) and trend for inferior OS (p=0.09).
Conclusions. As expected, PAS and SAS were heterogeneous in their clinical behaviour. PAS consisted mostly of non-breast AS in both males
and females, while SAS were primarily located in the breast of younger
female pts. SAS were detected at an earlier stage than PAS. Overall the
prognosis is limited and early detection in a localized stage is warranted.
0340
Overview of the development of catumaxomab in malignant
ascites
*C. Schmidt-Rimpler , A. Burges , P. Ruf , E. Schulze , M.M. Heiss , S.L. Parsons5
1
Fresenius Biotech GmbH, Medical Affairs, Munich, Deutschland, 2Clinic and
Policlinic, LMU Munich, Gynecology and Obstetrics, Munich, Deutschland,
3
TRION Research GmbH, Antibody Development, Munich, Deutschland,
4
Cologne-Merheim Medical Center, Cologne, Deutschland, 5Nottingham
University Hospitals NHS Trust, Nottingham, UK
1
2
3
1
4
Background. Malignant ascites (MA) is a manifestation of advanced
malignancies, associated with a poor prognosis and poor survival.
The trifunctional antibody catumaxomab (Removab®) is the first drug
worldwide with an approval (EU) for intraperitoneal (i.p.) treatment of
malignant ascites due to EpCAM-positive carcinomas. Catumaxomab
targets EpCAM (epithelial cell-adhesion molecule) on tumor cells and
CD3 on T cells in parallel. In addition, its Fc region binds to accessory
cells like macrophages and natural killer cells. These bindings induce
a simultaneous activation of immune cells resulting in an effective destruction of tumour cells.
Methods. The clinical development of catumaxomab in MA is based
on three key studies: a phase I/II dose finding study in patients with
MA due to ovarian cancer, a pharmacokinetic study and a pivotal II/III
study, the latter in patients with MA due to epithelial cancer. Further
studies are currently ongoing.
Results. In the dose-finding study a MTD of 10, 20, 50, 200 and 200 µg
i.p. was determined, resulting in the recommended dose of 10, 20, 50,
150 µg. In addition, first signs of efficacy could be shown in this phase I/
II study: Reduction of ascites flow, no puncture in 22 patients until end
of study, reduction of tumor cells in the ascites flow, which are regarded as the main cause of ascites. The phase II pharmacokinetic study
revealed that i.p. catumaxomab becomes detectable in plasma. In the
pivotal study a statistically significant and clinically relevant superio-
rity of catumaxomab over paracentesis has been shown in treatment of
MA. Moreover, the data indicate a positive influence of catumaxomab
on overall survival. The safety profile of catumaxomab is predictable
as it reflects its mode of action, i.e. the main adverse effects are typical
signs of an immunological reaction.
Conclusion. Catumaxomab administered as a sequence of four i.p. infusions resulted in a clear clinical benefit in the treatment of patients with
malignant ascites. The predictable and manageable safety profile underlines the positive benefit/risk ratio. Catumaxomab in malignant ascites
is further being investigated in several studies (CASIMAS, SECIMAS,
CARMA, ACT). Other indications, e.g. peritoneal carcinomatosis
and gastric cancer and other administration routes, e.g. intravenously
are under investigation. All carcinomas expressing EpCAM could be
potential targets for catumaxomab in the future.
0346
Interim analysis of a cooperative registry to optimize neoadjuvant treatment for large size, high grade non-rhabdomyo soft
tissue sarcoma (NRSTS; IAWS-2)
*J. Hartmann1, V. Grünwald2, F. Mayer3, A. Wolff4, H.-G. Mergenthaler5,
W. Blau6, I. Sturm7, V. Budach8
1
Universitätsklinikum Schleswig-Holstein Kiel, Klinik für Innere Med. II,
Hämatologie und Internische Onkologie, Kiel, Deutschland, 2Medizinische
Hochschule Hannover, Internistische Onkologie, Hannover, Deutschland,
3
Universität Tübingen, CCC Tübingen, Tübingen, Deutschland, 4Universität
Würzburg, Hämatologie/Onkologie, Würzburg, Deutschland, 5Klinikum
Stuttgart, Hämatologie und Internistische Onkologie, Stuttgart, Deutschland, 6Universitätsklinikum Gießen und Marburg, Internistische Onkologie,
Gießen, Deutschland, 7Charité – Universitätsmedizin Berlin, Hämatologie/
Onkologie, Berlin, Deutschland, 8Charité – Universitätsmedizin Berlin, Klinik
für Strahlentherapie, Berlin, Deutschland
Introduction. The role of adjunctive anthracycline and ifosfamide based
combination chemotherapy prior to or after resection in the treatment
of adult and childhood “so-called” NRSTS continues to be controversial. In order to examine whether concomitant chemotherapy with doxorubicin (DOXO) and ifosfamide (IFO) and radiation (RTX) improves
disease-free survival for patients with resectable, large (>5 cm), high
grade (G2/3) adult-type NRSTS compared to surgery alone (and RTX if
indicated/applicable) a multicenter register was launched.
Methods. Patients (pts) with locally advanced (stage III) or locally recurrent NRSTS were treated with IFO (3 g/sqm for 3 days)-DOXO
(60 mg/sqm, day 1) ×3 cycles – IFO (3 g/sqm for 2 days) ×2 cycles + RTX
50.4 Gy* – IFO-DOXO ×1 (*if indicated/applicable, otherwise IFO-DOXO ×5 cycles) prior to surgery. Key inclusion criteria were age ≤65 years at date of biopsy, histopathologically confirmed high grade NRSTS
according FNCLCC, size >5 cm, no evidence of metastatic disease, no
previous cytotoxic or radiation treatment. This interim analysis evaluates the pCR rate.
Results. 63 pts with locally advanced NRSTS were included, but 5 were
not eligible. Histologies were pleomorphic sarcoma, NOS (n=20), liposarcoma (11), synovial sarcoma (7), leiomyosarcoma (5), myxofribrosarcoma (6), MPNST (2), other (5). Median age was 50 yrs (range: 19–65).
Other pts characteristics: male/female ratio was 1.2; grade 2 (21), grade 3
(34), median size 10 cm (range: 4–23); localisation: extremity 36, central
10, head and neck 5, retroperitoneal 3, girdle 2. Fourty-two pts are currently evaluable: 35 completed treatment and surgery. Six pts stopped
treatment due to toxicity and 1 pt due to progressive disease. Pathological assessment according to Salzer-Kuntschik was performed in 38 pts:
14 pts achieved complete regression (grade 1) and 10 pts grades 2 and 3
(<10% vital tumor). Response rate by RECIST from pts who completed
therapy was: 2 CR (5 %), 12 PR (32%), 17 SD (45%) and 7 PD (18%). Pathological response did not correlate with response by RECIST since pts
with pCR still had radiological disease. Dose intensity of DOXO and
IFO was 89% and 81%, respectively.
Abstracts
Conclusions. 63% of all patients responded well to concomitant IFO-DOXO + RTX (regression grades 1–3, Salzer-Kuntschik). These preliminary
results in terms of pathologic response suggest that the combination of
neoadjuvant chemo- and radiotherapy may have a role in selected pts
with high risk NRSTS. Accrual is ongoing.
0360
Catumaxomab observational study to investigate efficacy and
safety profile in clinical practice – the CARMA study
*V. Kunzmann1, J. Sehouli2, B. Schmalfeldt3, P. Wimberger4, C.M. Kurbacher5,
G.-F. Tempelhoff6, F. Breuer7, H. Schulz7, M. Welslau8, D. Finas9, J. Sagasser10,
M. Kiehl11, S. Fruehauf11,12, M.M. Essing13
1
Medical Clinic and Policlinic II Würzburg, Würzburg, Deutschland, 2Charité
Campus Virchow, Clinic for Gynaecology and Obstetrics, Berlin, Deutschland, 3Technical University Munich, Clinic for Gynaecology, Munich,
Deutschland, 4University Essen, Clinic for Gynaecology, Essen, Deutschland,
5
Medical Centre Bonn Friedensplatz, Bonn, Deutschland, 6Clinic Aschaffenburg, Clinic for Gynaecology, Aschaffenburg, Deutschland, 7Private
Practice Pioh, Frechen, Deutschland, 8Private Practice Klausmann, Welslau,
Aschaffenburg, Deutschland, 9University Schleswig-Holstein, Clinic for
Gynaecology and Obstetrics, Lübeck, Deutschland, 10Clinic Augsburg, Clinic
for Gynaecology, Augsburg, Deutschland, 11Clinic Frankfurt/Oder, Medical
Clinic I, Frankfurt/Oder, Deutschland, 12Paracelsus-Clinic, Haematology and
Oncology, Osnabrueck, Deutschland, 13Fresenius Biotech GmbH, Medical
Affairs, Munich, Deutschland
Background. The trifunctional anti-EpCAM/anti-CD3 antibody catumaxomab is approved in the EU for intraperitoneal (i.p.) treatment of
malignant ascites in patients with EpCAM-positive carcinomas. Clinical data for catumaxomab are based on the randomized, pivotal trial
and several phase I/II trials. So far, the routine use of catumaxomab
in clinical practice has not been evaluated systematically. Therefore, a
large prospective observational study was started in 2010, investigating
the administration of catumaxomab in patients with malignant ascites
under routine conditions in daily clinical practice.
Methods. In this study, a total of 160 patients with malignant ascites due
to EpCAM-positive carcinomas (e.g. ovarian, breast, gastrointestinal
cancer) treated with i.p. catumaxomab under routine conditions in clinical practice will be evaluated. Participating centres are hospitals and
practices of oncologists in Germany and Austria. The following data are
being collected (amongst others): demographic factors, cancer disease,
distant metastasis, chemotherapeutic regimen, surgery, laboratory parameters, ascites signs and symptoms, management of catumaxomab
therapy, number of punctures, tumor response, survival, quality of life,
safety results. The data will be analyzed by descriptive statistical methods.
Results. The results of the first interim analysis are reported. The analysis includes 50 patients with malignant ascites and catumaxomab treatment. Data for therapy management, clinical efficacy, quality of life and
safety are presented. The collection of data is ongoing.
Conclusion. We report here the data of an interim analysis with catumaxomab in malignant ascites. This is the first systematic report including
a large patient number for the routine use of catumaxomab in clinical
practice.
0378
Ifosfamide, Carboplatin and Etoposide (ICE) in combination with
regional hyperthermia (RHT) in the treatment of chemo-refractory high-risk soft-tissue sarcoma (HR-STS)
*V. Buecklein1,2, C. Limmroth1, V. Milani1,2, L. Lindner1, S. Abdel-Rahman1,
W. Hiddemann1, R. Issels1,2
1
LMU Munich, Department of Internal Medicine III, University Hospital
Großhadern, Munich, Deutschland, 2HelmholtzZentrum Munich, CCG
Hyperthermia, Institute of Molecular Immunology, Munich, Deutschland
Background. A completed phase III trial (n=341, NCT00003052) showed
that the addition of RHT to anthracycline-based chemotherapy was beneficial in terms of tumor response and survival in patients (pts) with
locally advanced HR-STS (Lancet Oncol 2010). Treatment options in pts
with chemo-refractory HR-STS remain limited; however retrospective
data showed that ICE + RHT is safe and associated with tumor control
in this situation (ASCO 2009 abstract 10581). Here, we analysed the efficacy in pts with progressive or recurrent disease treated prospectively
in the aforementioned trial.
Methods. Pts (≥18 years, PFS ≤2) with locally advanced HR-STS without
(LA) or with metastases (LAM) showing progressive disease or relapse
after chemotherapy were enrolled. ICE consisted of ifosfamide 1.5 g/m2,
carboplatin 100 mg/m2 and etoposide 150 mg/m2 on days 1–4 followed
by G-CSF support. RHT was performed on days 1 and 3. Treatment was
repeated on day 28. Endpoints were toxicity (CTC criteria), response
(RECIST), progression-free survival rates (PFR) after 3 and 6 months
(EORTC criteria) and overall survival (OS).
Results. 21 pts (10 female, 11 male, median age 57 years) with tumors located at the trunk, abdomen or retroperitoneum (n=14) or extremities
(n=7) were analysed. Histological subtypes included liposarcoma (n=7),
leiomyosarcoma (n=4), MPNST (n=3) and others (n=7) with G2 (10 pts)
or G3 (11 its) tumors. 12 pts (57%) with LA and 9 pts (43%) with LAM
entered the ICE + RHT protocol. A median of four (range 1–8) ICE
cycles were applied combined with a median of six RHTs (range 2–16).
Haematological toxicity grade III/IV occurred in 14 pts (67%); fever in
cytopenia was seen in 4 pts (19%). Dose reduction was necessary in 43%
of all pts. In 18 pts evaluable for response, the disease control rate (0 CR,
2 PR, 8 NC) was 55%. The PFR after 3 and 6 months was 90% and 50%,
respectively. Median OS in pts with LA was 23 months (CI 95: 1–77) and
in pts with LAM 11 months (CI 95: 9.6–12.4).
Conclusion. ICE chemotherapy combined with RHT offers an effective
salvage therapy option in the treatment of chemo-refractory HR-STS,
especially for pts with locally advanced tumors or limited metastatic
disease.
0391
Can mathematical modelling help to cure glioblastoma multi
forme?
*A. Toma1, A. Mang1, S. Becker1, T.A. Schütz1, T.M. Buzug1
1
Institut für Medizintechnik, Universität zu Lübeck, Lübeck, Deutschland
Objective. Glioblastoma multiforme is the most aggressive primary
brain tumour and has a quite worse prognosis due to the various and
heterogeneous underlying processes. Most of these are complex and
still not completely understood. To this end, we introduce mathematical methods for modelling tumour growth, providing means for simplifying the actual biological activities. We focus on the interaction and
mutual dependence of the pre-dominant and most influencing factors
only, to gain a better understanding of in-vivo processes. Mathematical
modelling may open new ways for cancer prevention, clinical diagnostics and therapy. This requires the design of methods for simulating
the spatio-temporal distribution and progression of a brain tumour.
This can be achieved based on information obtained from in-vitro and
animal models.
Methods. The computer simulation is controlled by a couple of different
rules. For the migration of malignant glioma cells we use data obtained
from a glioma cell invasion assay. The remaining parameters like the
duration of the cell cycle are set according to values well-known from
literature. Glucose, oxygen and the matrix degraded enzymes (MDE),
such as the urokinase-type plasminogen activator or the matrix metalloproteinase are described as partial differential equations and are
steering the tumour growth: the cells are attracted towards areas with
higher nutrient concentration and may become necrotic in case of a
high consumption rate of nutrients. The influence of the location of the
tumour is described by the extracellular matrix. It is produced by cells
and degraded by the MDE. To this end, the tumour cells are capable of
migrating haptotactically through the extracellular space.
Results. The simulated tumour depicts a distribution that can typically
be observed in vivo: a big necrotic core surrounded by a rim of quiescent
cells and an outer rim of strongly diffusive glioma cells. This is a strong
characteristic of malignant brain tumours and is proven by in-vitro experiments.
Conclusion. Mathematical methods for modelling glioblastoma are not
yet ready for use in clinical practice. However, in the last few years the
models made a big step in providing an accurate and realistic description of cancer progression. Hence, in near future, the question given in
the title might be answered with “yes, indeed”. The model might then
indicate the main processes that have to be inhibited for prevention.
0441
Trabectedin and heat-shock in human sarcoma cells in vitro
*E. Kampmann1, B. Otremba1, S. Barth1, E. Strozyk2, R.D. Issels1,2
1
Klinikum der LMU München, Medizinische Klinik III, München, Deutschland, 2Helmholtz Zentrum München, KKG Hyperthermie, München,
Deutschland
Introduction. The completed randomized phase III EORTC/ESHO
Intergroup trial (NCT 00003052) showed that regional hyperthermia
combined with neoadjuvant chemotherapy is beneficial in terms of
tumor response and survival of patients with high-risk soft tissue sarcoma (Lancet Oncol 2010). Trabectedin (ET-743), approved as secondline therapy for advanced STS, is a DNA minor groove binder with an
unique mechanism of antiproliferative action. We investigate whether
Trabectedin under heat conditions is more effective in human sarcoma
cell lines.
Methods. Trabectedin and heat-shock at clinically relevant temperatures were examined in 4 different human cell lines: Fibroblasts (MRC-5),
leiomyosarcoma (SKUT-1), liposarcoma (SW872) and synovial sarcoma
(SW982). Cells were treated with 0.1–1000 pM trabectedin followed by
heat exposure in an incubator at 41.8°C and 43°C for 90 or 150 min. Cell
viability was assessed using the WST-assay and measuring clonogenic
survival. The expression of the heat-shock proteins HSP27, HSP70 and
HSP90 was analysed by immunoblotting.
Results. Human synovial sarcoma cells and leiomyosarcoma cells were
most susceptible to any type of heat-shock whereas fibroblasts were almost resistant. In all investigated cell lines, HSP27 and HSP70 were induced immediately after heat-shock but not HSP90. Trabectedin did not
influence the expression patterns of these HSPs. All cell lines showed
reduced viability after low doses of trabectedin (approx. 10–100 pM) at
37°C. Human synovial sarcoma cells were most susceptible and fibroblasts were most resistant. Trabectedin and heat-shock showed an additive effect in reducing clonogenic survival in human synovial sarcoma
cells and at high temperature-time doses (150 min/43°C) in leiomyosarcoma cells.
Conclusion. After in vitro heat exposure combined with trabectedin, heat-susceptible human synovial sarcoma and leiomyosarcoma cells show
additive effects in terms of reduced cellular viability. The mechanisms
of interaction between heat and trabectedin with regard to DNA repair
(nucleotide excision repair, homologous recombination repair) in these
human cell lines is under current investigation.
0446
Effectiveness of alkylating chemotherapy after chemo-radiotherapy with Temozolomide in patients with recurrent glioblastoma
*A. Mohr1, S. Rieken1, T. Welzel1, W. Wick2, J. Debus1, S.E. Combs1
1
Univ.-Klinikum Heidelberg, Strahlentherapie, Heidelberg, Deutschland,
2
Univ.-Klinikum Heidelberg, Neuroonkologie, Heidelberg, Deutschland
Introduction. Treatment of recurrent gliomas was often performed with
alkylating nitrosoureas as a standard approach. However, the change
of treatment standard after primary diagnosis fo glioblastomas (GBM)
adding temozolomide (TMZ) has lead to the fact that most patients with
recurrent gliomas have been treated by an alkylating chemotherapeutic
agent. In the present work we analyzed efficacy of nitrosoureas applied
for tumor progression after TMZ in patients with recurrent GBM.
Patients and methods. From 1999 to 2008, we treated 242 patients with
GBM with combined radio-chemotherapy with TMZ. At the time
of progression, 30 of the 242 patients were treated with nimustine
(ACNU). In 9 patients, ACNU as applied for first relapse, and in 15 and
4 patients for the second and third recurrence. 17 patients were treated
with ACNU mono, 13 with a combined therapy with ACNU and vepesid
(VM26; n=11) or cytarabine (ARA-C; n=2).
Results. The 6 and 12 months survival after therapy with ACNU was
56.7% and 31.1% respectively. Median survival after therapy with ACNU
was 7 months. The group of patients who received ACNU after the first
relapse of the tumour showed a higher survival with 77.8% at 6 months
compared to the group of patients treated with ACNU after the second
and third relapse with 42.9% at 6 months; moreover, median survival
was 9 months compared to 4 months after treatment for first compared
to second or third recurrence.
Conclusion. The treatment with ACNU seems to have advantages for
survival of patients treated with TMZ mainly in an early state of relapse.
0453
Proton and carbon ion radiotherapy for primary brain tumors
and meningiomas delivered with active rasterscanning at the
Heidelberg Ion Therapy Center (HIT): early treatment results and
study concepts
*S. Rieken1, D. Habermehl1, T. Haberer2, O. Jaekel2, J. Debus1,2, S.E. Combs1
1
Univ.-Klinikum Heidelberg, Strahlentherapie, Heidelberg, Deutschland,
2
Universitätsklinikum Heidelberg, HIT, Heidelberg, Deutschland
Purpose. To investigate toxicity and patterns of early failure after proton
and carbon ion therapy for gliomas and meningiomas.
Patients and treatment: 33 patients with gliomas (n=26) and meningiomas (n=7) were treated with carbon ion (n=26) and proton (n=7) radiotherapy. In 11 patients, particle irradiation was combined with photon
therapy. Temozolomide-based chemotherapy was combined with particle therapy in 17 patients. Particle therapy as reirradiation was conducted in 7 patients. Target volume definition was based upon CT, MRI and
PET imaging. Response was assessed by MRI examinations. Toxicity
was classified according to CTCAE v4.0.
Results. Treatment was completed and tolerated well in all patients. Toxicity was moderate and included fatigue (24.2%), intermittent cranial
nerve symptoms (6%) and single episodes of seizures (6%). At first and
second follow-up examinations, mean maximum tumor diameters had
slightly decreased from 29.7 mm to 27.1 mm and 24.9 mm respectively.
Nine glioma patients suffered from tumor relapse, among these 5 with
infield relapses, causing death in 8 patients. There was no recurrence or
progression in any meningioma patient.
Conclusion. Particle radiotherapy is safe and feasible in patients with
primary brain tumors. It is associated with little toxicity. Target voluJournal of Cancer Research and Clinical Oncology Suppl 1 · 2011 | 117
Abstracts
me definition is recommended to take functional imaging analysis into
account. A positive response of both gliomas and meningiomas, which
is suggested in these preliminary data, must be evaluated in further clinical trials.
0456
Blood-derived miRNA as potential biomarkers for glioblastoma
*P. Roth1, J. Wischhusen2, C. Happold1, P. Anoop Chandran2, S. Hofer1, G. Eisele1, M. Weller1, A. Keller3
1
UniversitätsSpital Zürich, Klinik für Neurologie, Zürich, Schweiz, 2Universität Würzburg, Würzburg, Deutschland, 3Universität Saarbrücken,
Saarbrücken, Deutschland
Background. Gliobastoma, one of the most aggressive human tumors,
has a poor prognosis. The detection and later monitoring of the disease
require biopsy or surgical resection and imaging technologies such as
MRI. A simple and economical blood test would be desirable in order to
allow for an early detection of progressive disease.
Methods. In this study, we compared the miRNA expression profile
in the peripheral blood from glioblastom patients compared to blood
samples from age- and sex-matched healthy controls using a microarray
platform.
Results. Of 52 significantly deregulated miRNA, 27 were up-regulated
(52%) while 25 miRNAs were down-regulated (48%). After correcting
for multiple testing, 5 miRNA remained significant with a p-value of
≤0.05. We then aimed at characterizing glioblastoma-specific miRNA
fingerprints that allow for a classification of the samples as tumor or
healthy controls. Using statistical learning techniques, a classification
was obtained with an accuracy of 81%, specificity of 79%, and sensitivity
of 83%. In a next step we analyzed the contribution of the deregulated
miRNA to different biological pathways. This revealed a contribution
of several miRNA to immune response mechanisms and an impact of
others on cell cyle regulation and cellular proliferation. Some miRNA
are involved in the process of apoptosis or angiogenesis.
Conclusion. These findings suggest that the deregulated miRNA in glioblastoma patients may be linked to important biological pathways. Further, this proof-of-principle study demonstrates that blood-borne miRNA profiles from glioblastoma patients contain characteristic patterns
that warrant further exploration with regard to their potential use as
disease-specific biomarkers.
0467
Chronic periodontitis as potential risk factor for the development of oral carcinoma – a retrospective case control study
*M. Moergel1, E.-J. Abt1, B. Al-Nawas1
1
Universitätsmedizin Mainz, MKG Chirurgie, Mainz, Deutschland
Background. Recent findings strongly support the possibility of oral carcinoma induction by chronic inflammation apart from smoking and alcohol ingestion. Since western industrialized countries show increasing
obsolescence and the incidence of chronic periodontitis rises with age,
the present study investigated the presence of chronic periodontitis as
independent risk factor for induction of oral carcinoma.
Methods. The present retrospective study was designed as case control
study. 186 patients treated for oral carcinoma at the Department for
Oral and Maxillofacial Surgery, University Mainz between 2003 and
2010 were included. 123 patients treated for affections other than malignancy (e.g. trauma) during the same period served as control. The
mean alveolar bone loss as main symptom for chronic periodontitis was
digitally measured on panoramic radiographs blinded to the patients
clinical history. Tumor location and TNM status, smoking and alcohol
consumption, age, gender, degree of education, body mass index and
oral hygiene were noted by a detailed questionnaire.
Results. The mean alveolar bone loss of patients with oral malignancy
was 4.3 vs. 2.3 within the control group. The difference was highly significant (p≤0.0001, 95% CI of difference: 1.08–1.68). The effect was independent from age and gender and an independent influence still detectable
after adjustment for confounder in a multiple logistic regression model.
As side note a higher BMI (body mass index) and a lower educational
level were negatively correlated with clinical parameter for oral hygiene
as well known risk factors for the development of chronic periodontitis
with rising age.
Discussion. The present study strongly supports the theory of oral carcinoma induction by presence of chronic inflammation as it is seen in patients with chronic periodontitis. Furthermore, the amount of alveolar
bone loss followed by epithelial migration which is seen only in a subpopulation of patients with inflammation of the periodontal mucosa,
additionally characterizes a cohort of patients at risk for oral malignancy. Prospective clinical trials are needed to investigate this special phenomenon. First in vitro studies point at a potential interaction between
specific periodontal bacteria and keratinocytes that might promote carcinogenesis or boost the invasive potential of carcinoma cells.
0484
Long circulating thermosensitive liposomes for triggered intravascular drug release
*L. Lindner1, M. Hossmann1, R. Schmidt1, L. Li2, G. van Rhoon3, H. Eibl4,
R. Issels5, A.M.M. Eggermont6, T. ten Hagen2, G.A. Koning2
1
Klinikum Großhadern, Medizinische Klinik III, München, Deutschland,
2
Erasmus Medical Center, Laboratory Experimental Surgical Oncology, Rotterdam, Niederlande, 3Erasmus Medical Center, Department Radiotherapy,
Rotterdam, Niederlande, 4Max-Planck-Institute for Biophysical Chemistry,
Göttingen, Deutschland, 5Helmholtz Zentrum Munich, Institute for Molecular Immunology, München, Deutschland, 6Institut de cancérologie Gustave
Roussy, Villejuif, Frankreich
Introduction. Thermosensitive liposomes (TSL) which become leaky
after mild heating (40–41°C) offer the possibility of drug targeting for
a variety of anticancer drugs. Synthetic 1,2-dipalmitoyl-sn-glycero-3phospho-glycero-glycerol (DPPG2) and 1,2-dipalmitoyl-sn-glycero-3phospho-glycero-glycero-glycerol (DPPG3) based TSL offer long circulation properties combined with fast drug release kinetics which are
crucial prerequisites for intravascular drug release. Here, we compare
DPPG2 and DPPG3 based DOX-TSL with low temperature sensitive liposomes (LTSL) based on lyso-PC with regard to PK, biodistribution
and antitumor effectivity in vivo.
Methods. TSL were prepared by the lipid film hydration and extrusion
method. DOX was loaded actively with a pH gradient to preformed TSL.
Tumor growth and tumor uptake studies with DOX-TSL were performed in BN 175 soft-tissue sarcoma extremity tumors of rats after 60 minutes of heating. Heat was applied by water bath or fiberoptic lamp.
Results. Plasma peak levels of DOX were doubled for DPPG2- and
DPPG3-based TSL as compared to LTSL (200 ng/µl vs. 100 ng/µl). This
difference was even greater after 60 minutes with DOX 150 ng/µl vs.
50 ng/µl, respectively. Within tumor tissue highest DOX concentrations
were detected for animals treated with PG2 LT-DOX (24.3 ng/mg ±1.7)
and PG3 LT-DOX (22.9 ng/mg ±0.2) compared to LTSL (9.93±1.6 ng/mg
Dox) and free DOX (3.63±1.69 ng/mg). In tumor growth studies with
DOX 2 mg/kg b.w. for DPPG3-TSL 4/6 complete tumor regressions and
2/6 long lasting disease stabilizations were observed compared to 6/6
progressions for standard DOX. For LTSL 1/6 delay in tumor growth
was seen wheras 5/6 tumors progressed.
Conclusion. Enabling high drug release rates at temperatures of 41°C and
high stability at body temperature, DPPG2 and DPPG3 are ideal molecules to obtain optimally formulated TSL for intravascular drug release.
0506
HLA-E contributes to an immune-inhibitory phenotype of glioblastoma stem-like cells
0041
The role of the medical report for psychosocial support of cancer
patients after discharge from the hospital
*F. Wolpert1, P. Roth1, K. Lamszus2, G. Tabatabai1, M. Weller1, G. Eisele1
1
University Hospital Zürich, Department of Neurology, Zurich, Schweiz,
2
University Hospital Hamburg-Eppendorf, Department of Neurosurgery,
Hamburg, Deutschland
*K. Book1, P. Herschbach1, C. Stuhr2, M. Peuker2, A. Heck2, E. Brähler2, K. Härtl3
1
Klinikum rechts der Isar, Roman Herzog Krebszentrum, München,
Deutschland, 2Universitätsklinikum Leipzig, Abteilung für Medizinische
Psychologie und Medizinische Soziologie, Leipzig, Deutschland, 3Klinikum
der Ludwig-Maximilians-Universität München, Klinik und Poliklinik für
Frauenheilkunde und Geburtshilfe, München, Deutschland
Cancer stem cells are an attractive target for immunotherapeutic approaches to glioblastoma. However, an immune inhibitory phenotype of cells currently classified as glioma-initiating cells (GIC) might
counteract recognition by immune effector cells. Here, we investigate
the contribution of the non-classical MHC molecule HLA-E to the immunosuppressive phenotype of GIC. HLA-E is expressed in GIC lines
and its expression is reduced upon differentiation of the GIC on serumcontaining conditions. HLA-E inhibits natural killer (NK) cell-mediated lysis of GIC since small-interfering RNA-mediated HLA-E gene
silencing enhances the immunogenicity of GIC. Furthermore, the use
of interferon-γ as a possible agent to boost an immune response against
glioblastoma cells might be limited by the upregulation of HLA-E on
the cell surface of GIC.
Supportivmedizin/Palliativtherapie
0012
The breast care nurse (BCN ) – a key position in the breast centre
team – the current situation
*I.M. Rack1, R. Saalmann1, S. Kubo2, S. Noeding1, W. Bader3
1
Klinikum Nordstadt, Frauenklinik, KRH, Kooperatives Brustzentrum,
Hannover, Deutschland, 2Das Brustzentrum Niederrhein, Ev. Krankenhaus
Bethesda, Brustzentrum, Mönchengladbach, Deutschland, 3Klinikum
Region Hannover GmbH, Frauenklinik, Hannover, Deutschland
In the last five years we can see how the career of BCNs, as nursing
specialists for breast diseases, has developed. Following the example of English speaking countries, such as Great Britain, Ireland and
Australia, this concept has expanded and is increasingly being put into
practice. In many breast centres the BCN is so well established that one
cannot imagine treating these patients without her active participation
in the team. She has a number of responsibilities; she is the main contact
person for the patients in the breast centre. From the time the diagnosis
is made and all the way through to the end of the therapy the patient
is accompanied and supported by the BCN. As far as the team is concerned, she is the coordinator and mediator in the breast centre as well
as an important connection to the social network and the cooperation
partners. At the German cancer convention in 2012 we would like to
point out the significance of the BCN and her varied duties in breast
centres. In the form of a lecture round we will talk about our experiences in the fields we work in, emphasising the positive effect our work has
on everyone concerned with the treatment of breast cancer. We would
like to show that the active involvement of BCNs results in a definite
improvement in the quality of care. The good experience in the practice could prompt the inclusion of BCNs in the ONKOCERT certificate
guidelines. A powerful team – the effect on the interdisciplinary communication and cooperation, and the quality of patient care – a doctor‘s
viewpoint. May we have a little bit more? The support of patients who
participate in national und international clinical drug trials – carving a
niche! Staying power and gumption required – a BCN job description:
introducing a structured concept of the work and importance of the
BCN in the daily life of the breast centre.
Background. Treatment of cancer involves different sectors within the
health care system. An important role for communication between
the sectors plays the medical report after discharge from the hospital.
However, even though around 30% of cancer patients experience psychosocial distress, medical reports rarely contain information on distress which impedes continuous psychosocial support. The aim of this
project was therefore to investigate whether the inclusion of a “psychooncological statement” within the medical report improves quality of
treatment from the patient’s and doctor’s perspective.
Methods. Patients with cancer were randomly allocated to the intervention or control group. Shortly before discharge, patients in the intervention group were assessed for their psychosocial distress with
the psychooncological basic-documentation, a short semi-structured
interview (t1). Results of the interview were included as a standardized
psychooncological statement in the medical report. The control group
received the medial report as usual. Few weeks after discharge (t2), patients in both groups were asked whether their doctor asked about their
psychosocial distress and whether they were satisfied with treatment.
Doctors in both groups received questions on whether the psychooncological statement (intervention group) or medical report (control group)
was helpful for communication and further treatment and whether they
asked the patient about psychosocial distress.
Results. 1179 cancer patients and 596 doctors participated at t2. Doctors
rated the psychooncological statement and medical report as helpful for
communication and further treatment. Contrary to expectations, the
psychooncological statement did not result in any differences between
the intervention and control group concerning communication about
psychosocial distress from the patient’s and doctor’s perspective or satisfaction with treatment. Overall, 40.8% of the patients and 74.3% of the
doctors indicated that they discussed psychosocial distress. However,
a correlation between satisfaction with treatment and communication
about psychosocial distress was found; patients who were not asked about distress were less satisfied.
Conclusion. Systematic inclusion of a psychooncological statement in
the medical report based on a short interview is feasible in clinical practice. Further research is necessary to investigate the impact of the medical report and written information on doctor-patient communication.
0043
Do oncological patients in young adulthood have specific psychological motives behind the wish to have children?
*K. Geue1, D. Richter1, R. Schmidt1, E. Brähler1
1
Universität Leipzig, Medizinische Psychologie und Medizinische Soziologie, Leipzig, Deutschland
Objective. Many young people suffering from cancer had not been
completed their family planning at the time of diagnosis. The issue of
desiring to have children is gaining more and more importance considering the increasing long term survival and the possibilities of fertility
preservation. Whereas during the acute phase of disease the desire to
have children fades into the background, the fulfilling of own children
comes to the fore after medical treatments and a good prognosis. The
decision for or against a child is strongly determined by emotional
motives. The aim of this study was to investigate whether and which
Abstracts
specific psychological motives oncological patients have behind the
wish to have children.
Methods. After a literature research the psychological motives behind
the wish to have children of cancer patients were collected postally with
a single questionnaire. Also experiences of experts in the oncological,
psychooncological and reproductive medical field were analysed. The
questionnaires mainly consisted of open questions. The evaluation was
made by categorisation of two staff members.
Results. Professional experience averaged over all experts (n=9, six
women) was thirteen years. The following anxiety-provoking motives
related to the wish for children were mentioned by the experts: the
wish for a child remains unfulfilled (n=7), negative health effects for
the child (n=8), concerns about the patient’s health risk (n=6), worries
about an unrealisable child care (n=4) and concerns about couple difficulties (n=3). Positive motivation towards childbirth implicates positive
recovery motivation and future prospects (n=9), symbolic immortality
(n=3), the improvement of the couple relationship (n=1) and an increased importance of family life (n=1). Mean age of patients was 34 years
at diagnosis, 80% want children in the future at this time. Patients’ major concerns about having a child were negative health prospects of the
child (n=7) and cancer recurrence (n=5). Patients associated only few
reasons in favour of childbirth. The results correspond essentially to the
childbearing motives reported in the literature.
Conclusion. The study clearly illustrates the existence of cancer-specific
childbearing motives whose awareness of and knowledge about is fundamental for a psychosocial care adjusted to the needs of young oncological patients.
0088
Belastungserleben von Patienten mit Brustkrebs unter der primär systemischen Therapie in Abhängigkeit ihres Risiko-Scores
*J. Schwickerath1, V. Tschuschke2, G. Karadaglis1, K. Evangelou1
1
St.Martinus-Hospital, Frauenklinik, Olpe, Griechenland, 2Universität Köln,
Medizinische Psychologie, Köln, Deutschland
Fragestellung. Über die psychische Belastung bei Brustkrebs betroffenen Patientinnen gibt es genügend wissenschaftliche Erkenntnisse.
Ebenso ist bekannt, dass die primär systemische Therapie eine nicht zu
unterschätzende Therapieoption darstellt. Bei diesem Behandlungsweg
wird aber nicht nur von den Frauen sondern auch von den Behandlern
oftmals die unnötige psychische Belastung über die Belassung des Tumors in situ als zusätzliches Konfliktfeld diskutiert. Wir haben über
unsere Studie, die wir bei 53 Patientinnen durchgeführt haben, diese
Fragestellung untersucht.
Methode. 53 Frauen, bei denen aus tumorbiologischer Sicht die Indikation zur Primärsystemischen Therapie bestand, wurden in die Studie
aufgenommen. Hierbei handelte es sich um Patientinnen, die in der
Frauenklinik/Brustzentrum zur Abklärung eines suspekten Tumors in
der senologischen Ambulanz vorgestellt und mittels minimal invasiver
Biopsie histologisch abgeklärt wurden. Nach Mitteilung des histologischen Befundes wurde ihnen ein Termin zur weiterführenden Abklärung im Rahmen eines stationären Aufenthaltes gegeben. Am 1. Tag
der stationären Betreuung erfolgte dann sowohl ein standardisiertes
Interview als auch die Übergabe der psychoonkologischen Fragebögen
– HADS, BSI, F-SozU K14, POMS. Zu diesem Zeitpunkt hatten die Patientinnen keine Kenntnis über das genaue Staging ihrer Krebserkrankung. Sie waren somit blind vor ihrer weiteren (möglichen) Prognose.
Erst in der nachfolgenden Zeit erfolgten die notwendigen Staginguntersuchungen. Nach Abschluss der Chemotherapie wurden die Patientinnen zur endgültigen sanierenden operativen Therapie wiederaufgenommen. Am Tag der stationären Aufnahme erfolgte wiederum das
nun 2. standardisierte Interview.
Ergebnisse. 53 Patientinnen wurden nach ihrer Einwilligung in die
Studie aufgenommen. Nach den St.-Gallen-Kriterien erfolgte eine Einteilung in ein mittleres oder hohes Risikoprofil. 49 Patientinnen konn-
ten letztendlich ausgewertet werden. 14 waren der Gruppe mit einem
High-Score und 35 dem mit dem mittleren Risiko zu geordnet worden.
Entsprechend dem Ulmer-Coping-Manual wurde das Interview 1 und
2 (prä- und post-primär-systemischer Chemotherapie) nach folgendem
Score ausgewertet: Pair 1 – Resignation – Hoffungslosigkeit/2 – Ablenkung v.d. Krankheit/3 – kognitive Strukturierung/4 – soziale Kontakte/5 – Compliance/6 – Fighting Spirit/7 – aktives Coping. In beiden
Gruppen zeigten sich schon beim 1. Interview deutliche Unterschiede
in der Einstellung zu der Diagnose, in der Einschätzung der Krankheit
– auch ohne genaue Kenntnis über den eigentlichen (fortgeschrittenen)
Zustand der Erkrankung – und letztendlich auch in der Beurteilung
ihres sozialen Umfelds. Diese Ergebnisse wurden auch bei der Auswertung des 2. Interviews bestätigt. Wobei sich hier erstaunliche Unterschiede im Wandel z. B betreffend Fighting Spirit, kognitive Strukturierung Ablenkung von der Krankheit gezeigt haben.
Schlussfolgerungen. Im Rahmen der Präsentation werden wir die Ergebnisse in Bezug auf die einzelnen Pairs sehr dezidiert darstellen und
entsprechend ihrer Wertigkeit diskutieren.
0100
Feasibility and barriers of bicycle training with patients undergoing haematopoietic stem cell transplantation
*M. Götte1, A. Fissmer2, T. Elter2, W. Bloch1, F.T. Baumann1
1
German Sport University, Department of Molecular and Cellular Sport
Medicine, Cologne, Deutschland, 2University of Cologne, Department I of
Internal Medicine, Center for Integrated Oncology, Cologne, Deutschland
Introduction. The haematopoietic stem cell transplantation (HSCT)
is associated with severe physical and psychological side effects, such
as muscle atrophy, loss of physical fitness and other consequences of
immobility. Since some studies have shown positive effects of physical
activity during the inpatient stay for HSCT [1], this study focused on
examining the implementation of controlled endurance training and
analyzing the inhibitory factors for bicycle training during HSCT.
Methods. This study included 32 patients undergoing autologous or allogene HSCT over a period of 10 weeks. Endurance training was performed with a bicycle ergometer four times a week for 10–35 minutes.
Participation in bicycle training and the reasons for non-participation
were ascertained.
Results. Percentage participation on average was 43.9 % and showed a
significant positive trend over the period of the study (on average 0.43%
per day, p=0.008). Implementation of bicycle training was rarely possible on the day of HSCT and days 4 to 6 after HSCT. The most frequent
causes for non-participation were medical contraindications (70.1%), in
particular acute GvHD, infections and thrombocytopaenia (<10,000/µl
blood). In 15.2% bicycle training couldn’t take place for organizational
reasons (e.g. time management, other therapies) and in 14.8% for subjective complaints (pain, nausea, lack of motivation). Lack of motivation
was individually taken the rarest reason of all. There were no differences
in the participation with regard to diagnosis or transplant.
Discussion. Bicycle training was feasible during all phases of HSCT and
could be integrated into the daily routine of the hospital. Lack of motivation was very rare what underlines a great willingness and interest
of the patients in bicycle training even during the intensive treatment
[2]. Therefore it should be tried to avoid the interruptions of exercise
training because of medical contraindications and during the sensible
days of HSCT. Individually adapted exercise programmes like walking,
strengths training and relaxation training [3] are needed in addition to
bicycle training to increase the frequency of physical activity. Future
studies should focus on concepts to eliminate the revealed inhibitory
factors and find ways to maintain physical activity during the inpatient
stay.
1. Jarden et al (2009). DeFor et al (2007), Baumann et al (2005)
2. Vgl. Midtgaard et al (2009), Maddocks et al (2009)
3. Chang et al (2008), DeFor et al (2007), Kim & Kim (2006), Mello et al (2003)
0103
Pilot study on fatigue levels in patients with lung cancer: correlations with muscle strength and 6-minute walk tests
0102
Muscle strength in patients with lung cancer associated with
lung-cancer-specific symptoms: results of a pilot study
*S. Hummler1, M. Zoz2, M. Thomas2, C.M. Ulrich1, G. Huber3, J. Wiskemann1,4
1
Nationales Zentrum für Tumorerkrankungen, Präventive Onkologie,
Heidelberg, Deutschland, 2Thoraxklinik, Innere Medizin-Onkologie, Heidelberg, Deutschland, 3Institut für Sport und Sportwissenschaft der Universität Heidelberg, Heidelberg, Deutschland, 4National Center for Tumor
Diseases and University Clinic Heidelberg, Division of Medical Oncology,
*B. Hoffmann1, S. Hummler2, M. Zoz3, M. Thomas3, C.M. Ulrich2, G. Huber1,
J. Wiskemann2
1
Institut für Sport und Sportwissenschaft der Universität Heidelberg,
Heidelberg, Deutschland, 2Nationales Zentrum für Tumorerkrankungen,
Präventive Onkologie, Heidelberg, Deutschland, 3Thoraxklinik, Innere
Medizin-Onkologie, Heidelberg, Deutschland
Lung Cancer (LC) patients often experience physical and psychological impairment during the course of their disease. The aim of our pilot
study was to analyse the difference of muscle strength values of LC patients compared to healthy people and to explore whether a correlation
between muscle strength and lung cancer symptoms exists. 39 patients
with lung cancer (56% NSCLC, 44% SCLC) with a median age of 62
(range 44–83) from the Thoraxklinik in Heidelberg have been assessed
for muscle strength by using Hand-Held Dynamometry. The following
muscle groups were tested on both sides: elbow extension, elbow flexion,
hip abduction, hip flexion, knee extension and knee flexion. Clinical
symptoms were documented by using the FACT-L Lung cancer subscale
(LCS). Almost all of the enrolled subjects (87%) were pretreated with
chemotherapy. Reference data in healthy populations showed on average muscle strength values [measured in Newton (N)] of 364 N ±80 for
knee extension, 238 N ±53 for hip abduction and 149 N ±39 for hip flexion (no data for knee flexion available). Values for lung cancer patients
were considerably lower: 190 N ±73 (−47.62% ±19.38) for knee extension,
130 N ±42 (−44.93% ±14.9) for hip abduction and 129 N ±47 (−13% ±24.17)
for hip flexion. In the upper extremities the healthy reference values
showed 209 N ±61 for elbow flexion and 144 N ±39 for elbow extension.
Values for lung cancer patients were again clearly lower with 147 N ±53
(−28.17% ±20.24) for elbow flexion and 125 N ±46 (−12.37% ±21.94) for
elbow extension. Pearson correlation showed a positive correlation between LCS and muscle strength for men [elbow flexion r=0.44; p=0.045
(dominant side), elbow extension r=0.51; p=0.018 (not dominant side),
hip abduction r=0.65; p=0.001 (dominant side) and r=0.50; p=0.024 (not
dominant side)]. Pearson correlation between LCS and muscle strength
for women showed a negative but not statistically significant correlation.
Our findings indicate that lung cancer patients experience muscular weakness especially in the lower extremities compared to the healthy reference population. Main differences compared to similar age
groups were observed in knee extension, hip abduction and elbow flexion if analyzed by age. A positive correlation between LCS and muscle
strength was observed in men, but surprisingly not among women. Further research in larger populations is needed to explore the differences
in gender.
Lung cancer patients often suffer from fatigue due to their disease, side
effects of treatment or the multidimensionality of burden. The aim of
this pilot study was to explore associations between levels of fatigue and
physical performance parameters. As part of this pilot study, a total of
39 lung cancer patients were recruited in the Thoraxklinik Heidelberg
(NSCLC 56%, SCLC 44%). Irrespective of current treatment and stage
of disease patients were enrolled and assessed with the multidimensional fatigue inventory (MFI) questionnaire. Moreover, isometric muscle
strength via hand-held dynamometry and 6-minute walk test (6MWT)
was performed. The patient population comprised of 22 male patients
and 17 female patients, with a median age of 62 (range 44–83). Initial
Pearson correlation analyses revealed a significant correlation between
the MFI subscore physical fatigue (PF) and 6 minute walk distance
(6MWD) in male patients (r=−0.525, p=0.015), but no correlation in female patients. Also no correlations between isometric muscle strength
and other fatigue variables were observed. Table 1 shows a summary of
the mean values (± SD) for MFI, HHD and 6MWD for lung cancer pts.
compared to the healthy reference population.
These pilot data are in contrast to several published studies which reported significant correlations between fatigue levels and physical performance (e.g. for patients with breast cancer). Because of the low patient
number we can only speculate, if this effect is an artifact of the sample
size or reflects a difference in self-perception with respect to physical
strength (and thus a difference in the severity of fatigue) in male and
female lung cancer patients. Further studies with more patients are needed to discern possible gender-specific differences.
Tab. 3 Mean values for MFI, HHD, 6MWD for LC pts. compared to the
healthy reference population
MFI
(subscore PF)
HHD
(knee extension)
6MWD
(m)
Male
Female
Male
Female
Male
Female
Lung cancer
pts. (n=39)
11,1
(SD 4,6)
12,9
(SD 4,0)
225
(SD 64)
148
(SD 60)
411
(SD 108)
Healthy ref.
population
9,1
(SD 1,4)
9,7
(SD 1,5)
419
(SD 49)
297
(SD 56)
434
(SD
112)
597
(SD 97)
514
(SD 68)
0107
Psychooncological interventions for gastrointestinal cancer
patients
*R. Hirth1, E. van der Meer2, M. Pross1, B. Schicke3
1
DRK Kliniken Berlin, Klinik für Chirurgie, Berlin, Deutschland, 2HumboldtUniversität zu Berlin, Institut für Psychologie, Berlin, Deutschland, 3Tumorzentrum Berlin e.V., Berlin, Deutschland
Purpose. Gastrointestinal tumours are very common among male and
female cancer patients. Diagnosis as well as subsequent therapy usually
induces great emotional stress in these patients. They suffer from somatic (fatigue and exhaustion) and psychological (anxiety and tension)
disorders. Emotion-regulation strategies are most important for these
Abstracts
patients to overcome the impacts resulting from the disease: physical
impairments, bad constitution, and fundamental changes to their whole life. This study compares the effectiveness of two different psychooncological interventions: relaxation therapy vs. cognitive structured
short-term psychotherapy, applied during the medical after-treatment
of gastrointestinal cancer patients.
Hypotheses. (1) Cancer patients who receive psychooncological interventions suffer from significantly less anxiety compared to a control
group without intervention. (2) A cognitive structured short-term psychotherapy reduces the anxiety of cancer patients significantly more
than a relaxation therapy.
Background. The cognitive psychological intervention is based on a processing model of emotion regulation developed by Hwang (2006). The
model describes the development of emotion as controlled by sensation
and behaviour in the context of subjective appraisal. In a first step emotions are processed in a way to support social desirability. This leads to
reappraisal of emotional events (Gross et al., 1989). In a second step the
remaining negative emotions are suppressed. This results in adaptive vs.
maladaptive behaviour, influenced by the level of anxiety, the capacity
to suppress unwanted thoughts, and the sense of self-efficacy.
Methods. The longitudinal study is being conducted during the medical after-treatment (chemotherapy or irradiation). Sample: approx.
n=280 patients with gastrointestinal tumours in the Surgical Clinic of
the German Red Cross Hospitals Berlin Koepenick, randomized sample. Sessions: 14 different measuring points (t1 to t14), 2 inpatient sessions, 12 ambulant sessions. Cognitive psychological intervention: different topics (e.g. diagnosis, fatigue, resources), based on the cognitive
structured short-term psychotherapy. Relaxation therapy: progressive
muscular relaxation following Jacobson, the patient is lying or sitting.
Variables collected: physical (skin conductance, pulse rate), questionnaire data (PO-Bado, HADS, ERQ, SAM), general information (tumour
location, tumour progression, number of medical consultations).
Results. First results are expected to be available by the end of 2011.
0110
Psychological distress of cancer patients and their partners –
comparison on pair level and influence of sex
*H. Götze1, J. Ernst1, R. Schmidt1, J. Dorst2, G. Romer3, E. Brähler1
1
Universitätsklinikum Leipzig, Department für Psychische Gesundheit, Abteilung für Medizinische Psychologie und Medizinische Soziologie, Leipzig,
Deutschland, 2Universitätsklinikum, Hämatologie, Leipzig, Deutschland,
3
Universitätsklinikum Hamburg-Eppendorf, Klinik für Kinder- und Jugendpsychiatrie, -psychotherapie und -psychosomatik, Hamburg, Deutschland
Background and objectives. It is undisputed that cancer represents a major psychological distress for patients and their partners. However, to
date there are few studies about the characteristic of anxiety and depression of cancer patients and their partners which include the correlation
within the couple considering gender aspects. This study was part of the
German multi-site research project Psychosocial Services for Children
of Parents with Cancer supported by the German Cancer Aid (Deutsche
Krebshilfe, grant #108303) and was accomplished of 2009–2012 at five
locations (Hamburg, Berlin, Heidelberg, Magdeburg and Leipzig). This
investigation focused on the psychological distress of cancer patients
with minor children on pair level and showed sex differences.
Methods. In 113 cancer patients and their partners with minor children
anxiety and depression after the acute treatment were explored using
the Hospital Anxiety and Depression Scale (HADS). Correlation within
the couples was computed depending on sex.
Results. There was a great correlation between the psychological distress
of the cancer patients with underage children and their partners (anxiety: r=0.323, p<0.01); depression: r=0.362, p<0.01). At the level of the couple there were no significant mean differences in anxiety and depression. Similar results were shown for the constellation female patient and
male partner, too. If cancer patients were male, than female partners
were more anxious than the patient (MW=8.65 vs. 6.62, p=0.02) and the
correlation was not significant. In terms of anxiety every third cancer
patient with underage children was more distressed than the partner,
every third was less distressed and every third showed the same distress
than the partner. In 40% of the studied couples, the partners were more
depressed than the patients. The female partners were more anxious
than the male patients in every second relationship and half of the male
patients were more depressed than their female partners. In 43% of the
couples the male partners were more depressed than ill women.
Conclusion. With regard to psychological distress there is a strong correlation between cancer patients with underage children and the partners
which in the context of treatment must be considered.
0113
Physical exercise training in patients with non small cell lung
cancer (NSCLC): preliminary results of a feasibility study
*L.J. Kühr1, S. Hummler1, J. Wiskemann1,2, U. Abel2, M. Zoz3, C. Ulrich1,
M. Thomas3
1
National Center for Tumor Diseases and University Clinic, Medical
Oncology, Heidelberg, Deutschland, 2National Center for Tumor Diseases
and German Cancer Research Center, Preventive Oncology, Heidelberg,
Deutschland, 3Thoraxklinik, Thoracic Oncology, Heidelberg, Deutschland
In the course of their disease patients with NSCLC often experience impaired psychological and physical functioning resulting in a reduced
quality of life (QoL). The aim of the study was to explore the feasibility
and the effects of an eight weeks combined muscle strength and endurance training on physical capacity and QoL. In this open, prospective,
single center study 40 patients (pts) with NSCLC undergoing adjuvant
or palliative chemo- or radiotherapy were enrolled. Physical status was
assessed by using the 6 minute walk test (6MWT) for endurance and
by using the Handheld Dynamometer (HHDM) for strength (flexion
and extension of elbow, hip and knee). Psychological performance was
measured by standardized questionnaires (MFI, FACT-L, PHQ-9). Data
were collected at baseline (T0) and after the 8 weeks sports intervention
(T1). Pts were instructed to train at least 5 times/week in the inpatient
setting. After discharge pts were instructed to train in a home-based
setting at least 3 times/week for a period of 8 weeks. Feasibility was defined as an adherence of two trainings per week during at least 6 weeks
(out of 8 weeks of the intervention). For this preliminary analysis only
HHDM flexion of the elbow and extension of the knee were considered.
As of the date of this analysis 21 pts (16 male, 12 female) had reached
T1, with another 7 pts having discontinued the intervention because of
adverse events (death, pain, fatigue) or withdrawal. All patients had stage IIA–IV disease. Median age was 61 yrs (range: 22 to 75 yrs). 64% of
the pts were adherent, with 75% pts completing the intervention. The
21 completers showed a significant improvement in the 6MWT (mean
change: 54.3 m, p<0.012). In terms of strength measurement only knee
extension improved significantly (mean change 1.2 N/kg body weight;
p<0.0001), whereas elbow flexion did not show significant differences.
No changes in QoL were observed. The preliminary results indicate that
physical exercise training is feasible in the inpatient and outpatient setting of advanced NSCLC. An effect of the physical exercise training was
found both for endurance and strength. The results regarding QoL are
in agreement with other single arm studies where an improvement of
QoL could not be detected either. This might be due to the small sample
size. Further research is required to investigate the effects on physical
capacity and quality of life conclusively.
0126
Emotional memory in breast cancer survivors: Neuropsychological functioning and neuronal correlates
*J. Wirkner1, C. Hamm2, A. Löw1, M. Weymar3, A.-M. Struck1, A.O. Hamm1
1
University of Greifswald, Department of Biological and Clinical Psychology, Greifswald, Deutschland, 2University Medicine Greifswald, Department
of Psychiatry and Psychotherapy, Greifswald, Deutschland, 3University of
Florida, NIMH Center for the Study of Emotion and Attention, Center for
Psychophysiology, Gainesville, FL, USA
Objective. Chemotherapy and endocrine therapy of breast cancer are
accompanied by a wide spectrum of side effects, including a decline of
cognitive functions that diminish quality of life and well-being. While such impairments are frequently described in self-reports, empirical
findings are inconsistent and the underlying neuronal mechanisms are
not fully understood. Here, we examine cognitive functioning of breast
cancer survivors using neuropsychological testing as well as event-related potentials during an emotional long-term memory task.
Methods. Female breast cancer survivors (n=12) after chemotherapy
and endocrine therapy (tamoxifen, aromatase inhibitors) were compared with a sample of healthy matched controls. We assessed memory
(WMS-R, VLMT) and attention (TAP). In addition, participants viewed a series of emotional and neutral pictures, followed by an unexpected recognition memory test one week later and high-density event-related potentials were recorded to examine underlying brain mechanisms
of attention and emotional memory.
Results. In neuropsychological testing, breast cancer survivors were
characterized by subtle impairments and exhibited larger interindividual variance than controls. During encoding, emotional stimuli evoked larger late positive potentials signaling enhanced attention towards
motivationally relevant materials in both groups. Brain potentials during recall showed enhanced positivity for correctly remembered old
compared to correctly classified unseen items (‘old/new effect’) and
were larger for emotional compared to neutral stimuli. This pattern of
results was shown in breast cancer survivors as well as in matched controls.
Conclusions. Cognitive changes following cancer therapy are subtle and
objective measures of cognitive functions revealed no strong overall impairment in (emotional) memory and attention.
0140
Effects of a 15-month rehabilitative exercise program in prostate
cancer patients following a radical prostatectomy – first results
of the ProRehab Study
*E.M. Zopf1, M. Braun2, S. Machtens3, J. Zumbé4, W. Bloch1, F. Baumann1
1
Deutsche Sporthochschule Köln, Institut für Kreislaufforschung und Sportmedizin, Molekulare und Zelluläre Sportmedizin, Köln, Deutschland, 2Heilig-Geist-Krankenhaus, Köln, Deutschland, 3Marienkrankenhaus, Bergisch
Gladbach, Deutschland, 4Klinikum Leverkusen, Leverkusen, Deutschland
Background. Over 60,120 new cases of prostate cancer (PCa) are reported annually in Germany. Despite the increasing incidence and the common treatment-related side effects there is a lack of supportive measures
for male patients and only few studies have evaluated physical activities
in the after-care of PCa. The Cancer Society North Rhine-Westphalia
(NRW), the German Sport University Cologne and the State Sport Association NRW set themselves the goal to establish rehabilitative sports
groups particularly for PCa patients and to evaluate the effects of the
offered exercise program.
Methods. In cooperation with 4 acute clinics 107 PCa patients following
a radical prostatectomy were recruited into this randomized-controlled
and patient-preference trial. Within a 15-month intervention patients
exercise in a pre-established rehabilitative sports group once a week for
60 minutes. Additionally patients are asked to exercise a second time
independently. Patients in the control group do not participate in the
intervention. The outcomes of the study include: aerobic endurance performance, PA levels, quality of life, incontinence, erectile dysfunction
and specific blood values.
Results. The study started off in October 2007 and will be completed by
the end of the year 2011. First intermediate results concerning the effects
of the offered exercise program show improvements in PA levels and
quality of life and no significant changes in PSA or testosterone levels.
Discussion. The ProRehab study is presumably the first randomizedcontrolled trial with such a long exercise intervention and is therefore
likely to promote long-term lifestyle changes in PCa patients. By combining science, practice and public relations an interdisciplinary and
multi-centric project was initiated. The findings of our study and future
investigations will help optimize exercise recommendations for PCA
patients. Further and more detailed results will be available at the time
of the meeting.
0153
Distress, acceptance and knowledge of psychooncological facilities by patients with colorectal cancer – results of a representative study in Bavaria
*A. Beraldi1,2, E. Kukk2,3, G. Schubert-Fritschle4, J. Engel4, P. Herschbach3,5,
P. Heußner1
LMU, Psychoonkologie Med III, München, Deutschland, 2Tumorzentrum,
München, Deutschland, 3Technische Universität, Sektion Psychosoziale
Onkologie, München, Deutschland, 4Tumorregister, München, Deutschland, 5Roman-Herzog Krebszentrum, München, Deutschland
1
Background. Psychooncological studies about distress usually take place
during primary care and lack of representativeness. Little is known about distress and needs of patients when back in their familiar environment. In our study this absence of representativeness could be avoided
by the recruitment procedure and by the cooperation with the Tumour
Register of Munich (TRM). The following questions were investigated:
1) What is the prevalence of distress, depression and anxiety in patients
with colorectal cancer? 2) Which are predictive factors of distress, depression an anxiety? 3) How is the acceptance and knowledge of psychooncological facilities in the neighborhood? 4) Which are predictive
factors of acceptance and knowledge of psychooncological facilities? 5)
Which offers of psychooncological treatment can be found in the region?
Method. Patients with a colorectal tumour were recruited by their hospital surgeon and received 3 months after inclusion a questionnaire
concerning socio-demographic and medical information, acceptance
and knowledge about psychooncological facilities as well as psychosocial distress, depression and anxiety. We adjusted our sample for age and
sex according to the data of the TRM, so that the resulting sample was
representative for the catchment area of the TRM. At the same time we
carried out an internet research recording all psychooncological facilities in the catchment area of the TRM.
Results. N=534 patients. Mean age was 68.9 years (SD=11.33). 27.6% of
the patients presented metastases. 50.8% received chemotherapy. 26% of
the sample presented distress. 12.4% of the patients had elevated anxiety
and 14.8% elevated depression scores. 52% of the sample did not know
any psychosocial support facility. Only 1.2% of the patients made use
of support. 55.8% answered that they would accept or probably/perhaps
accept support. Predicitive factors for psycho-social distress were not
talking to the general practitioner, psychotherapy in the past and chemotherapy. Predictive factors for acceptance were psychotherapy in the
past and distress. In our sample patients from rural regions were better informed than patients from the city. The outpatient care situation
showed that 10% of the patients did not have a psycho-social support
in the vicinity (20 km) of home. Outpatient psychooncological support
and resident haemato-oncologists showed the strongest undersupply in
rural regions.
Abstracts
0154
Perception and attitudes of professionals regarding age and
need oriented education of children of parents with cancer
*A. Beraldi1, M. Köllner1, S. Tari2, W. Hiddemann1, P. Heußner1
LMU, Psychoonkologie Med III, München, Deutschland, 2lebensmut e.V.,
1
The cancer disease of a parent affects the whole family and may present
an enormous distress factor. Parents are often uncertain, if and how to
talk about the disease to their children. 56% of the parents do not talk
about the imminent death of the other parent although the correlation
between deficient communication and the manifestation of mental disorders has been demonstrated (Siegel et al., 1996). The contribution of
the family counseling funded by lebensmut e.V. at the university hospital Großhadern in Munich consists of the parents‘ support to prevent
their children from developing mental disorders by education, consultation and therapeutic interventions. Another relevant contribution
consists in sensibilizing all involved professionals (e. g. doctors, nurses,
psychotherapists, teachers) in order to offer prevention or to recognize
needs in time. Appropriate support may range from the correct information to specific questions (e.g. „May I tell my daughter that I have
breast cancer? May I bring my children to the ward? Will they bear it?“)
to therapy sessions for the children. The better all involved professionals
are informed about how to deal with children of parents with cancer the
better parents can be supported. The clinical experience however shows
that professionals too, are often uncertain and ambivalent regarding the
children‘s involvement in the disease management. The objective of present explorative study is to assess these observations. We aim to explore
with the help of a questionnaire the perception, attitudes and cognitions
of the different staff members (doctors, nurses, psychotherapists, pastoral care, social workers) regarding the education of children of cancer
patients. Preliminary results will be presented. Depending on the study
results, information and education programmes for professionals shall
be developed and provided on the long run.
0158
Evaluation of a new course on teaching of erectile dysfunction
following pelvic surgery in men with prostate or bladder cancer
in undergraduate medical education
V. Müller-Mattheis1, C. Schulz1, R. Schmelzer1, A. Mortsiefer1, T. Rotthoff1,
P. Albers1, A. Karger1
Heinrich-Heine-Universität Düsseldorf, Urologie, Düsseldorf, Deutschland
1
Introduction. Talking to patients who suffer from sexual problems is
a relevant but under-represented issue in medical education. Besides
knowledge for diagnosis and treatment of sexual disorders also specific
communication skills (e.g. in history taking) are mandatory as much
as an accepting mindset for talking about tabooed themes. As a part of
the development and implementation of a longitudinal communication
curriculum CoMeD, an interdisciplinary training course concentrating
on erectile dysfunction was introduced in 2010 by the Departments of
Urology and Psychosomatic Medicine & Psychotherapy. Training concept (a) and student’s evaluation (b) are presented.
Methods. (a) The multi-stage development process included needs-assessment to determine student’s needs and interests, defining learning
objectives and teaching methods. We produced instructional material
and provided special training sessions for course teachers and simulated patients. (b) Participating students evaluated the training course in
reference to subjective learning curve, practical relevance, and a global
quality appraisal each by 5-point LIKERT scaling.
Results. (a) We could develop a new CoMeD training course with following contents of teaching: urological knowledge especially of surgical
pelvic anatomy and postoperative problems in patients having undergone radical cystectomy/prostatectomy, interview with simulated patients
(sexual history taking), interview with real prostate cancer patients suffering from erectile dysfunction, feedback and discussion. (b) Student’s
mean evaluation was good (overall results of three term cohorts, n=173).
Conclusion. Introduction of an interdisciplinary training course providing explicit urological knowledge as well as communication skills
could successfully be accomplished and was much appreciated by our
students. The authors see this approach as highly valuable for further
medical curriculum development and assimilating specific psychooncological skills.
0161
Quality of life in long-term survivors of breast, colorectal, and
prostate cancer – First results from the CAESAR study
*V. Arndt1, L. Koch1, H. Bertram2, A. Eberle3, S. Schmid-Höpfner4, C. Stegmaier5, A. Waldmann6, S. Zeissig7, H. Brenner1
1
German Cancer Research Center (dkfz), Clinical Epidemiology and Aging
Research (C070), Heidelberg, Deutschland, 2Cancer Registry of North RhineWestphalia, (Münster Region), Münster, Deutschland, 3Bremen Cancer
Registy, Bremen, Deutschland, 4Hamburg Cancer Registry, Hamburg,
Deutschland, 5Saarland Cancer Registry, Saarbrücken, Deutschland,
6
University Hospital Schleswig-Holstein, Institute of Clinical Epidemiology, Lübeck, Deutschland, 7Cancer Registry Rhineland-Palatinate, Mainz,
Deutschland
Background. The CAESAR-study (Cancer Survivorship – a multi-regional population-based study) was started in October 2008 to study
important quality of life aspects in long-term survivors (5+ years) after
diagnosis of breast, colorectal or prostate cancer.
Methods. The study is based on a joint analysis of several populationbased samples of cancer survivors from various cancer registries across
Germany (Bremen, Hamburg, Münster/North Rhine-Westphalia,
Rhineland-Palatinate, Saarland, Schleswig-Holstein). Potential study
participants were identified by the participating cancer registries and
were either contacted directly by the pertinent cancer registry or the
treating physician, depending on the federal legislation. The questionnaire included internationally validated standardized instruments
(e.g. EORTC Quality of Life Core Questionnaire, Fatigue Assessment
Questionnaire, Geriatric Depression Scale, Benefit Finding Scale, Post
Traumatic Growth Inventory). It was planned that a total of approximately 6700–7000 survivors would be eligible and participate.
Results. The recruitment started in August 2009 and lasted until April
2011. The actual number of over 7100 cancer survivors who filled out
the questionnaire exceeded the anticipated number. Depending on the
region specific recruitment schemes up to 88% of all contacted survivors
completed the questionnaire. First results from the Saarland VERDI cohort, a cohort which has been repeatedly contacted over the first ten years after diagnosis, indicate that long-term cancer survivors experience
more restrictions in role, emotional, cognitive, and social functioning
than controls from the general population. Further in-depth analysis as
well as results from the other regions will be presented.
Conclusions. Our preliminary results indicate that quality of life is a topic of high relevance for long-term survivors. Furthermore, detriments
in psychosocial functioning persist over years even in cancer survivors
considered to be cured.
0171
Treatment decision-making at the end of life in oncology: results
of a qualitative study on perceptions and ethical views of physicians in Germany and England
*J. Schildmann1, J. Tan1, J. Vollmann2
1
Ruhr-Universität Bochum, Institut für Medizinische Ethik und Geschichte
der Medizin, NRW-Nachwuchsforschergruppe „Medizinethik am Lebensende: Norm und Empirie“, Bochum, UK, 2Ruhr-Universität Bochum, Institut
für Medizinische Ethik und Geschichte der Medizin, Bochum, Deutschland
Resarch question. Limitation of treatment is part of the care for patients
with incurable cancer. We explored the perception and ethical views of
oncologists working in Germany and the United Kingdom regarding
these decisions.
Methods. Qualitative semi-structured interviews with physicians working in oncology in Germany and England were carried out. Interviews
were audiotaped and transcribed. Transcripts were coded by identifying major themes of the interviews using constant comparison, in order
to examine similarities and differences between oncologists across the
whole sample.
Results. 17 (Germany) and 12 (United Kingdom) research interviews
were analysed. Interviews varied in length between 27 and 73 minutes.
Respondents from both countries named a variety of treatment modalities which may be limited in the context of care for patients with
incurable cancer. After standard clinical criteria for decision-making
(e.g. performance status), perception of the life circumstances of the patient (e.g. being a mother of young children) as well as highly individual
aspects of the physician-patient relationship (e.g. parallels between the
biographies of physicians and patients biographies) were reported to
most influence these treatment decisions. Discussions with colleagues
and the multidisciplinary team were emphasised as correctives to make
the decisions less subjective; these were emphasised as strategies by oncologists working in the United Kingdom. Physicians in both countries
reported that non-harming treatment was given to patients who did not
accept the initial recommendation of oncologists to stop treatment. The
duty not to harm was cited as the rationale to limit treatment even if
there was a wish on side of the patients to receive further interventions.
Conclusions. This study indicates that decisions about limitation of medical treatment are based on numerous medical and non-medical factors. Potential strategies for dealing with clinical and ethical challenges
in end stage cancer will be discussed.
0184
Implementation of a multidisciplinary psychosocial screening
tool with touch-screen technology in a German Comprehensive
Cancer Center
*A. Brechtel1, J. Walther2, K. Bikowski2, D. Jäger2, W. Herzog3
1
Nationales Centrum für Tumorerkrankungen, Psychoonkologische Ambulanz, Heidelberg, Deutschland, 2Nationales Centrum für Tumorerkrankungen, Heidelberg, Deutschland, 3Klinik für Allgemeine Innere Medizin und
Psychosomatik, Heidelberg, Deutschland
Objective. The purpose of our presentation is to describe the implementation of a multidisciplinary psychosocial screening in a Comprehensive Cancer Center (CCC) setting using touch-screen technology illustrating barriers, necessary frameworks and setting-specific adaptations.
Background. Psychosocial research emphasizes the need for early identification of distress, and there is an increasing empirical support for
the importance of systematic psychosocial screening of cancer patients.
However, the practical issues of implementing psychosocial screening
as an integral part of a comprehensive and patient-oriented cancer treatment in a CCC have been rarely addressed or investigated so far. Besides various paper-based screening tools, there is a growing interest in
the use of touch-screen technology. Experiences with this technology
and respective advantages have been described in the international literature.
Methods. We implemented a touch-screen screening instrument addressing not only psychosocial distress, but also nutritional aspects
as well as patients’ interest in the offer of various counselling services.
Revisions and necessary adaptations are made by a multidisciplinary
working group.
Results. We found various barriers to implement this technology as an
integral part of the cancer treatment. A special challenge seemed to be
to adopt the screening process to the existing or newly established clinical units of cancer treatment in our CCC. Each clinical unit has its own
culture and needs to be addressed respectively. One major barrier was
the attitude of involved personnel who felt that the screening would be
burdensome for patients.
Conclusions. The implementation of such a screening tool and procedure requires a lot of preparatory work and the adaptation to settingspecific frameworks. Besides specific technical requirements the multidisciplinary communication and exchange as well as the training of
the involved personnel present important tasks. The acceptance from
all involved disciplines represents a major prerequisite for the successful
implementation and integration in routine care.
0186
Inwieweit profitieren Brustkrebs betroffene Frauen besonders
bezüglich der Langzeitwirkung von psychoedukativen Seminaren? – Ergebnisse einer Nachbefragung 6 Jahre später
*J. Schwickerath1, E. Reuter1,2
1
St. Martinus-Hospital, Frauenklinik, Olpe, Deutschland, 2Psychonkologische Schwerpunktpraxis, Olpe, Deutschland
Nach der Diagnose Brustkrebs entwickeln die betroffenen Frauen
unterschiedliche Strategien, um mit der Erkrankung und ihren Folgen
wieder ins Leben zurückzufinden. Um den Frauen in dieser schweren
Zeit auf ihrem Weg zu helfen, bieten wir seit 2001 sog. psychoedukative
Patientenseminare an. Ziel dieser Seminare ist es auch, die Patientenkompetenz der Betroffenen zu steigern. Wir verstehen unter diesem Begriff, dass die Frauen in hohem Maße wünschen und letztendlich auch
in der Lage sind, bei der Behandlung ihrer Erkrankung gleichberechtigt
und eigenverantwortlich mitzuarbeiten. Dafür sind Entwicklung von
Sachverstand und Wissen erforderlich, sowie der Mut und das Selbstbewusstsein, mit den Behandlern auf gleicher Augenhöhe zu sprechen.
Über die wissenschaftliche Evaluation unserer bisherigen 14 Seminare (n:195) haben wir nachweisen können, dass alle Teilnehmerinnen
betreffs ihres Kohärenzgefühls und ihres Coping-Verhaltens in der
Post-Befragung eine Steigerung angegeben haben. Uns hatte nun interessiert, wie weit diese positive Lebensveränderung trotz der Diagnose
angehalten hat, respektive ob sich diesbezüglich Jahre später eine Änderung ergeben hat. Wir haben die Seminarteilnehmerinnen aus den Jahren 2001 bis 2005 betreffs unserer Studie angeschrieben. 95 Frauen, mit
einer durchschnittlichen Zeitspanne zwischen Patientenseminarende
und Beginn der Befragung von 72 Monaten, konnten wir letztendlich
in die Studie aufnehmen. Die Teilnehmerinnen haben auch Jahre später die durch die Seminare gewonnene Steigerung ihrer Lebensqualität
über die emotionale Stabilisierung, Verbesserung der Selbstfürsorge
und der Compliance beibehalten und – nach ihren Aussagen – noch
steigern können. Die Ergebnisse unserer Studie zeigen, dass es sich auch
bezüglich der Langzeitwirkung lohnt, den betroffenen Frauen solche
Seminare anzubieten.
Abstracts
0190
Exercise and cancer – how do physically active and inactive cancer patients differ in social cognitive variables from the Theory of
Planned Behavior?
0192
Evaluation of expectations, utilization and satisfaction with
classical homeopathy as add-on treatment for breast cancer
survivors
*N. Ungar1,2, M. Sieverding1, C. Ulrich2, J. Wiskemann2,3
1
University of Heidelberg, Psychological Institute, Heidelberg, Deutschland,
2
National Center for Tumor Diseases, Preventive Oncology, German Cancer
Research Center, Heidelberg, Deutschland, 3National Center for Tumor
Diseases, University Clinic, Medical Oncology, Heidelberg, Deutschland
A. Glenz1, M. Lavall-Gottschalt1, B. Schlehofer2, B. Schlehe3, A. Schneeweiss4,
C. Sohn3,4,5, T. Strowitzki6,1, *C. v. Hagens6,1
1
Universitätsfrauenklinik, Ambulanz für Naturheilkunde, Gynäkologische Endokrinologie und Fertilitätsstörungen, Heidelberg, Deutschland,
2
Medizinische Klinik, Innere Medizin, Klinik für allgemeine Innere Medizin
und Psychosomatik, Heidelberg, Deutschland, 3Universitätsfrauenklinik,
Geburtshilfe und Pränataldiagnostik, Heidelberg, Deutschland, 4Universitäts-Klinikum, Gynäkologische Onkologie, NCT (Nationales Centrum für,
Heidelberg, Deutschland, 5Universitätsfrauenklinik, Allgemeine Frauenheilkunde & Geburtshilfe, Heidelberg, Deutschland, 6Universitätsfrauenklinik,
Gynäkologische Endokrinologie und Fertilitätsstörungen, Heidelberg,
Deutschland
Objectives. The current recommendation for cancer patients is to exercise moderately 150 minutes a week. Despite many positive effects of
physical activity, many cancer patients are quite physically inactive. The
Theory of Planned Behavior by Ajzen which is based on social cognitive
variables can be helpful to explain physical activity. Do physically active and inactive patients differ in these social cognitive variables? That
means, do they have a different intention, attitude, perceived behavioral
control and subjective norm towards exercising? This pilot-study should
furthermore identify which of these variables can predict the intention
to be physically active.
Methods. 63 patients (m=39, w=24; mean=60 years) of different cancer
entities and different outpatient therapy regimes (50% chemotherapy at
present) were recruited in the National Center for Tumor Diseases in
Heidelberg. They had to fill out a questionnaire assessing their physical
activity, variables of the Theory of Planned Behavior and socio-demographic variables.
Results. 27 patients of the sample were classified as physically inactive
(<150 minutes/week), 36 as physically active. Conducting t-tests, the
groups did significantly differ in all variables of the theory of planned
behavior: active people had a higher intention to exercise 150 minutes in
the next 4 weeks (p<0.001), a higher perceived control (p<0.001), a better attitude towards the exercise recommendation (p<0.01) and an increased subjective norm (p<0.01). Regarding physically active patients,
their intention to exercise regularly 150 minutes a week can be predicted
by their subjective norm (attitude and perceived behavioral control are
no significant predictors; R2=0.24) In contrast, for inactive people the
only significant predictor for their intention is their attitude (subjective
norm and perceived behavioral control have no influence), which is able
to explain 54% of the variance by itself.
Discussion. The Theory of Planned Behavior is a useful tool to distinguish between physically active and inactive cancer patients. It can be
concluded that it might be promising to conduct further intervention
studies based upon this theory. It might be helpful to increase the attitude towards exercising to make inactive patients more motivated to be
physically active.
Objective. Patients often disclose complementary and alternative treatments towards their oncologists who on their part often have only
limited experience in this field. Add-on treatments with classical homeopathy with highly diluted remedies offer the special advantage to
avoid potentially dangerous drug-drug interactions. Therefore special
consultation-hours for classical homeopathy for breast cancer survivors
in different stages of their treatment were established at a large university breast cancer centre and expectations, utilization and satisfaction
with homeopathic add-on treatments were evaluated by using short
questionnaires.
Methods. Patients completed the validated questionnaires ID BC-Pass
(7 point Likert scale) and the PHQ-D. In addition they rated their 3 most
bothering symptoms with a 6-point Likert scale from 1 (very good) to 6
(very poor) and answered questions about expectations, concurrent use
of medication, over the counter treatments and non-pharmacological
treatments. Thereafter homeopathic case history, repertorisation, treatment with the selected remedy and shorter follow-up consultations took
place. Treatments lasted for at least 6–12 weeks. At the end of the add-on
treatment the questionnaires were completed again.
Results. Within 3 years 568 patients at different stages of their disease
were informed about various possibilities of complementary and alternative treatment options. This included details about the special consultation-hours for classical homeopathy. At this consultation 203 of
them already received a remedy for acute symptoms or for attenuation
of typical symptoms related to the forthcoming treatment. 173 patients
started a classical homeopathic treatment consisting of case history, repertorisation and up to 11 follow-up consultations as add-on treatment
together with a variety of standard treatments. Of the latter, 105 patients
(61%) gave informed consent and completed questionnaires before and
after the add-on treatment. At the end of the homeopathic treatment an
improvement of the respective main symptoms of 2 points from 5 (poor)
to 3 (satisfactory) was noted. Depression and anxiety assessed by the
PHQ remained unchanged. Physical functioning and overall satisfaction with life assessed with the BC-PASS had improved.
Conclusions. Classical homeopathic add-on treatments were accepted
by a substantial part of breast cancer survivors of all stages and may
contribute to stabilisation or improvement of bothering symptoms.
0209
Psychooncological support needs assessment in hematology –
implementation, acceptance and results
*A. Koch1, M. Herold1, H. Göbel2
1
HELIOS Klinikum Erfurt, 4. Medizinische Klinik, Hämatologie und internistische Onkologie, Hämostaseologie, Erfurt, Deutschland, 2HELIOS Klinikum
Erfurt, Tumorzentrum, Erfurt, Deutschland
Objectives. The psychosocial support of cancer patients with initial diagnosis has improved due to the certification of numerous organ tumor
centers. However, it shows that the full supply by certified psychooncologists is currently not yet possible due to economic restrictions. A
sustainable model needs to be implemented into hospital workflow that
allows access to psychooncological support offers and is economical as
well.
Methods. Assignments of the patients to psychological support cannot
happen solely by physicians or nursing staff, because they often do not
assess the actual need properly. Realization of evidence based screening
diagnostics to assess the need has proven to be reliable and valid in several studies. However, psychooncological screening methods in the hematology (diagnoses: ICD-10 C81-96) are quite new and are controversially discussed within other organ tumor centers. Aim of this study is
to analyze the approach of the Hornheider Screening Instrument (HSI)
in clinical routine and to evaluate the acceptance of the questionnaire.
Results. The following results and conclusions are preliminary. The oneyear clinical outcomes will be presented at the congress. Within the first
6 months period of survey, 179 patients with hematooncologic diagnosis
were treated. The return ratio of the HSI questionnaire was 65%. For
32% of the respondents, psychological treatment identified to be needed.
Primarily, patients reported to be burdened physically (54%) and mentally (43%). 36% of the respondents considered their family especially
burdened. 19% of the patients described information deficits concerning
their tumor disease. 15% expressed the desire for psychological support
and 3% were already in outpatient psychotherapy.
Conclusions. The screening method used proves to be practical. The
question about the best time to assess the patients’ burdens and wishes for psychooncological support remains. Furthermore, it could be
observed that the mental strain and need for support increases under
chemotherapy or occurrence of relapses. Continuous follow up surveys might be necessary. A consultation service cannot satisfy the needs.
Psychooncological liaison services, which are integrated into the stationary routines, are useful and suitable.
0263
Effects of aquatic exercise on quality of life and activities of daily
living in breast cancer patients with secondary arm lymphedema
*B. Roling1, *D. Hermann1, F.T. Baumann1
1
Deutsche Sporthochschule, Köln, Deutschland
Introduction. Secondary arm lymphedema is one of the most feared and
multidimensional complication following breast cancer disease and treatment (Micke et al. 2000). Patients suffer from progressive and chronic
dysfunctions particularly of the upper extremity, resulting in physical,
psychological and social impairments which may affect quality of life
and activities of daily living (Hull 2000, Isermann 2006). The prevailing treatment of lymphedema is currently the complex physical therapy which can improve the physical condition. However, psychosocial
impairments are not considered sufficiently. A holistic therapy is needed. Due to the specific hydrodynamic properties, aquatic exercise may
present such a therapy approach. Although aquatic exercise has already
been implemented in the oncological rehabilitation, it has not attracted
much interest in research (Baumann & Schüle 2008). In order to reduce
this gap between science and practice, this study investigated the effects
of a semiweekly aquatic therapy over twelve weeks on quality of life and
activities of daily living in breast cancer patients with secondary arm
lymphedema.
Methods. Nine women participated in a semiweekly aquatic therapy over twelve weeks. Findings were assessed via four questionnaires
(FLQA-I, Freiburger Fragebogen zur körperlichen Aktivität, EORTC
QLQ-C30, EORTC QLQ-BR23) and measurement of arm circumference at five times (baseline, after six and twelve weeks of the intervention,
three- and six-months follow-up).
Results. Aquatic exercise had immediate positive, partly statistically significant effects on quality of life and lymphedema symptoms, especially
arm symptoms (baseline-after 12 weeks: p=0.022). But no long-term effects were noted. Conversely, activities of daily living decreased during
the intervention and showed an increase in the follow-ups.
Discussion and conclusion. This study provides first evidence of multidimensional effects of aquatic exercise not only on activities of daily
living and quality of life in breast cancer patients, but also lymphedema
condition itself. However, permanent positive effects can only be achieved by long-term and regular participation. In related studies of Tidhar
& Katz-Leurer (2009), Hayes et al. (2009) and Box et al. (2004) similar
results are shown. Further studies have to be conducted in order to specify the exact effects of aquatic therapy on lymphedema and to define
precise exercise recommendations for breast cancer patients.
0264
The influence of a long hike on psychological parameters of
patients after breast care treatment
*S. Metzner1, I. Germ1, L. Thiele1, S. Gräfingholt1, W. Bloch1, F. Baumann1
1
Deutsche Sporthochschule Köln, Institut für Kreislaufforschung und
Sportmedizin, Abteilung für molekulare und zelluläre Sportmedizin, Köln,
Deutschland
Years after the diagnosis, patients suffer of psychiatric problems that,
to them, seem a lot more serious than their physical deficits. Of meaning are depressions, anxiety and attention disorders (Burgess et al.
2005, Heckl & Weis 2006). Long hikes (810 km, 10,000 m high, 22 km/
day, 6 weeks) along the French Camino de Santiago are supposed to
improve this psychological condition (Brämer 2001). Woman diagnosed with breast cancer (n=22, age: 53±7 years, post diagnosis 1,8±1 year,
BMI: 23,5±3,58 kg/m2), whose acute treatment had been completed, were
observed in relation to quality of life (EORTC QLQ C-30 and BR-23)
attention/awareness (MAAS) and anxiety and depression (HADS). Test
subjects were free to choose their own speed and resting periods. Questionnaires were completed at the beginning, after a 2-month training
interval, and after the 2nd, 4th and 6th week of the hike. For the evaluation of long term effects, 6 and 12 months after the intervention all
questionnaires were filled in again. The results show significant improvement in nearly every area, for example: global health status (T1=67.4,
T7=77.1, p<0.001), depression scale (T1=3.4, T7=2.4, p<0.001) as well
as anxiety scale (T1=7.8, T7=4.9, p<0.001) and attention span (T1=58.7,
T7=64.3, p<0.001). Compared to the training phase, the improvement of
all values during the hike are to be highlighted. Studies showing similar
results (McNeely et al. 2006) emphasize the big influence of the moderate exercise. Furthermore, the influence of nature seems to be important
for a better feeling (Brämer 2001, Gebhard 1993). This aspect is not to be
under estimated during post treatment of breast cancer patients, and
should there for be implied strongly, for example in form of hiking. Alternatives and/or additional offers to rehabilitate, such as this, should
therefore become established in the future and become subsidized by
health insurances in order to sustain increase of self-initiative and individual responsibility.
Abstracts
1. Brämer B (2001) Wandern neu entdeckt. Warum es sich lohnt wieder mehr zu
Fuß zu reisen (elektronische Version). Burg & Steigen 3:22–28
2. Burgess C, Cornelius V, Love S, Graham J, Richards M, Ramirez A (2005) Depression and anxiety in women with early breast cancer: five year observational
cohort study. BMJ (Clinical research ed.) 330:702–705
3. Gebhard U (1993) Erfahrung von Natur und seelische Gesundheit. In: Seel H-J,
Sichler R, Fischerlehner B, Mensch und Natur. Psychologische Aspekte einer
problematischen Beziehung. Opladen, S. 127–147
4. Heckl U, Weis J (2006) Medizinpsychologische Aspekte der Patientin mit
Mammakarzinom. In: Kreienberg R, Jonat W, Volm T, Möbus V, Alt D (Hrsg.),
Management des Mammakarzinoms. Springer Medizin Verlag, Heidelberg,
S. 469–487
5. McNeely, ML, Campbell, KL, Rowe, BH, Klassen, TP, Mackey, JR & Courneya, KS
(2006) Effects of exercise on breast cancer patients and survivors: a systematic
review and meta-analysis. Canadian Medical Association Journal 175(1):34–41
0293
Attitudes towards euthanasia. The impact of the experience of
supporting a dying relative
*N. Köhler1, H. Götze1, L. Gansera1, S. Berger1, R.-D. Kortmann2, E. Brähler1
1
Universitätsklinikum Leipzig, Abteilung f. Medizinische Psychologie und
Medizinische Soziologie, Leipzig, Deutschland, 2Universitätsklinikum Leipzig, Klinik für Strahlentherapie und Radioonkologie, Leipzig, Deutschland
Introduction. It is a point of debate whether euthanasia should be part
of medical practice. The current study investigates the attitudes of bereaved family members who had experienced end-of-life care towards
euthanasia. In this abstract, we present preliminary results. The study
was sponsored by the German Cancer Aid (Deutsche Krebshilfe e.V.).
Methods. We have conducted an online survey with people who had lost
a close relative to cancer during the last 12 months. Participants were
asked whether indirect, passive, active euthanasia and assisted suicide
should be part of medical practice. The results of this survey were compared with those of a survey of the general German population from
2001 (Schröder 2003). The participants of the online survey were mostly
female and of younger age than the general population, the two groups
were matched according to age and sex.
Results. In general, most bereaved family members approved the idea
of indirect and passive euthanasia being part of medical practice. Bereaved family members of cancer patients (approx. 90%) significantly
more often wanted indirect and passive euthanasia to be part of medical
practice than the general population (approx. 66%). Regarding active
euthanasia and assisted suicide, the differences between both groups
were much smaller. 70% and 67% of the bereaved family members vs.
55% and 60% of the general population wanted those forms of euthanasia to be part of medical practice.
Conclusions. On possible explanation for the stronger support of euthanasia by bereaved family members may be the experience of supporting
a dying relative. Since the survey of the general German population was
conducted about ten years ago, it seems also possible that the acceptance
of euthanasia may have increased since then in the general population.
0298
National survey of physicians’ communicative competence training in medical education
*C. Kloepfer1, A. Spieser1, J. Weis1
1
Klinik für Tumorbiologie, Psychosoziale Abteilung, Freiburg, Deutschland
Purpose. Communication between physicians and patients is an important component in medical services. Compelling evidence from clinical
trials indicates that good communication skills of health professionals
show positive effects on physicians (burn-out prophylaxis, increased job
satisfaction etc.) as well as on patients (particularly with regard to can-
cer patients increased treatment adherence, psychological functioning
etc.) and therefore influences therapeutic response. The National Cancer Plan of Germany, coordinated by the Federal Ministry of Health has
in line with more patient-centred approach the aim to improve physician-patient communication in medical education and medical care of
cancer patients. The aim of this study was to describe the status quo of
the medical undergraduate and postgraduate education and residency
training in terms of communication skills.
Methods. In order to examine the status quo of training communication skills in medical services, a structured questionnaire was developed
separate for undergraduate/ postgraduate medical education and for
residency training programs. The undergraduate/ postgraduate questionnaire was applied between January and June 2011 at 1122 medical
lecturers of German universities, accordingly the residency questionnaire was applied in July 2011 to 1164 directors of clinician institutes
and oncology associated medical services. The questionnaires surveys
educational objectives, pedagogic tools, didactics, time frames, structural circumstances, examination methods, etc. Descriptive analysis of
the data (performed with SPSS for Windows, Version 18) includes mean
values, standard deviation and percentage of the main questionnaire
issues.
Results and conclusions. The current study aspire an overview of training
communication skills and social competencies in German medical education and medical care services of cancer patients. First results indicate
complexity and heterogeneity with regard to structural conditions and
with regard to implementation of communication skills training. The
study results will provide important data to describe the need for improvement of communication skills training within medical education.
0299
Life goals, depression and quality of life in cancer patients
*P. von Blanckenburg1, M. Bodenbenner1, N. Conrad1, W. Rief1, C. Exner1,2,
U. Seifart3
1
Philipps Universität Marburg, Klinische Psychologie und Psychotherapie,
Marburg, Deutschland, 2Universität Leipzig, Klinische Psychologie, Leipzig,
Deutschland, 3Rehabilitation Clinic Sonnenblick, Marburg, Deutschland
Purpose. A cancer diagnosis affects the pursuit of patients’ life goals. Discrepancies occur between the importance of a life goal and the success
in achieving it. The aim of the present study was to compare subjective
importance and success in attainment of life goals in cancer patients
with a normative sample. Further objectives were to examine associations between life goal discrepancies and patients’ well-being (quality
of life/depressive symptoms), and to identify the predictive value of life
goal adjustment two years later.
Methods. A sample of 82 inpatients (female: 5.9%; mean age: 52.6; SD:
8.0) was recruited during oncological rehabilitation. Attributes of six
different life goal domains were measured using the Life Goal Questionnaire (GOALS). Depressive symptoms were assessed with the Center
for Epidemiologic Studies Depression Scale (CES-D) and global quality of life using the short WHO-Quality of Life Questionnaire (WHOQOL-BREF). Relevant medical and demographic data were recorded. A
subsample (n=28) was reassessed two years later.
Results. Intimacy (e.g. to have a close relationship) was the most important life goal domain and significantly more important to oncological patients than to controls. Altruism (e.g. to act unselfishly), power
(e.g. to exert influence) and variation (e.g. to live an exciting life) were
less important. Patients experienced greater success in attaining the life
goal intimacy and less success in the domains achievement (e.g. to improve skills continuously), affiliation (e.g. to have many social contacts),
power and variation. With the use of hierarchical multiple regression
analyses – after controlling for demographic variables – the overall life
goal discrepancy was associated with depression (adjusted R2=0.180,
p<0.001) and global quality of life (adjusted R2=0.260, p<0.01). The most
influential life goal domains were intimacy and affiliation. Additionally,
the general life goal adaption was associated with higher global quality
of life after two years and not associated with depressive symptoms.
Discussion: Discrepancies in the importance and perceived success in
attaining life goals were associated with the subjective well-being of
cancer patients. Particularly relationship-orientated life goals seem to
play a major role in patients’ well-being. The results suggest that patients
could profit from psychological interventions that foster life goal adaptation to enhance the global quality of life in cancer survivors.
0307
Certified cancer centre and specialized outpatient palliative care
*K. Neuwöhner1, *R. Wildner2
1
Klinik Dr. Hancken GmbH, Zentrum f. Palliativmedizin, Stade, Deutschland,
2
Klinik Dr. Hancken GmbH, Palliativteam Niederelbe, Stade, Deutschland
Introduction. Since April 1st, 2007, in accordance with the Social Code
Book V (SGB V), patients with statutory legal insurance are entitled to
specialized outpatient palliative care (SAPV). The legislator intended
these services for insured persons suffering from an incurable disease,
with limited life expectancy and a special need for care. Following the
directives of the Federal Joint Committee ca. 170 specialized palliative home care services were founded in Germany since 2007 and set to
work until 2011. Only few were integrated in certified cancer centres.
The reason is, cancer centres are often departments of hospitals and the
medical and nursing staff members cannot cross the legal borderline
between inpatient and outpatient services in Germany.
Method. In the regional cancer centre of Stade, certified since 2004 by
ESMO, a specialized palliative home care service was founded at January 1st, 2011, with a coordinator and five cooperating oncologists with
certificates in palliative medicine and three cooperating palliative care
nurses. The managing board of the hospital offered the staff members to
change the employment contracts and split their working time with the
inpatient and outpatient service in a flexible way.
Results. The specialized palliative home care service of the cancer centre attended 60 patients from January until July 1st, 2011 with advanced
cancer disease and in a terminal status of the disease, with averaged
27 days of care. Nursing and medical staff members of the hospital paid
about 500 house visits to their patients. Further results will be presented.
Conclusion. There was an increased demand for specialized palliative
home care. The needs were on a high level of complexity and involved
medical, nursing, psycho-social and spiritual requirements. The most
impressing positive experience on both sides, staff members and patients and their families was the continuity of caring across the borderline between inpatient and outpatient services.
0333
Physical activity in colorectal cancer patients: a review of clinical
trials
*W. Jensen1, K. Oechsle1, C. Bokemeyer1, W. Bloch2, F.T. Baumann2
1
University Medical Center Hamburg-Eppendorf, Department of Oncology/
Hematology/Bone marrow transplantation with section of Pneumology,
Hamburg, Deutschland, 2German Sport University Cologne, Department of
Molecular and Cellular Sport Medicine, Institute of Cardiovascular Research
and Sport Medicine, Cologne, Deutschland
Background. The positive effect of physical activity in primary prevention of colorectal cancer (CRC) is well known. In addition, recent
studies suggest a positive impact of physical exercise on survival in patients (pts) with early stage CRC. The aim of this review analysis was to
summarize feasibility and efficacy data on physical training programs
in CRC pts.
Methods. A PubMed database analysis was performed searching for clinically relevant trials on physical activity and training programs in pts
with localized and advanced CRC.
Results. A total of 8 studies (3261 pts) entered this analysis. Physical activity was assessed by questionnaires in 5 studies. Metabolic equivalent
task-hours per week (MET/h/w), was calculated additionally in 4 of
them. These 5 trials consistently demonstrate improved cancer-specific
and overall survival in physically active pts with localized CRC compared with less active pts. In a further study, increased cardiovascular
fitness was associated with improved quality of life after curative CRC
treatment. Two studies showed a beneficial effect of low- and high-intensity exercise on markers of tumor inflammation and proliferation
in pts with localized and advanced CRC. This represents still the only
study in pts with advanced CRC. Interventional studies evaluating specific training programs are rare and, until today, convenience evidence
of positive effects of physical activity on disease- or treatment-related
symptoms in pts with advanced CRC is lacking. Furthermore, systematic analyses of dietary and other lifestyle factors should be included in
these evaluations.
Conclusion. Various positive effects of physical activity could be demonstrated in pts with CRC, but specific trials evaluating different training
programs and their efficacy on tumor/treatment-related symptoms are
needed for clinical practice recommendations. In addition, they should
respect aspects of life style and nutrition. Therefore, we have initiated a
randomized controlled trial to determine the impact of aerobic exercise
or strength training program on physical capacity, quality of life, symptom control, as well as biological parameters in pts with advanced CRC
undergoing palliative chemotherapy.
0342
Tobacco and alcohol consumption five years after partial laryngectomy
*H. Danker1, D. Wollbrück1, A. Meyer1
1
Universität Leipzig, Medizinische Psychologie und Medizinische Soziologie, Leipzig, Deutschland
Background. Tobacco and alcohol consumption are major risk factors
for the development of laryngeal cancer. As a high proportion of patients continue to smoke and drink after surgery, the risk for adverse health effects remains stable. The aim of the study was the identification of
conditions that increase the probability of health risk behaviors among
partial laryngectomy patients.
Patients and methods. We surveyed 151 laryngeal cancer patients five years after partial laryngectomy. Post-operative alcohol and tobacco consumption, socio-demographic, medical, and psychosocial parameters
were investigated.
Results. At the time of the survey 22% were smokers. Patients who had
no or little social support were at a higher risk (OR=8.67) to continue
smoking in comparison to those with adequate social support. In 28% of
the male participants alcohol consumption was at a harmful level. Only
two of the respondents associated their alcohol consumption with the
development of the disease. 44% of the participants identified smoking
as the cause of the disease. Unlike smoking, the chance of alcohol consumption was increased by high social support after surgery (OR=11.20).
Discussion. Health risk behavior is often maintained after an illness of
laryngeal cancer. Whereas the harmfulness of smoking appears widely
known, this is far less the case with respect to alcohol. This could also
be reflected in the fact that social support stimulates the consumption
of alcohol on the one hand and prevents smoking on the other hand. A
need for professional education and support seems appropriate given
the study results.
Abstracts
0347
Fear of recurrence and disease progression in long-term
(≥5 years) cancer survivors – a systematic review of quantitative
studies
*L. Koch1, L. Jansen1, H. Brenner1, V. Arndt1
1
German Cancer Research Center (dkfz), Division of Clinical Epidemiology
and Aging Research, Heidelberg, Deutschland
Background. Increasing proportions of men and women diagnosed with
cancer will become long-term survivors (≥5 years post-diagnosis). However, survivors may continue to experience negative effects of cancer
and/or treatment, including fear of recurrence (FoR). FoR was shown
to be highly prevalent in cancer survivors and found to be negatively
associated with quality of life (QoL) and related to a variety of possible
determinants like race, or optimism. Only few studies have examined
FoR specifically in long-term cancer survivors. Knowledge on FoR and
other possible psychosocial burdens in long-term survivors is crucial to
ensure adequate surveillance and support for this group of survivors.
Methods. Multiple databases including PUBMED, EMBASE, and PsycINFO were searched to identify relevant articles. Seventeen articles
were included. Data were extracted by two reviewers and summarized
following a systematic scheme.
Results. Even five or more years after initial diagnosis, cancer survivors
suffer from FoR. Most studies report low or moderate mean FoR scores,
suggesting that FoR is experienced in modest intensity by most longterm survivors. Studies including long-term and short-term survivors
indicate no significant change of FoR over time. Lower level of education, lower level of optimism and being Hispanic or White/Caucasian
were found to be associated with higher levels of FoR. Significant negative associations were reported between FoR and QoL as well as psychosocial well-being. All but three studies were conducted in the USA.
General cut-offs for severity/clinical significance of FoR have not been
defined yet.
Conclusions. FoR at modest intensity is experienced by most long-term
cancer survivors. Future studies should address determinants and consequences of FoR in more detail. Validated instruments providing cutoffs for severity/clinical significance of FoR should be developed and
utilized. Efficient interventions should be implemented to reduce detrimental effects of FoR.
0352
Training physical activity in cancer patients
*C. Kerschgens1, J. Langenhorst1, A. Holzgreve2
1
Vivantes Rehabilitation GmbH, Onkologie, Berlin, Deutschland, 2Vivantes
Stiftung, Berlin, Deutschland
Summary. A training program for cancer patients during chemo and/
or radiotherapy is feasible. Patients with metastatic disease show differences in physical status and psychosocial issues compared to patients
treated in adjuvant settings.
Introduction. Much information has been given concerning physical
activity and exercise training in cancer patients, mostly related to prevention of cancer or cancer recurrence. Therefore patients in the adjuvant setting, namely women with breast cancer were targets of these
interventions. Less is known about training activities in cancer patients
treated in a palliative setting. Moreover most of these patients are not
able to join the athletic program, which is financed by the German health insurance system (Rehasport).
Material and methods. Beginning in August 2010 a weekly program
was offered, which included a 90-minute training session, consisting of
30 minutes of exercises in strength and endurance with sports equipment, 30 minutes of coordination and balance and 30 minutes of relaxation (PMR). The program was open to all interested patients who
underwent chemo and/or radiotherapy at the time. The program was
conducted by sports therapists and constantly supervised by a trained
oncologist. Each patient was scheduled to participate for 6 months. At
the beginning and end of the program assessments were performed.
These included a 6-minutes walking test, an assessment for CIPN and
questionnaires concerning psychosocial issues and well-being (PHQ
and EORTC-LQ).
Results. From August 2010 to May 2011 17 patients were enrolled in the
program, median age was 58.41 y, 6 male and 11 female pts. 7 patients
had metastatic disease and were treated in palliative intention, 10 patients were women with breast cancer in an adjuvant therapy setting.
The 6-MGT in pts with metastatic disease showed a median result of
398 mts. (120–528) and in pts with adjuvant therapy 565.1 mts (435–670).
The CIPN-assessments classified the neuropathy according to the CTC,
highest level of CIPN in all pts was sensory CTC grade I, in 84% of the
pts with metastatic disease and 20% of the pts in the adjuvant setting.
Concerning the psychosocial evaluation depressive symptoms were detected in 62.5% of the adjuvant treated pts and 42.8% of the palliative
treated pts. Quality of life according to the EORTC was equally scored
by adjuvant and palliative treated pts. The majority of palliative treated
pts. was not able to continue the program over 6 months, reasons were
progressive disease and concomitant worse condition. An interview
was done with all pts at the end of the program; all pts mentioned the
program to be helpful to regain physical activity and well-being.
Discussion. Our program showed good acceptance in adjuvant and palliative treated pts. In the performed assessments the palliative treated
pts showed clearly poorer performance in their physical activity (6MGT
and CIPN) but better or equivalent status in psychosocial issues and
quality of life.
0354
Movement therapy in nature based on the Scandinavian philosophy of outdoor life (Friluftsliv)
*S. Meier1, S. Tari1, W. Hiddemann1,2, P. Heußner1,2,
lebensmut e.V., Psycho-Onkologie, München, Deutschland, 2Klinikum der
LMU, Medizinische Klinik und Poliklinik III, München, Deutschland
1
The positive effects of moving and staying in motion on the quality of
life of cancer patients have been scientifically proven many times. At
the same time using the soothing effects of nature is a simple and valuable approach, but in contrast it is rarely implemented. In September
2009, the Outdoor Active program of the Association lebensmut e.V.
in cooperation with the Psycho-Oncology at the Medical Clinic III at
the Hospital of the University of Munich has started. In a four-weekly
period easy day hikes to the nearby surrounding are organized, which
take place in any weather condition. The group is composed of a maximum of eight patients, a psycho-oncologist, a sports scientist and
two dogs. Patients receive at registration a detailed consultation from
the psycho-oncologist and then have to bring medical clearance from
their doctor. The tours are selected according to a defined list of criteria
and pre-tested. In addition to formal criteria such as distance, elevation profile, route conditions and the season, the legal insurance criteria
have to be met. Furthermore, care is taken all the tours to be planned
are easily performed, and the transfer of movement in everyday life is
possible. The rediscovery of nature and discovering new things is an
important aspect for the participants. Perception, relaxation or strengthening exercises as well as meditations are offered as part of the „Active
Outdoors“ program; the following principle applies: In nature it is not
important to measure how much one has moved or how far one has
walked. The crucial thing is „to be“ and to be noted that one is moving,
living and simply enjoying the moment. To date, a group of participants
are regularly taking part in the tours. To be observed is that individuals
are independently taking part in the active tours and making their own
trips. And along with the development of new environment out of everyday life, also the living environment of many patients has expanded:
they draw self-assurance and strength from their experience during the
„Active Outdoors“ tours.
0368
Benefit finding and posttraumatic growth in long-term colorectal cancer survivors: prevalence, determinants, and associations
with quality of life
*L. Jansen1, M. Hoffmeister1, J. Chang-Claude2, H. Brenner1, V. Arndt1,3
1
Deutsches Krebsforschungszentrum (dkfz), Klinische Epidemiologie
und Alternsforschung, Heidelberg, Deutschland, 2Deutsches Krebsforschungszentrum (dkfz), Epidemiologie von Krebserkrankungen, Heidelberg, Deutschland, 3GEKID, Cancer Survival Working Group, Heidelberg,
Deutschland
Background. Research on quality of life of colorectal cancer survivors
has mainly focused on downsides of cancer survivorship like long-term
symptoms and restrictions in quality of life. But studies have shown that
cancer survivors may also report positive changes in the context of their
disease, like benefit finding (BF) and posttraumatic growth (PTG). To
get further insight into BF and PTG in long-term colorectal cancer survivors, the aim of this study is to investigate the prevalence of BF and
PTG and to determine what socio-demographic, clinical, and psychosocial factors distinguish colorectal cancer survivors who show a high
level of BF and PTG from those who experience only low levels.
Methods. This analysis includes patients with colorectal cancer from
a population-based case-control study (DACHS-study) carried out in
southwest Germany (Rhine-Neckar-Odenwald and Heilbronn Region).
BF, PTG, and quality of life were assessed five years after diagnosis in
483 colorectal cancer patients using the benefit finding scale, the posttraumatic growth inventory, and the EORTC QLQ-C30. Prevalence of
BF and PTG, determinants of moderate to high BF and PTG, and the
association between BF, PTG, and quality of life were investigated.
Results. Almost all survivors experienced BF and PTG at least to some
degree and 64% and 46% of the survivors experienced moderate to high
levels of BF and PTG, respectively. Survivors with the highest level
of education and with higher depression scores reported less BF and
PTG. PTG increased with increasing stage and self-reported burden of
diagnosis. Quality of life only correlated weakly with PTG (Pearson’s
r=0.1180, p=0.0112) and not with BF (r=0.0537, p=0.2456).
Conclusion. Our results show that BF and PTG are highly prevalent
among long-term colorectal cancer survivors. Thus, to get a comprehensive understanding of the adjustment of cancer patients after diagnosis, negative as well as positive consequences of cancer survivorship
need to be investigated. As quality of life was only weakly related to BF
and PTG, the generally reported high global long-term quality of life
after cancer cannot be directly explained by these positive adjustments.
0390
Effect of a four-week bicycle tour on the prostate specific
antigen, total testosterone, and interleukin-6 value in prostate
cancer patients
*M. Müsgens1
1
Deutsche Sporthochschule, Institut für Kreislaufforschung und Sportmedizin – Abteilung molekulare und zelluläre Sportmedizin, Köln, Deutschland
Introduction. Prostate cancer is nowadays in the male population with
about 20% one of the most common malignant tumor [4]. This urological tumor can occur at the age of 45 years and be diagnosed, but the
probability is very low, succumb to this disease at such an early stage [2].
The framework for the diploma work is a four-week bicycle trip from
Cologne to Marseille, with eight participants who suffer from prostate
cancer. The focus of this study is on three medical parameters, namely
the prostate-specific antigen, the total testosterone and the interleikin-6.
These parameters are tested for the effect of a prolonged endurance performance on the bike. The measurements were made one week before
and one week after the bike tour and six months after the intervention.
Results. The follow-up measurements showed a slight reduction in PSA
level, but this development can not be explained as the sole cause of the
bike tour. Regarding the measured testosterone concentration, a significant reduction of the first to the third measurement was identified. These results support previous studies in which the cycling is an effective
rehabilitative agent for prostate cancer patients to reduce the total testosterone value in the long term. The data of the cytokine interleukin-6
showed no significant changes by the endurance bike ride and mostly
remained at a constant concentration level.
Discussion and conclusion. This study has no elevated PSA and interleukin-6 levels after a four-week bicycle tour can be measured. Related to
testosterone, there was a significant reduction in concentration in the
follow-up measurement. Causes that may lead to an influence of testosterone has behavioral characteristics such as physical training, nutrition, sleep, alcohol consumption, smoking and stress [3]. Furthermore,
it is scientifically proven that endurance sports often leads to a decrease
in testosterone concentration [1]. However, further studies have to be
conducted, in order to better understand the effects of a physical endurance stress on PSA, testosterone and interleukin-6 in prostate cancer
patients.
1. Diederich S et al (2007) Hormonelle Veränderungen durch Ausdauersport.
Blickpunkt der Mann 5(4):36–41
2. Hautmann R, Huland H (2006) Urologie
3. Sommer F (2006) Männergesundheit. Blickpunkt der Mann 4(3):5–10
4. Stenzl A (2009) Prostatakarzinom
5. Baumann FT, Herweg C, Schüle K (2008) Bewegungstherapie und Sport bei
Krebs
0392
The attending physician between psychosocial challenge and
medical requirement – Orientation to needs in an oncologic
practice
*U. Hoppenworth1, *C. Sokol1, M. Fischer2, F. Adam2
1
Hoppenworth/Sokol, Hildesheim, Deutschland, 2megapharm, Sankt
Augustin, Deutschland
The integration of psychosocial care within medical treatment poses a
special challenge to hospitals and oncological practices. According to
epidemiological estimations about 40–50% of all cancer patients develop physical and mental problems as a result of their cancer. Studies
show that early psychosocial and psychooncological support is useful to
counter chronification, to improve the therapy compliance of patients
and to improve their quality of life. With the aid of the Hornheider
Fragebogen the Oncologist is able to recognize at an early stage whether patients are under psychological pressure. Our project is based on
the analysis of more than 20,000 questionnaires, which were collected
between 1998 and 2011. Through this survey it was possible to identify
the care required by cancer patients with different tumours receiving
ambulatory treatment, both on a singular and comparative basis. By
analyzing the data it will be possible to gain insights on similarities
and differences in the experiences of patients and their coping strategies taking into account their sociopsychologic and sociodemographic
background. Furthermore specific core disorders will be identified. In
summary this study is able to provide the empirical base for a more accurate indication for psychooncological treatment and not least could
improve patients‘ quality of life.
Abstracts
0409
Enhanced oxygen capacity results in fatigue-reduction and
improvement of quality of life
*M. Bernhörster1, L. Vogt1, K. Schmidt1, A. Lungwitz1, C. Thiel1, E. Jäger2,
W. Banzer1
1
Goethe Universität, Sportmedizin, Frankfurt, Deutschland, 2Krankenhaus
Nordwest GmbH, Hämatologie und Onkologie, Frankfurt, Deutschland
Introduction. There is moderate evidence that physical activity is beneficial in cancer treatment. Patients improve in endurance and muscle
strength as well as physical, social and psychological functioning. However, to our knowledge only limited data is available regarding the
relationship between performance enhancement and quality of life
improvements during cancer treatment. Therefore we aimed to explore
the dependence of changes in oxygen uptake, quality of life and cancer
related fatigue (CRF) during a 4-month period.
Methods and materials. Aerobic exercise capacity (VO2peak), quality
of life and fatigue symptom (EORTC QLQ-C30) were obtained in 101
cancer patients (30–77 years). After initial examination patients were
given the opportunity to engage in supervised and/or home-based training interventions. Patients were re-examined after 16 weeks and stratified into 3 sub-groups (terciles) with respect to the absolute change in
VO2peak.
Results. Depending on the absolute change of VO2peak (1.9±1.7; 1.8±0.8;
5.7±2.8 ml/kg/min) there were significant differences in the quality of
life improvement and cancer-related fatigue reduction. Nevertheless,
patients in the upper third, with initially high levels of fatigue, were
as likely to show a minimum 10% enhancement in VO2peak as patients with low or medium fatigue levels. Subjects with a minimum 10%
VO2peak -increase had a 2.6 times higher chance to obtain a 20% fatigue symptom reduction.
Conclusions. In the present study almost all patients of the mixed diagnosis cancer population improved their exercise capacity and demonstrated enhanced QoL after 16 weeks of supervised and/or home-based
exercise training. The findings point toward a relationship of exercise
capacity enhancement, quality of life improvement and fatigue symptom reduction during cancer treatment. Beside the retrospective analysis, that is not capable to clearly demonstrate causal dose-responserelationships, the study is limited in consideration of the fact, that CRF
is a multidimensional complex of different affections. Additional data is
necessary to determine the most effective parameters of exercise for fatigue management including the types, mode, intensity, frequency and
duration of exercise regimes. Developing exercise programs that incorporate these factors will allow patients to reduce CRF in an optimum of
time and energy expenditure.
0419
Integrating palliative care into comprehensive breast cancer
therapy – first experiences
*R. Wuerstlein1,2, S. Frechen2,3, J. Wolf2,4, M. Hellmich2,3, P. Mallmann2,5,
N. Harbeck1,2, R. Voltz2,3, J. Gaertner2,3
1
Universitätsklinik, Brustzentrum, Köln, Deutschland, 2CIO, Köln-Bonn,
Deutschland, 3Universitätsklinik Köln, Z. für Palliativmedizin, Köln, Deutschland, 4Universitätsklinik, Klinik für Innere Medizin I, Köln, Deutschland,
5
Universitätsklinik, Frauenklinik, Köln, Deutschland
Background. The integration of palliative care (PC) early in the disease trajectory of life limiting diseases is explicitly recommended by the
World Health Organisation (WHO). This recommendation was included in the administrative directives for principles of cancer care in our
institution. The aim of this study was to assess, at what point in the disease trajectory patients with breast cancer (BC) were first provided PC
and whether – over one year – an earlier integration of PC could be
achieved.
Objective. A retrospective systematic chart analysis of a two year period
was performed. We assumed that seeing patients relatively early during
the course of the illness would be reflected by seeing patients that would
be not already in a reduced performance status and/or experiencing
symptoms that are indicators for advanced disease (e.g. dyspnoea). Therefore, the first PC consultation for every BC patient seen by the PC
support team was analyzed to assess in what physical condition patients
receive first PC consultation and what burdening symptoms they already experienced.
Results. Many patients were already in a reduced physical state and were
experiencing burdening symptoms. After a one-year period, the number of burdening symptoms identified at first PC consultation and the
admissions to the in-patient PC ward decreased while non-PC physicians increasingly requested PC support for psychosocial interventions.
Conclusion. Though some degree of development towards a better understanding of PC competencies and the early integration approach
could be demonstrated, the adoption of the WHO recommendation
alone did not suffice to integrate PC into routine BC therapy early in
the course of the illness. Therefore, the development of disease specific
guidelines in an interdisciplinary comprehensive-cancer-care setting is
advocated. A standard operating procedure for the CIO (centrum of integrated oncology) Cologne-Bonn was developed and will be presented.
0433
New German Hospice and Palliative Care Registry
*L. Radbruch1, T. Montag2, K. Neuwöhner3, G. Lindena4, F. Nauck5
1
Universitätsklinikum, Klinik für Palliativmedizin, Bonn, Deutschland, 2Universitätsklinikum, Zentrum für Palliativmedizin, Köln, Deutschland, 3Universitätsklinikum Bonn, Abteilung für Palliativmedizin, Bonn, Deutschland,
4
CLARA Klinische Forschung, Kleinmachnow, Deutschland, 5Universitätsmedizin, Abteilung Palliativmedizin, Göttingen, Deutschland
Introduction. Data from clinical studies should be rounded off with
clinical practice data especially in patients with multiple comorbidities or end of life state for improving processes of care. The German
Palliative Care Association (DGP) starts a hospice and palliative care
registry collecting a defined core data set and subsequent feedback and
benchmarking for quality improvement of hospice and palliative care
in Germany.
Methods. Interested outpatient and inpatient institutions providing
specialized hospice and palliative care SHPC announce their participation. Precondition is the collection of the core data set electronically
and patient consent. The core data set includes patient demographic
data, diagnoses and impact, disease severity, symptom incidence and
severity, selected drug and other treatment options as well as outcome
death or discharge – in inpatients –, admission to a hospital – in outpatients – and evaluation of the care process by the team. These data sets
are to be de-identified and uploaded to the registry via a secure line. The
evaluation is fed back to the participating facilities of SHPC and they
additionally receive comparison data of other centers, also summarized
by facility type for benchmark purposes.
Results. The core data set was defined in 2009, newly discussed and
slightly changed considering the experiences. Primary program providers were made interested to include the core data set in their programs.
The registry allows comparing the structure and indication quality of
SHPC facilities, benchmarking processes and results, each with deidentified data for the participating institutions. It also offers data for
scientific evaluation of major interest across settings.
Discussion. Hospice and palliative care treatment SHPC facilities are
working under regionally varying conditions with room for improvement concerning provision of care, kind of care and interdisciplinary
cooperation, qualification, quality of care and reimbursement. A specific issue is the recognition and definition of the patient’s referral to
specialized hospice and palliative care in time. The participation in the
registry is voluntary and the motivation of facilities is crucial to share
the adjunctive costs. DGP is optimistic to successfully implement and to
achieve the necessary supra-regional and supra-institutional participation. The experiences with the preliminary quality improvement project
hospice and palliative care evaluation HOPE provide confidence.
0461
Evaluation of the impact of a 3-month strength training on
immune system, fatigue and quality of life in women with breast
cancer undergoing chemotherapy
*S. Frisse1, L. Gerland2, S. Latta1, W. Bloch2, N. Harbeck1, F.T. Baumann2
1
Uniklinik Köln, Frauenklinik, Brustzentrum, Köln, Deutschland, 2Deutsche
Sporthochschule Köln, Institut für Kreislaufforschung und Sportmedizin,
Abteilung für molekulare und zelluläre Sportmedizin, Köln, Deutschland
Background. 80–96% of breast cancer patients experience fatigue during
chemotherapy (Bardwell 2008), causality remains unexplained (Glaus
1996). Most patients are subjectively more restricted by fatigue than by
pain or nausea (Arndt 2006). Studies showed positive effects of endurance training on the intensity of fatigue. The range of studies about feasibility and efficiency of exclusive strength training in the rehabilitation
of breast cancer patients experiencing fatigue is so far insufficient (De
Backer 2009). The impact of physical activity on the immune system is
not yet resolved unambiguously.
Objective. The study aims at analyzing the development of parameters
of the immune system, fatigue and quality of life in breast cancer patients executing strength training during chemotherapy.
Methods. 40 breast cancer patients in adjuvant chemotherapy are involved 6–12 weeks after surgery: 20 patients each are assigned to the
intervention and to the control group. Strength training is executed twice a week for about 60 minutes for a period of 12 weeks. The following
parameters are analyzed at the beginning and after 12 weeks: parameters of the immune system (e.g. erythrocyte-flexibility and cytokines),
fatigue via standardized questionnaire MFI-20 as well as quality of life
based on the questionnaires EORTC QLQ-30 and QLQ-23. Fatigue and
quality of life are examined additionally in week 6.
Results. The analysis of all results is expectedly done in the end of 2011.
Bettering of fatigue is noticeable by trend. Parameters of the immune
system are not yet interpreted. By the time of presentation, more comprehensive data will be available.
Discussion. A positive tendency concerning fatigue can be considered as
a surplus for breast cancer patients. Although the number of test persons is comparatively small, a heterogeneous collective of patients becomes apparent. Improvement of quality of life and attenuation of fatigue
would be considered as a major success.
0463
Evaluation of the impact of a 3-month strength training on
strength parameters, EMG and oxidative stress of breast cancer
patients during chemotherapy
*L. Gerland1, S. Frisse2, S. Latta2, W. Bloch1, N. Harbeck2, F.T. Baumann1
1
Deutsche Sporthochschule Köln, Institut für Kreislaufforschung und
Sportmedizin, Abteilung für molekulare und zelluläre Sportmedizin, Köln,
Deutschland, 2Unifrauenklinik, Brustzentrum, Köln, Deutschland
Background. Evaluations of the effect of strength training in oncological
rehabilitation are rare. The impact of physical activity on the immune
system is not yet verified definitely. It is assumed that regular physical
activity has positive effects on oxidative stress (Gago-Dominguez 2007).
Studies have shown significant improvement of muscular strength of
cancer patients after intensive strength training (Quist et al 2006, Galvao et al 2007, Battaglini et al 2007). Studies implementing EMG-measurement in strength tests of breast cancer patients could not be found.
Aims. The study aims at analyzing the development of strength parameters, EMG and oxidative stress and antioxidative capacity of breast
cancer patients executing strength training during chemotherapy.
Methods. The study is organized as a prospectively randomized and
controlled preference study. 40 breast cancer patients in adjuvant chemotherapy are involved 6–12 weeks after surgery for 12 weeks: 20 probands each are assigned to the intervention and to the control group.
Strength training is executed twice a week for about 60 minutes, consisting of 7 routines in 3 sets of 8–12 dynamic repetitions. The training is
constantly supervised. Subjective intensity is controlled during exercise
by modificated RPE-scale, aiming at local muscular exhaustion. The
following parameters of both control and intervention group are analyzed in the beginning and after the 12 weeks: parameters of the immune
system (oxidative stress, antioxidative capacity), strength is examined
by isometric and isokinetic tests of upper and lower extremities including EMG-measurement.
Results. The examination of all results is scheduled for the end of the
year 2011. An increase of muscular strength is noticeable by trend. Parameters of the immune system have not yet been interpreted. By the time
of presentation, more comprehensive data will be available.
Discussion. A significantly positive tendency concerning strength parameters can be considered a surplus for cancer patients. Although the
number of test persons is comparatively small, a heterogeneous collective of patients becomes apparent. The current tendencies suggest the
integration of an intensive strength training program into the rehabilitation of mastocarcinoma patients.
0470
Subjective performance of memory and concentration in patients with brain metastases before and after radiotherapy
A. Cole1, S. Janssen1, M. Bremer1, *D. Steinmann1
1
MHH, Strahlentherapie, Hannover, Deutschland
Purpose. To prospectively assess the progress of neurocognitive functions in patients with brain metastases from any solid primary treated
with radiotherapy to the brain.
Patients and methods. Adult patients with brain metastases (n=50) with
or without surgery (n=10 vs. n=40) were treated with radiotherapy (RT)
based on different dose-fraction schemes according to the patient’s status: whole-brain RT (n=29) or hypofractionated stereotactic RT (n=21)
were performed. In the control group breast cancer patients without
cranial involvement (n=29) were treated with whole-breast radiotherapy to the breast or chest wall after surgical excision of the tumourous
breast tissue. Patients were recruited between May 2008 and December
2010 to subjectively evaluate cognitive function before RT, 6 weeks, 3
and 6 months after irradiation. For assessment of the neurocognitive
status the relatively new German questionnaires for self-perceived deficits in attention (FEDA) and for acquisition of experiences with every
day memory (FEAG) were used.
Results. After a limited survival in patients with BM (4.3 months), 20 patients (40%) died. Patients with operation (4.1 mo) lived longer than patients without surgery (6.8 mo) and hfSRT (9.9 mo) provided a better
survival than WBRT (2.9 mo). In patients with BM attention and memory status decreased at every point of time while it stayed relatively
stable in the control group. Differences in progress explored between
the two groups were significant in all three FEDA scales distractibility
and deceleration of mental processes (p=0.049), exhaustion and deceleration of activities (p=0.002) and decrease in motivation (p=0.035)
but not in every day memory as assessed with the FEAG questionnaire.
Without operation patients had a better memory (p=0.039). As a trend
patients with hfSRT rather then WBRT had better performances in all
subscales.
Conclusion. NCF in patients with BM declined for all 4 scales at every
point of time after RT while breast cancer patients stayed more stable.
Abstracts
0471
Occurrence and impact of pain, insomnia, fatigue symptom
cluster in 207 cancer patients with pain treatment: a secondary
data analysis
*M. Gunga1, M. Landenberger1, P. Jahn1
1
MLU Halle, IGPW, Halle, Deutschland
Objective. Cancer patients experience a variety of symptoms either as
a result of their disease or in consequence of their treatment. These
symptoms occur frequently, in a non random distribution, in groups
or clusters. In a definition from Kim et al. (2005) „A symptom cluster
is defined as consisting of 2 or more symptoms that are related to each
other and that occur together” (p. 278). The intention of this secondary
data analysis was to examine patterns of symptom clusters over time at
four different measuring times and their impact on global health status
and functionality.
Method. The basis of this analysis is a cluster-randomized multicenter
trial with the title “Improvement of pain related self management for
oncologic patients through a transinstitutional modular nursing intervention” (Jahn et al. 2010). Patients were included if they had diagnosed
malignancy, persistent pain >3 days and average pain intensity ≥3/10.
The trial was conducted on 18 wards in 2 German university hospitals.
The analysis of the present study is carried out with the help of the “PIFcluster” (pain-insomnia-fatigue-cluster), a common cancer symptom
cluster. A patient in the study complied the “PIF-cluster” conditions if
in each case pain-, insomnia- and fatigue-measured values were higher
than 30 out of 100.
Results. 207 patients participated (average age: 56.8±12.3 years, 57.5%
male). 160 (77.3%) participants showed a PIF-cluster at baseline. 136
(65.7%) of these patients met the terms of the PIF-cluster at the secondary measurement (the day before discharge). Furthermore 113 (54.6%)
persons matched the PIF-cluster seven days after discharge and 68
(32.9%) persons matched it 28 days after discharge. It becomes apparent
that if somebody showed a new occurred PIF-cluster at a later measuring point, his global health status and functionality values were ordinarily significant poorer. Such a patient shows on average a −12.7 points
lower value for global health status, −9.4 points for physical function,
−39.2 points for role function, −2.8 points for emotional function, −4.5
points for cognitive function and −18.2 points compared with the first
measuring point.
Conclusion. To sum up this longitudinal research shows that symptom
clusters are relative stable during a certain period and that the occurrence or loss of symptom clusters has direct effects on the patient’s quality of life and his functionality.
Urologische Tumoren
0031
Combined anti-inflammatory, immunomodulatory and angiostatic treatment in patients with castration-refractory prostate
cancer: a phase II study of Imatinib with Pioglitazone, Etoricoxib,
Dexamethasone and low-dose Treosulfan
*A. Reichle1, M. Vogelhuber1, S. Feyerabend2, T. Südhoff3, M. Schulze4,
J. Hübner5, R. Oberneder6, M. Baier7, A. Rübel7, K. Birkholz7, A. BakhshandehBath8, R. Andreesen1
1
University Hospital, Department of Hematology and Oncology, Regensburg, Deutschland, 2University Hospital, Department of Urology, Tübingen,
Deutschland, 3Hospital, Department of Hematology and Oncology, Passau,
Deutschland, 4Outpatient Center, Urology and Oncology, Markkleeberg,
Deutschland, 5J.W. Goethe University, Department of Oncology, Frankfurt,
Deutschland, 6Hospital, Department of Urology, Planegg, Deutschland,
7
Novartis Pharma GmbH, BU Oncology, Nürnberg, Deutschland, 8Outpatient Center, medical oncology, Hamburg, Deutschland
Background. With a median overall survival of about 19 months, therapeutic options for patients (pts) with castration-refractory prostate
cancer (CRPC) are still limited. Release and continuous production of
pro-inflammatory cytokines may account for its resistance towards cytotoxic drugs. Therefore, this phase II study analyzed the PSA-response
rate in pts with CRPC to combined biomodulatory agents in pts with
CRPC.
Methods. In 11 German centers, 69 pts with histologically confirmed
CRPC (according to EAU guidelines) were enrolled. In the 6 months
core phase pts were continuously treated with daily doses of imatinib
mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone until
PSA progression. Pts responsive to study medication were allowed to
enter an extension phase until disease progression or intolerable toxicity occurred. During the study, PSA-values, ECOG performance status
and QoL were continuously assessed.
Results. The core phase of this study was finished in July 2009. 18 patients were allowed to enter the extension of the study and two of these
pts are still ongoing As of June 2011 they have been on study medication
for 27 months. At baseline the median PSA value was 45.3 ng/ml (range
5–3603). The majority of pts had PSA doubling times of 50 to 100 days.
Of the 61 evaluable pts, 23 pts (37.7%) were considered as PSA responders with a confirmed PSA decline of at least 50%. Within the responders PSA decreased from 278.9 (±784.1) to 8.8 (±11.6) ng/ml during the
treatment period. Median time to PSA progression, PSA response and
overall survival were not achieved. 14 of the 38 non-responders (36.8%)
showed a stable disease. A total of 32 patients (52%) showed a decrease
in PSA during treatment in the core phase of the study. In some pts the
therapy led to complete resolution of bone lesions.
Conclusions. The study evaluated a new multi-targeted approach for pts
with CRPC. This multi-targeted approach led to an impressive response
rate of 37.7%, although the substances have shown limited efficacy in
single therapeutic use. Two patients are still ongoing in the extension
phase and have received study medication for 27 months (as of June
2011). A good PSA response and manageable toxicity make this combination treatment to an alternative treatment option to present regimens.
0033
Effect of intravenous zoledronic acid (ZOL) on bone metabolism
in patients (pts) with metastatic bone disease in prostate cancer
(PC) and breast cancer (BC): the ZOTECT study
*J. Gschwend1, T. Maurer1, T. Heck1, M. Muth2, A. Rübel2, K. Birkholz2,
T. Bauer3, M. Ziller3, P. Hadji3
1
Klinikum rechts der Isar, Technische Universität, Urologische Klinik,
München, Deutschland, 2Novartis Pharma GmbH, BU Oncology, Nürnberg,
Deutschland, 3Phillips-Universität, Klinik für Gynäkologie, Gynäkologische
Endokrinologie und Onkologie, Marburg, Deutschland
Background. Approximately 75% of pts with BC or PC will develop bone
metastases (BM), which influence bone metabolism and increase the
incidence of skeletal related events (SREs). The treatment of pts with
ZOL reduces the incidence and delays the onset of SREs. The primary
objective of this study was to access the course of several bone markers
under therapy with ZOL and the correlation with disease outcomes,
as recent studies showed strong correlations between the level of bone
markers and SREs.
Methods. This prospective, single arm, open-label study investigated
the effect of ZOL (4 mg IV q4wks given for 4 continuous months) on
bone markers (CTX, PINP, RANKL, OPG) in PC and BC pts with BM.
A final follow-up was conducted after 12 months. Secondary objectives
included the relationship between metastatic sites assessed by bone scan
and the level of bone markers at study entry, analgesics score and pain
assessment, the relationship between pain and SREs and the course of
bone markers, SRE rate, quality of life, Estradiol and PSA changes.
Results. Between May 06 and August 08, 99 BC pts and 301 PC pts were
recruited at 98 German sites. The course of OPG and RANKL was not
significantly influenced by ZOL, however the level of PINP and CTX
significantly decreased to stable values (p<0.0001) and 75% of the pts
showed reduced PINP and CTX levels after 4 months of therapy. No
significant differences between BC and PC pts were observed. Pts with
high EOD (extension of disease) score had higher PINP and CTX baseline values and also showed a reduction in PINP and CTX. Average PSA
values of PC pts were reduced from 168.5–92.5 µg/l. During the trial a total of 13 SREs occurred in 11 pts. A slight pain reduction with correlation
to the bone markers was detected. ZOL was generally well tolerated and
the adverse events were in accordance with the known safety profile.
Conclusion. Four months therapy with ZOL significantly reduced the
level of the bone markers PINP and CTX in 400 BC or PC pts with BM.
The reduced bone turnover marker levels were confirmed 8 months later
at the final assessment of the study. ZOL did not significantly influence
the levels of RANKL and OPG. This results support earlier evidence for
normalization of bone marker levels under therapy with ZOL. The trial
confirms that ZOL reduces bone resorption which has a positive effect
on the risk for SREs and improves clinical outcomes in pts with BM
from BC or PC.
0052
Interim analysis of a non-interventional study of everolimus in
metastatic renal cell carcinoma after the first anti-VEGF therapy: Subgroup analysis to evaluate second-line everolimus after
sunitinib
*L. Bergmann1, P.J. Goebell2, U. Kube3, M. Kindler4, T. Köpke5, J. Janssen6,
M. Schulze7, J. Schmitz8, S. Fries9, A. Köhler10, F. Overkamp11, M. Stähler12,
C. Doehn13, A. Jakob14, G. Guderian15, T. Steiner15,16
1
Universitätsklinik, Medizinische Klinik II, Frankfurt, Deutschland, 2Universitätsklinik, Abteilung für Urologie, Erlangen, Deutschland, 3Praxis für
Urologie, Chemnitz, Deutschland, 4Praxis f. Onkologie, Berlin, Deutschland,
5
Universitätsklinik, Abt. f. Urologie, Münster, Deutschland, 6Onkologische
Praxis, Westerstede, Deutschland, 7Praxis für Urologie, Markkleeberg,
Deutschland, 8St. Johannes Hospital, Arnberg, Deutschland, 9Outpatient
Center für Onkologie, Bamberg, Deutschland, 10Onkologische Praxis,
Langen, Deutschland, 11Onkologische Praxis, Recklinghausen, Deutschland,
12
Universitätsklinik, Abt. f. Urologie, München, Deutschland, 13Urologische
Praxis, Lübeck, Deutschland, 14Klinik Offenburg, Hämatologie/Onkologie,
Offenburg, Deutschland, 15Novartis Pharma, Nürnberg, Deutschland,
16
Klinikum Erfurt, Abt. f. Urologie, Erfurt, Deutschland
Introduction. Everolimus (EVE, Afinitor®) is approved for the treatment of metastatic renal cell carcinoma (mRCC) after failure of antiVEGF therapy. However, little data is available on EVE after failure of
1 VEGFR-TKI. Here, we report prospective non-interventional data on
second-line EVE in routine use after failure of sunitinib.
Methods. A prospective, multi-center non-interventional study for
patients with mRCC was initiated in Germany in 08/2009 to evaluate
EVE after the first anti-VEGF therapy in routine clinical use. Accrual
is ongoing. Safety and effectiveness (time from first EVE intake to progression due to any cause [TTP]) of EVE were analyzed in a pre-planned
interim analysis after 100 patients had been enrolled and followed for
≥3 months. Monitoring of 19% of patient data was carried out. Since
the majority of patients treated first-line with a VEGFR-TKI received
sunitinib, we chose to investigate this subgroup in this ongoing trial.
Results. 113 patients were enrolled at 59 centers between 08/2009 and
07/2010. Most common therapy prior to EVE was sunitinib and 59 patients were treated with second-line EVE after sunitinib. Other prior
therapies were sorafenib, cytokines and bevacizumab. Patients in the
sunitinib subgroup were followed for a median 124 days until the cut-off
date. Median duration of prior sunitinib treatment was 12.7 months. At
the time of analysis 23 patients in the subgroup had discontinued the study. As for the overall population, the median duration of treatment with
EVE for this subgroup was not yet reached. Median time from first EVE
intake to progression due to any cause (TTP) was 9.7 months (95% CI:
6.3 mo.; n.r.) for the sunitinib subgroup compared to 9.7 months (95%
CI: 6.0 mo.; n.r.) for the overall population. The incidence of adverse
events was similar for the sunitinib subgroup and the overall population (59% and 61% of patients with adverse events, respectively).
Conclusions. This non-interventional study provides prospective data
on second-line EVE after failure of sunitinib in routine use. The results
of this ongoing study confirm the safety and effectiveness of EVE in an
early treatment setting.
Abstracts
0084
TCAM2-celline: the right model for seminoma studies?
*U. Eppelmann1, F. Gottardo1, J. Wistuba1, F. Wübbeling2, M. Burger2,
S. Schlatt1, S. Kliesch1, C. Mallidis1
1
Universitätsklinikum Münster, Centrum für Reproduktionsmedizin und
Andrologie, Münster, Deutschland, 2Universität Münster, Institut für Numerische und Angewandte Mathematik, Münster, Deutschland
Background. Germ cell tumours (GCTs) constitute over 60% of all malignancies diagnosed in men between the ages of 17 and 45 years. Of
these, the most frequent are seminomas and embryonal carcinomas.
Although testicular tumours have excellent cure rates, the success of
the therapy is dependant on the accuracy of diagnosis and choice of
treatment. Derived from a human seminoma, TCAM2 cells constitute
the main model for in vitro studies of the condition. Despite their wide
spread use, they have only been partially characterised, hence questions
remain regarding the homogeneity of TCAM2 and as a consequence
there are doubts as to how representative the cell line is of the true pathological state. Raman microspectroscopy is a laser based non invasive
technique which can provide a detailed chemical fingerprint of a living
cell and as such is being increasingly employed in medical research.
Our aim was to systematically assess the Raman spectral profiles of our
TCAM2 cell line, in order to determine its homogeneity and to identify
any cellular sub populations.
Materials and methods. TCAM2 cells were streaked onto suprasil microscope slides and either air dried or dessicated. Raman spectra were
obtained using the Horiba LabRAM ARAMIS system. After determination of the optimal analytical settings, a map consisting of a 200 spectral array was obtained from 20 cells/grouping. A further 200 cells/
grouping were assessed using duoscan providing an overall spectral
average of the cells’ constituents. Beyond broad peak assignments, spectra were further analysed using Principal Component Analysis (PCA),
Clustering Methods, Sparsity Separation and Harmonic Analysis. Results were compared to control spectra obtained from the previously
characterised mouse embryonic fibroblast cell line.
Results. Overall spectral accumulations showed the assessed TCAM2
cells to possess one of three distinct patterns. Closer examination of
peak distribution and relative size indicated that although there were
similarities in the spectra differences were prominent in Raman shifts
in the 809, 1002, 1032, 1450 and 1608 cm−1 regions. Desiccated samples
did not differ substantially from the air dried samples indicating that
Raman vibrations were not influenced by the presence/absence of water.
Comparisons with spectra obtained from mouse embryonic fibroblasts
showed distinct differences.
Conclusions. Our findings of three differing spectral fingerprints is suggests that TCAM2 comprise three differing cell populations and adds
further credence to the proposal that the cell line is not homogeneous
but is made up of seminoma cells, apoptotic cells and differentiated embryonic carcinoma cells.
0086
Patient education for radical prostatectomy: Physician’s point of
view of multimedia support vs. standard procedure
*A. Ihrig1, J. Huber2
1
Universitätsklinik Heidelberg, Klinik für Allgemeine Innere Medizin und
Psychosomatik, Heidelberg, Deutschland, 2Universität, Urologische Klinik,
Objective. Objective of this study is to assess physician’s point of view of
multimedia support in preoperative patient education for radical prostatectomy.
Methods. Eight physicians educated more than two hundred patients
for radical prostatectomy randomized either multimedia supported or
with standard procedure. We interviewed the physicians to assess their
point of view concerning possible advantages and differences.
Results. All physicians rated multimedia supported education significantly better than standard procedure. Main reasons were better comprehensibility, the visual presentation, and greater ease in explaining
complex issues. Objective time measurement showed no difference
between both educations. Nevertheless major disadvantage was the impression that multimedia supported education lasted longer. Moreover,
physicians had the impression that some details could be further improved. Given the choice, every physician would decide for multimedia
support.
Conclusion. Physicians appreciate multimedia support in preoperative
education. Contrary to their impression, multimedia support does not
prolong patient education. Therefore, patients and physicians likewise
profit from multimedia support for education and counseling. The readiness of physicians is a possible obstacle to this improvement, as their
view is a key factor for the transition to everyday routine. Therefore, our
results could alleviate this possible barrier for establishing multimedia
supported education in clinical routine.
0091
Patho-histological correlation of MRI findings with the results
of biopsies and radical prostatectomies in MRI-guided prostate
biopsy at 1.5T
*D.G. Engehausen1, K. Engelhard2
1
Universitätsklinikum Erlangen, Urologische Klinik, Erlangen, Deutschland,
2
Martha Maria Krankenhaus Nürnberg, Abteilung für Radiologie, Nürnberg,
Deutschland
Introduction. In diagnostic management of patients with elevated or raising PSA levels the described method offers a reasonable alternative to a
repeated systematic multi-site TRUS guided prostate biopsy. Purpose is
to investigate the diagnostic valency of MRI-guided biopsy in detecting
and localizing prostate cancer.
Method and materials. 65 patients with elevated PSA levels (PSA>4 ng/
ml, mean 10.6 ng/ml) and episodes of prior tumor negative TRUS-guided biopsies (1–5, mean 1.6) underwent MRI-guided prostate biopsy in
a 1.5T scanner (Magnetom Espree, Siemens Healthcare, Erlangen). Localization of tumor suspected areas was done with an endorectal and
two body-phased array coils using a T2-weighted TSE sequence, a diffusion weighted (DWI) protocol inclusive an ADC-map and a gadolinium contrast enhanced 3D-gradient echo sequence. After removing the
endorectal coil the biopsy device was inserted into the rectum and 2 to
6 (mean 4.5) core biopsies were taken manually in a supine position of
the patient. A patho-histological correlation was done between tumor
suspected MRI areas and biopsy results of these regions. In 23 men with
radical prostatectomy following cancer diagnosis each of 104 tumor
containing biopsy cores of the suspected regions was correlated with
the sites of tumor location in the pathological specimens.
Results. All tumor-suspected areas could be successfully punctured.
Prostate cancer was found in 43%, benign prostate hyperplasia (BPH) in
66%, prostatitis in 38% and normal prostate tissue in 5%. With respect
to cancer depiction MRI-guided biopsy showed a sensitivity, specificity,
accuracy, negative and positive predictive value of 75%, 100%, 86%, 100%
and 75% respectively. With reference to the correlation of tumor localization in the pathological specimens and biopsy sides in MRI of tumor containing biopsy cores a sensitivity of 96%, a specificity of 98%, an
accuracy of 97% could be demonstrated. The negative predictive value
was 96% by a positive predictive value of 98%. In 9 patients with at first
tumor negative MRI-guided biopsy results cancer was found in follow
up over 26 months by TRUS-guided biopsy or transurethral resection
(TUR).
Conclusion. MRI-guided prostate biopsy is suitable and accurate in detecting and localizing prostate cancer, missing a rest of tumors which
can only be diagnosed in clinical follow up.
0106
MicroRNAs in renal cell carcinoma: Diagnostic implications of
serum miR-1233 levels
*J. Ellinger1, L.M. Wulfken1, R. Moritz2, C. Ohlmann3, S. Holdenrieder4,
V. Jung3, F. Becker3, E. Herrmann2, G. Walgenbach-Brünagel4, A. von Ruecker5, S. Müller1,5
1
Universitätsklinikum Bonn, Klinik und Poliklinik für Urologie und Kinderurologie, Bonn, Deutschland, 2Universitätsklinikum Münster, Klinik und
Poliklinik für Urologie, Münster, Deutschland, 3Universitätsklinikum des
Saarlandes, Klinik und Poliklinik für Urologie, Homburg/Saar, Deutschland,
4
Universitätsklinikum Bonn, Institut für Klinische Chemie und Klinische
Pharmakologie, Bonn, Deutschland, 5Universitätsklinikum Bonn, Institut für
Pathologie, Bonn, Deutschland
Objective. MicroRNA expression is altered in cancer cells, and microRNAs could serve as diagnostic/prognostic biomarker for cancer patients. Our study was designed to analyze circulating serum microRNAs
in patients with renal cell carcinoma (RCC).
Methods. We first explored microRNA expression profiles in tissue and
serum using TaqMan Low Density Arrays in each six malignant and benign samples. The findings were validated using quantitative real-time
PCR (TaqMan MicroRNA Assays).
Results. The Low Density Arrays identified 109 microRNAs circulating
at higher levels in cancer patients’ serum, and 36 microRNAs were upregulated in serum and tissue of RCC patients. Seven candidate microRNAs were selected for verification based on the finding of up-regulation in serum and tissue of RCC patients (analysis of miR-7-1*, miR-93,
miR-106b*, miR-210, miR-320b, miR-1233 and miR-1290 levels in serum
of healthy controls (n=30) and RCC (n=33) patients). miR-1233 was increased in RCC patients, and thus validated in a multicentre cohort of
84 RCC patients and 93 healthy controls (sensitivity 77.4%, specificity
37.6%, AUC 0.588). We also studied 13 samples of patients with angiomyolipoma or oncocytoma, whose serum miR-1233 levels were similar
to RCC patients. Circulating microRNAs were not correlated with clinical-pathological parameters.
Conclusions. MicroRNA levels are distinctly increased in cancer patients, although only a small subset of circulating microRNAs has a
tumor-specific origin. We identify circulating miR-1233 as a potential
biomarker for RCC patients.
0138
The accreditation of an interdisciplinary prostate cancer centre:
a survey among regional urologists
*J. Kramer1, D. Baumunk1, A. Magheli1, C. Stephan1, M. Schostak1, K. Miller1,
S. Weikert1
1
Charité – Universitätsmedizin Berlin, Urologie, Berlin, Deutschland
Introduction. Interdisciplinary Prostate Cancer Treatment Centres
(IPC) according to the criteria of German Cancer Society (DKG) aim at
improving the quality of care for prostate cancer patients. The perception of such treatment centres among regional urologists is unknown.
We report the results of a survey among urologists of the region 2 years
after accreditation of the Charité Berlin IPC.
Methods. Two years after the DKG accreditation an anonymous survey was conducted among the outpatient urologists of the region. The
effects of the IPC accreditation on the quality of the treatment, the intersectional cooperation and the admission policy of the urologists were
evaluated. Moreover, the acceptance of the centre’s medical education
program and adherence to treatment recommendations were studied.
The survey was based on questions applying the Likert scale for measurements of personal views.
Results. A total of 134 urologists of the region were asked to take part
in the survey. Of these, 61 (46%) completed the questionnaire. IPCs accredited by the DKG are generally well accepted by the majority (n=40,
66%) of the queried urologists. However, only 17 (28%) confirmed im-
provements in the intersectional cooperation between outpatient and
hospital urologists, while 36% refused this fact and 36% were unsure.
Only 18 (30%) experienced a higher quality of the patient care following
the IPC accreditation, but 20 (33%) neglected this explicitly. As few as 16
(26%) changed their admission policy in favour of the centre, and 11%
admitted fewer patients to the IPC. For the remaining 46% the accreditation of the IPC had no impact on their admission policy. The majority
of the interviewed urologists regularly made use of the medical education offered by the centre. Only 16 (26%) never participated in educational activities of the centre. The work of the centre in general was rated
“good” or “very good” by the majority, but 8% still felt the work to be
“inadequate”. The majority of urologists (77%) adhered to the treatment
recommendations given by the centre, while only 8% neglected to do so.
Conclusion. IPC’s in general are well accepted among urologist of the
outpatient sector. However, improvements of the quality of care were
not observed by the queried urologists and consequently the accreditation of the IPC had no relevant impact on the admission rate. IPC may
facilitate evidence based treatment for prostate cancer through educational activities and treatment recommendations.
0142
Timing of catheter removal after radical retropubic prostatectomy (RRP): Has delayed catheter removal due to anastomotic
leakage adverse effects on early continence?
*P.J. Olbert1, K. Simonis1, A. Hegele1, R. Hofmann1
1
Universitätsklinikum Giessen und Marburg GmbH, Standort Marburg,
Klinik für Urologie und Kinderurologie, Marburg, Deutschland
Introduction. Early catheter removal within the first week is a common
strategy in the postoperative management after RRP. Patient convenience is increased, however, the patients expectations as well. In case
of anastomotic leakage, catheter removal is usually delayed for 1 to
2 weeks, and many patients are concerned about detrimental effects of
later catheter removal, especially in terms of continence. This work was
conducted to compare early continence in patients with early vs. delayed catheter removal in cases of anastomotic leakage.
Patients and methods. 128 consecutive patients have been evaluated
prospectively between Jan. and November 2008. In 70% of patients, the
catheter was removed on POD5 or 6 after documentation of a sufficient
vesicourethral anastomosis by cystogram. In 30%, the cystogram revealed anastomotic leakage. In these patients, the catheter was removed 1
or 2 weeks later, depending on the extent of the paravasation. Early continence was assessed before hospital discharge (in average 3 days after
catheter removal) and after 3 months by a standardized Pad-Test and
documentation of Pads needed/24 h.
Results. The standardized PAD test showed comparable results postoperatively (17 vs. 12 g) and after 3 months (2.5 vs. 2.7 g). The number of pads
needed/24 h was 3.2 vs. 3.5/24 h at hospital discharge and 2,3 vs. 4,0/24 h
at 3 months. The differences detected were not statistically significant.
The portion of patients needing 0 and 1 pads/24 h was 28 vs. 7% postoperatively and 40 vs. 25% at 3 months in favor of the early catheter removal
cohort. This difference reached statistical significance (p<0.05).
Conclusions. Despite comparable objective early continence using a
standardized PAD test, delayed catheter removal due to anastomotic
leakage after RP appears to affect daily life continence and quality of
life – as measured by the patients’ need to use pads – negatively.
Abstracts
0155
Percentage of positive nodes after radical prostatectomy and
pelvic lymphadenectomy: correlation with oncological outcome
measures
*P.J. Olbert1, J. Hoffmann1, F. Brüning1, A. Hegele1, R. Hofmann1
1
Universitätsklinikum Giessen und Marburg GmbH, Standort Marburg,
Klinik für Urologie und Kinderurologie, Marburg, Deutschland
Introduction. Lymphadenectomy is an integral part of oncological surgery in many tumor entities. In prostate cancer (PC), pelvic lymphadenectomy gives essential staging- and prognostic information and might
trigger adjuvant therapy. In low volume lymph node involvement, it
can be curative as well with excellent long term survival data. However,
the body of evidence is limited as far as lymphadenectomy in low risk
patients and the extent of lymphadenectomy are concerned. This work
was conducted to evaluate whether the number of removed nodes and
lymph node density could serve as prognosticators after radical protatectomy.
Patients and methods. The institutional PC database was evaluated for
classical clinical and pathological data (age, pTNM-stage, preoperative
PSA and Gleason grading) and for the numbers of all removed lymph
nodes and of lymph node metastases. Lymphadenectomy included external iliac, obturator fossa and hypogastric nodes. χ2 and Mann Whitney U test were performed to compare sets of variables, multivariate
regression analysis was used to evaluate the influence of other parameters on lymph node status. Kaplan Meier curves and log rank tests were
done to display and compare time-event correlations.
Results. 914 patients were included in the analysis, 10.8% were node positive. Mean Follow up was 51 months. The presence of lymph node metastases was independently predicted by T-stage, Gleason score and initial
PSA. N-stage was significantly associated with biochemical Progression
and with reduced cancer specific survival, but not with OS. In our patient cohort and in the given follow up, a higher lymph node yield was
associated with better progression free and overall survival, without
reaching statistical significance. In N+ patients, lymph node density did
not affect survival, nor did the presence of extranodal tumor growth.
Conclusions. Within the limitations of this retrospective study (mid
term FU, consequently low number of events), the total number of removed lymph nodes appears to be more important than the ratio of
affected nodes in N+ patients. This implicates a pivotal role of pathologically undetected lymph node metastases and supports the concept of
extended lympadenectomy in intermediate to high risk patients. More
prospective studies on lymphadenectomy in PC are warranted.
0170
Family history of prostate cancer and psychosocial distress in
affected men
*K. Herkommer1, A. Dinkel2, M. Kornmayer1, P. Herschbach2, J. Gschwend1
1
Klinikum rechts der Isar der TU München, Klinik für Urologie, München,
Deutschland, 2Klinikum rechts der Isar der TU München, Klinik für Psychosomatik und Psychotherapie, München, Deutschland
Objective. Positive family history is a strong risk factor for the development of prostate cancer (PC). Thus, it seems reasonable that patients
with a familial history of prostate cancer might worry about passing
their disease to their kin, which might lead to the experience of distress.
This study aimed at investigating the effect of family history of prostate
cancer on psychosocial distress in affected men.
Material and methods. Nationwide 3527 patients who were treated
with radical prostatectomy between 2000 and 2005 were included in
this study and completed a mail survey in 2009. Mean current age
was 71.2 years (SD=6.5; range 45–92). The patients were divided into 3
subgroups according to their family history: 68.0% (n=2.399) sporadic,
25.9% (n=915) familial (at least one first-degree relative with PC), and
6.1% (n=213) hereditary (according to the Johns Hopkins criteria). Can-
cer-specific distress was assessed with the Questionnaire on Distress in
Cancer Patients – Short Form (QSC-R10), depression and anxiety were
assessed with a short form of the Patient Health Questionnaire (PHQ-2,
GAD-2). We investigated the influence of family history, age at diagnosis (<64 vs ≥65), and biochemical recurrence on psychosocial distress.
Results. The prevalence of cancer-specific distress was 16.4%. Regarding
specific concerns, feeling physically imperfect (12.3%), sleep problems
(6.5%) and fear of disease progression (6.2%) were most prevalent; feeling
pain was least prevalent (1.5%). Depression and anxiety were prevalent
in 6.0% and 6.3%, respectively. Age at diagnosis was associated with each
psychosocial distress measure (p<0.001), i.e. younger patients showed
higher distress. Biochemical recurrence was associated with higher
cancer-specific distress (p<0.001) and with higher depression as well as
anxiety scores (p<0.01). Family history was not directly associated with
the distress measures, and did not interact with age at diagnosis or biochemical recurrence. An exploratory analysis did not reveal differences
in psychosocial distress between patients with familial or suspected
hereditary prostate cancer.
Conclusion. Long-term prostate cancer survivors showed low rates of
psychosocial distress. Patients who had received diagnosis at age before
65 and those who had experienced biochemical recurrence in the meantime reported higher cancer-specific distress, depression and anxiety.
Family history of prostate cancer showed neither a direct nor a moderating effect on psychosocial distress. Our data does not allow the decision whether this is due to successful coping, low literacy in genetics, or
some other variables.
0196
Clinical evaluation of a structured report of functional prostate
MRI
*M. Quentin1, D. Blondin1, J. Klasen1, J. Kuhlemann1, C. Buchbender1,
F. Miese1, G. Antoch1, P. Albers2, C. Arsov2
1
Institut für Diagnostische und Interventionelle Radiologie, Uniklinik Düsseldorf, Düsseldorf, Deutschland, 2Klinik für Urologie, Uniklinik Düsseldorf,
Düsseldorf, Deutschland
Background. For patients with elevated or increasing prostate specific
antigen (PSA) levels and negative biopsy, prostate MRI seems to be a
useful tool for cancer localization. Nevertheless suspicious MRI findings need verification by biopsy.
Objective. To establish and to evaluate a standardized functional prostate MRI examination reporting scheme.
Methods. Prostate MRI examinations with T2-weighted images, T1weighted images, diffusion imaging, and perfusion imaging of 52 consecutive patients were performed on a 3T scanner. The inclusion criteria
were: elevated PSA levels (>4 ng/ml), unsuspicious digital rectal examination and at least one prior negative biopsy. The MRI localisation
report followed a standardized scheme. Follow-up ultrasound-guided
targeted biopsy was then performed based on the structured report and
its success rated was documented.
Results. 16 of the 52 patients had suspicious MRI findings and were biopsied under guidance of the standardized localisation scheme. 11 patients
(69%) had positive biopsies (Gleason score 6 to 9). Five patients had negative biopsies.
Conclusion. A standardized reporting scheme of suspicious findings in
prostate MRI leads to higher success rates of ultrasound guided targeted
biopsy as compared with repeated nonspecific transrectal ultrasonography biopsy.
0220
Evaluation of CEA and Ca19-9 in transitional cell carcinoma of the
bladder – serological and immunhistological findings
*A. Hegele1, V. Mecklenburg1, P. Barth1, P. Olbert1, R. Hofmann1
1
Philipps Universität, Klinik f. Urologie, Marburg, Deutschland
Introduction and objectives. Following prostate cancer bladder cancer
represents the second most frequent malignancy of the GU tract and the
ninth most common cause of cancer worldwide with rising incidence.
Since reliable markers predicting presence, muscle invasiveness or metastatic TCC have not been established up to now, cystoscopy, causing
discomfort to the patients (pat), represents still the goldstandard in diagnosis of TCC. The aim of the present study was to evaluate the clinical
value of CEA and Ca19-9 as a tumor marker in the diagnosis of TCC
and to determine the relationship between the marker levels and the
histopathological results.
Material and methods. Between 06/2008 and 02/2010 CEA and Ca19-9
were prospectively determined in 231 pat (173 m, 58 f, mean age 70 y) before undergoing TUR-B of a suspect bladder tumor. Additionally 11 pat
(9 m, 2 f, median age 66 y) were presented initially with metastatic TCC.
Immunhstochemical examinations (CEA and Ca19-9 staining) were
performed in TUR-B specimens of 83 pat.
Results. After TUR-B no malignant bladder tumors were found in
71 pat. These pat served as controls. 14 pat with malignant bladder tumors but histological excluded TCC were excluded from analysis. In 146
pat histological examination showed TCC: 74% (n=108) with superficial,
non-muscle invasive (NMIBC) and 26% (n=38) with muscle-invasive
(MIBC) bladder cancer. Compared to controls pat with TCC showed
neither significant different CEA (p=0.234) nor Ca19-9 (p=0.061) levels.
Pat with MIBC (n=38) showed significant elevated CEA (p=0.008) and
Ca19-9 serum levels (p>0.001) compared to NMIBC (n=108). In local
advanced MIBC and/or presence of lymph node metastases (≤pT3±N+,
n=19) only Ca19-9 was significantly elevated (p=0.04) compared to
MIBC confined on the bladder muscle (pT2No, n=19). Concerning
TCC-grading significant higher CEA (p=0.031) and Ca19-9 (p=0.001)
serum levels were found with rising grading. Pat with metastatic TCC
showed compared to non-metastatic TCC the highest serum levels of
Ca19-9 (p=0.003) but not for CEA (p=0.105). Immunhistochemical staining in 83 patients revealed a strong correlation between staining intensitiy and serum levels for Ca19-9 (p=0.004) but not for CEA (p=0.478)
Conclusion. In conclusion our prospective data clearly show that neither CEA nor Ca19-9 serum levels are helpful tools in primary diagnosis
of TCC. When during routine examination CEA and Ca19-9 levels are
elevated and a gastrointestinal malignancy can be excluded you have to
keep in mind existence of CEA/Ca-19-9 producing TCC and consecutively to check the urologic tract. Our date show a correlation of CEA
and Ca19-9 serum levels with stage and grade of TCC disease confirmed
by immunhistochemical findings. Ca19-9 is more promising as CEA.
Utility of Ca19-9 serum levels monitoring response to therapy have to
be checked in further studies as well as role of Ca19-9 as a prognostic
factor in TCC.
0225
Influence of prostate volume on oncological and clinical outcome
after radical prostatectomy due to prostate cancer
*A. Hegele1, T. Laumeier1, F. Brüning1, P. Olbert1, R. Hofmann1
1
Philipps Universität, Klinik f. Urologie, Marburg, Deutschland
Materials and methods. Between 01/2007 and 06/2010 RRP was performed in 454 men. Data were analyzed using the data bank of the “Prostate Cancer Center” Marburg.
Results. Median PV was 59.4 g (20–209). Due to R2-resection 2 patients
were excluded from analyses. Patients with a R1-resection (n=91, 20%)
showed compared to R0-resection (n=361, 79,6%) a significantly lower
PV (54 g vs. 60 g, p=0.048). PV>60 g (n=168) showed significantly elevated iPSA (p<0.001), higher BMI (p=0.02), prolonged hospital stay
(p=0.015), prolonged indwelling catheter (p=0.039) and more frequent
blood transfusion (p=0.002). Operation time (p=0.2), urinary continence (p=0.2) and postoperative lymphoceles (p=0.08) showed no significant differences. A positive correlation between R1-resection and pTlevel was evident (pT2c:16.8%, pT3a: 29%, pT3b: 44.6%, pT4: 75%).
Conclusion. Despite aggravated intraoperative conditions during RRP
in enlarged PV oncologic outcome was not negatively influenced with
a lower rate of R1 resections. R1-situation showed a positive correlation
with pT-levels. Large PV showed prolonged hospital stay and longer indwelling catheter without influencing functional outcome. So enlarged
PV is not a contraindication to perform a RRP neither focusing oncological nor clinical outcome.
0240
Residual tumor resections (RTR) in patients with germ cell tumor
relapse and salvage-chemotherapy (GCT)
*C. Winter1, C. Bingöl1, P. Albers1
1
Universität Düsseldorf, Urologische Klinik, Düsseldorf, Deutschland
Introduction. Residual tumor resections (RTR) after chemotherapy of
patients with germ cell tumors (GCT) usually reveal vital cancer in only
10–15% of cases. Residual tumor resections (RTR) after salvage chemotherapy have been underreported and their role in the treatment of GCT
patients with relapse may be even more important.
Methods. A retrospective analysis was performed in 180 GCT patients
who underwent 192 RTRs in 2 centers (Kassel and Düsseldorf) from
07/2003 until 07/2011. The RTR database was queried for relapsed patients who received salvage chemotherapy [conventional chemotherapy
(CCT) and HDCT)] and a subsequent residual tumor resection. Fiftyfive (30.5%) patients in this situation were identified and analyzed.
Results. Histology of all RTR specimens revealed in 34% (66/192) necrosis, in 34% (66/192) mature teratoma and an already high percentage
of vital cancer in 32% (61/192) vital cancer due to an overall high rate
of intermediate and poor prognosis patients (52%). In patients (n=55)
who received salvage chemotherapy (CCT/HDCT) vital cancer in RTR
specimen was found in 22 specimens (40%). This was significantly higher compared to 29% of patients with vital cancer (39/137) in patients
without salvage chemotherapy (p=0.0137). Furthermore, in HDCT patients’ vital cancer rate of the resected specimen was 42% (10/24) and there
was no difference to patients who received CCT salvage chemotherapy
only (41%). With a follow-up of 16 months (0–79) 7 of 18 (39%) evaluable
patients with vital cancer relapsed (39%) including two in-field retroperitoneal recurrences (11%). Two patients died to tumor progression.
Conclusion. The percentage of vital tumor in the resected residual tumor after salvage chemotherapy (CCT/HDCT) is much higher than in
patients after first-line conventional-dose chemotherapy. Residual tumor resection after salvage chemotherapy is necessary to guarantee a
long-term survival after CCT/HDCT by elimination of possible viable
components in residual tumor specimens.
Introduction. Enlarged prostate volumes (PV) aggravate radical surgery
in prostate cancer (f. e. radical prostatectomy). How far PV influence R1resection and clinical outcome after radical prostatectomy is unclear.
Aim of this study was to investigate the possible relationship between
PV and intra-, post- and pathological parameters after radical retropubic prostatectomy (RRP).
Abstracts
0250
Prediction of favourable outcome in metastatic castration-resistant prostate cancer patients treated with docetaxel rechallenge
*M. Heck1, M. Thalgott1, M. Retz1, P. Wolf2, T. Maurer1, J. Gschwend1,
H. Kübler1
1
Technische Universität München, Urologische Klinik, Klinikum rechts der
Isar, München, Deutschland, 2Technische Universität München, Institut für
Medizinische Statistik und Epidemiologie, München, Deutschland
Objective. Chemotherapy with docetaxel is the standard first-line cytotoxic treatment in metastatic castration-resistant prostate cancer
(mCRPC). In patients with good clinical response at first-line chemotherapy, docetaxel rechallenge has been proposed for further treatment.
In the present study, we analysed the effectiveness of docetaxel rechallenge and sought to identify clinical variables predicting favourable oncological outcome.
Patients and methods. We retrospectively evaluated the outcome of
44 patients with mCRPC who were treated with 3-weekly docetaxel at
first-line chemotherapy and rechallenge plus prednisone/ prednisolone
between 1999 and 2011. All patients received at least 2 cycles of docetaxel
rechallenge. The endpoints were PSA-progression-free survival (PSAPFS), overall survival (OS). Furthermore, we analysed the impact of pretreatment variables on PSA-PFS and OS. Median PSA-PFS and OS were
determined by Kaplan-Meier curves. The effect of clinical variables on
PSA-PFS and OS was statistically analysed by a log-rank test or Cox
regression with hazard ratios. All analyses were performed using a 0.05
level of significance.
Results. 44 patients were included on analysis. At a median follow-up
of 26.4 months (range 9.8–89.8 months) after the first administration of docetaxel, 24 (54.5%) patients had died. Median PSA-PFS was
5.9 months (95% CI 3.5–6.8 months) and median OS was 21.8 months
(95% CI 19.9–23.7 months) after initiation of docetaxel rechallenge.
36 patients achieved PSA-reduction ≥50% at first-line chemotherapy.
Out of these 10 (27.8%) patients also responded with PSA-reduction
≥50% at docetaxel rechallenge. PSA-reduction ≥50% at first-line chemotherapy with docetaxel was the only pre-treatment variable that correlated significantly with prolonged PSA-PFS (p=0.01) and OS (p=0.03).
Patients with PSA-reduction ≥50% at first-line chemotherapy showed a
median OS of 22.1 months since initiation of docetaxel rechallenge in
comparison to 7.2 months in patients with <50% PSA reduction.
Conclusion. Docetaxel rechallenge is an effective treatment option in
selected docetaxel-pretreated patients with mCRPC. PSA-reduction ≥
50% at first-line docetaxel chemotherapy predicts superior PSA-PFS and
OS in a docetaxel rechallenge regimen.
0252
Molecularbiological detection and topography of lymph node
micrometastasis in intermediate and high risk prostate cancer
treated with extended lymphadenectomy
*M. Heck1, R. Nawroth1, L. Vitzthum1, M. Bandour1, M. Souchay1, G. Weirich2,
T. Schuster3, J. Gschwend1, M. Retz1
1
Technische Universität München, Urologische Klinik, Klinikum rechts der
Isar, München, Deutschland, 2Technische Universität München, Institut
für Pathologie und pathologische Anatomie, München, Deutschland,
3
Technische Universität München, Institut für Medizinische Statistik und
Epidemiologie, München, Deutschland
Objective. Detection of lymph node metastases is an important predictor for biochemical recurrence free survival after radical prostatectomy.
In the present study we sought to establish a method for molecular detection and localization of lymph node metastases that are not identified with standard histopathological examination using quantitative
reverse-transcriptase (qRT)-PCR. We present results of the first 30 prostate cancer patients treated with radical prostatectomy (RP) and extended lymphadenectomy (eLAE).
Material and methods. All prostate cancer patients were treated with RP
and eLAE. Inclusion criteria were Gleason Score ≥7 or PSA ≥10 ng/ml or
clinical T-stage ≥2b (intermediate and high risk prostate cancer). Each
lymph node (LN) was divided into two halves. One half was examined
by a pathologist applying conventional histopathology. The second half
was assessed by frozen section histopathology as well as prepared for
RNA extraction followed by qRT-PCR. For detection of occult disseminated prostate cancer cells in LNs we established a qRT-PCR protocol
with the markers prostate specific antigen (PSA) and prostate-specific
membrane antigen (PSMA) which are expressed in prostate cancer cells
but not in blood or lymph nodes. 201 LNs of 19 bladder cancer patients
were used to establish a threshold for qRT-PCR results. qRT-PCR was
determined positive if at least one marker (PSA and/ or PSMA) was above the threshold.
Results. 717 LNs of 30 patients (median 24 LNs/ patient) were analyzed
by conventional histopathology and qRT-PCR. Histopathological examination was positive (pN1) in 25 (3.5%) LNs of 6 (20%) patients. All of
them were confirmed to be positive by qRT-PCR. 81 (11.7%) out of 692
histopathologically negative LNs (pN0) were positive using qRT-PCR
corresponding to 14 (58.3%) out of 24 node-negative patients (pN0). All
patients with Gleason score 8–10 had either histopathological positive
LNs or qRT-PCR-positive LN-micrometastasis. 60% of histopathologically positive lymph nodes were located outside the obturatoric region.
More than one half (56%) of qRT-PCR-positive LN-micrometastases
were located outside the obturatoric region.
Conclusion. Results of the first 30 patients of our mapping study support
an extended lymphadenectomy in order to remove LN-micrometastases in patients with intermediate and high risk prostate cancer. Follow-up data will validate if there is a correlation between the molecular
detection of occult disseminated tumor cells in LNs and biochemical
recurrence.
0260
Robot-assisted radical cystectomy should not be restricted to the
young and fit patients
*G. Niegisch1, P. Albers1, R. Rabenalt1
1
Heinrich-Heine-Universität, Medizinische Fakultät, Urologische Klinik,
Düsseldorf, Deutschland
Objective. New operative techniques in urooncology, e.g. robot-assisted
surgery, are preferably performed in younger and fitter patients. We searched to evaluate whether and how this selection bias may confound
results of robot-assisted radical cystectomy.
Methods. Patients undergoing open radical cystectomy (ORC) were
compared to patients with robot-assisted radical cystectomy (RARC)
regarding perioperative parameters, histological features and complications (Mann Whitney U test, Pearson’s χ2-test). Additionally, subgroup
analysis of patient <70 years and ≥70 years was performed.
Results. Between 08/08 and 08/11, 70 patients underwent ORC and 21 patients RARC. RARC patients were younger (66 [43–79] vs. 72 [48–86] years, p=0.006) and had less comorbidities as measured by Charlson Comorbidity Index (CCI; 4 [2–8] vs. 6 [3–11], p=0.003) than ORC patients.
Hospital stay was shorter (15 [8–25] vs. 19 [10–116] days, p=0.001), blood
loss (400 [10–2200] ml vs. 800 [100–6000] ml, p=0.027) as well as transfusion rate lower (0 [0–4] vs. 2 [0–12] packed red blood cells [PRBC]
intraoperative, p<0.001), and operation time longer (430 [190–620] vs.
360 [195–640] min, p=0.017) in RARC patients. Lymph node metastases
were more frequent in ORC patients (RARC: 15% pN+, ORC 34% pN+,
p=0.029). In patients ≥70 years differences between RARC (n=8) and
ORC (n=43) were observed regarding duration of hospital stay (RARC:
15 [11–18], ORC: 18 [12–100], p=0.002), transfusion rate (RARC: 0 [0–2],
ORC: 4 [0–12] PRBC, p=0.008 ) and operation time (RARC: 440 [380–
540], ORC: 345 [195–565] min, p=0.012). RARC patients <70 (n=13) years
had less comorbidities than ORC patients (n=27) of the same age (CCI
3 [2–8] vs. CCI 5 [3–11], p=0.002). Duration of hospital stay was shorter
in young RARC compared to ORC patients (16 [8–25] vs. 22 [10–116],
p=0.018). Transfusion rate was lower in RARC patients (0 [0–4] vs. 2
[0–12] PRBC intraoperative, p=0.038) while no difference in blood loss
was observed. Neither in the analysis of the whole groups nor subgroup
analysis revealed differences in the rate of postoperative complications.
Conclusions. Despite prolonged operation time, especially older patients
seem to profit from RARC (faster reconvalescence, lower blood loss).
Restricting new operation techniques to the young and fit might underestimate the advantages of these techniques. Further prospective
validation of these results is needed, e.g. within multi-centric databases.
0289
Clinical outcome of combined Iodine-125 seed brachytherapy
and image-guided intensity modulated external-beam radiotherapy for low intermediate risk prostate cancer
*J. Boda-Heggemann1, G. Welzel1, S. Mohamed1, M. Bohrer1, *Y. Abo Madyan1, M. Polednik1, M.-S. Michel1, J. Schaefer1, J. Kosakowski1, N. Behnam1,
F. Wenz1
1
Universtiät Medizin Mannheim, Strahlentherapie, Mannheim, Deutschland
Purpose. Combination of low-dose rate (LDR) brachytherapy and external-beam radiotherapy (EBRT) has been shown to be a promising
treatment modality in low intermediate risk prostate cancer. We retrospectively assessed clinical outcome, acute and late toxicity of combined
image-guided intensity-modulated EBRT with Iodine-125 seed implantation for low intermediate risk prostate cancer (patients with one parameter violating the criteria for low risk disease).
Patients and Methods. Between 2004 and 2009, 25 consecutive low
intermediate risk prostate cancer patients (median age 66 years, median
initial PSA 6.5 mg/dl, median Gleason-score 7) received LDR-brachytherapy with Iodine-125-seed implantation (120 Gy MPD) followed by
IG-IMRT (image-guided intensity modulated radio therapy) with a
median dose of 45 Gy. Image guidance was performed with stereotactic
ultrasound and cone-beam CT. Primary end points of this retrospective
evaluation were overall survival (OS), biochemical disease free survival
(BDFS), acute and chronic gastrointestinal (GI) and genitourinary (GU)
toxicity based on RTOG and LENT-Soma scales. Both acute and late
toxicity were compared to pre-radiation symptoms (graded by LENTSoma scores) on a patient-to-patient basis.
Results. Median follow-up (FU) was 42 months. Except one patient,
who died of a glioblastoma multiforme 49 months after radiotherapy,
all patients are alive. Actuarial 2-year and 4-year BDFS rates were 95.8%
and 91%, respectively. Two patients did not reach an adequate PSA-nadir and received further therapy. The only statistically significant risk
factor for biochemical relapse was the value of PSA nadir (p=0.007).
Before therapy, no GI symptoms higher >2 in any patient were observed, maximal level of GU symptoms was LENT-Soma °2 in 3 patients.
Two patients had complete erectile dysfunction (°4) and 2 patients had
a °2 prae-therapeutic erectile dysfunction. In the acute phase, maximal
GI/GU toxicity was RTOG °2. At the end of IMRT treatment, 3 patients
had RTOG °2 GU toxicity, and 5 patients had RTOG °2 GI toxicity. At
the first FU (median: 6 weeks after IMRT), 7 patients had RTOG °2 GU
toxicity, and 2 patients had RTOG °2 GI toxicity. Maximal late GI toxicity at last FU (median 39 months, range 8-70 months) was LENT-Soma
°2 in 8 patients, and GU toxicity °3 and °4 in 1 patient each. By last FU,
2 patients suffered °2, 9 patients °3 and 7 patients °4 erectile dysfunction.
Conclusions. Iodine-125 seed brachytherapy in combination with imageguided IMRT is an effective and low-toxicity treatment option for low
intermediate risk prostate cancer patients. The only significant toxicity
observed is erectile dysfunction. The rate compares favorably to literature data after surgery and high dose EBRT.
0315
Two clinical trials assessing safety and efficacy of trastuzumab
(Herceptin) as a monotherapy or in combination with gemcitabine/cisplatin in patients with metastasized urothelial cell
carcinoma overexpressing HER2
U. Rebmann1, T. Klotz2, *G. Melhorn1
1
Diakonissenkrankenhaus Dessau, Urologische Klinik, Dessau, Deutschland,
2
Klinikum Weiden, Urologische Abteilung, Weiden, Deutschland
Background. Prognosis for invasive urothelial cell carcinomas (UCC) is
poor. Since HER2 is overexpressed in about 30% of patients, two clinical
trials assessed Trastuzumab (T) treatment in patients with metastasized urothelial cell carcinomas overexpressing HER2.
Methods. Patients (pts) with HER2 overexpression (score 2+ or 3+)
UCC, ECOG performance status 0–2, at least one measurable lesion,
and adequate organ function. Trial ML17599 included pts with tumor
progression after previous platinum-based chemotherapy. T monotherapy with initial dose of 4 mg/kg T, weekly maintenance dose of 2 mg/kg
was given until progression or intolerable toxicity. Trial ML17600 included chemotherapy naïve pts. T (4 mg/kg loading dose, 2 mg/kg weekly)
was given in combination with gemcitabine (1200 mg/m2 on day 1, 8
and 15) and cisplatin (70 mg/m2 on day 2). After 6 cycles, T maintenance
continued until progression or toxicity. The primary endpoint was progression-free survival (PFS) for both studies.
Results. Both trials were prematurely terminated due to low recruitment. ML17599: 5 pts were included. The median age was 66 years, all
pts were male. There were 2 pts with HER2 score 2+ and 3 pts with score 3+. Median PFS was 2.5 months and median overall survival (OS)
14.7 months. One patient achieved stable disease, resulting in an OS of
39 months. Most adverse events (AEs) were of mild to moderate severity.
Only one pt experienced grade 3 toxicity (dyspnea). ML17600: 13 patients were included (10 male, 3 female pts). The median age was 69 years.
There were 8 pts with HER2 score of 2+ and 5 pts with score 3+. Median
PFS was 11.0 months and median OS 14.9 months. 5 pts achieved a response (2/13 complete response, 3/13 partial response), and 6/13 pts had
stable disease, resulting in a clinical benefit rate of 84.6%. Hematological
toxicities grade 3/4 occurred in 9 pts (69.2%). Other grade 3/4 toxicities
included cardiac arrhythmia in 2 pts, constitutional symptoms in 2 pts
and hypertension in 1 pt.
Conclusion. As a result of low patient numbers in both trials, it is not
possible to make a general statement about the efficacy of T either as
a monotherapy or in combination with chemotherapy in patients with
metastasized UCC. Some patients may benefit from well tolerated monotherapy. For combination therapy, response rate, PFS and OS appear
to be higher.
0327
MARC-2: An open label, single arm trial to characterize patients
with metastatic renal cell carcinoma treated with everolimus
after failure of the first VEGF-targeted therapy
M. Staehler1, L. Bergmann2, V. Grünwald3, U. Keilholz4, C.-H. Ohlmann5,
F. Schaller6, *L. Strassl6, K. Junker7
1
Ludwig-Maximilians-Universität München Klinikum Großhadern, Urologische Klinik und Poliklinik, München, Deutschland, 2Johann-Wolfgang Goethe Universitätsklinikum, Frankfurt, Deutschland, 3Medizinische Hochschule Hannover, Hannover, Deutschland, 4Charitè Campus Benjamin Franklin,
Berlin, Deutschland, 5Universitätsklinikum des Saarlandes, Homburg/Saar,
Deutschland, 6iOMEDICO AG, Freiburg, Deutschland, 7Universitätsklinikum
Jena, Jena, Deutschland
Introduction. Clinical research in metastatic renal cell carcinoma is ongoing and the number of treatment options is going to increase. Characterization of patients most likely to benefit from a specific targeted agent
has not yet been sufficiently addressed. Most patients are treated with
Abstracts
sequenced systemic medications based on the clinical course of the disease. So far, no reliable biomarkers exist to predict treatment outcome
of the selected regimen in the individual patient. Thus, further investigation is needed to understand the treatment outcome and effects of
the selected drugs in vivo. In the MARC-2-study, patients treated with
everolimus will be characterized by serum and tissue markers in order
to identify a pattern which could be suggestive of treatment outcome of
everolimus after one VEGF-targeted therapy.
Methods. Over a period of 2 years 80 patients are to be enrolled at about 12 study centers in Germany. Major inclusion criteria are confirmed
predominantly clear cell renal cell carcinoma, metastatic disease, failure of exactly 1 prior VEGF-TKI therapy, no pretreatment with mTOR
inihibitors or bevacizumab. Tumor response will be assessed according
to RECIST 1.1. Safety assessments include recording adverse events and
monitoring of laboratory parameters. Primary objective is to assess
the rate of patients free of disease progression after 6 months of treatment with everolimus. Secondary objectives are assessment of relation
of biomarkers to the clinical benefit, progression free survival, overall
survival, objective response rate and the safety profile. Part of MARC2 are extensive explorative assessments: Blood samples for biomarker
projects are taken pre-treatment and at different time points during the
treatment until the end of study treatment. Histopathological classification of tumor samples will be performed. Biomarker projects include: Serum protein profiling by using SELDI-TOF-MS; quantification of
Treg cells in blood samples; identification of serum metabolic biomarkers; polymorphisms in genes related to the VEGFR signaling pathway;
expression analysis of the mTOR-pathway in tumor samples. Pre-dose
blood samples for everolimus trough levels will be collected for pharmacokinetics. Tumor assessments by functional MRI will be performed
within a substudy at selected sites.
Results. MARC-2 was initiated in February 2011; the 1st patient was
enrolled in March 2011. Until July 2011, 9 sites have been initiated and
9 patients were recruited.
0369
Perioperative outcome in laparoscopic and da Vinci assisted
partial nephrectomy in tumours >4 cm
*H. Zenginli1, M. Giessing1, P. Albers1, R. Rabenalt1
1
Uniklinik Düsseldorf, Urologie, Düsseldorf, Deutschland
Background. EAU Guidelines recommend partial nephrectomy as standard treatment for renal tumours smaller than 4 cm. Data on outcome
up to date is rare and needs to be elucidated in further studies. We present the results of our series of laparoscopic (LPN) and da Vinci assisted
partial nephrectomy (daViPN) in kidney tumours larger than 4 cm.
Objective. To analyze the outcome regarding technical feasibility, morbidity, mortality, efficacy and complicationrate of LPN and daViPN for
tumours ≥4 cm.
Methods. In total, 190 patients were treated for renal tumours at our institution from 08/2008 through 03/2011. In 61 patients, elective LPN and
5 da Vinci assisted partial nephrectomies (01/2011 through 03/2011) were
performed. Patients were grouped according to tumour size: group A
(40 patients) with tumours <4 cm and group B (21 patients) with tumours ≥4 cm. The 5 da Vinci-assisted partial nephrectomies were not
significantly different in outcome and were not analyzed separately.
Results. In 40 patients (group A) a tumour <4cm (1–3.9) in 21 patients
(group B) a tumour ≥4 cm (4.0–8 ) was found. Median operative time
(MOT) was 132 (40–300) minutes (A) and 159 (40–330) minutes (B;
p<0.142). Median ischemia time was 18 (0–63) minutes (A) and 26 (0–
48) minutes (B; p<0.094) . Median blood loss (MBL) was 199 (0–1800)
ml (A) and 364 (0–2000) ml (B; p<0.187). Histopathological results
revealed positive surgical margins in two (A) and in one patient (B).
Malignant tumours were found in 26 patients (A) and 15 (B). Benign
tumours 14 (A) and 6 (B). There was no significant difference between
the two groups regarding complication rate, morbidity and mortality in
one year follow-up. In respect of the da Vinci assisted PN in 3 patients a
tumour <4cm (group A) and two patients with a tumour ≥4 cm (group
B) were treated. Outcome of the da Vinci assisted PN regarding complicationrate, morbidity or mortality did not differ significantly from
the laparoscopic approach so that this data was not analyzed separately.
Conclusions. Minimal invasive PN in tumours >4 cm is feasible in expert centers with a high patient volume without increasing morbidity
or mortality.
0375
Penile cancer – incidence, mortality and survival in Saxony,
2000–2008
S.J. Klug1,2, W.-D. Böhm3, *A. Neumann1, A. Gonsior4, L.-C. Horn5, C. Kriegel4, J.-U. Stolzenburg4, M. Wirth6, R. Stabenow7, . Klinische Krebsregister
Sachsen2,8,9,10,11
1
Universitätsklinikum Carl Gustav Carus, Tumorepidemiologie/Universitäts
KrebsCentrum, Dresden, Deutschland, 2Regionales Klinisches Krebsregister, Dresden, Deutschland, 3Gemeinschaftspraxis für Urologie, Dresden,
Deutschland, 4Universitätsklinikum Leipzig, Klinik und Poliklinik für
Urologie, Leipzig, Deutschland, 5Universitätsklinikum Leipzig, Institut für
Pathologie, Leipzig, Deutschland, 6Universitätsklinikum Carl Gustav Carus,
Klinik und Poliklinik für Urologie, Dresden, Deutschland, 7Gemeinsames
Krebsregister der Länder Berlin, Brandenburg, Mecklenburg-Vorpommern, Sachsen-Anhalt und der Freistaaten Sachsen und Thüringen, Berlin,
Deutschland, 8Tumorzentrum Leipzig, Leipzig, Deutschland, 9Tumorzentrum Chemnitz, Chemnitz, Deutschland, 10Tumorzentrum Ostsachsen,
Görlitz, Deutschland, 11Südwestsächsisches Tumorzentrum, Zwickau,
Deutschland
Research question. This study estimated the incidence, mortality and
survival of penile cancer patients in Saxony, Germany, from 2000 to
2008.
Methods. Data from five population-based clinical cancer registries covering the entire state of Saxony were collectively analyzed. Additionally, data of the epidemiological Common Cancer Registry for East
Germany (GKR) were used. Incidence and mortality overall and over
time (2000–2008) were estimated. Five-year survival rates for primary
penile cancers were estimated with the Kaplan Meier estimator; overall,
by TNM and by UICC states.
Results. In total, 301 penile cancer cases were reported from 2000 to
2008. The overall standardized incidence rate (ESR, European population) was 1.2 per 100,000. Most penile cancers occurred in men aged
60–79 years. The majority of all penile cancer cases were localized at
the glans penis. The overall standardized mortality (ESR) was 0.4 per
100,000 during the years 2000 to 2008. The total relative 5-year survival
was 71.9% (95% confidence interval 65.1–78.7%). Survival by TNM and
UICC classification will be presented.
Conclusion. In conclusion, incidence rates were similar to those in the
Nordic countries, whereas the mortality was slightly higher in comparison to the Nordic countries and the United States. However, the number
of cases was small.
0410
Is there an association of the polymorphisms in the MDR1-gene
with the sensitivity to paclitaxel in human renal cell carcinoma
in vitro?
*P. Reinecke1, N. Jallal1, H.E. Gabbert1
1
Deutschland
Objective. Human renal cell carcinomas (RCCs) are highly resistant to
conventional chemo- and radiotherapy. Recently it has been shown,
that human RCCs response differently to the antineoplastic agent pac-
litaxel. In addition to the MDR1-phenotype the polymorphisms in the
MDR1-gene contributes to drug resistance. Therefore, after analyzing
the MDR1-phenotype we defined the polymorphisms in the MDR1-gene C3435T, G2677T and G1199A in a model of two chromophobe RCC
cell lines (chrompho-A and -B) with an „intrinsic paclitaxel resistance”
and a model of two RCC cell lines of the clear cell type (clearCa-21sens
and clearCa-21res) with an „acquired paclitaxel resistance”.
Methods. MTT-Assay, RT-PCR, Rhodamin-efflux-assay, flow cytometry, DNA-sequencing.
Results. 1.) After exposure to paclitaxel the model with the intrinsic resistance showed an IC50 of 0,08 µM in the paclitaxel-sensitive chrompho-A and 387,5 µM in the paclitaxel-resistent chrompho-B whereas in
the acquired model an IC50 of 0,38 µM in clearCa-21sens and >1000 µM
in clearCa-21res was detected by MTT-assay. In all cell lines exposure to paclitaxel in combination with curcumin resulted in an additive
growth inhibitory effect. 2.) It has been proven on mRNA-level that Pglycoprotein (P-gp) was expressed in all cell lines. 3.) By flow cytometry
an amount of 18% ±2 of P-gp positive cells in chrompho-A and 30% ±3
P-gp positive cells in chrompho-B was detected while the clear cell lines have a comparable amount of P-gp positive cells in clearCa-21sens
(41% ±2) and in clearCa-21res (42,5% ±1). 4.) The functionality of P-gp
was detected in all cell lines by Rhodamin-efflux-assay whereas in the
cell line clearCa-21res an eight-fold higher efflux than in the cell line
clearCa-21sens became evident. 5.) Analyzing the polymorphisms in
the MDR1-gene in untreated cells the “silent” C3435T polymorphism is
evident in both models. The intrinsic model showed the G2677T polymorphism in the paclitaxel-resistant chrompho-B and G1199A in both
cell lines proven by DNA sequencing. In the acquired model the G2677T
polymorphism could be observed in both cell lines, but the G1199A polymorphism only in the cell line clearCa-21sens.
Conclusion. The MDR1-phenotype is associated with the sensitivity to
paclitaxel in human renal cell carcinoma. Furthermore our results show
first evidence for association of MDR1-polymorphism and sensitivity to
paclitaxel in a model of “intrinsic” and “acquired” paclitaxel resistance.
0438
Plasmacytoid urothelial carcinomas of the bladder harbor complex genomic aberrations
*B. Keck1, S. Wach1, C. Ellmann1, F. Kunath1, R. Stoehr2, H. Taubert1, A. Hartmann2, B. Wullich1
Urologische Universitätsklinik Erlangen, Urologie, Erlangen, Deutschland,
Universitätsklinikum, Pathologisches Institut, Erlangen, Deutschland
1
2
Aim. To investigate whether plasmacytoid urothelial carcinomas (PUC)
are characterized by distinct chromosomal aberrations differing them
from conventional muscle invasive transitional cell carcinomas (TCC)
of the bladder and whether there are molecular events leading to the
known loss of membranous E-cadherin expression.
Methods. Analysis of 25 PUC was performed by conventional comparative genomic hybridization (CGH). Chromosomal regions were defined
as characteristic if they were found in at least 20% of the tumors analyzed. Regions differing from whole-chromosomal signal ratio by at least
three standard deviations (SD) were classified as chromosomal gains
or losses. Heterochromatic and centromeric regions known to display
unreliable signal ratios were excluded from analysis. Additionally copy
number variation of CDH1 (E-Cadherin) was analyzed using polymerase chain reaction (PCR; n=19).
Results. Chromosomal aberrations were found in all PUCs analyzed. In
an average, 11.0 (1–17) aberrations per tumor were detected. Recurrent
gains were found at 1q (40%), 3p (24%), 6p (32%), 7q (20%), 11q (64%), 15q
(32%), 16q (40%), 17p (76%), 17q (88%), 20q (72%), 21q (32%), recurrent
losses at 4q (72%), 5q (36%), 6q (60%), 13q (24%), and Xq (40%). PCR analysis showed heterozygous deletion of CDH1 in 68% of the PUC, whereas amplification was detected in only 3%.
Conclusion. PUCs are characterized by a high genomic instability with
aberrations that are even more complex than what has been described
for conventional muscle invasive TCCs. However, no specific aberrations were detected that would allow to discriminate PUCs from conventional TCCs. Gains at 11q, 17q, 17p and 20q as well as losses at 4q and 6q
are found in the vast majority of PUCs and could therefore represent
important chromosomal regions that are involved in PUC carcinogenesis. These chromosomal aberrations are in line with other molecular
variations of PUC like loss of membranous E-cadherin that are linked
to the aggressive behaviour of PUC. Copy number variation analysis
indicates heterozygous deletion of CDH1 as one underlying mechanism
of this molecular event.
0443
The incidence of intrathoracic lymph node metastases and longterm outcome after pulmonary metastasectomy for metastatic
renal cell carcinoma
*N. Kudelin1, S. Bölükbas1, M. Eberlein1,2, J. Schirren1
Dr. Horst Schmidt Klinik, Thoraxchirurgie, Wiesbaden, Deutschland, 2Carver College of Medicine, Division of Pulmonary, Critical Care and Occupational Medicine, Iowa City, USA
1
Objective. To investigate the incidence of intrathoracic lymph node metastases and long-term outcome after pulmonary metastasectomy (PM)
for metastatic renal cell carcinoma (RCC).
Methods. The office records of 116 consecutive patients (82 men, age
61.7±9.0 years) who underwent PM and systematic lymph node dissection with curative intend from January 1999 through December 2009
were reviewed from a prospective database. Patients’ characteristics
and the following data were recorded: disease-free-intervall (DFI) from
nephrectomy to the diagnosis of metastasis, systematic chemotherapy
before surgical intervention, surgical procedures, pathohistological
results, morbidity, mortality, survival and possible prognostic factors
were analyzed
Results. The overall 5-year-survival and 10-year survival rates were 49%
and 21%, respectively. Morbidity and mortality rates were 13.8% and 0.9
%, respectively. 40 patients (34.5%) had systematic therapy before metastasectomy. Partial regression was observed in 27.5% (11/40). Complete
resections (R0) could be achieved in 108 patients (93.1%). Intrathoracic
(hilar and/or mediastinal) lymph node metastases were found in 46.6 %
of the study population. Median survival was 56.6±9.2 months. Patients’
age (≥70 years; p=0.003), female gender (p=0.016) and number of metastases (≥2 metastases; p=0.012) were associated with inferior survival
after pulmonary metastasectomy in the univariate analysis. Short DFI
(<24 months, p=0.15) or long DFI (≥60 months, p=0.10) from nephrectomy to the diagnosis of metastasis, as well as the presence of thoracic
lymph node metastases (p=0.10) and type of lung resection (p=0.80)
had no statistical significant impact on survival. Patients’ age remained
the only significant prognostic factor when the Cox proportional hazards model was applied.
Conclusions. PM can be performed safely and offers long-term survival in selected patients. Systematic lymph node dissection should be
demanded due to high prevalence of thoracic lymph node metastases.
Patients aged ≥70 years should be selected carefully for PM.
Abstracts
0006
Multiprofessional cooperation in the Oncological Centre in
Berlin-Spandau
*J. Potenberg1, G. Sproßmann-Günther2
1
Ev. Waldkrankenhaus, Innere Abteilung, Berlin, Deutschland,
2
Ev. Waldkrankenhaus, Apotheke, Berlin, Deutschland
Before the certification of the centre itself some components of the
Oncological Centre had to have certified: 2000 Pharmacy of the Paul
Gerhard Diakonie/2005 Breast Centre/2009 Centre of colorectal cancers/2009 Centre of gynecological cancers. The first certification was
the manufacturing of cytotoxic agents. 2010 396 patients were treated
with antineoplastic drugs in our hospital. Calculated doses were checked by the pharmaceutical software Zenzy. Before the application of
the cytostatics the informed consent of the patient was obtained. This
consent describes side effects of each single drug that is to be given (e.g.
heart failure by trastuzumab). After the treatment the side effects was
estimated and the objective response of the tumour was evaluated using
RECIST criteria. Therapy protocols describe the course of events and
the handling of side effects of chemotherapy and the complications caused by the tumour.
Nausea and Emesis/Treatment of pain/Fever and neutropenia/Infections/Mucositis, diarrhea, constipation/Handling of thrombosis.
For a structural detection of side effects and the estimation of the performance status of the patient a „therapy check was developed. This
therapy check is orientated on the CTC criteria, suited also for patients
in studies. 2010 the haematological laboratory performed 5000 tests, including blood pictures, diagnosing leucaemias and neoplastic diseases
in ascites und pleura fluid. Studies are an integral part of the quality assurance in the treatment of neoplastic diseases. Patients have the possibility getting drugs that aren’t approved yet. The high rate proportion of
patient (e.g. 20% in breast centre) is a great challenge. In 2008 the outpatient cancer centre in the Ev. Waldkrankenhaus was created. It contains
20 places for infusion therapy. Hospital doctors and free practicing physicians are working together under one roof. This collaboration made
sure a 24 h/7 d care of patients including CT-scans and intensive care
around the clock. Quality circles and the tumour conferences facilitate the compliance of guidelines. The tumor conferences are the core of
the oncological centre. Here alls the tumour specialists are represented
enabling the multiprofessional decision pondering several therapeutic
options:
Visceral, thorakal and orthopaedic surgeons/Pathology, Radiology,
Pharmacy/Radiotherapy, Oncology.
Several other professions are represented: Psychooncology, breast care
nurses, social workers and the palliative care team. The concerted deliberation gives the effective decision, which is recorded and filed. The
individual patient gets his or her file containing all the important findings. With the complete file the patient can obtain every opinion if he
or she wishes so.
0050
Patients with metastatic solid tumors who receive their treatment in a community based oncology group practice live longer.
*R. Weide1, S. Feiten2, V. Friesenhahn2, J. Heymanns1, K. Kleboth2, U. Mergenthaler2, J. Thomalla1, C. van Roye1, H. Köppler1
Praxisklinik für Hämatologie und Onkologie, Koblenz, Deutschland,
Institut für Versorgungsforschung in der Onkologie, Koblenz, Deutschland
1
2
Background. Overall survival of patients (pts) with metastatic (met) solid tumors is known from controlled prospective trials (CPT). Results
from CPT are biased due to necessary patient selection. No data exist
so far about the outcome of unselected pts with met solid tumors who
receive routine care treatment in a community based oncology group
practice.
Patients and methods. Retrospective overall survival analysis of all pts
with met breast cancer, non small cell lung cancer, colorectal cancer and
pancreatic cancer who received their treatment between 1995–2011 in an
oncology group practice in Germany. Overall survival was determined
from the start of palliative therapy until death.
Results. Median overall survival in 403 pts with met breast cancer was
30 months [Weide R et al (2009), Onkologie 32(3):107–113] compared to
24–28 months in CPT. Median overall survival of 86 pts with Her2-positive met breast cancer was 33 months [Weide R et al (2010), Senologie,
7:159–160] compared to 25 months in CPT. Median overall survival in
119 pts with met NSCLC was 11 months [Köppler et al (2009), Clin Med
Oncol, 3:63–70] compared to 6–9 months in CPT. Median overall survival in 206 pts with met colorectal cancer was 21 months [Köppler et
al (2010), Eur J Cancer Care 19:795–802] compared to 20–24 months in
CPT. Median overall survival in 84 pts with met pancreatic cancer was
42 weeks [Köppler et al (2004), J Support Oncol 2:159–163] compared
to 12–24 weeks in CPT. Psychosocial distress has been shown to be lower compared to hospital settings [Mergenthaler et al (2011) Ann Oncol
22:931–938]. Additional data will be presented.
Conclusions. Overall survival of patients with metastatic solid tumors
who receive their treatment in a community based oncology group
practice compares favorably with the survival achieved in CPT. This
survival advantage may be due to the cumulative oncology experience,
continuity of care due to a constant patient-oncologist relationship, better patient compliance and lower psychosocial distress of patients and
caregivers.
0054
Cancer patients’ use of dietary supplements and non prescription drugs – An evaluation of the Cancer Information Service,
German Cancer Research Center, Heidelberg
*B. Hiller1
1
Deutsches Krebsforschungszentrum, Krebsinformationsdienst,
Introduction. Many cancer patients believe that standard treatment is
not enough. They use antioxidants during chemotherapy or radiation,
detoxifying agents after treatment, homeopathy to cope with side effects and immune boosters to reduce the risk of relapse, often without
telling their physicians. Problems are well documented, e.g. unwanted
side effects and pharmacokinetic interaction with conventional cancer
treatment. Even a negative impact on therapy outcome is discussed.
Methods. To evaluate prevalence and patterns of self-medication among
cancer patients in Germany, the National Cancer Information Service
at the German Cancer Research Center conducted a telephone survey in
2010. 659 Cancer patients using the service’s toll free information hotline were asked, whether they used any over-the-counter (OTC) drugs,
dietary supplements or other medication on their own initiative. Answers were indexed according to lists of pharmaceuticals licensed within Germany or the European Union. For classification of substances
without registration, dietary supplements etc., the Cancer Information
Service’s own database was used as a reference.
Results. 51 % of the callers used self-administered drugs or supplements
at the time of the interview, most often without telling their physicians. The 338 patients named 620 different substances. Most common
were selenium, zinc and m

Cancer Research Clinical Oncology HIJ 30th German Cancer Congress

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