scientific report 2011 - Istituto Nazionale dei Tumori

Transcription

SCIENTIFIC REPORT
2011
Fondazione IRCCS Istituto Nazionale dei Tumori
Via G. Venezian, 1 - 20133 Milan - Italy
THE ISTITUTO NAZIONALE DEI TUMORI
ADOPTS A HOLISTIC APPROACH TO
CANCER, IN PARTICULAR BY PLACING
THE ILL PERSON AT THE HEART
OF ITS PHILOSOPHY OF CARE
AND RESEARCH
FONDAZIONE IRCCS
ISTITUTO NAZIONALE
DEI TUMORI
PREVENTIVE
NUTRITION
ETIOLOGICAL EPIDEMIOLOGY
PREDICTIVE
MOLECULAR PROFILE
GENETIC SUSCEPTIBILITY
THERAPY RESPONSE
PARTICIPATORY
PATIENT ADVOCACY GROUPS
QUALITY OF LIFE
PERSONALIZED
TARGETED THERAPIES
EARLY DETECTION
PRECLINICAL RESEARCH
TARGET DISCOVERY
BIOMARKERS DISCOVERY
CLINICAL TRIALS
PALLIATIVE CARE
Istituto Nazionale dei Tumori
FONDAZIONE IRCCS
ISTITUTO NAZIONALE
DEI TUMORI
www.istitutotumori.mi.it
Comprehensive Cancer Center
SCIENTIFIC REPORT
2011
FONDAZIONE IRCCS
ISTITUTO NAZIONALE
DEI TUMORI
CONTENTS
Introduction
Clinical Activity Data
4
10
RESEARCH ACTIVITY
Prostate Cancer Program
Breast Cancer: Outline of Clinical and Preclinical Research
Lung Cancer Program
Melanoma Program
Personalized Treatment of Sarcoma
Novel Approaches to Determine the Prognosis and Response
to Treatment in Mature B-Cell Malignancies
Development of Radiopharmaceuticals for Tumor
Characterization, Molecular Imaging, and Therapy
Pediatric Brain Tumors
14
18
22
28
32
36
40
44
CLINICAL-SCIENTIFIC STRUCTURE
Scientific Directorate
Descriptive Studies and Health Planning
Tumor Registry and Environmental Epidemiology
Preventive and Predictive Medicine Department
52
58
59
61
Epidemiology and Prevention
Nutritional Epidemiology
Evaluative Epidemiology
Analytical Epidemiology
Medical Genetics
Molecular Basis of Genetic Risk, Polygenic Models
Molecular Basis of Genetic Risk and Genetic Testing
Hereditary Digestive Tract Tumors
Experimental Oncology and Molecular Medicine Department
62
63
64
65
66
67
68
69
71
Immunobiology of Human Tumors
Molecular Therapies
Molecular Immunology
Biomarkers
Molecular Mechanisms of Cell Cycle Control
Molecular Mechanisms
Immunotherapy of Human Tumors
Tumor Genomics
Molecular Targeting
Molecular Pharmacology
Pathology and Laboratory Medicine Department
73
74
75
76
77
78
79
80
81
82
85
Anatomic Pathology Units 1, 2 &3
SIMT, Immunohematology and Transfusion Medicine
Laboratory Medicine
Surgery Department
86
88
89
91
Gastrointestinal, Hepatopancreatobiliary Surgery
and Liver Transplantation
Colorectal Surgery
Breast Surgery
Melanoma and Sarcoma
Diagnostic Endoscopy and Endoscopic Surgery
Otolaryngology Surgery
Gynecologic Oncology
Thoracic Surgery
Plastic and Reconstructive Surgery
Urologic Surgery
Pediatric Surgery
Laser Therapy
Day Surgery
92
93
94
95
96
97
99
100
101
102
103
104
105
Medical Oncology Department
107
Hematology and Allogeneic Bone Marrow Transplantation
Medical Oncology 1
Medical Oncology 2
Pediatric Oncology
Adult Sarcoma Medical Treatment
Head and Neck Cancer Medical Oncology
Medical Day Hospital
Anesthesia, Intensive Care, Pain Therapy,
and Palliative Care Department
108
109
110
111
112
113
114
117
Clinical Anesthesia
Intensive Care
Palliative Care, Pain Therapy, and Rehabilitation
Supportive Care in Cancer
Clinical Nutrition
Diagnostic Imaging and Radiotherapy Department
118
119
120
121
122
125
Radiology and Diagnostic Imaging 1
Nuclear Medicine
Radiotherapy 1
Radiotherapy 2
Medical Physics
126
127
129
130
132
135
136
SHARED RESEARCH RESOURCES
Cardiology
Tobacco Control
Clinical Psycology
Medical Statistics, Biometry, and Bioinformatics
Tissue Bank
Functional Genomics Core Facility
Cancer Proteomics - Molecular Mechanisms
140
141
142
143
145
146
147
EDUCATION AND TRAINING
148
PUBLICATIONS
154
INDEPENDENT ETHICS COMMITTEE
178
ONGOING CLINICAL STUDIES
179
ONGOING PROJECTS SUPPORTED BY DIFFERENT
ORGANIZATIONS
196
Introduction
4
The Scientific Directorate
supported the development
of research resources
In 2011, the Scientific Directorate supported the development of research
resources both at a national and international level by taking part in a variety of
conferences and meetings.
At a national level, in July a commission comprised of members of the National
Commission on Health Research at the Health Ministry and of the Lombardy
Region conducted a Site Visit at our Institute to evaluate its scientific contributions
and confirm its recognition as a research and care centre. For our IRCCS it was
good opportunity to assess the Institute’s performance and to provide an
overview on some of our achievements such as the genetic counseling procedure
established by the Genetic Medicine Unit; the Prostate Program, one of the multidisciplinary core program developed under the auspices of the Scientific
Directorate, and the Biomild project, aimed at developing a non-invasive test for
early diagnosis of lung cancer. On that occasion, we were also very proud to
announce that, after a comprehensive certification process, the Fondazione IRCCS
Istituto Nazionale dei Tumori of Milan (INT) has been certified as one of sixteen
European Neuroendocrine Tumors Centers of Excellence (CoE) in December
2010.
Regarding issues related to research funding, number of permanent staff and
tenure track, in 2011 the Scientific Directorate has kept the lines of communication open both with the Region and the Health Ministry. Also, we were honored
to host the Health Minister who visited the Institute for the inauguration of a
state-of-the-art Unit of Metabolic Therapy.
As a member of the Technical-Scientific Committee of the CNAO, the new
National Center of Oncological Hadrotherapy opened in Pavia, we point with satisfaction to the start of the Center's clinical activity in September 2011 with a
treatment on the first of a series of patients with cordoma, a pathology for which
INT is a main center of reference.
The key role played by our Institute in the regional health sector was confirmed by
the participation in the Health and Welfare session of the World Regions Forum
(WRF), an initiative established by the Lombardy Region to promote exchanges
5
Scientific Report 2011
between regions all over the world where local management is particularly influential because of its vicinity to the most pressing needs of the population. The pilot
project of the WRF in the area of Healthcare, “Cancer Care and Biobanks”, relies
on the experience gained by our Institute as a actuator of the Lombardy
Oncology Network (ROL): the ROL has in fact been developing a Virtual Biobank
as a result of the networking of a series of “real” biobanks organized according to
shared criteria and, whose activities are subject to the same standard of quality
and regulations.
The collaboration between INT and Nerviano Medical Sciences (NMS) made possible by the coordination of ROL has been developed as a result of an
organizational strategy devised by the Scientific Directorate to overcome the crisis
of the traditional model of anticancer drugs discovery and development caused by
the shift from cytotoxic anti-cancer compounds to the so-called targeted therapies
(drugs with specific molecular targets or intelligent drugs). This new strategy is
based on the concept of network and aims at developing a synergy between care
and research in order to ensure greater appropriateness of the therapies and scale
economies both for diagnosis and for treatment of oncology patients in Lombardy,
Marco A. Pierotti, Scientific Director
Introduction
6
a region with 10 million inhabitants and an incidence of about 50,000 new
cases/year. The new strategy is aimed at advancing research by creating the conditions for an integration of the Academy (in its Target Discovery and Validation
components), the pharmaceutical industry (3D Phase) and a clinical network
structured for clinical studies.
As a first result, in 2011 ROL/NMS issued a call for independent clinical research
projects and 31 study proposals have been selected to receive scientific and organizational support from INT and from the Department of Clinical Development of
NMS. A call for pre-clinical projects has also been issued and 8 research proposals
have been selected to be implemented with the collaboration of NMS. The strategy and the new initiatives were illustrated in national (WRF meeting, 28 -30 Sept.;
Forum Ricerca Sanitaria in Cernobbio, 7-8 Nov.) and international contexts (WIN
Symposium, 6-8 Jul.; Bioeconomy International Conference in Rome, 28-29 Nov;
Conference “Molecular Diagnostics for Cancer Drug Development Europe”
Frankfurt, 6-7 Dec) where they attracted some interest.
On an international level, thanks to the cooperation with Nerviano Medical
Sciences, our Institute was able to plan and implement an agreement with a nanotechnology team lead by Mauro Ferrari (President of the Methodist Hospital
Research Institute, Houston) and Ennio Tasciotti (University of Texas Health
Science Center at Houston), which resulted in a research project on nanotechnology in oncology for a new concept of drug delivery in mesothelioma.
More in general, concerning its international activity, in 2011 the Scientific
Directorate has strengthened the wide network of relations that was built up over
the years also thanks to the presence of the Scientific Director in the Board of the
Organisation of European Cancer Institutes (OECI). In 2011 two European projects in which our Institute is a partner were started. In January, the kick-off
meeting of the Eurocan Platform (EP) took place, a project aimed at improvement
in the key areas of prevention, early diagnosis, and therapies. The EP project
involves 28 partners from various European Countries among which are all the
major European Comprehensive Cancer Centers. Also, the first meeting of the
Scientific Advisory Board (SAB) of TRANSCAN was held in 2011. TRANSCAN is
an inter-European ministerial project where the Scientific Director was chosen as
representative for Italy. The SAB identified “Validation of biomarkers for personalized cancer medicine” as the theme for a first call for collaborative research
projects.
In 2011, the Scientific Director was invited to continue to contribute to the selection of new Integrated Cancer Research Site (SIRIC) coordinated by the French
National Institute of Cancer; the sites that will obtain the SIRIC label will receive
substantial support to more efficiently organize their multidisciplinary research
programs and disseminate the results. The Scientific Director was also invited to
7
complete the evaluation on the new Translational Research department created at
the Deutsche Krebs Forschung Zentrum in Heidelberg.
Regarding the research activity conducted within our Institute, a project on tumor
microenvironment was granted 1.8 milion Euros per year funding for 3 years
(which may be extended for up to a further 2 years) from the Italian association
for cancer research (“AIRC 5x1000” funding scheme). In order to improve and
facilitate clinical research within the Institute, the creation of a new Clinical Studies
Office has been approved; it will support researchers teams - both from organizational and practical points of view. In an initial phase the new office was mainly
equipped to provide data management and biostatistical support.
The research at our Institute explored a variety of innovative research fields in
oncology: an overview of the work and accomplishments of the various
Departments and Units can be found, as always, in the pages of this Report.
Notwithstanding the difficulties connected with the still unresolved issue of the
research staff (lack of a tenure track, stop to the creation of new permanent positions), we note with great satisfaction a further increase of the Institute’s Impact
Factor for 2011 (2353.98) and number of publications (450), exceeded last year’s
already excellent result.
450
2353.98
426
2274.62
465
2272.32
415
2250
338
1503.55
366
1686.65
293
1559.97
SHED PAPERS
309
1390.49
320
1349.13
287
1188.21
275
1215.17
CT FACTOR
Introduction
8
Patients are at the heart
of the daily activities of our
1920 employees
The Fondazione IRCCS - Istituto Nazionale dei Tumori (INT) is one of the main
national and international referral center for the treatment and study of cancer.
Our organization and management are dedicated to finding solutions to the clinical
problems posed by the evolution of cancer types in every stage of their development, through prevention, prediction, diagnosis, and treatment (surgery, medicine,
radiotherapy), rehabilitation, psychologic support, pain therapy, and palliative care.
Patients are at the heart of the daily activities of our 1920 employees. INT has 482
beds and in 2011 admitted 22,800 patients, performing over 100,000 diagnostic
tests, laboratory assays, radiotherapy sessions and medical visits. We value our
patients as persons and, knowing that cancer can be a life changing experience, we
strive to listen to their voice: we are therefore proud to collaborate with voluntary
associations advocating patients’ right.
INT is one of the largest comprehensive cancer centers in Italy. Since its establishment, this public institution has aimed to provide the highest standard of patient
care. Our Institute is, however, an IRCCS, that is an institute for cancer treatment
and research. Our mission, therefore, is not only to provide existing treatments but
also to lay the foundations for new ones by pursuing preclinical and clinical
research and swift translation into better prevention, diagnosis, therapy, rehabilitation, and improved quality of life.
Revolutionizing cancer care is for us a tradition we want to live up to. Innovation
was in our genes from the beginning: in 1925, when the decision to open a new
institute entirely and exclusively devoted to the study and care of cancer was
taken, the idea was new and controversial at least in Italy. In a more recent past,
our Institute was the first in Italy to prepare a tumoral monoclonal antibody and
research on biological and molecular characterization of cancers performed in our
laboratories led to the identification of oncogenes at the origin of thyroid cancer
and to the translation of some biomarkers from bench to bedside.
9
We are the first Italian oncology IRCCS in terms of scientific productivity. Even
under hard economic times, we are exceedingly grateful and proud to have the
trust and confidence of the major national and international funding institutions:
the Ministry of Health and the Regional Authorities, the Ministry of University and
Research (MIUR), the European Commission, the Italian Association for Cancer
Research (AIRC), the Fondazione Cariplo, and the Association Bianca Garavaglia
(supporting the pediatric area) to name but a few of the institutions that enable us
to participate in the challenging everyday task of trying to defeat cancer. Finally, we
would like to thank the large number of Italian tax payers who chose to assign
their 0.5% income tax contribution to this Institution.
Gerolamo Corno, Director General
10
Clinical activity data
clinical activity data
Medical Direction is responsible for the management and
organization of selected areas of the hospital: environmental health, surveillance and prevention of infectious
diseases in both patients and healthcare workers, risk
management, organization of outpatient activities and admissions, quality control of services provided, and management of all necessary documentation for patients at
the INT. These activities are carried out in accordance
with the strategies and objectives of the Foundation, following the normatives of the ISO 9000 and the Joint
Commission. The first managerial aspect of Medical Direction is related to risk management, carried out with the
aim of providing safe care of patients through control visits and reducing adverse events whenever feasible. A second aspect involves management of clinical data; Medical
Direction provides support and drives the collection and
elaboration of data – that characterize both outpatient
and inpatient activities - as well as its management in activities involving the Region and Ministry of Health. Medical Direction also controls the congruency of hospital admissions through verification and eventual correction, in
both the immediate and later stages, of monthly data sent
to the Region, which are necessary for proper economic
reporting. Medical Direction performs verification of
healthcare documentation for periodic Regional controls
by selecting arbitrary clinical charts to confirm that
proper codes have been used, and that there are no
anomalies in the services provided. The data shown are
derived from those relative to the clinical activities at INT,
elaborated by Medical Direction.
INPATIENTS BY GEOGRAPHICAL
GEO
OGRAPHICAL AREASS
(OVERALL 12,380)
Central Italy
Italian Islandss
6%
6%
Southern Italy
13%
Northwest Italy
6%
Lombardy
62%
Northeast Italy
6%
Outside
de Italy
11%
%
OUTPATIENTS BY
B GEOGRAPHICAL AREAS
(OVERALL 8,424)
Central Italy
3%
Italian Islands
Southern
thern Italy
3%
7%
Northwest Italy
5%
Northeast Italy
4%
Lombardy
78%
OUTPATIENTS VISITS
2004
2005
2006
2007
2008
2009
2010
2011
Surgery
64,289
60,602
59,715
61,560
56,217
51,774
52,757
52,358
Medical Oncology
49,481
55,394
61,424
61,983
62,402
90,463
86,060
87,483
Diagnostic Imaging & Radiotherapy
18,685
16,966
17,926
17,537
16,846
14,673
16,702
16,715
Anesthesia, Intensive Care,
Palliative Care
32,292
31,141
32,038
33,735
30,929
18,316
25,960
29,487
Transfusion Unit
9,093
7,342
6,997
6,581
6,766
7,163
6,955
6,862
Private Patients
12,937
13,301
14,519
7,932
15,083
14,170
16,201
17,818
186,777
184,746
192,619
189,328
188,243
196,559
204,635
210,723
Total
11
INPATIENTS: AVERA
AVERAGE
AGE LENGTH OF STAY (LENGTH
(LENGTH OF
OF STAY>1
STAY>1 DAY)
DAY
AY
Y))
10.23
Average length of stay
9.03
8.91
8.95
8.34
8.49
8.53
8.49
7.42
8.52
7.69
6.23
5.96
7.32
7.35
5.47
5.66
Surgery
7.16
5.8
7.23
7.23
26
7.26
5.90
5.90
5.92
Overall
66.15
4.93
Medical Oncology
INPATIENTS OVERTHE
OVERT
THE YEARS (LENGTH
(LENGTH OF
OF STAY>1
STAY>1 DAY)
DAY)
6945
6925
6735
6705
Number of inpatients
6347
6250
5959
6174
5804
5574
5508
5347
5452
5594
5045
Surgery
g y
Medical Oncology
gy
SURGIC
SURGICAL
CAL PROCEDURES
(OVERALL
(OVER
RALL 6,555)
P
ediatric surgery
Pediatric
6,7%
Gastrointestinal and
hepatopancreatobiliary surgeryy & Liver transplantation
6,5%
Urologic surger
ry
surgery
7,7%
Colorectal surge
ery
surgery
9,4%
Cranio-m
maxillo-facial surgery
Cranio-maxillo-facial
1 9%
1,9%
Senology
17,4%
Melano
oma and Sarcoma
Melanoma
15,6%
Otolaryngology surgery
10,1%
Gyneco
ologic surgery
Gynecologic
6,6%
Diagnostic and surgical endoscopy
0,1%
5987
7
5965
Plastic and reconstructive
nstructive surgery
9,8%
Thoracic surgery
8,1%
5427
13
RESEARCH ACTIVITY
Prostate cancer program
Breast cancer: outline of clinical and preclinical research
Lung cancer program
Melanoma program
Personalized treatment of sarcomas
Novel approaches to determine prognosis
and response to treatment in mature B-cell malignancies
Development of radiopharmaceuticals
for tumor characterization, molecular imaging, and therapy
Pediatric brain tumors
Multidisciplinary Programs
14
prostate cancer program
Riccardo Valdagni Group Leader
Nadia Zaffaroni Preclinical activities and protocols Group Leader
PROJECT GROUP
T. Magnani - Project Manager
M.F. Alvisi - Statistician
B. Avuzzi - Fellow in Radiation Oncology
L. Bellardita - Psychologist
A. Candosin - Secretary
S. Catania - Data Entry
S. Donegani - Psychologist
C. Marenghi - Medical Oncologist
T. Rancati - Expert in radiation modeling, Data Manager
E. Ronchi - Scientific Secretary
V. Tresoldi - Psychologist
PARTICIPATING DEPARTMENTS AND UNITS
Diagnostic Imaging and Radiotherapy
Experimental Oncology and Molecular Medicine
Medical Oncology
Medical Statistics and Biometry
Palliative Care, Pain Therapy, and Rehabilitation
Pathology and Laboratory Medicine
Preventive and Predictive Medicine
Psychology
Supportive Care in Cancer
Urologic Surgery
PROSTATE CANCER PROGRAM
The Prostate Cancer (PC) program is a translational multidisciplinary program with
exper tise in epidemiology, experimental oncology, pathology, imaging, urologic surgery,
radiation oncology, medical oncology, palliative care, and psychology. Since 2005, the
clinical team has been offering patients with PC a multidisciplinary approach in all
stages of disease (in 2011, about 980 multidisciplinary visits were carried out as first
examinations, second opinions, follow-up of patients on active surveillance or watchful
waiting). Clinical cases are discussed weekly to share decisions, individualize therapeutic
and observational strategies, enroll patients in trials, and verify adherence to
institutional guidelines and quality assurance. Considerable attention is paid to quality
of life and psychological issues. Patients and their families can rely on dedicated
psychologists in the decision-making phase and throughout the course of the disease.
Some of the ongoing research is summarized below.
15
Development of novel approaches for the inhibition of cell survival factors in preclinical
models of androgen-independent PC. Based on the observation that G quadruplexes
(G4) exist not only in telomeres, but also in the promoter of several oncogenes, we
focused our attention on the effects exer ted by a new class of naphthalene diimides,
which can reversibly bind to G4 structures, on the expression of the c-myc and hTERT
genes in PC cell lines. Quantitative RT-PCR data showed down-regulation of c-myc,
which was paralleled by a significant reduction of the expression levels of hTERT. Inhibition of the two oncogenes seemed to represent the primary cause of drug-induced
impairment of telomerase catalytic activity in PC cell lines.
miRNAs in PC: expression profiling and functional analysis. We have previously shown
that miR-205 is down-regulated in PC compared to adjacent non-neoplastic tissue and
acts as a tumor-suppressor in human prostate, as its reintroduction in PC cells rever ts
the epithelial-to-mesenchymal transition. To gain insight into this early loss of miR-205
and into the mechanisms of PC development, we investigated the physiological role of
miR-205 in normal prostate. We found that miR-205 par ticipates in a network involving
Np63, an alternatively spliced isoform of p63, which is essential for maintenance of the
basement membrane in prostate epithelium. At the molecular level, Np63 is able to
enhance miR-205 transcription by binding to its promoter, whereas miRNA can posttranscriptionally limits the amount of Np63 protein, mostly by affecting proteasomal
degradation of Np63 rather than through a canonical miRNA/target interaction. Functionally, miR-205 is able to control the deposition of laminin-332 and its receptor
integrin-4. Hence, pathological loss of miR-205, as widely observed in prostate cancer,
may favor tumorigenesis by creating discontinuities in the basement membrane. We
also demonstrated that therapeutic replacement of miR-205 in prostate cancer cells
can restore basement membrane deposition and 3D organization into normal-like acinar structures, thus hampering cancer progression.
Cells and matricellular proteins as accomplices in PC. Mast cells (MC) are c-Kit-expressing cells, best known for their primary involvement in allergic reactions, but recently
reappraised as impor tant players in cancer promotion and inhibition. In par ticular, we
focused on the role of MCs in PC development. In PCs from both tumor-prone transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and human patients, MCs
are specifically enriched and degranulated in areas of well-differentiated (WD) adenocarcinoma, but not around poorly differentiated (PD) foci that coexist in the same
tumors. We derived novel TRAMP tumor cell lines, representative of WD and PD variants, and through pharmacologic stabilization or genetic ablation of MCs in recipient
mice, we showed that MCs promote WD adenocarcinoma growth but are dispensable
for PD tumors. WD tumors rely on MCs for matrix metalloprotease 9 (MMP-9) provision, as reconstitution of MC-deficient mice with wild-type but not MMP-9(-/-) MCs
was sufficient to promote their growth. In contrast, PD tumors are MMP-9 self-competent, consistent with an epithelial-to-mesenchymal transition. Such a dual source of
MMP-9 was confirmed in human tumors, suggesting that MCs may be a good target for
early-stage prostate cancer. Interestingly, in testing whether MC targeting could block or
delay tumorigenesis in tumor-prone TRAMP mice, we observed a high incidence of
early and aggressive tumors, characterized by a neuroendocrine (NE) signature and cKit expression. Taken together, these data underscore the contribution of MCs in tumor
progression and uncover a new, opposite role of MCs in protecting against the occurrence of aggressive NE variants in prostate cancer.
16
Active surveillance evaluated as an alternative to radical therapies in low risk PC. Selected
patients are followed-up clinically and diagnostically (PSA and biopsy), and offered curative treatment if the PC appears to progress, thus limiting over treatment. Two
protocols are open to enrollment: the PRIAS international prospective study, which,
from September 2007 to December 2011, included 209 patients; the SA INT protocol,
from March 2005 to December 2011, included 145 patients. The hypothesis to be confirmed is that <5% patients will develop clinical progression by a positive bone scan
during their lifetime. Patients on active surveillance are proposed side protocols aimed
at evaluating new biomarkers and non-invasive diagnostic tests in blood and urine samples. As of December 2011, more than 90 patients accepted to par ticipate in the
collection.
Open label Phase II study of vaccination with survivin peptides in PC patients in biochemical failure (PROVAX study). This trial, star ted in late 2010, is evaluating a novel vaccine
combination (survivin peptides and IMP321) in 20 hormone-naïve or refractory
patients with biochemical recurrence. Vaccine peptides, restricted for different HLA-I
alleles, are emulsified in Montanide® ISA 51 VG and administered weekly for 8 weeks
and then every 4 weeks thereafter. IMP321 is given prior to every second vaccination
at the same site. In patients experiencing clinical benefit at the end of vaccination, the
entire vaccine cycle will be repeated. A “safety run-in phase” was included to assess the
toxicity of vaccine combination; the first three subjects were treated and observed for
4 weeks before star ting enrolment. No adverse event was experienced during the first
vaccinations and enrollment star ted in early 2011. The study is still open. In October
2011, the protocol was amended to schedule a new induction phase for patients with
increasing levels of PSA (≥2 ng/ml and <5 ng/ml in two consecutive blood samples,
compared to baseline values) during the maintenance phase.
Predictive models of late rectal toxicity after high-dose PC radiotherapy (RT). New RT
techniques to treat PC with high doses and a high level of precision are being studied.
However, a significant propor tion of patients still experience acute and late toxicity,
since organs at risk are unavoidably included within the high dose region. Although predicting RT morbidity can prevent fur ther deterioration of quality of life and help
introduce treatment corrections to personalize therapy, little attention and inadequate
effor ts have been devoted to the development of easy-to-use tools that use individual
dosimetric, clinical, and genetic risk factors, and which are able to predict the sideeffects of RT. The group involved in the project also par ticipated in two studies
(AIROPROS 0101 and AIROPROS 0102) that assessed predictors of rectal toxicity. The
results gave impor tant indications about the modeling of rectal bleeding in addition to
other acute and late rectal complications. The data from AIROPROS 0102 were also
used to develop nomograms and ar tificial neural network models to predict acute and
late rectal toxicity after RT of PC. These are the first user-friendly tools repor ted in the
literature for evaluating the probability of individual radio-induced rectal toxicity. A pilot
study was also designed to identify genetic markers predicting late rectal bleeding.
Patients were selected within the AIROPROS 0101 trial, and this pilot study showed
that individual dose-volume information coupled to the patient’s genetic profile might
help to explain, on the basis of dose-volume histograms, the quality and unexpected
rectal bleeders, as well as the unpredicted absence of late toxicity in some individuals.
The group is currently involved in a prospective multicenter study (DUE 01, promoted
by San Raffaele Scientific Institute) focused on assessing predictors of genitourinary
(GU) toxicity and erectile dysfunction (ED) after PC high dose RT. The final aim of the
study is the development of predictive models for GU toxicity and ED with inclusion of
dosimetric, clinical, and genetic risk factors.
17
In the domain of prediction of rectal toxicity, a new pilot study is recruiting patients
with the aim of evaluating the correlation between toxicity insurgence and plasma levels of a panel of inflammatory markers. This study includes patients undergoing radical
prostatectomy, radical RT, and adjuvant RT. Both absolute levels of inflammatory markers and their kinetics as a function of radiation dose and follow-up time are being
evaluated. Results from this pilot study could be used prospectively to identify radiosensitive patients and to optimize their RT protocol.
Keywords: translational research, multidisciplinary approach, experimental therapeutics
PUBLICATIONS
Gandellini P, Profumo V, Folini M, Zaffaroni N. MicroRNAs as new therapeutic targets and tools
in cancer. Expert Opin Ther Targets. 2011; 15(3): 265-79.
Pittoni P, Tripodo C, Piconese S, Mauri G, Parenza M, Rigoni A, Sangaletti S, Colombo MP. Mast
cell targeting hampers prostate adenocarcinoma development but promotes the occurrence of
highly malignant neuroendocrine cancers. Cancer Res. 2011; 71(18): 5987-97.
Valdagni R. Prostate cancer units: has the time come to discuss this thorny issue and promote
their establishment in Europe? Eur Urol. 2011; 60(6): 1193-6.
18
breast cancer program
Maria Grazia Daidone Group Leader
Breast Imaging
Experimental Oncology and Molecular Medicine
Medical Oncology
Pathology
Preventive and Predictive Medicine
Senology
BREAST CANCER: OUTLINE OF CLINICAL AND
Major unresolved scientific problems surrounding breast cancer (BC) are related to:
increasing incidence, prevention, early diagnosis, disease progression, treatment, and
resistance to clinical treatments and their toxicity. The heterogeneity of human BC, in
terms of genetic susceptibility, clinical behavior, molecular profiles, and even histomorphologic features, represents a major obstacle to the solution of more effective
therapies. Investigations at the genetic and transcriptional levels have shown that such
heterogeneity may be explained by: a) varying susceptibility to malignant transformation of different mammary cells; b) progression of breast carcinogenesis that is not
necessarily stepwise or linear, from well-differentiated to poorly differentiated tumors,
which is also complicated by the finding that; c) no single dominant pathway or histologic presentation has emerged in BC, whereas mutation within a single pathway has a
dominant role during progression in vir tually all tumor types. High throughput technical
approaches for molecular analyses have prompted a new classification of human BC
and provided a new paradigm for reducing disease complexity, unraveling biological
heterogeneity. This will help to better identify those destined to develop BC among atrisk women, and, among patients, those who will develop new disease manifestations
for more rational planning of therapeutic strategies.
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INT has traditionally provided the highest quality and level of innovation in designing
and developing new approaches to the multidisciplinary treatment of women with BC.
This tradition has led to landmark accomplishments, such as the introduction of new
standards of therapy that are now common practice in the field of oncology. Investigations designed and conducted at INT have demonstrated the possibility of limiting the
extent of surgical removal of BC, thus avoiding mastectomy in many women with relatively small tumors without compromising the chance of successful eradication of
disease. These achievements originate in an approach that merges different disciplines
into a common effor t for the ultimate benefit of patients. There are several key
elements of success, but the most relevant are the creation of a dedicated team of clinical investigators suppor ted by a centralized and unique team for data management
and analysis, the establishment of exper tise in the development of new drugs against
metastatic BC, to rapidly implement new discoveries in the treatment of cases with
early BC, and constant exchange among different laboratories of the Depar tment of
Experimental Oncology and Molecular Medicine and the Units of the Depar tment of
Preventive and Predictive Medicine. In all these respects, the approach to BC at INT
has always been translational and multidisciplinary, and this tradition is maintained in
the current organization of clinical and experimental services devoted to the treatment
and study of BC, also including par tnerships with pharmaceutical industry.
This project represents one of the first effor ts to outline the biology underlying the
distinct risk situations for BC by applying novel approaches for molecular analysis and
target validation to case series recruited at INT in the last decades in the context of
epidemiologic or chemoprevention studies and adjuvant/neoadjuvant treatments. Investigations are focused on: a) effects of different metabolic/nutritional factors on relevant
biomolecular features; b) effects of lifestyle changes on biomarkers and molecular signatures of proven prognostic relevance; c) interaction between host (including ECM
features) and tumor factors; d) new genetic risk factors, including variants of uncer tain
significance in BRCA genes; e) gene expression fingerprints associated to with distinct
new disease manifestations and response to different treatment protocols; f) functional
analyses of genes whose expression affects tumor progression and treatment
resistance; g) at a preclinical level, effect of novel chemopreventive and/or antitumor
therapies. To improve our understanding of BC and to develop clinically-useful strategies, we need better understanding of host factors (including age, diet, life style,
metabolic syndrome, environmental factors, polymorphisms, and mutations in susceptibility genes), tumor microenvironment (growth factors, infiltrating cells, and cytokines),
and genomic changes occurring in cancer cells. At INT, we have a unique oppor tunity
to investigate these aspects taking advantage of: 1) dedicated infrastructure; 2) wellannotated biological samples; 3) a well-established philosophy for cancer and normal
tissue acquisition, storage, and distribution to research Units; 4) updated follow-up
information and validated dietary questionnaires; 5) improvements to overcome intrinsic limitations for genomic studies due to technical ar tifacts and/or to limited sample
size; 6) well-trained teams with specific skills in different disciplines.
Specifically, during 2011 we focused on the following:
a) Expression of androgen receptors (AR) was evaluated on more than 500 primary
BC. Co-expression of AR and estrogen receptors (ER) was observed in 65% of cases,
and ER negative tumors were shown to be AR positive in 45% of cases. Such findings,
together with the evidence of an association between AR expression and favorable
clinicopathologic features, provide suppor t to the hypothesis that AR positive tumors
are well differentiated and largely hormone responsive.
20
b) In this study, which is the first that is prospectively assessing the relationship
between the presence of metabolic syndrome and BC risk, we observed an association
in postmenopausal women. When considering different BC subtypes defined by receptor status, metabolic syndrome was associated with a significant increase of ER-positive,
PgR-positive, HER2-negative tumors, but not ER- and PgR-negative, HER2-positive
tumors. Hyperglycemia, defined by high serum glucose, and insulin resistance, defined
by high HOMA-IR, were impor tant risk factors for BC both in pre- and
postmenopausal women, and also in those who were diagnosed after 55 years of age.
For this latter subset of women, a decreased risk for elevated SHBG concentrations has
also been found. The implication is that altered glucose metabolism is a risk factor for
BC and should be considered in prevention initiatives.
c) Wild-type FOXP3 induction in BC cell lines through an inducible Tet-off system
showed higher in vitro migration ability and increased invasion capacity of WT-FOXP3induced compared with non-induced cells. In addition, GeneSet Enrichment analysis of
differentially expressed genes between FOXP3-induced and non-induced cells indicated
FOXP3-induced expression of several genes implicated in migration and metastasis,
with an enrichment in molecules involved in pathways of TGF-beta signaling and the
epithelial-to-mesenchymal transition, as well as in focal adhesion, strongly suggesting an
involvement of FOXP3 in tumor cell dissemination.
d) In the framework of collaborative studies within international consor tia, three allelic
variants have been identified on chromosomes 12p, 12q, and 21q which are associated
with an increased risk of BC in the general population, as well as three allelic variants,
two of which are close to ESR1, associated with an increased risk of developing BC in
women carrying a mutation in the BRCA1 and BRCA2 genes.
e) The investigation on differentially expressed microRNAs in different BC molecular
subtypes (basal, HER2+, and luminal, as defined by the expression of genes ESR1 and
ErbB2) showed downregulation of miR-190b, miR-375, and miR-342-5p in tumors
belonging to the basal subtype. Using a Gene Ontology approach, these microRNA
were shown to be associated with terms like mitochondrial matrix, carbohydrate catabolic process and mitochondrial respiratory chain, thus suggesting a possible alteration
of carbohydrate metabolism in basal tumors. Experiments are currently ongoing to verify this possibility.
f) The effect of the combination of 4-oxo-4-HPR with paclitaxel (PTX) in BC cells
showed that the retinoid is able to strongly inhibit the growth of both ER+ and triple
negative cells, and to synergistically improve the cytotoxic activity of PTX. These results
suggest that the retinoid could be a suitable substitute for microtubule poisons. In collaboration with the University of Milan (Prof Della Valle), chemical modification of the
structure of 4-oxo-4-HPR is currently under investigation in order to increase its solubility and, consequently, bioavailability.
g) A database collecting information related to clinicopathologic features, metabolic
syndrome, patient follow-up, and availability of biological specimens (tumor material,
blood, serum and plasma, collected with informed consent) has been established and
will represent an added value of this project for future studies.
This project enables a better working relationship among specialists in cellular and
molecular biology, pathology, medical oncology, and epidemiology. Therefore, even
though within an ambitious perspective, this project represents a star ting point for a
broader plan.
Keywords: metabolic syndrome, genetic risk, gene expression profile, microRNA profile,
microenvironment
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PUBLICATIONS
Daidone MG, Zaffaroni N, Cappelletti V. Strategies to translate preclinical information to breast
cancer patient benefit. J Natl Cancer Inst Monogr. 2011; 2011(43): 55-9.
Marchini C, Gabrielli F, Iezzi M, Zenobi S, Montani M, Pietrella L, Kalogris C, Rossini A, Ciravolo V,
Castagnoli L, Tagliabue E, Pupa SM, Musiani P, Monaci P, Menard S, Amici A. The human splice
variant 16HER2 induces rapid tumor onset in a reporter transgenic mouse. PLoS One. 2011;
6(4): e18727.
Endogenous Hormones and Breast Cancer Collaborative Group, Key TJ, Appleby PN, Reeves GK,
Roddam AW, Helzlsouer KJ, Alberg AJ, Rollison DE, Dorgan JF, Brinton LA, Overvad K, Kaaks R,
Trichopoulou A, Clavel-Chapelon F, Panico S, Duell EJ, Peeters PH, Rinaldi S, Fentiman IS, Dowsett
M, Manjer J, Lenner P, Hallmans G, Baglietto L, English DR, Giles GG, Hopper JL, Severi G, Morris
HA, Hankinson SE, Tworoger SS, Koenig K, Zeleniuch-Jacquotte A, Arslan AA, Toniolo P, Shore RE,
Krogh V, Micheli A, Berrino F, Barrett-Connor E, Laughlin GA, Kabuto M, Akiba S, Stevens RG,
Neriishi K, Land CE, Cauley JA, Lui LY, Cummings SR, Gunter MJ, Rohan TE, Strickler HD.
Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of
13 studies. Br J Cancer. 2011; 105(5): 709-22.
Milne RL, Goode EL, García-Closas M, Couch FJ, Severi G, Hein R, Fredericksen Z, Malats N,
Zamora MP, Arias Pérez JI, Benítez J, Dörk T, Schürmann P, Karstens JH, Hillemanns P, Cox A,
Brock IW, Elliot G, Cross SS, Seal S, Turnbull C,Renwick A, Rahman N, Shen CY, Yu JC, Huang CS,
Hou MF, Nordestgaard BG, BojesenSE, Lanng C, Grenaker Alnæs G, Kristensen V, Børrensen-Dale
AL, Hopper JL, DiteGS, Apicella C, Southey MC, Lambrechts D, Yesilyurt BT, Floris G, Leunen
K,Sangrajrang S, Gaborieau V, Brennan P, McKay J, Chang-Claude J, Wang-Gohrke S,Radice P,
Peterlongo P, Manoukian S, et al. Confirmation of 5p12 as a susceptibility locus forprogesteronereceptor-positive, lower grade breast cancer. Cancer Epidemiol Biomarkers Prev. 2011; 20(10):
2222-31.
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lung cancer program
Ugo Pastorino Group Leader
Thoracic Surgery
Radiodiagnostics
Polygenic Inheritance
Tumor Genomics
Cancer Proteomics
LUNG CANCER PROGRAM
The incidence and mortality of lung cancer have constantly declined during the last three
decades in male populations of Europe and the US, mainly as a consequence of effective
smoking control policies. This reduction is by far the most important determinant of the
reduction in total cancer mortality observed for all sites. In the same period, however, the
cure rates for lung cancer have not significantly improved, and the 5-year survival rate of
all detected lung cancers remains below 15%.
Beyond the specific question of mortality reduction, a decade of clinical research on lowdose CT (LDCT) screening has markedly changed our knowledge on the natural history
and biology of lung cancer. In fact, collateral studies of the Multicentric Italian Lung Detection (MILD) project have provided new insight into the genetic determinants of tobacco
addiction, chronic obstructive pulmonary disease, and coronary calcification as independent risk factors for lung cancer, frequency of interstitial lung disease and bronchial
diverticula, along with the value of tissue and blood biomarkers. After 15 years of extensive research on circulating DNA, we have demonstrated that miRNA signatures in
plasma can not only detect lung cancer 2 years earlier than LDCT, but can also predict
the aggressiveness of disease and distinguish indolent from lethal cancers. This discovery
will help clarify why the most virulent forms of lung cancer elude LDCT screening and
will open new perspectives in the early detection and management of lung cancer.
SCREENING AND RANDOMIZED TRIALS
Our screening program started with the pilot study on 1035 volunteers in Milan in 2000
and was followed up in 2005 by a randomized trial comparing annual or biennial LDCT
with observation, namely MILD. This included 4099 participants, 1723 randomized to the
control group, 1186 to biennial LDCT screening, and 1190 to annual LDCT screening.
The MILD trial has now entered its 7th year. In the follow-up stopped in November
2011, we reported 9901 person-years for the pilot study and 17,621 person-years for
the MILD trial. Forty-nine lung cancers were detected by LDCT (20 in biennial and 29 in
the annual arm), of which 17 were identified at baseline examination; 63% were of stage I
23
and 84% were surgically resectable. Stage distribution and resection rates were similar in
the two LDCT arms. The cumulative 5-year lung cancer incidence rate was 311 per
100,000 in the control group, 457 in the biennial, and 620 in the annual LDCT group (P
= 0.036); lung cancer mortality rates were 109, 109, and 216/100,000 (P = 0.21), and
total mortality rates were 310, 363, and 558/100,000, respectively (P = 0.13). Total mortality in the pilot study was similar to that observed in the annual LDCT arm at 5 years.
There was no evidence of a protective effect of annual or biennial LDCT screening. Furthermore, a meta-analysis of the four published randomized trials showed similar overall
mortality in the LDCT arms compared with the control arm.
BIOMARKERS
miRNAs represent a class of molecules that have the capacity for simultaneous regulation
of hundreds of genes and entire networks of biological processes. We previously identified diagnostic and prognostic miRNA signatures in tissue and plasma samples of lung
cancer patients detected by spiral-CT screening. In plasma samples, we also looked at signatures able to predict lung cancer in samples collected up to 2 years before lung cancer
CT detection. We identified 4 signatures: i) risk to develop lung cancer (RD), ii) risk to
develop the aggressive form of lung cancer (RAD), iii) presence of disease (PD), and iv)
presence of aggressive disease (PAD).
One of main criticisms of our previous work concerned the use of pools of 5-6 plasma
samples of disease free subjects, instead of individual samples. During the last year, we
were able to enlarge the validation set and analyze the robustness of our signatures on
individual samples collected from 53 CT-detected lung cancer patients and 100 disease
free individuals. Our results from studying plasma and normal tissue of lung cancer
patients lead us to consider the influence of the tissue microenvironment on cancer
development.
Epithelial cancers are now considered not to be simply the result of abnormal growth of
cancer cells, but rather the result of complex interactions of cancer cells with stromal
components and cells of the immune system. In particular, it has been demonstrated that
stromal “activated fibroblasts” are able to promote the development of several tumors by
inducing angiogenesis, remodeling the extracellular matrix, and inducing epithelial-mesenchymal transition through the activation of several pathways such as TGF-β or Wnt.
The refined signatures, composed of a total of 24 miRNAs, were validated on samples
collected from the 53 patients and 65 controls. The previous results were confirmed or
ameliorated: for the two signatures of risk and diagnosis, we observed a specificity and
sensitivity higher than 80% and for the two signatures of aggressiveness a very high specificity (>96%) and ~88% sensitivity. Moreover, two of the 53 patients within the validation
set developed neoplasms (one bronchial alveolar carcinoma [BAC] and one benign
tumor). The plasma samples collected before CT-detection were both positive for the RD
signature but negative for the RAD one; the sample collected at the moment of the CTdetection in the BAC patient was also positive for the PD signature, but not for the PAD
one.
We are studying the role of activated fibroblasts on tumor development. We were able
to establish several fibroblast cultures from surgical specimens of lung cancer patients and
to identify those with high levels of alpha-smooth muscle actin (α-SMA), a marker of
fibroblast activation. In particular, a major question concerned the plasma miRNAs that
were able to predict the aggressive form of lung cancer (RAD signature), and whether
they are a signal of some event in the normal lung. This hypothesis could potentially
24
explain why we can observe their deregulation as early as two years prior to lung cancer
development. Expression of the six most deregulated miRNAs of the RAD signature was
analyzed in fibroblast cell lines with high and low α-SMA levels. The three miRNAs that
were most up-modulated in the RAD signature (mir-197, mir-28-3p, and mir-17) were all
significantly over-expressed in activated fibroblasts. Of the three down-modulated miRNAs, two (mir-101 and mir-21) were generally under-expressed in activated fibroblasts
and one (mir-451) was not detectable by qRT-PCR.
STEM CELLS
The identification of lung tumor cancer stem cells (CSC) and associated markers may be
useful for optimization of therapeutic approaches and to provide predictive and prognostic information in lung cancer. We reported the presence of highly tumorigenic CD133+
subpopulation of cells displaying stem-like features and chemoresistance to conventional
drugs in primary non-small cell lung tumors (NSCLC). We demonstrated that in vivo cisplatin treatment of lung tumor graft models, which closely resemble the features of
parental primary tumors, resulted in enrichment of the chemoresistant CD133+ fraction.
In particular, an increased of CD133+CXCR4+ subset was observed which we speculated is involved in metastatic process.
Furthermore, new combination strategy to overcome CSC-induced resistance to conventional cytotoxic compounds are evaluated, and the in vivo efficacy of a differentiating
agent (i.e. ATRA) in depleting the tumor stem-like pool was assessed. ATRA treatment
was able to partially deplete the component of CD133+/CXCR4+ cells as shown by fluorescence-activated cell sorting (FACS) analysis, an effect that may account for the
increased latency in tumor re-growth after combination therapy compared to cisplatin
alone.
Similar results were also obtained using an innovative in vitro model that allows the
recovery of highly purified and viable tumor cells from tumor grafts that retain the features of the parental tumors which grow as spheroids in serum-free medium (cancer
tissue originated spheroids, CTOS). Exploiting CTOS culture from several tumor graft
models, we tested the efficacy of ATRA treatment partially depleting the CSC chemoresistant fraction.
We also investigate the role of CSC in the metastatic process, demonstrating that the
induction of EMT in a primary cell line generated a subset of CD133+cells negative for
the epithelial antigen EpCAM that strongly express CXCR4, a chemokine receptor shown
to be involved in metastatic progression in different tumor types. The CD133+/CXCR4+/
EpCAM- phenotype may identify a particular subset of lung cancer stem cells endowed
with the ability to disseminate and to initiate secondary tumors. To support this theory,
we used FACS to examine the presence of CD133+/ESA-/CXCR4High subpopulation in
primary tumors and corresponding lymph node metastases, and we found that a fraction
of CD133+/ESA- cells, strongly expressing CXCR4, were detectable in metastasis but not
in primary tumors. Moreover, the phenotypic study of spontaneous lung metastases
derived from subcutaneous injection of the H460 lung cancer cell line revealed enrichment for the CD133/CXCR4 double positive population in metastases compared to
parental tumors. Thus, a distinct subset of CD133+ migrating CSCs, possibly generated
through the EMT process, could be responsible for formation of metastases.
INFLAMMATION AND CANCER
It has been shown in a large study cohort of MILD participants that simple CT might
provide complementary information for lung cancer risk stratification. Specifically, airflow
obstruction is a strong independent predictor of lung cancer and suggests that increased
mean lung density may also have an important value in determining prognosis.
Conversely, no association between the features of emphysema as assessed by
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automated CT analysis and lung cancer was observed. All of these findings are important
to stratify the risk of lung cancer for future prospective evaluations.
Other smoking-related inflammatory abnormalities have been extensively evaluated in
MILD. Although these have not been demonstrated to be linked to lung cancer, their
assessment should not be avoided in the lung cancer screening setting. It has been shown
that asymptomatic screening participants may develop relevant interstitial lung diseases
(ILDs). Some of these ILDs should be not overlooked as they carry a prognosis even
worse than many lung cancer subtypes. Although atherosclerotic vascular disease
accounts for more deaths and disability than all types of cancer, the importance of
detecting subclinical atherosclerosis and targeting prevention of future cardiovascular
events is only now starting to be highlighted in the lung cancer screening setting. In the
MILD trial, it has been shown that that routine evaluation of coronary artery calcium
score is feasible and provides relevant prognostic information.
LUNG FIBROBLASTS
In co-injection experiments with lung cancer cells, we observed that lung fibroblasts isolated from different sources have pro-tumorigenic potential and influence composition of
the extracellular matrix (ECM). Compared to tumors generated by injection of A549
cells alone, heterotypic tumors displayed strongly increased levels of COL6A3 and
MMP2, slightly increased levels of SPARC and reduced CTSL and CTSC, indicating the
influence of fibroblasts on ECM composition. Tumors generated by co-injections were
also more likely to metastasize to the lung. Moreover, culturing of primary lung cancer
cells with CAF conditioned medium (CM) also resulted in similar transcriptional regulations of ECM-related genes, and increased levels of MMP2 were detected in tumors
derived from injection of CM treated cells.
Signals from the microenvironment have also been shown to modulate different aspects
of carcinogenesis and, in particular, contribute to tumor heterogeneity through induction
of epithelial-mesenchymal transition (EMT). This process could also result in modulation
of the subpopulation of cancer cells endowed with higher tumor forming potential, operationally defined as CSC. In preliminary experiments, exogenous stimuli can regulate the
CD133+ phenotype of lung cancer cells. TGF-beta treatment resulted in an increase in
CD133+ cells both in A549 cells (5-fold increase) and in a primary lung adenocarcinoma
cell line established in our laboratory (LT73; 10-fold increase), also confirming a link
between EMT induction and acquisition of the stemness phenotype by cancer cells in
lung cancer. Furthermore, stimuli from CAFs can de novo generate CD133+ cells. LT73
cells contain a small subpopulation of CD133+ cells (0.1%) which remains stable during
culturing. Through FACS sorting, a line devoid of CD133 expressing cells was generated
(LT73 CD133neg) and cultured in the presence of medium conditioned by CAFs (CM)
or directly co-cultured with CAFs. After both treatments, appearance of CD133 positive
cells could be demonstrated, while cells with this phenotype were undetectable after culturing in normal conditions. Accordingly, expression of stemness related genes (OCT4,
NANOG, alpha6ITG) was increased in LT73 CD133neg after treatment with CM from
different fibroblast cultures demonstrating a direct influence of stromal components on
the modulation of the CSC pool. Taken together, these data demonstrate that cross-talk
between fibroblasts and cancer cells can dictate ECM composition and regulate CSC
content and dissemination of lung cancer suggesting that identification of factors responsible for this cross-talk could be instrumental in devising novel therapeutic strategies.
GENOME-WIDE ANALYSES
Associations between clinical outcome of cancer patients and the gene expression signature in primary tumors at the time of diagnosis have been reported. We tested whether
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gene expression patterns in non-involved lung tissue might correlate with clinical stage in
lung adenocarcinoma (ADCA) patients, comparing the transcriptome of non-involved
lung samples from 60 ADCA smoker patients of clinical stage I versus 60 patients with
stage >I. Five candidate genes were down-regulated in stage >I and in lung ADCA tissue
compared to non-involved tissue. Studies in vitro indicated that four of the genes
(SLC14A1, SMAD6, TMEM100, and TXNIP) inhibited colony formation of lung cancer cell
lines transfected to overexpress these genes, suggesting their potential tumor-suppressor
activity. Individual variations in the transcriptional profile of non-involved lung tissue may
reflect individual predisposition to tumor aggressiveness in patients with lung ADCA.
Non-involved lung tissue from cancer patients surgically resected for a lung ADCA
(n=40) or for a lung metastasis from a non-lung cancer (n=40) was also analyzed by
genome-wide transcriptional analysis to identify a transcriptional signature associated
with risk of these pathological conditions. Comparison of the gene expression pattern in
the two groups pointed to a transcriptional signature enriched for genes involved in the
extracellular matrix (ECM)-receptor interaction pathway. Seven of 11 genes identified in
this pathway encode collagen chains, suggesting that individual variations in transcript levels of these genes in non-involved lung tissue may modulate the risk of metastatic spread
to the lung. By qPCR, results for collagen genes COL3A1, COL4A1, and COL4A2 were
confirmed in the discovery series and validated in an independent series of 36 lung
metastases and 47 lung ADCA patients. Overall, analysis by qPCR of the two series combined indicated statistically significant 1.2-fold up-regulation of COL4A1 and COL4A2
transcript levels in patients with lung metastasis of a non-lung cancer. Transcriptional upregulation of collagen genes in normal lung tissue may be associated with individual risk
of lung metastasis.
We have also started a study on the transcriptional profile of non-involved lung tissue
from 300 lung ADCA patients in association with clinical parameters related to chronic
obstructive pulmonary disease (COPD), and in particular with forced expiratory volume
in 1 second (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio. We are using the
Illumina microarray platform which allows detection of expression levels of about 48,000
transcripts.
CARCINOGENESIS
We carried out an extensive FCM analysis of the immunological profile of lung tissues
isolated from 52 patients. For each, the frequency (determined as % of all CD45+ leukocytes) of 11 different cellular subsets was characterized in three different tissue samples
(based on an operational classification of the surgical samples as “normal/far”, “adjacent”
and “tumor” tissue). The investigated subsets included: CD3+CD4+ and CD3+CD8+ T
lymphocytes, CD19+ B cells, CD14+ monocytes, and CD4+ FOXP3+ regulatory T cells.
In addition, we looked at activated T cells expressing either HLA-DR or CD69. All tissue
samples, including those defined as “normal” and “adjacent” contained a sizeable fraction
(5-9%/CD45+) of recently activated (HLA-DR+, or CD69+) T cells. Furthermore, the
comparison of frequency of each of the subsets indicated, in several instances, a significant skewing in the distribution in tumor tissue compared to normal and adjacent tissues.
In particular, no difference was found for any subset between normal and adjacent
tissues, while an increased frequency, in tumor tissue, of CD3+ T cell and CD19+ B cells,
activated HLA-DR+ T cells and CD69+ CD8+ T cells was found. In addition, conventional
CD4+ FOXP3+ regulatory T cells were at higher frequency in the neoplastic tissue compared to normal/adjacent tissues. In contrast, significant reduction in monocytes was
observed in tumor tissue compared to normal and adjacent tissues. Interestingly, we also
found the presence of CD8+ T cells expressing FOXP3 in tumor tissue. This subset was
recently described by us in melanoma samples as an “early effector” subset. Taken
together, these results suggest that: a) both normal/adjacent and neoplastic lung tissues
27
are actively involved in ongoing immune responses as documented by presence of
recently activated (HLA-DR+/CD69+) T cells; b) conventional regulatory T cells accumulate selectively in neoplastic tissue, but are also found in surrounding normal tissues; c)
the presence of CD8+ FOXP3+ T cells is consistent with the early phases of generation
of anti-tumor immunity in neoplastic tissue; d) neoplastic tissue has a specific immunological profile compared to the normal/adjacent tissues.
EXPERIMENTAL MODELS
We used p53+/- mice and replaced their hematopoietic cells with those from p53 wild
type Thy 1.1 congenic mice in order to avoid the prominent lymphoid transformation.
The initial idea of promoting lung cancer in such chimeric mice by lung delivery of inflammatory agents as they develop osteosarcomas at a high rate. Lung inflammation was then
studied in the context of bleomycin-induced pulmonary fibrosis. Fibrosis results from
inflammatory tissue damage and impaired regeneration. In the context of bleomycininduced pulmonary fibrosis, we demonstrated that the matricellular protein SPARC
distinctly regulates inflammation and collagen deposition depending on its cellular origin.
Reciprocal Sparc-/- and WT bone marrow chimeras revealed that SPARC expression in
host fibroblasts is required and sufficient to induce collagen fibrosis in a proper inflammatory environment. Accordingly, Sparc-/- >WT chimeras showed exacerbated
inflammation and fibrosis due to the inability of Sparc-/- macrophages to down-regulate
TNF production because of an impaired response to TGF-b1. Hence, the use of bone
marrow cells expressing a dominant negative form of TGF-bRII under the monocyte-specific CD68 promoter, as a decoy, phenocopied Sparc-/- donor chimeras. Our results
point to an unexpected dual role of SPARC in oppositely influencing the outcome of
fibrosis. The pro-inflammatory condition of SPARC-KO>WT chimeras is now exploited
to test whether total body radiation and bleomycin-induced lung injury render mice
prone to lung cancer.
Keywords: lung cancer, early diagnosis, biomarkers, inflammation
PUBLICATIONS
Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabrò E, Croce CM, Pastorino U,
Sozzi G. MicroRNA signatures in tissues and plasma predict development and prognosis of
computed tomography detected lung cancer. Proc Natl Acad Sci USA. 2011; 108(9): 3713-8.
Sangaletti S, Tripodo C, Cappetti B, Casalini P, Chiodoni C, Piconese P, Santangelo A, Parenza M,
Arioli I, Miotti S, Colombo MP. SPARC oppositely regulates inflammation and fibrosis in
bleomycin-induced lung damage. Am J Pathol. 2011; 179: 3000-10.
Frullanti E, Galvan A, Falvella FS, Manenti G, Colombo F, Vannelli A, Incarbone M, Alloisio M,
Nosotti M, Santambrogio L, Gonzalez-Neira A, Pastorino U, Dragani TA. Multiple genetic loci
modulate lung adenocarcinoma clinical staging. Clin Cancer Res. 2011; 17: 2410-6.
Sverzellati N, Guerci L, Randi G, Calabrò E, La Vecchia C, Marchianò A, Pesci A, Zompatori M,
Pastorino U. Interstitial lung diseases in a lung cancer screening trial. Eur Respir J. 2011; 38(2):
392-400.
Diciotti S, Sverzellati N, Kauczor HU, Lombardo S, Falchini M, Favilli G, Macconi L, Kuhnigk JM,
Marchianò A, Pastorino U, Zompatori M, Mascalchi M. Defining the intra-subject variability of
whole-lung CT densitometry in two lung cancer screening trials. Acad Radiol. 2011; 18(11):
1403-11.
Pastorino U, Rossi M, Rosato V, Marchianò A, Sverzellati N, Morosi C, Fabbri A, Galeone C, Negri
E, Sozzi G, Pelosi G, La Vecchia C. Annual or biennial CT screening versus observation in heavy
smokers: 5-year results of the MILD trial. Eur J Cancer Prev. 2012; 21(3): 308-15.
28
melanoma program
Mario Santinami Group Leader
Licia Rivoltini and Andrea Anichini Preclinical activity and protocols
Group Leaders
PARTICIPATING UNITS
Melanoma and Sarcoma - Coordinator
Medical Oncology
Pathology
MELANOMA PROGRAM
Malignant melanoma continues to be a considerable medical issue because of the
unsatisfactory efficacy and significant toxicities of currently-available drugs, and the rising incidence of the disease worldwide, which has doubled in the last 10 years with
over 160,000 cases. Currently, over 90% of patients present with only primary
melanoma at the time of first diagnosis. Although resection of the primary tumor is curative in many cases, some 20-30% of patients will eventually die of their cancer. Patients
with distant metastases and/or stage IV disease have a very poor prognosis with a
median survival of 8 months and a 2-year survival rate of 11%. Established in 2000, the
Melanoma Program is a multidisciplinary approach involving surgeons, dermatologists,
oncologists, pathologists, and experimental scientists, all involved in patient care and
research. This integrated network offers patients the highest standards of care and
improves issues related to melanoma diagnosis and therapy by increasing current
knowledge about biology, genetics, and interaction with the host environment.
The projects of this multidisciplinary program:
• Offer melanoma patients the most promising therapeutic strategies, based on a careful selection at the individual level of tumor features and disease stage
• Perform extensive and coordinated preclinical and clinical studies aimed at understanding the mechanisms of action of novel anti-melanoma therapies and pathways of
resistance, with par ticular attention to immune responses and immunotherapy
• Understand the strategies utilized by melanoma cells to restrain tumor immunity
from the very early phase of disease and promote disease progression, and to identify
pharmacological tools for the recovery of effective immune responses.
29
Several integrated research projects are ongoing, fostering fur ther understanding of: a)
genetic alterations that promote tumor transformation and progression; b) the role of
altered intracellular signaling pathways in promoting melanoma cell survival, resistance
to programmed cell death and escape from immune control; c) the role of pro-inflammatory crosstalk between tumor and stroma in promoting tumor growth and
progression; d) identification of molecular markers of progression; e) identification and
pharmacological targeting of cancer stem/initiating cells within the tumor population.
From a clinical point of view, crucial questions are approached with the goal of developing novel and more effective therapeutic strategies, by combining emerging
treatments and drugs (including vaccines) with more conventional therapies, both in
experimental models and clinical trials.
Novel therapeutic approaches. Phase I-II clinical trials testing the most promising therapeutic strategies have been activated within the multidisciplinary clinical program, and
patient recruitment is in progress. These include vaccination strategies with tumor antigens as recombinant proteins (MAGE3, PRAME and NY-Eso1, ASCI strategy),
immunomodulation of anti-CTLA4 antibodies in combination with chemotherapy
(NIBIT trial), and novel BRAF and MEK inhibitors. Studies focused on evaluating the
immunological effects occurring in treated patients are performed through dedicated
monitoring of tumor T cell immunity, frequency and function of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) together with cytokine/chemokine
serum profiling.
Recently, based on consistent preclinical and initial clinical data, we have designed a randomized clinical protocol testing whether immunomodulating agents can synergize with
standard therapies in improving specific tumor immunity to increase clinical benefits.
Specifically, in patients with intradermal/subcutaneous melanoma lesions, we will test
electrochemotherapy (ECT) either alone or in combination with proton pump
inhibitors or intratumor injection of low dose IL-2. The study will be aimed at testing
whether the combinatorial approach can induce positively modulate tumor immunity
(in terms of increase in tumor-specific CD8+ and/or CD4+ T cells and decrease of
immunoregulatory cells such as Tregs and immunosuppressive myeloid components of
different origin) either at the systemic or local level. Clinical benefit, as improved TTP
or effects on distant untreated tumor lesions, will be also determined by clinical and
pathological assessment.
Study of immunoregulatory pathways. The evaluation of the phenotypic and functional
features of immunosuppressive cells (such as Tregs and MDSCs), the molecular pathways leading to their accumulation and the impact that these cells may have on the
clinical course of melanoma patients has allowed us to gain information about: i) the
expression of LAG-3 as marker of activated Treg present at the tumor site, displaying
stronger immunosuppressive activity; ii) the role of tumor exosomes in conver ting
myeloid cells into MDSC, and the immunosuppressive/pro-tumorigenic proper ties of
these cells generated either in vitro or in vivo in melanoma patients; iii) immunomodulation by drugs, such as cyclophosphamide or proton pump inhibitors (esomeprazole),
on Treg and MDSC in vitro or in vivo, of treated patients. Specific studies have been
conducted to study the metabolic impact, and par ticularly the impact of glycolysis,
hypoxia, and associated pH dysregulation in the tumor microenviroment, on different
arms of the immune responses. On the basis of the data produced in vitro, ex-vivo, and
in different melanoma murine models, we discovered that pH regulation can profoundly
influence tumor-specific immunity and that drugs interfering with such a pathway (e.g.
proton pump inhibitors or the omeprazole family) may represent a valid therapeutic
30
strategy to recover immune-mediated tumor control. A patent about the immunomodulating role of proton pump inhibitors in cancer has been proposed and is presently
under evaluation.
Molecular studies on markers for melanoma progression. We have analyzed the results
of gene expression and microRNA profiling studies in archival sentinel lymph node
biopsy (SNB) samples to evaluate transcriptional profiles for the identification of markers to be exploited for the stratification of stage III patients according to prognosis. We
have evidence that tumor-positive SNB from patients with node involvement at
regional complete lymph node dissection and poor prognosis at 5 years follow-up possess distinct transcriptional patterns, which are mostly due to immune response
regulated genes in the sentinel lymph node. Analysis of the miRNA profiles and preliminary assessment of the miRNA-mRNA target pairs identified a set of miRNA and
immune response regulated genes, thus suppor ting the hypothesis that miRNA can
influence melanoma progression by regulating immune response processes ongoing in
the sentinel lymph node. In order to evaluate mutated BRAF as a circulating molecular
marker for disease progression, we have analyzed mutated BRAF in metastatic
melanoma lesions and in plasma of melanoma patients. About 50% of melanoma tissues
are positive for the T1799A variant (V600E) by sequence analysis, while the mutation is
detected in 60% of cases by allele-specific real-time PCR-based detection with
improved sensitivity. Circulating BRAFV600E is detected in 70% of patients, fur ther indicating intratumor heterogeneity for the mutation.
mRNA and miRNA profiling of MDSC induced in vitro by melanoma exosomes. Prelimi-
nary results pointed out a role for mRNA and miRNA carried by melanoma exosomes
in modulating molecules involved in regulation of immune processes in monocytes.
Monocytes treated with melanoma exosomes show a transcriptional pattern involving
IL-6 and HIF1α. Melanoma exosomes carried miRNA targeting genes involved in the
MDSC response and mRNA regulating TGF-β signaling.
Mechanism of action of ipilimumab in metastatic lesions. The availability of the antiCTLA-4 mAb ipilimumab, for therapy of advanced melanoma, has led to the first
randomized phase III study showing improved survival in metastatic disease. The use of
ipilimumab is based on the hypothesis that CTLA-4 blockade may suppress a negative
pathway of immunity, which is thought to be dominant in neoplastic tissues of advanced
cancer. Therefore, blockade of CTLA-4 by ipilimumab is expected to activate T-cell–
mediated responses at the tumor site. However, immunologic monitoring of neoplastic
tissues from patients treated with ipilumumab has not been previously performed. To
address this issue we carried out a detailed immunohistochemical analysis of metastatic
lesions removed before and after ipilimumab therapy from a melanoma patient. We
found that objective tumor response, seen in one of two post-therapy lesions, was
associated with a specific immunological profile, which was not seen in either the pretherapy or post-therapy non-responding lesion. The neoplastic tissue of the regressing
lesion was characterized by increased infiltration by activated (HLADR+) CD3+ T cells
that expressed cytolytic effector markers, by the presence of CD1a+ dendritic cells,
and by a lower frequency of FOXP3+ lymphocytes. These results suggest that
ipilimumab promotes infiltration of neoplastic tissues by dendritic cells and T cells and
promotes functional differentiation of T cells to cytolytic anti-tumor effectors.
A subset of melanoma characterized by selective expression of the AXL receptor tyrosine kinase (RTK). The identification of new subsets of melanomas based on analysis for
RTK expression may lead to the development of new and targeted therapies based on
the usage of specific RTK inhibitors. In this study, we found that a subset of melanomas
(38% of 58 cell lines investigated) express RTK AXL, a member of the TAM (Tyro3,
AXL, and MER) family of receptors. AXL was specifically expressed by a subset of
MITF-negative melanomas lacking expression of melanocyte differentiation antigens.
31
AXL was functional in these tumors as shown by analysis of downstream signaling pathway activation following stimulation with the ligand (GAS6). Inhibition of AXL
expression by siRNA, or treatment of melanoma cells with a selective inhibitor (R428),
suppressed motility, invasiveness, and ability of neoplastic cells to heal a wound and
migrate across endothelial cell layers. These results suggest that AXL is a potential therapeutic target in a subset of MITF-negative melanomas.
Keywords: tumor vaccines, immune escape, BRAF/MEK inhibitors, melanoma stem cells
PUBLICATIONS
de Vries IJ, Castelli C, Huygens C, Jacobs JF, Stockis J, Schuler-Thurner B, Adema GJ, Punt CJ,
Rivoltini L, Schuler G, Coulie PG, Lucas S. Frequency of circulating Tregs with demethylated
FOXP3 intron 1 in melanoma patients receiving tumor vaccines and potentially Treg-depleting
agents. Clin Cancer Res. 2011; 17(4): 841-8.
De Milito A, Canese R, Marino ML, Borghi M, Iero M, Villa A, Venturi G, Lozupone F, Iessi E,
Logozzi M, Della Mina P, Santinami M, Rodolfo M, Podo F, Rivoltini L, Fais S. pH-dependent
antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition
of tumor acidity. Int J Cancer. 2010; 127: 207-19.
Del Vecchio M, Mortarini R, Tragni G, Di Guardo L, Bersani I, Di Tolla G, Agustoni F, Colonna V,
Weber JS, Anichini A. T-cell activation and maturation at tumor site associated with objective
response to ipilimumab in metastatic melanoma. J Clin Oncol. 2011; 29: e783-8.
32
personalized treatment of sarcomas
Paolo G. Casali Group Leader
PARTICIPATING UNITS
Adult Sarcoma Medical Treatment - Coordinator
Biomarkers
Clinical PET
Evaluative Epidemiology
Laboratory Medicine
Melanoma and Sarcoma
Molecular Diagnostic laboratory
Palliative Care
Molecular Basis of Genetic Risk, Polygenic Models
Tumor Genomics
PERSONALIZED TREATMENT OF SARCOMAS
OVERVIEW
Soft tissue and bone sarcomas, including GISTs, are rare and highly heterogeneous
tumors. Heterogeneity is firstly related to their ubiquitous anatomical origin. In this
regard, applying good surgical principles to all sarcoma primary sites is not feasible. In
par ticular, retroperitoneal and thoracic sarcomas have a poorer prognosis, primarily for
surgical reasons. It is realized that new therapeutic avenues should be explored for
these tumors, exploiting all disciplines, from surgery to radiation and medical therapy.
Heterogeneity is also related to the pathology of these tumors, as there are dozens of
histological subtypes. It is well-known that the natural history of sarcomas differs substantially depending on the histological subtype. In the last few years, it has also
become clear that histologic subtypes possess distinct cytogenetic and molecular profiles that affect sensitivity to medical therapies, including cytotoxic and targeted agents.
These latter have mechanisms of action that are more specifically dependent on the
molecular profile of the tumor. This poses new challenges to medical therapy of sarcomas, reinforcing the need to personalize medical treatment, mainly exploiting
knowledge of deregulated molecular profiles. In this regard, GISTs constitute a tumor
model that the sarcoma medical community has had the privilege to explore, and the
model can now be tested in other types of sarcomas. In par ticular, it is clear that the
current approach to sarcomas should be highly personalized, on a highly multidisciplinary basis. GISTs constitute an advanced platform, but other sarcomas are catching up
rapidly, as new targeted agents are becoming available at a steady pace.
33
The aim of this group is to strengthen the institutional research platform, aimed at gaining new insights on the antitumor activity of cytotoxics and molecular targeted agents
in selected types of sarcoma, including the rarest ones. New insights will also be gained
on how to incorporate these medical therapies into multidisciplinary treatment strategies, with insights even in the most challenging clinical presentations of sarcoma. New
avenues in the methodology of clinical research will be attempted, so that an additional
value of the project will be the assessment of new strategies for clinical research,
potentially serving as a model for other rare tumors. The patient populations include all
patients affected by sarcoma, which for practical reasons are mainly divided into adult
soft tissue sarcoma, GIST, small blue round cell sarcoma, osteosarcoma, chordoma and
chondrosarcoma, and rare histological types.
The group has the goals of:
• Strengthening the institutional infrastructure for clinical studies on new agents in sarcoma. The aim of the infrastructure is to place the INT in the best position to launch
and/or to join phase II and phase III clinical studies on new agents in sarcoma.
• Suppor ting the institutional infrastructure for translational research related to the
targeted use of new molecular agents in sarcoma. The infrastructure will aim to place
the INT in the best position to perform translational research on the use of new
agents in sarcoma in tailored manner.
• Suppor ting the sarcoma networking coordinated by the INT to allow prospective
and retrospective studies even on the rarest sarcoma subtypes and presentations. The
INT coordinates the Italian Network on Rare Tumors, which is a powerful means to
perform prospective and retrospective studies on rare presentations, with regards to
their natural history and sensitivity to treatments.
• Studying the clinical utility of new targeted agents for treatment of sarcoma. Targeted
agents imply considerable rethinking of clinical methodology (e.g., with regard to tumor
response, assessment etc.). However, only centers with a large number of patients can
embark on such a project, through systematic clinical observations and studies focusing
on treatment strategies.
• Developing and testing new methodologies for clinical research in rare tumors. An
effor t will be made to test new options firsthand at least on the rarest presentations.
RELEVANT OUTPUT
During the third year of the project, global international collaboration among sarcoma
centers was strengthened. The ESMO International Conference on Sarcoma & GIST
was organized by INT and planned for March 2012; beyond the educational intent, the
event is a crucial moment for the sarcoma community, aimed to share new investigational studies and methodologies in sarcomas.
Several clinical trials on rare sarcoma subtypes are ongoing or just completed:
1. Phase II trial on nilotinib in pigmented villonodular tenosynovitis. This is a rare condition in which tumor growth is sustained by CSF1R/CSF1 through an autocrine/
paracrine loop that is potentially inhibited by nilotinib. Enrollment has just been com-
34
pleted and data analysis is ongoing. Results on the activity of imatinib were published in
collaboration with other European centers.
2. Phase II trial on the activity of NGR-TNF, a fusion protein derived from NGR and
TNF. We postulated that vascular sarcoma histotypes could show a par ticular sensitivity
to this compound.
3. Two phase II trials in imatinib-pre-treated chordoma: a) lapatinib, an EGFR inhibitor :
the final results will be presented at ASCO 2012 b) everolimus + imatinib, currently
enrolling.
4. Four phase II trials on GIST: a) everolimus + imatinib in imatinib-naïve patients with
a PDGFRA D842V mutation; b) regorafenib, a BRAF inhibitor, as third line therapy; the
results of this completed international trial will be presented at ASCO 2012; c) BKM
120, a PI3K-inhibitor, as third line therapy; d) third generation TKI-inhibitor (Dovitinib)
in high dose imatinib pretreated patients.
5. Phase III trial in advanced pretreated liposarcoma/leiomyosarcoma: eribulin versus
dacarbazine.
6. Phase II trial on siromilus + sorafenib in advanced pretreated osteosarcoma: it is an
Italian Sarcoma Group trial, planned on the published results on the activity of
sorafenib alone in this setting of patients.
7. Phase II multicentric international trial on denosumab in bone giant cell tumor :
interim analysis of this enrolling trial was presented both at CTOS 2011 and ASCO
2011.
8. Phase II randomized vs placebo double-blinded trial con IPI926 in advanced chondrosarcoma.
9. Activity of sunitinib in advanced sarcoma patients treated at our institution was
updated in a presentation at CTOS 2011. The animal model is under study in order to
identify the mechanism of action of the drug.
We first published our data on sunitinib ina lveolar soft par t sarcoma, confirming its
antitumor activity, based on biological rationale. We repor ted that sunitinib is active
both by a direct antitumor effect and an antiangiogenic mechanism.
We established the activity of imatinib in chordoma, with a publication on the final
analysis of the phase II study.
We repor ted on the activity of dacarbazine +/- doxorubicin in clear cell sarcoma in
advanced setting in a pooled series treated within the project of the National Rare
Cancer Network.
Regarding myxoid liposarcoma, the results of the Italian Sarcoma Group phase II study
on neoadjuvant trabectedin was accepted for publication in 2012. A pooled retrospective analysis (INT, Royal Masden London) of the activity of trabectedin in advanced
uterine leiomyosarcoma was published, and the activity of ifosfamide in well differentiated/dedifferentiated liposarcoma was confirmed and presented at ASCO 2011.
A position paper on the surgical approach of retroperitoneal sarcomas was published,
due to the complexity of surgery in this disease and the lack of a standardized
approach. Based on the consensus statements from European and Nor th American
exper t sarcoma surgeons, the paper was aimed to describe a reproducible and standardized approach to these tumors. A detailed description of the different procedures
according to the variety of different presentations was made.
35
Finally, the results of the phase III Italian/Spanish Sarcoma Groups were accepted for
publication in 2012: in high risk localized sarcoma patient population, randomized to
receive three or five cycles of chemotherapy in addition to local treatment, with no difference was detected in overall survival.
Keywords: sarcomas, rare sarcoma subtypes, genetic alterations
PUBLICATIONS
Gronchi A, Frustaci S, Mercuri M, Martin J, Lopez-Pousa A, Verderio P, Mariani L, Valagussa P, Miceli
R, Stacchiotti S, Dei Tos AP, De Paoli A, Longhi A, Poveda A, Quagliuolo V, Comandone A, Casali
PG, Picci P. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a
randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin
Oncol. 2012; 30(8): 850-6.
Stacchiotti S, Longhi A, Ferraresi V, Grignani G, Comandone A, Stupp R, Bertuzzi A, Tamborini E,
Pilotti S, Messina A, Spreafico C, Gronchi A, Amore P, Vinaccia V, Casali PG. Phase II study of
imatinib in advanced chordoma. J Clin Oncol. 2012; 30(9): 914-20.
36
novel approaches / mature b-cell malignancies
Paolo Corradini Group Leader
PARTICIPATING UNITS
Hematology and Bone Marrow Transplantation - Coordinator
Immunobiology of Human Tumor
Medical Oncology 3
Medical Statistics and Biometry
Pathology
Proteomic Laboratory
Radiology and Diagnostic Imaging
NOVEL APPROACHES TO DETERMINE PROGNOSIS AND
RESPONSE TO TREATMENT IN MATURE B-CELL
MALIGNANCIES
OVERVIEW
Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) are mature B-cell
cancers with an incidence that increases with age. Despite novel drugs, MM remains
incurable for the vast majority of patients, with a highly variable outcome in different
prognostic subgroups. The same applies to CLL: the disease is incurable and prognosis
is extremely variable depending upon several clinicopathological factors. The selection
of the most appropriate treatment (chemo-immunotherapy or stem cell transplantation
[SCT]) must include knowledge of the clinical and genetic prognostic factors of the
patient. For example, the limited duration of response after autologous SCT for MM
patients with t(4;14)(p16;q32), t(14;16)(q32;q23) and 17p13 deletions highlights the
need to develop a risk-adapted treatment strategy. The same is true for CLL patients
carrying the 17p13 deletion. From an idealistic point of view, treatment strategies
should be tailored based on clinical risk determination, adverse genetic prognostic factors, and host features. Although there is some data from gene expression profiling
studies, there are no clear and firm conclusions on prognostic relevance and applicability in a clinical setting. While flow cytometry, cytogenetics, and molecular analyses may
provide impor tant prognostic information for both MM and CLL, they are not routinely
used, and not frequently used together in a prospective fashion. Modern treatment
protocols lead to complete remission (CR) in a considerable propor tion of patients
with MM and CLL. However, many patients will ultimately relapse, implying that the
achievement of a clinical CR is compatible with a significant amount of residual malignant cells. For these reasons, a comprehensive approach prospectively integrating
clinical and laboratory data is required for better stratification of patients, which will in
turn translate into better allocation of healthcare resources.
37
Our major objective is to analyze the pre-treatment clinical and biological features of
patients to determine their value in predicting disease response and survival. In par ticular, focus is placed on four main research areas: i) the genetic features of tumors
(cytogenetics and FISH studies of MM cells, detection of MM stem cells, validation of
the 17-gene expression-based risk-stratification model, identification of circulating MM
specific miRNAs, use of a proteomic strategy on both leukemic cells and plasma specimens to identify novel proteins as biologic indicators of prognosis and response to
treatment for CLL); ii) the immunological evaluation of the host and tumor interaction
(evaluation of the T cell, natural killer cell and myeloid derived suppressor cell compar tment); iii) monitoring of minimal residual disease (multiparameter flow cytometry and
molecular methods); iv) assessment of bone lesions using a novel imaging method
[whole body magnetic resonance imaging (DW-MRI)]. A fundamental goal of this project is to find a panel of biomarkers that can be easily and routinely used in a clinical
setting.
RELEVANT OUTPUT
Promising results have been obtained during the last year of activity. In par ticular, we
have demonstrated that:
• The number of lesions revealed by diffusion weighted MRI (DW-MRI) is significantly
higher than that revealed using standard radiological examinations. There was a significant difference in the number of lesions detected in patients with symptomatic MM
compared to patients in follow-up. Complex image analysis defined a diffusion coefficient (ADC, apparent diffusion coefficient) that is inversely correlated with tumor
cellularity. In par ticular, most patients with MM had lesions characterized by a median
ADC of 0.7, with a narrow standard deviation. The ADC value increases with response
to treatment. Monitoring of the ADC value allows functional and morphological evaluation of bone lesions, indicating the enormous potential of applying DW-MRI for
evaluation of MM.
• Circulating miRNAs can be detected and analyzed by quantitative RT-PCR in peripheral blood plasma samples of MM patients. We have characterized a specific circulating
miRNA signature that differentiates MM patients from healthy subjects. It was possible
to identify a correlation between the levels of specific circulating miRNAs and prognostic factors defined by ISS and cytogenetics. Fur ther studies are aimed at identifying the
role of differentially-expressed miRNAs in the plasma of myeloma patients. Preliminary
results indicate that miRNAs present in the peripheral blood could be used for disease
monitoring in MM patients. The same methodology is being used to study smoldering
MM.
• Elevated levels of serum amyloid A (SAA) protein in plasma of CLL patients were
identified using a proteomic strategy. To detect new plasma biomarkers in CLL patients,
surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF) mass
spectrometry was applied. The analysis revealed statistically significant differences in
SAA expression between the plasma of LLC patients and healthy subjects (P=0.002). In
addition, SAA levels are elevated in the plasma of patients with an unfavorable cytogenetic profile (try12; del17 del11) compared to patients with normal or other
38
cytogenetic status (P=0.02). In CLL patients, SAA plasma levels also positively correlated with a peripheral lymphocyte doubling times of less than one year (P=0.009).
Although preliminary, these data suggest that elevated SAA levels are associated with
unfavorable prognostic markers and suppor t the view that inflammation is implicated in
development of CLL.
• Clonogenic MM cells can be stained using the Hoechst side population and Aldefluor
assays. These methods are used to quantify MM stem cells and assess their role as a
surrogate marker for clinical response during therapy.
We have star ted a collaboration with the experimental depar tment of our Institution
with the aim of applying array comparative genomic hybridization (aCGH) and single
nucleotide polymorphism (SNP) arrays to study new emerging molecular subgroups
with prognostic significance for MM patients enrolled in clinical trials.
A new phase III trial aimed at comparing bor tezomib, cyclophosphamide and dexamethasone versus lenalinomide cyclophosphamide and dexamethasone in patients with
multiple myeloma at first relapse or primary refractory has initiated. With this project,
we plan to integrate clinical and biological data from patients enrolled with the ultimate
goal of finding a panel of biomarkers that can be easily and routinely used in a clinical
setting. Samples are being collected by each REL (Rete Ematologica Lombarda, Lombardy Hematology Network) center par ticipating in the project and sent to our
laboratory for biological studies. Since the beginning of the trial (April 2011), 45
patients have been enrolled Peripheral blood and BM samples are being collected at
study entry, after the first three cycles during the induction phase, at the end of the
induction phase, at the end of the consolidation phase, and thereafter every 4 months
for at least one year. We have therefore collected 75 vials of positively selected
CD138+ plasma cells. Fifteen patients have completed the first 3 cycles and four
patients the 6 cycles, and all biological samples have been collected. The plasma samples from the PB of all patients have been stored for miRNA analysis. Using
multiparametric flow cytometry, we are studying fresh blood samples to assess the
presence of MM progenitor cells that may be used as a surrogate marker for clinical
response to a given drug combination. We are also assessing the correlations between
the presence of specific T-cell subsets, natural killer (NK) cells, myeloid derived suppressor cells (MDSC), and the response to proposed therapies to provide data regarding a
potential tumor-promoting (or tumor-inhibiting) role for each subset of MM patients.
Keywords: multiple myeloma; response to therapy; biomarkers; chronic lymphocytic
leukemia
39
PUBLICATIONS
Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C,
Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL,
Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network.
Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus
dexamethasone as induction therapy before, and consolidation therapy after, double autologous
stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.
Lancet. 2010; 376(9758): 2075-85.
Dodero A, Crocchiolo R, Patriarca F, Miceli R, Castagna L, Ciceri F, Bramanti S, Frungillo N, Milani
R, Crippa F, Fallanca F, Englaro E, Corradini P. Pretransplantation [18-F]fluorodeoxyglucose
positron emission tomography scan predicts outcome in patients with recurrent Hodgkin
lymphoma or aggressive non-Hodgkin lymphoma undergoing reduced-intensity conditioning
followed by allogeneic stem cell transplantation. Cancer. 2010; 116(21): 5001-11.
Sarina B, Castagna L, Farina L, Patriarca F, Benedetti F, Carella AM, Falda M, Guidi S, Ciceri F,
Bonini A, Ferrari S, Malagola M, Morello E, Milone G, Bruno B, Mordini N, Viviani S, Levis A,
Giordano L, Santoro A, Corradini P; Gruppo Italiano Trapianto di Midollo Osseo. Allogeneic
transplantation improves the overall and progression-free survival of Hodgkin lymphoma
patients relapsing after autologous transplantation: a retrospective study based on the time of
HLA typing and donor availability. Blood. 2010; 115(18): 3671-7.
40
development of radiopharmaceuticals
Emilio Bombardieri Group Leader
PARTICIPATING UNITS
Nuclear Medicine - Coordinator
Molecular Therapies
Medical Oncology
Prostate Program
DEVELOPMENT OF RADIOPHARMACEUTICALS FOR
TUMOR CHARACTERIZATION, MOLECULAR IMAGING,
AND THERAPY
All the radiopharmaceuticals used in Nuclear Medicine for tumor imaging provide not
only morphological data, but also impor tant information on the biology of cancer tissue
such as aggressiveness, proliferative activity, hypoxia, and amino acid uptake. All these
parameters can be considered as prognostic factors and may be useful at tumor presentation for selection of the most effective treatment. Metabolic imaging in monitoring
treatment response can overcome the intrinsic limitations of morphologic assessment
of tumor response. In recent years, many new radiopharmaceuticals were developed
and investigated based on specific recognition and binding to tumor targets. The same
radiopharmaceuticals proposed for tumor imaging, when labeled with radioisotopes
with high activity, may be able to deposit a sufficient amount of radiation energy to kill
cancer cells. The radioisotope therapy includes different steps: choice of a specific target on cancer cells; selection of a metabolic ‘bullet’ that can bind the target with high
affinity; radiolabeling of the probe to localize disease; and finally, identification of the
radionuclide with the best physicochemical characteristics (positron, beta or gamma
emission). In the case of thyroid cancer, which in advanced stages is currently treated
with radioiodine, the development of an individual dosimetry and the better knowledge
of its biology could greatly improve treatment strategies. This project is focused on the
development of: a) 3’-deoxy-3’- 18 F-fluorothymidine (18 F-FLT) as a radiopharmaceutical
for clinical PET; b) radiolabeled somatostatin analogues for radioreceptor therapy of
neuroendocrine tumors (NET); c) a radiolabeled monoclonal antibody fragment
directed to prostatic specific membrane antigen (PSMA) both as diagnostic tracer and
therapeutic agent for prostate cancer ; d) novel techniques for radiopharmaceutical and
nuclear medicine, and to provide biological insights to optimize therapy of thyroid cancer.
41
Development of
18
F-FLT as a radiopharmaceutical for clinical PET. The major objective
of this study is to differentiate malignant from normal tissues and measure cancer cell
proliferation. The tracer under investigation is 18F-fluorothymidine (18 F-FLT), which can
be used for diagnosis and monitoring the effectiveness of anticancer treatments. In particular, this tracer will be assessed in both pre-clinical and clinical studies in patients
with locally advanced breast cancer undergoing neoadjuvant chemotherapy.
New radioreceptor therapy for NETs. The radiolabelling of somatostatin analogues with
lanthanides or lanthanide-like radiometals has already been optimized using beta emitters such as 90Y and 177 Lu, and with 68 Ga for PET. Here, the objective is to evaluate
whether the combined treatment with 177 Lu-DOTA-TATE and 90Y-DOTA-TATE can
exploit the different emission energy of the two radionuclides to improve the killing
effects on both micro- and macro-metastases.
Development of immunological probes against PSMA. PMSA is a transmembrane protein that is overexpressed in prostatic cancer. The anti-PSMA single chain Fv, after
radiolabeling, can detect prostate cancer cells better than traditional anti-PSA antibodies due to its binding to the cell surface. Both positron and electron emitting
radioisotopes are considered for radiolabeling since the reliable tracers used for diagnostic imaging can potentially be utilized for therapy when conjugated with 131 I, 90 Y, or
177
Lu.
Novel approaches for treatment of thyroid cancer. Here, the first step will be to investi-
gate the expression of IGFBP7 and TIMP3, rearrangement of the oncogenes RET/PTC,
and the mechanism of tumor response to combined treatment with gimatecam and
HSP90 or the MEK inhibitor CI-1040. When radioisotope therapy with 131 I is used, pretreatment dosimetry is essential to establish the optimal activity and to maximize the
dose of irradiation.
Original method for
18
F-FLT synthesis. An easy production of
18
F-FDG has been
patented. The radiopharmaceutical fulfills the requirements of the Pharmacopea (sterility, pyrogenicity, pH, chemical and radiochemical purity, analysis of residual reagents).
Animal models bearing breast cancer tumors have been studied to compare the uptake
of 18F-FLT with 18 F-FDG and to determine 18 F-FLT uptake and behavior, and in par ticular its relationship with the biology of cancer tissue (cell proliferation, necrosis,
prognostic markers). Studies using micro-PET have confirmed the feasibility of an in
vivo approach. A clinical protocol has been approved by an Independent Ethics Committee, which entails evaluation of early response to primary chemotherapy (AT+CMF)
in patients with locally advanced breast cancer, stage T2-4,N0-3,M0. A PET evaluation
with 18 F-FLT is planned at the beginning of treatment, after the first cycle, and at the
end of the treatment prior to surgery. 18 F-FLT uptake will be compared with pathological response, prognostic parameters, proliferative indices, and other modalities of
diagnostic imaging. This ongoing study aims to validate the use of 18 F-FLT PET as an
early predictor of response to chemotherapy. At present, 11 patients have entered the
clinical study; our preliminary observations show that tumor lesions (both primary cancer and lymph node metastases) take up 18 F-FLT with different intensity, and the tracer
was also useful to localize distant metastases.
Radioreceptor therapy of NETs. These investigations have continued with tyr(3)-octreotate (TATE) bound to DOTA with 90 Y or 177 Lu radioisotopes (90Y-DOTA-TATE and
177
Lu-DOTA-TATE). Having noted the individual effect of therapies with 90 Y and 177 Lu
labeled somatostatin analogues, and taking into consideration the different proper ties
42
of both radionuclides, combination treatments with 90 Y and 177 Lu peptides is being evaluated, especially in tumors with heterogeneous proper ties. The limiting factor in this
case is the combined toxicity caused by the radiolabelled peptides. Data from animal
studies have shown that the association of different radioisotopes was more effective in
the overall survival of mice. The combination of 90 Y-DOTA-TATE and 177 Lu-DOTA-TATE
determined a 62% survival rate at 150 days after therapy compared to the same rate
of survival at 88 days after 90 Y-DOTA-TATE alone and 96 days after 177 Lu-DOTA-TATE
alone. Preliminary results in our group on patients treated with four therapeutic cycles
alternating 5.55 GBq 177 Lu-DOTA-DATE and 2.6 GBq 90 Y-DOTA-TATE suggest that the
treatment is well tolerated with only rare cases of transient and mild hematological
toxicities. The protocol adopted (repeated cycles with 5.5 GBq of 177Lu DOTA-TATE
and 2.6 GBq of 90Y DOTA-TATE) resulted in an objective response in 21 of 26 cases
(80.1%), and included 8 par tial responses (30.1%), one complete response (3.8%), and
12 stable disease (46.1%). Side effects were limited to transient leucopenia in a few
cases; no renal toxicity was described. On the basis of these results, it is planned to
increase the activity of the radiopharmaceuticals injected (7.4 GBq for 177 Lu and 3.7
GBq for 90Y) to fur ther improve clinical response in patients with advanced disease that
is refractory to traditional approaches.
Radiolabeled monoclonal antibody fragment against PSMA. The murine monoclonal
anti-PSMA engineered fragment (D2B) has been radiolabeled with different radionuclides that are suitable for diagnostic imaging (111 In) and therapy (131 I and 90 Y). The
conditions for radiolabeling have been studied along with the stability of the fragment
and its affinity, all with satisfactory results. Animal models based on cell lines having different expression of the antigen of interest (PC3-PSMA, cells transfected with PSMA,
and PC3-WT, the same line not expressing the antigen) have been prepared. Initial data
have shown that the biokinetics of the D2B fragment is better than the intact antibody,
and tumor visualization is very clear within 6 hours after injection, and the tumor/background ratio is more favorable. In addition, the specificity of D2B uptake results very
high with the fragment, which detects only lesions expressing PSMA. Pre-clinical studies
in animal bearing tumor expressing (LNCaP\tPC3-PSMA) or not expressing (wtPC3)
the antigen have been performed. Preliminary experiments of tumor localization have
been performed with the anti-PSMA scFv fragment (D2B) fluorecinated with cys5.5
dye. Tumor visualization was evident within 3 hours after injection and tumor visualization is very clear within 6 hours after injection with reduced background compared to
localization with the entire antibody.
The same antibody fragment has been radiolabeled with different radionuclides suitable
for diagnostic imaging (111 In and 131I) and therapy (131 I). Radiolabeling conditions are
now well established and we demonstrated stability and maintained reactivity of the
fragment after labeling. In vivo studies with the above murine model using a 131I radiolabeled scFv fragment have been performed indicating that the optimal
tumor\background ratio is obtained at 24 hours. Ongoing fur ther experiments with 131I
and 111 In radioisotopes will hopefully enable to optimize these reagents for diagnostic
imaging of prostate cancer.
Biological characterization of thyroid cancer and new therapeutic approaches. In particular, the genetic mechanisms in thyroid cancer are being studied (BRAF mutations,
RET/PTC and TRK oncogenes in papillary cancer, and PAX8/PPARgamma
rearrangements and RAS mutations in follicular cancer). The development of new anticancer drugs is ongoing by identifying the role of the RET/PC (TPC-1) translocation,
the BRAF V600E (BCPAP and NIM1) mutation, and the double lesions BRAF
V600E/PI3K E54K (K1). The antiproliferative activity of gimatecan, a topoisomerase
inhibitor, and several agents that affect the transduction pathway such as the HSP90
inhibitor 17-AAG and the MEK 1/2 inhibitor CI-1040 are under investigation. Considering the radiometabolic treatment of differentiated thyroid cancer, individualized
dosimetry has been developed to demonstrate the potential clinical advantages in
43
maximizing the therapeutic activity of 131 I according to the pre-treatment bone marrow
dosimetry (Benua Leeper method). A multicenter Italian study was also carried out to
calculate the absorbed dose both in bone marrow and in lesions in patients treated
with fixed activity ranging from 3.7 to 12 GBq. The median [range] of the absorbed
dose to bone marrow was: 0.50 [0.20–1.50] Gy. This implies that the fixed activity currently used in these types of treatment could be increased for most patients. Lesion
evaluation in the multicenter study gave an indication of a strong reduction of lesion
uptake in two subsequent cycles. If this is confirmed with fur ther observations, a convenient treatment strategy of metastatic patients should be based on unequivocal
staging of metastatic patients before the first treatment (124I-PET), followed by maximized administrations.
Keywords: molecular imaging, radiopharmaceutical development, radiometabolic therapy
PUBLICATIONS
Zacchetti A, Martin F, Luison E, Coliva A, Bombardieri E, Allegretti M, Figini M, Canevari S. Antitumor effects of a human dimeric antibody fragment 131I-AFRA-DFM5.3 in a mouse model for
ovarian cancer. J Nucl Med. 2011;52(12):1938-46.
Lopci E, Chiti A, Castellani MR, Pepe G, Antunovic L, Fanti S, Bombardieri E. Matched pairs
dosimetry: 124I/131I metaiodobenzylguanidine and 124I/131I and 86Y/90Y antibodies. Eur J
Nucl Med Mol Imaging. 2011;38 Suppl 1:S28-40. Review.
Chiesa C, Maccauro M, Romito R, Spreafico C, Pellizzari S, Negri A, Sposito C, Morosi C, Civelli E, Lanocita R, Camerini T, Bampo C, Bhoori S, Seregni E, Marchianò A, Mazzaferro V,
Bombardieri E. Need, feasibility and convenience of dosimetric treatment planning in liver
selective internal radiation therapy with (90)Y microspheres: the experience of the National
Tumor Institute of Milan. Q J Nucl Med Mol Imaging. 2011;55(2):168-97. Review.
44
pediatric brain tumors
Maura Massimino Group Leader
PARTICIPATING UNITS
Pediatric Unit, Coordinators: Maura Massimino, Filippo Spreafico
Pediatric Radiotherapy
Pediatric MRI Radiodiagnostics
Cancer Proteomics
Nuclear Medicine
Clinical Epidemiology and Trial Organization
Palliative Care and Rehabilitation
Psychology
Neuropathology (Università La Sapienza, Rome)
Neuropathology (Istituto Neurologico Carlo Besta, Milan)
Unit of Experimental Oncology (CRO, Aviano National Cancer Institute)
Acquired brain lesions Unit (IRCCS Eugenio Medea, Bosisio Parini)
Many Neurosurgical Units in the Lombardy Region and throughout Italy
PEDIATRIC BRAIN TUMORS
Pediatric Oncology manages and studies pediatric age cancers with a theoretic age
range of 0-15 years (21 years in Nor thern Europe and USA). In common practice, the
15-21 year limit is for those otherwise typically pediatric cancers also presenting in
adults (neuroblastoma, nephroblastoma, medulloblastoma) that are best studied and
treated in a pediatric oncology setting.
The multidisciplinary goals are:
• Improving treatment strategies and number of cured children
• Reducing the risk of relapse
• Improving salvage treatment
• Understanding clinical and biological prognostic factors
• Providing adequate and continuous follow-up
• Organizing tailored rehabilitation
• Preventing, recognizing, and treating late-effects
• Providing, whenever needed, genetic counseling
The size of the problem is that 1-2 children under 15 years/10,000 each year suffers
from cancer. In Italy, there has been a definite increase in the incidence of 2% per year
in the last 20 years, and the expected new cases/year are now around 1800. The
increase is especially related to more leukemias, brain tumors, and neuroblastoma.
Childhood cancer remains, however, a rare disease representing 1-2% of all cancers.
Dying for cancer is the first cause of death for disease in childhood, but survival has
increased from 65% in 1983-85 to 75% in 1992-1994 and over. Childhood cancer is
not a disease but rather a “world of disease”, different for histology, site of origin, race,
sex and age, among others. A large interest is presently concentrated on reducing the
costs in late-effects for cure.
45
PEDIATRIC BRAIN TUMORS AS A FIRST MODEL OF
MULTIDISCIPLINARY CARE
Brain tumors are the most common solid tumor in childhood and are the second most
frequent childhood malignancy after leukemia. They account for 15% to 20% of all primary brain tumors. These tumors are now the leading cause of death from childhood
cancer. Around 350-400 new cases are diagnosed yearly in Italy. The INT, and in par ticular the Pediatric and Radiotherapy Units, have a long-standing experience in the
management of pediatric brain tumors. Every year, about 60-70 new patients are submitted to adjuvant treatment after surgery consisting of radiotherapy and
chemotherapy depending on histological diagnoses, extent of disease, and age of
patients. Around 400 patients cured for brain tumors are in active follow-up consisting
of thorough clinical examination, MRI, neurological, endocrinological, psychiatric, and
psychologic neuro-cognitive counseling when requested. Patient accrual during the last
three years (2009-2011) is shown in the figure.
220
200
200
180
2009-2011 Patients accrual
160
140
120
108
112
100
80
57
60
553
47
40
40
21
20
0
Central Nervous
System
Soft tissue
sarcomas
Rare tumors
Neuroblastoma
Bone sarcoma
Malignant
lymphoma
Wilms tumor
Histiocytosis
MAIN TRIALS
Medulloblastoma. Among pediatric brain tumors, medulloblastoma (MB)represents the
most frequent malignant entity. Our effor ts have been concentrated in the previous 10
years on the creation, application, and evaluation of an innovative trial for metastatic
tumors combining, in the adjuvant setting, intensive chemotherapy, tailored craniospinal
irradiation delivered according to a non-conventional technique called HART (hyperfractionated accelerated radiotherapy), and post-radiation chemotherapy whose
intensity has been determined by pre-radiation response to drugs. This trial, which has
become the most used treatment in Europe for this patient sub-setting, allows an overall survival at 10-years of 70% versus compared to 40% for historical data. The actions
in the multidisciplinary setting have allowed to determine: chemo-responsiveness during
the early phase of treatment whose results have driven total craniospinal HART doses
and post-HART treatment, thus sparing those children with a more curable tumor from
higher radiation doses and more intensive chemotherapy, including, for those who
needed, two myeloablative thiotepa courses. Questions about different prognoses in
metastatic tumors are also being explored from pathological/biological points of view
with front-line central review differentiating MB subtypes and looking at markers in
both immunohistochemistry and FISH that can fur ther stratify tumor features and out-
46
come, such as p53, MYCN and MYC, nuclear beta-catenin, survivin, GAB, YAP, and FILA.
• The multidisciplinary team including Pediatrics, Pediatric Radiotherapy and Radiodiagnostic MRI will lead in Italy, together with other extra-institutional par tners for
neurosurgery and neuro-pathology, the upcoming standard risk MB protocols. Moreover, in the upcoming European protocol for standard risk MB, which will fur ther
stratify patients according to biologically-different prognostic subgroups, we are preparing to centrally check the quality of radiotherapeutic plans using a software system
called VODCA that will be disseminated to two other complementary pediatric radiotherapy centers in Italy, in order to assure the best available treatment in all the
par ticipating centers.
Ependymoma. It is the second most common malignant tumor in children. In the last
18 years, our Unit has coordinated clinical national trials, pathological and biological
studies, and neurocognitive outcome evaluation and has provided much guidance for
the for thcoming SIOP (International Society of Pediatric Oncology) study. This study is
a comprehensive program to improve the accuracy of diagnosis and explore different
therapeutic strategies in children, adolescents, and young adults with a primary diagnosis of intracranial ependymoma. It will include a centralized review of pre and
postoperative imaging to confirm that removal of the tumor is complete and to get
advice from a panel of key opinion leaders for second look surgery if needed. It will
also include a central review of pathology to confirm histological diagnosis and to
prospectively identify disease subgroups and/or correlate patient response to
treatment. After surgery and central review of imaging and pathology, patients will be
enrolled in one of three clinical studies according to the outcome of the initial surgical
resection (residual disease vs no residual disease), according to age or eligibility/suitability to receive radiotherapy.
• Also in this setting, apar t from front-line central pathology review, use of VEC (vincristine, etoposide, cyclophosphamide) chemotherapy as a standard, solicitation of
second-look surgery, which were all derived from Italian experience, a special role will
be given to hypofractionated radiotherapy boost for postoperative residual disease.
This adjuvant treatment was originally conceived in our Institute and the first results
will be presented in June at the ISPNO (International Symposium of Pediatric Neurooncology). Here again, in the context of the multidisciplinary effor ts, the indications for
radiotherapy need to consider a better local control by applying non-conventional fractionation on a smaller volume and using all the technological developments required by
any single patient with any individual disease presentation. The possibility to give a conformational treatment with an accurate neoplastic target that limits therapeutic dose
only to tumoral tissue arises from the availability of high-quality imaging, reproducible
immobilization systems, computerized system for vir tual simulation, imaging fusion,
three dimension treatment plans, and technology miniaturizing. As for the MB protocol,
the quality of radiotherapy will be nationally checked by us.
BIOMARKERS
Cerebrospinal fluid proteome from Central Nervous System (CNS) pediatric tumors:
patient related pattern. Cerebrospinal fluid (CSF) cytology is the gold standard for diag-
nosing leptomeningeal dissemination, which provides crucial information for a correct
therapeutic approach in brain tumors. Sensitivity of combined CSF cytology and neuroimaging studies, however, remain relatively low. Changes in CSF protein composition
have been shown to reflect pathological processes in the CNS, such as tumor growth.
• We seek to characterize the CSF proteome of pediatric primary CNS tumors to
identify CSF biomarkers predictive of tumor proclivity to leptomeningeal spread or
related to patient clinical outcome. We have preliminarily piloted a label-free shotgun
approach based on a high sensitive nano-LC-MS/MS linear ion trap-FT mass spectrometry to define the CSF protein pattern from four children with MB. A total of 257
proteins and 147 non-redundant proteins were detected with extremely high
47
stringency (confidence 99-100%). Protein functional classification based on Gene
Ontology indicated that many of these proteins are involved in CNS disorders. These
preliminary results indicate that the annotation capabilities presented provide specific
information about CSF proteins and are a convenient method to design iterative and
targeted follow-up experiments. We will apply the above-described proteomic strategy
on a initial series of 30 children with primary CNS tumors, whose CSF has been
already prospectively banked at diagnosis and at different timing of their disease
course, upon institutional review board and ethical committee approval. A comparison
of CSF from patients and controls will be done using highly sensitive proteomic
approach for protein mapping, classification and identification in minimal amounts of
CSF. Correlation with patient clinical and histological variables will also be explored.
One of the points of major clinical relevance will be elucidating possible correlation
between putative tumor-specific CSF proteins and presence/development of
leptomeningeal dissemination. A larger cohor t of patients, prospectively recruited from
the host institution and other Italian and European collaborating institutions, will be
characterized for CSF proteome once the first phase of the proposed project has identified reliable CSF candidate markers of disease progression/recurrence. It is believed
that markers predictive of early tumor progression or leptomeningeal metastasis can
allow for timely and appropriate treatment of high-risk children with primary CNS
tumors, or even more impor tantly, for sparing unnecessary therapies in low-risk
patients. Standardization and validation of putative biomarkers are needed to give
widespread acceptance.
Identification of microRNA biomarkers from cerebrospinal fluid. These will be investi-
gated in a number of brain tumors using CSF from pediatric lymphoma patients as
controls. We will compare the expression pattern of the miRNAs analyzed in relation
to cancer type, pathologic and molecular subtype, relevant clinical and pathologic features (gender, age, tumor size, location, WHO grade) as well as outcome parameters
(surgical management, response to therapy, survival). Validation of the obtained results
will be performed in an independent cohor t of body fluid samples from pCNS patients
subsequently collected throughout the course of the project.
Pediatric malignant glioma. Progress star ting from the worst case scenario of diffuse
intrinsic pontine glioma. Pediatric gliomas are the third most common malignant tumors
in children and comprise a heterogeneous collection of CNS neoplasms distinct from
adult gliomas based on histopathological, clinical, and molecular characteristics.
Although the distinctive molecular features of pediatric gliomas are rapidly emerging,
this information has not yet resulted in improved patient benefits. The present proposal
aims at retrospectively and prospectively evaluating relevant prognostic and predictive
biomarkers that may impact stratification criteria of patients with glioma. Both tumorderived and circulating markers will be considered, with par ticular emphasis on diffuse
intrinsic pontine gliomas (DIPG), a dreadful glioma subgroup showing less than one
year of median survival, with less than 10% of patients surviving for two years or
longer. We established a novel, promising treatment protocol of DIPG including ERBB1targeted monoclonal antibody administration that will be launched as a phase II trial
with the aim of ameliorating patient outcome and correlating biomarkers of treatment
response. Finally, a novel pharmacologic approach to systemic treatment of CNS
tumors will be assessed in pre-clinical models in order to evaluate whether temporary
and reversible opening of the blood-brain barrier may improve antitumor drugs uptake
in these chemoresistant tumors. The present project will thus explore novel treatment
approaches to pediatric gliomas and provide evidence for the use of molecular
biomarkers for prognostic and therapeutic stratification purposes. To achieve these
goals, we will:
• Evaluate the prognostic and predictive potential of known and novel tumor-derived
molecular markers frequently involved in pediatric glioma
• Evaluate the novel treatment strategy of DIPG children with radiotherapy,
nimotuzumab and vinorelbine
48
• Assess circulating molecules (micro-RNAs and serum-soluble proteins) as
prognostic/predictive biomarkers in DIPG patients
• Assess a pre-clinical model of pharmacological strategies to overcome the
blood-brain barrier and enhance CNS tumor sensitivity to cytotoxic drugs.
NEW DRUGS
A phase 1 study of LDE225 in pediatric patients with refractory or recurrent
medulloblastoma or other tumors potentially dependent on the Hedgehog signaling pathway. Our Unit has been selected as the only Italian center for this
first-in-children trial. Aberrant activation of the hedgehog (Hh) signaling pathway is linked to the pathogenesis of several types of cancer, such as MB, basal
cell carcinoma (BCC), and rhabdomyosarcoma. Hh signaling has also been
described to play a role in neuroblastoma, hepatoblastoma, high-grade glioma,
and osteosarcoma. Aberrant Hh signaling is involved in tumorigenesis through
dysregulation of the cell-cycle, protection against apoptosis, and modulation of
angiogenesis. Smoothened (Smo) is a positive regulator of Hh signaling and
therefore may be an impor tant therapeutic target. Approximately 25% of sporadic MBs are repor ted to have mutations that activate the Hh pathway
through loss of function mutations in protein patched homolog (also known as
patched [PTCH] or suppressor of fused [SuFu]); or gain of function mutations
in Smo.
In addition, patients with Gorlin Syndrome, a condition characterized by a
PTCH mutation, have an increased tendency to develop BCC, MB,
rhabdomyosarcoma, and ovarian carcinoma. LDE225 is a potent, selective, and
orally bioavailable Smo antagonist. Suppression of Gli1 mRNA expression in
skin, a marker of Smo inhibition, has been observed in a dose/exposuredependent manner. The primary purpose of this study is to evaluate the safety
of LDE225 in a pediatric patient population and to define the maximum tolerated dose (MTD) of LDE225 in children with advanced solid tumors that are
potentially dependent on the Hh signaling pathway (recurrent or refractory
MB, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high-grade glioma, or
osteosarcoma) and have progressed despite standard therapies or for which
no standard treatment options exist. Pediatric malignancies driven by Hh aberrations represent an area of high unmet medical need, and LDE225, a specific
and potent Smo antagonist, may be an effective treatment for these diseases.
A total of 6 patients have been treated so far reaching the for th stratum.
OUTCOME
Diffusion Tensor Imaging to study radiation-induced damage and its correlation
with neuro-cognitive outcome. This study is being conducted on a selected
population of cured children from at least 3 years and submitted, among other
treatments, to focal radiotherapy (RT). The intrinsic toxic effect of tumor, surgery, and adjuvant therapies, especially radiotherapy, on brain tumors is well
known and appears at a temporal distance with characteristic cognitive deficits
(IQ, attention, memory, etc). White matter (WM) can be better characterized
by a par ticular application of MRI called DTI (diffusion tensor imaging). By the
study of the direction in which water molecules diffuse in brain parenchyma,
DTI is able to give information about the ultrastructural integrity of the WM
(myelinization, fiber diameter and consistence, inter cellular spaces, cytoskeleton). Literature data has shown that, after RT, DTI parameters and median
diffusivity are abnormal even after ending treatment.
49
• The aim of this research is evaluation of the association between neurocognitive/psychological deficits after treatment, and in par ticular to focal and
WM damage quantified by DTI. Studying patients treated with focal RT would
allow correlation of RT volume and doses with MRI alterations and intellectual
damages to identify possible critical areas in the genesis of cognitive deficits.
The identification of more damaged structures in patients treated with RT
could theoretically contribute to better RT planning aimed at saving more fragile areas and reducing the incidence of cognitive and learning problems, and
thus the need for rehabilitation and school assistance, facilitating social reentry.
Statistically significant association of such parameters could bring new knowledge about the pathogenesis of WM damage.
PSYCHOLOGICAL SUPPORT
Internalizing problems, anxiety, depression, withdrawal, and consequent social
problems are frequently observed in children with brain tumors. Effective
(complete, truthful, consistent, comprehensible, gradual and continuous, and
tailored) communication to the child about his/her condition is associated with
better psychological outcome. To fulfill this goal, suppor t for parent-child communication was created, which consists in a booklet able to explain the normal
functioning of the brain and the possibility of its damage in tumors and treatments. This tool has been distributed to a consistent number of patients and
the effects will be assessed with tailored instruments (Child Behavior Checklist
[CBCL]) and a semi-structured interview to understand the difference in the
quantity and quality of internalizing problems, comparing a new patient group
with a previously repor ted group of 64 children that were not given this special suppor t.
AUXOLOGIC SUPPORT
The Nuclear Medicine Unit has a long-standing experience in diagnosis and
treatment of endocrine complications of oncological treatments. More than
300 pediatric patients treated for brain tumors or other solid tumors with an
endocrine morbidity are now in active follow-up as outpatients for endocrine
monitoring. Among these, over 100 patients are undergoing growth hormone
replacement therapy. In addition to routine activities, several research projects
studying modifications of endocrine profiles in patients with neoplasms are
ongoing.
Keywords: brain tumors, tailored treatment, functional outcome, prognosis
PUBLICATIONS
Massimino M, Bode U, Biassoni V, Flischhack G. Nimotuzumab for pediatric diffuse
intrinsic pontine gliomas. Expert Opin Biol Ther. 2011; 11: 247-56.
Massimino M, Gandola L, Barra S, Giangaspero F, Casali C, Potepan P, Di Rocco C,
Nozza P, Collini P, Viscardi E, Bertin D, Biassoni V, Cama A, Milanaccio C, Modena P,
Balter R, Tamburrini G, Peretta P, Mascarin M, Scarzello G, Fidani P, Milano GM, Sardi I,
Genitori L, Garrè ML. Infant ependymoma in a 10-year AIEOP experience with omitted
or deferred radiotherapy. Int J Radiat Oncol Biol Phys. 2011; 80: 807-14.
Massimino M, Solero CL, Garrè ML, Biassoni V, Cama A, Genitori L, Di Rocco C, Sardi I,
Viscardi E, Modena PG, Potepan P, Barra S, Scarzello G, Galassi E, Giangaspero F,
Antonelli M, Gandola L. Second-look surgery for ependymoma: the Italian experience. J
Neurosurg Pediatrics. 2011; 8: 246-50.
51
CLINICAL SCIENTIFIC STRUCTURE
Surgery Department
Anesthesia, Intensive Care, Pain Therapy,
and Palliative Care Department
52
scientific directorate
SCIENTIFIC DIRECTOR
Marco A. Pierotti, PhD
+39 02 2390 2300
[email protected]
STAFF MEMBERS
Tiziana Camerini, Maths D
Aurora Costa, Biol Sci D
Cecilia Melani, MD, PhD
LOMBARDY ONCOLOGY NETWORK (ROL)
Rosaria Bufalino
Elisa Ferri, B Eng
Marco Tricomi, B Eng
SECRETARIAT
Eleonora De Palo
Laura Ballariano Rossi
Lucia De Zorzi
INFORMATION TO PATIENTS
Antonio Florita, B Litt
INTERNATIONAL RELATIONS
AND LINGUISTIC CONSULTANT
Daniela Majerna, B Phil
GRANT OFFICE
Valeria Anselmi, B Litt
Marco Asioli
Sabrina Braghieri, BA
Claudia Casoli
Stefania Didonè
Isabella Russo
BIOMEDICAL LIBRARY
Rossella Ballarini
Marina Calderisi
EDITORIAL OFFICE
Rosaria Parentela
TUMORI - EDITORIAL ASSISTANT
Elena Morittu
The responsibilities of the Scientific Directorate traditionally include: the coordination of research and education activities, planning of scientific policy and
evaluation of scientific projects (Committee of the Scientific Directorate);
management of the institutional relationships with key health authorities at a
regional and national level; supporting researchers seeking public and private
funding (Grant Office); giving access to information resources in support of
ongoing research programs (Biomedical Library); the enhancement of communication and collaboration among all cancer-related institutions in Lombardy
(Lombardy Oncologic Network); the supervision of the Institute's scientific
communication, the promotion of effective health communication with the
larger public, and the development of education materials for patients (Office
of Communication).
Working in tight cooperation with the Technology Tranfert Office (TTO), the
Scientific Directorate also facilitates the transfer of inventions and knowledge
from INT labs to the public.
Every year the Scientific Directorate organizes a Research Day: the 2011 edition was held on June 13th at INT. Every year the meeting offeres an
opportunity to look back to the scientific accomplishments achieved during
the year, and to look forward to the future of research by recognizing three
young scientists.
53
COMMITTEE OF THE SCIENTIFIC DIRECTORATE
Alessandro M. Gianni, Deputy Scientific Director
Vincenzo Mazzaferro, Deputy Scientific Director
Mario Santinami, Deputy Scientific Director
Franco Berrino, until May 2011
Emilio Bombardieri
Paolo Corradini
Maria Grazia Daidone
Martin Langer
Ugo Pastorino
Giuseppe Pelosi
Francesco Reitano
Vito Corrao, Chief Medical Officer
Gustavo Galmozzi, Medical Director
This Committee is the Institutional Reviewer Board (IRB) and assists the Scientific Director
in defining the Strategic Scientific Program and the contents of the correlated educational
activities.
Its main objectives are:
• definition of research areas at INT
• approval of multidisciplinary research projects
• approval of the development of the research projects at a scientific and administrative
level
• evaluation of scientific quality and feasibility of newly proposed clinical studies prior to
their submission to the Independent Ethics Committee
• evaluation of the educational programs for residential and non-resident courses,
approval of applications by physicians and researchers of the INT to spend training periods
in other countries, and applications by foreign researchers to spend training periods in INT.
54
In 2011 Dr Franco Berrino, for many years head of the Department of Preventive and Predictive Medicine and a member of the Committee, retired after a successful scientific career.
An internationally renowned epidemiologist, Dr Berrino has been active in cancer research
and cancer control for almost 40 years and has published over 250 peer-reviewed scientific
papers. He carried out several population-based etiological studies on tobacco, alcohol,
occupation, and environmental pollution and, more recently, pioneered research on the role
of diet in the etiology of tumors. His internationally renowned studies helped shaping cancer prevention policies in many countries. Dr Berrino, who is currently studying the impact
of metabolism on cancer, will however complete the research projects he is involved in as
PI, and will continue to advise and collaborate with the Scientific Director in the management of the Department. The Committee says farewell to Francesco Reitano and welcomes
Vito Corrao as a Chief Medical Officer.
GRANT OFFICE
The Grant Office (G.O.) has the mission to support research activities within the Institute,
facilitating access to external financing, national and international, by looking for relevant
information in the appropriate media, making direct contact with public and private funding
agencies, and swiftly providing information to potentially interested researchers.
Announcements regarding funding possibilities are constantly updated in the “Calls for
Application” section of the Institute Intranet website, on the Scientific Directorate web
page.
It is the G.O.’s duty to help investigators in preparing and submitting grant applications, promoting collaborations among the researchers working at INT and in other public services,
helping them to collaborate on research projects.
Other goals of the G.O. are:
• To stimulate and constantly support researchers, giving methodological guidelines and
meeting organizational needs, particularly in the conduction of multidisciplinary research
activities.
• To assist researchers, from the funding request to the completion of the task, monitoring
their results, and adherence and achievement of the defined objectives. The monitoring
activity also includes administrative supervision.
At the Scientific Directorate office, a database has been created and is continuously
updated according to emerging new needs. The database stores information regarding
research projects from submission to conclusion. To monitor scientific productivity, a database of all publications from the INT has been created: it is thus possible to know in real
time the number of publications and their Impact Factor. These tools allow a more efficient
collaboration with the Administration in the evaluation of scientific productivity of each
individual Researcher, Unit, and Department and the Institute as a whole.
The G.O. office keeps in contact with the officers in charge of research at the Ministry of
Health and at the Health Management offices of the Lombardy Region. G.O.’s activities
include the management of ongoing Institutional Projects and the design of calls aimed at
distributing the funding coming from the 5‰ tax donation. In 2011, the G.O. supported
INT researchers in: 70 applications for public funding (Ministry of Health, the Lombardy
Region, Ministero dell’Istruzione, dell’Università e della Ricerca); 110 applications to private
national funding agencies and 26 international funding bodies.
LOMBARDY ONCOLOGIC NETWORK (ROL)
Throughout the regional network of organizations and professionals, an innovative model
for delivering healthcare to cancer patients, has been established by regional Lombardy government. The Lombardia Cancer Network (ROL: “Rete Oncologica Lombarda”) connects
all cancer resources of the region, with 10,000,000-plus citizens, in an effort to improve
55
quality of cancer care and patient data sharing. ROL is based on clinical cooperation,
exchange of information and sharing and integration of existing cancer facilities. ROL,
started in 2006 is aimed at creating “an integrated network of health and social services
devoted to cancer patients” to provide a framework for facilitating the exchange of information, capacity, and expertise, research facilities implementation and to offer a more
accurate diagnosis, treatment, and control of cancer. ROL’s main goal is the assessment of
appropriateness of cancer care on a population basis in order to improve the quality of
care focusing on the cost/efficacy ratio to reduce healthcare costs.
INT, with the coordination of Scientific Directorate, has been the implementing body of
ROL since its start-up. ROL includes 58 oncology premises and is testing innovative solutions for distance sharing of health data pertaining to a regional population by introducing a
structured hospital discharge program focused on a unified “in/out-patient clinical discharge
report”. Its semantics were defined so as to design a cancer-oriented “minimum clinical data
set” that can spare physicians any data input in excess of what they are ordinarily required
for clinical purposes. Reports can be shared over the network among centers treating the
same patient.
In addition, teleconsultation facilities, asking for second opinions as well as to refer patients
from one center to another, will be implemented by using the same master document.
The implementation of ROL was aimed to design evidence-based clinical practice guidelines
for all solid tumors developed through a consensus process among the oncology community to make a comprehensive impact on clinical oncologic practice.
A set of common clinical practice guidelines are annually updated and for each solid cancer,
guidelines list all main clinical presentations (“disease phases”), along with their “treatment
options” (either “standard”, “individualized”, or “investigational”). ROL upgraded the existing
non-structured electronic clinical discharge report into a field-based resource, with both
free-text and codified fields. Two codified fields enlist, respectively, disease phases as per
guidelines, and the corresponding treatment options. If they match, the strategic medical
decision is considered tentatively “appropriate”.
Currently, the instrument is being incorporated stepwisely within the information systems
of all oncology facilities, though a central web-based tool is also available. In 2011, more
than 36,000 reports were released. Appropriateness assessment proved feasible on a pilot
set of patients. A research project is ongoing to detect causes of mistakes and mismatches,
by automatically analyzing free-text fields. A training effort is ongoing to improve clinicians’
learning curve on semantics.
In 2011, ROL has expanded its field of activity to clinical and translational research and has
contributed to the creation of a virtual tissue bank, and in particular in the definition of
homogenous criteria for the storage of biological samples to be adopted by all participating
centers, with the network information system as an added value. The collaboration with
Nerviano Medical Sciences started in 2010 was crucial; this joint effort is organizing studies
for clinical drug development by research groups in the ROL/REL (Lombardy hematologic
network) area. In 2010 and 2011, two calls for independent clinical research has been
issued by the Scientific Director of INT, and 46 study proposals have been selected to be
supported for their scientific organization in collaboration with the Department of Clinical
Development of NMS. Similarly, in 2011, a call for pre-clinical research has been issued and
8 scientific proposals of research have been selected to be implemented with the collaboration of NMS.
PATIENT INFORMATION
The Scientific Directorate actively participates in the organization of an innovative model of
providing information to cancer patients in Italy by establishment of a National Service of
Information in Oncology through ongoing multicentric projects in collaboration with the
Istituto Superiore di Sanità, and the main Italian Associations of Volunteers, sponsored by
Alliance Against Cancer and the Ministry of Health. The main goal is to create a comprehensive cancer care model offering the most advanced diagnosis and treatment techniques
56
and information support with the best quality available, improving doctor-patient communication and patient empowerment.
This will assure better treatment compliance, thereby allowing patients to fully participate in
the decision making process in cancer care. Since 2005, INT Information Point (IP) supports
patients and their families, by meeting their informational needs, was implemented in 2010
and 2011. This IP is part of the Italian IP network, a community based on shared strategies,
guidelines, tools and aims to establish a qualified and formally recognized service for information in oncology. The activity and results of the IP network were described and discussed
in the scientific paper:“National Cancer Information Service in Italy: an information points
network as a new model for providing information for cancer patients”, Tumori. 2011; 97:
510-6.
Furthermore in 2011, the Scientific Directorate participate in the publication of the “Manuale per la comunicazione in Oncologia” (Handbook for communication in oncology) with
the aim to present and promote experiences, knowledge and achievements of “the
National Information Service in Oncology”, proposing it as an innovative organic and systematic model, characterized by tools and procedures that are shared and coordinated.
BIOMEDICAL LIBRARY
The INT Library is affiliated to the European Association for Health Information and
Libraries. It offers on site access to a large collection of basic science paper journals and
reference books and electronic access to full text journals, bibliographic databases and electronic books. The mission of the INT Library, specialized in oncology, is to provide access
and management services aimed at meeting the needs of physicians, researchers and students for the efficient retrieval of information necessary for best patient care, advanced
research and post graduate education.
Through the participation to the SBBL and Bibliosan consortia, the Library’s electronic
resources give access to over 9,000 titles can be looked up alphabetically (including the
oncology-focused journals currently subscribed by INT) that can be consulted through “A
to Z”, an online virtual catalogue that collects and updates the links to publisher’s web sites.
The library also offers access to specialized data banks of bibliographic references and electronic documents such as Medline, Toxnet, Embase, CODIFA (Drug Information Services),
Springer E-book (over 1000 e-books are available via Springer Publisher) and Springer
Images.
In addition, data banks concerning trends of citation references between scientific papers
offer the scientists the possibility to evaluate a ranking index of scientific journals in the
different disciplines (Journal Citation Reports) and to take into account the scientific relevance of individual papers being recognized by the global researcher community (ISI Web
of Knowledge).
The Library’s collection is supplemented by interlibrary loan services with access to the
following catalogues:
• GIDIF-RBM: a consortium of key Italian biomedical libraries (over 5,000 titles from 41
biomedical libraries);
• SBBL: Biomedical Library System of Lombardy (6,200 titles from 16 libraries);
• BIBLIOSAN: a network of 50 Italian Research Institutions sponsored by the Italian Ministry of Health (over 4,100 active collections of scientific journals) .
The library is also a member of ACNP, the National Archival Collection of Periodicals, and is
thus linked to over 2,300 Libraries in Italy and over 110,000 journals. The Italian framework
Nilde (Network for Inter-Library Document Exchange) which allows libraries to request
and supply documents via web. Library customers can access RefWorks, personal bibliographic management software designed to help researchers gather, manage and store
information, as well as generate citations and bibliographies. The library staff aims at inform-
57
ing the public about all services offered. In addition to disseminating information via the
constantly updated Intranet Library web page, various courses were held in order to help
researchers gather information more easily.
The following seminars were held:
• Bibliographic Research using Pubmed (The database of the National Library of Medicine)
Speaker: Dr Vanna Pistotti
• Facebook, Twitter and Social Media: New Tools for Medical-Scientific Update
Speaker: Dr Eugenio Santoro
• How to write a Scientific Paper
Scientific coordinator: Dr Francesco Leo
The Library manages an in-house database and updates the collection of publications of
INT investigators, and calculates their Impact Factor to respond to periodic queries from
the Management Control and Ministry of Health.
EDITORIAL BOARD OF TUMORI
In 2011, the Editorial Board of Tumori received 756 manuscripts for publication. In the same
year, 6 issues containing 154 reviews, original articles, and case reports were published. Five
thousand copies per issue were printed.
EDITORIAL OFFICE
The Editorial Office coordinates and manages all activities relative to the production of
materials that describe the clinical and scientific activities of the Institute. In addition, the
editorial office oversees the publication of the annual Scientific Report and Brochure, and
provides support to individual departments in the preparation of more specific materials
such as brochures and meeting reports.
AWARDS AND RECOGNITIONS
• Our Institute has been certified a European Center of Excellence for the
diagnosis and treatment of Neuroendocrine Tumors by the European
Neuroendocrine Tumor Society (ENETS).
• The Comitato Ospedaledonna of the Osservatorio Nazionale sulla salute della
Donna (O.N.Da) awarded the Fondazione IRCCS Istituto Nazionale dei Tumori
with 3 “Bollino Rosa” prizes for its care in the research and treatment of female
diseases and its attention to the specific needs of the admitted women.
• Dr Emilio Bombardieri, director of Nuclear Medicine, was conferred the title of
“Ambassador Award City of Milan”. May 2011.
• Dr Andrea Necchi of the Urology Unit was conferred the 1st “Gianni
Bonadonna Prize for New Drug Development in Oncology”. Milan, 1st July
2011.
• The paper “Retroperitoneal Lymph Node Dissection with No Adjuvant
Chemotherapy in Clinical Stage I Nonseminomatous Germ Cell Tumours: LongTerm Outcome and Analysis of Risk Factors of Recurrence” by Dr. Nicola
Nicolai et al. of the Urology Unit was conferred the Bracci 2011 Prize, Società
Italiana di Urologia (SIU). Rome, 23-26 October 2011.
• Prof Alessandro M. Gianni, director of Medical Oncology 2, was conferred the
Pier Camillo Beccaria 2011 Prize, Associazione “Angela Serra” per la Ricerca sul
Cancro for new therapies in lymphomas. Modena, 5 December 2011.
58
descriptive studies and health planning
The Descriptive Studies & Health Planning Unit (DSHP)
carries cancer research in the field of public health and
promotes studies for planning cancer control. In 2011, a
number of projects were run by DSHP at the
international and national level.
INTERNATIONAL PROJECTS EUROCHIP-3. During
2011: a) activities on cervical cancer screening in Lithuania, Latvia, Estonia, Romania, and Bulgaria were started.
Estonia colleagues concluded their study and published
results; b) a study on the availability status of cancer indicators in the EU cancer registries was concluded and
presented at various meetings; c) consensus on an European list of cancer rehabilitation indicators was reached;
d) discussion on strategies for the reduction of cancer
cost (at unvaried outcomes) for breast cancer and childhood acute lymphoblastic leukemia were performed. All
activities are described on the web site
http://www.tumori.net/eurochip.
EPAAC. DSHP started the work of the “Task Force on
cancer cost at population level” coordinating three European activities: a) ecologic regression analysis between
socioeconomic indicators and cancer survival; b) discussion on a common European Deprivation Index to be
used across Europe; c) common methodology to
estimate cancer cost data across Europe.
NATIONAL PROJECTS CAREMORE. During 2011, final
analyses were performed. The project showed that in Italy
cancer registries, prior to involving new sources of data,
we are able to collect population-based information on
economic support, home assistance, and other facilities,
while no data on nutritional and psychological rehabilitation could be retrieved.
“I TUMORI IN ITALIA”. During 2011, the website
www.tumori.net was continuously updated.
“API-FALCONARA”. During 2011, DSHP concluded reanalysis of the case-control study (after study sample
enlarging) which confirmed the previous results: in proximity of the refinery there was an excess risk of death
(for leukemia and non-Hodgkin lymphoma) for elderly
living in that area for more than 10 years.
Keywords: Cancer control, cancer indicators, cancer epidemiology
HEAD
Andrea Micheli, Sociologist, PhD (until 30th June)
Marco A. Pierotti, PhD (interim since 1st July)
RESEARCH STAFF
Paolo Baili, PhD
Elisabetta Meneghini, PhD
Francesca Di Salvo, Statistics D
Roberta Ciampichini, Statistics D
ADMINISTRATIVE PERSONNEL
Camilla Amati, BA, Ilaria Casella, Stefania
Saltarelli, Agatina A. Cifalà, Camilla Amati, BA
TECHNICIANS
Mirko Esposito (up to February 2011), Alberto
Turco, Simone Bonfarnuzzo
RELEVANT NOTES
Collaborations
International level:
EUROCHIP-3: (subsidized by the European
Commission-EC). The project was designed to
improve information and knowledge on cancer
control in the European Union in various fields.
EPAAC (subsidized by the European CommissionEC).
DSHP coordinates the activity on cancer cost data
collection across Europe.
DYNAMO-HIA on the development of a dynamic
modeling tool to assess health impact of health
policies (project subsidized by EC and coordinated
by the Erasmus University in Rotterdam).
EUROCARE on cancer survival comparison across
Europe. DSHP works on life tables estimations and
on the related demographic studies.
National level:
CAREMORE (subsidized by Italian Welfare
Ministry) is a population-based study aimed to
identify the rehabilitation services used by cancer
prevalent cases based on cancer registry (CR)
databases.
performance in cancer research using bibliometric
measures.
I TUMORI IN ITALIA (subsidized by Centro
Controllo Malattie, Italian Welfare Ministry) for
constantly updates two web-sites on cancer
epidemiology and on relation between diet and
health. STUDIO API FALCONARA (subsidized by
ARPAm-Marche Region). This population-based
case-control study investigated the association
between residential petrochemical exposure and
leukemia-lymphoma mortality risk in Falconara
Marittima in collaboration with the Epidemiology
Unit of the Marche Region.
Micheli A, Di Salvo F, Lombardo C, Ugolini D, Baili P,
A Pierotti M. Cancer research performance in the
European Union: a study of published output from
2000 to 2008. Tumori. 2011; 97(6): 683-9.
ROL (subsidized by Lombardy Region) for
descriptive analysis of data collected by the
Lombardy Oncologic Network.
HORMONES and BREAST CANCER (BC)
performing statistical analysis in studies on BC
etiology and participating in international
collaborative studies. IF (subsidized by AIRC) is
aimed to study national and international
Publications
Secreto G, Meneghini E, Venturelli E, Cogliati P,
Agresti R, Ferraris C, Gion M, Zancan M, Fabricio
AS, Berrino F, Cavalleri A, Micheli A. Circulating sex
hormones and tumor characteristics in
postmenopausal breast cancer patients. A crosssectional study. Int J Biol Markers. 2011; 26(4):
241-6.
Contributions
Andrea Micheli is on the editorial board of
“Tumori” and “Epidemiologia & Prevenzione”.
Andrea Micheli and Paolo Baili are referees for
“Tumori”. Andrea Micheli is referee for European
Journal of Public Health, Annals of Oncology, and
Journal of Clinical Oncology.
59
59
cancer registry and environmental epidemiology
The activity of Cancer Registry and Environmental Epidemiology in 2011 comprised the following: data
collection and processing for incidence data from the
Varese Province for 2006-2007; in-depth analyses for survival and quality of care for the most frequent tumors;
tutorship for six cancer registries in the Lombardy region.
Screening evaluation: analysis of effectiveness for breast
(female) and colorectal cancer
Congenital malformation registry: data collection for
four Lombardy provinces and data quality control and
management
Occupational cancer: managing the Occupational Can-
cer Monitoring System in six Italian Regions. Risks by site
and economic branch are estimated; cases likely to be of
occupational origin are detected and suggested for compensation. Firms with carcinogenic risk are identified and
examined for the presence of occupational carcinogenic
hazards.
Environment and cancer: exposure to traffic via GIS are
obtained and carcinogenic risk for childhood leukemia are
estimated.
Keywords: cancer registry, occupation, environment
HEAD
Paolo Crosignani, DSc, MD, PhD
RESEARCH STAFF
Martina Bertoldi, DSc
Paolo Contiero, DSc, PhD
Enrica Costa, DSc
Lauda Di Grazia, DSc
Rosaria Fissi, DSc
Emanuela Frassoldi, DSc
Daniela Gada, DSc
Mariarosa Ruzza, DSc
Giovanna Tagliabue, MD, PhD
FELLOWS
Alessandro Borgini, DSc
Edoardo Bai, MD, PhD
Enrico Oddone, MD, PhD
Milena Calati, DH
Lucia Preto, DSc
Eugenia Sanoja, DSc
Tiziana Codazzi, Imma Favia, MSc Anna
Maghini, MSc Clotilde Viganò, MSc
TECHNICIANS
Sabrina Fabiano, DSc
Alessandra Scaburri, DSc
Andrea Tittarelli, MSc
RELEVANT NOTES
Collaborations
IARC, International Agency for Research on Cancer;
AIRTUM, Italian Association of TUMor Registries;
ENCR, European Network of Cancer Registries;
EUROCARE, EUROpean CAncer Registries;
CAREMORE, CAncer REgistry model on
rehabilitation; RARECARE, Surveillance of rare
cancers in Europe; EPIC, European Prospective
Investigation into Cancer and Nutrition; ICBDSR,
International Clearinghouse for Birth Defects
Surveillance and Research; ISS, Gruppo di
Coordinamento Nazionale Malformazioni Congenite
Fondazione; IRCCS, Ospedale Maggiore Policlinico;
ASL di Brescia, Como, Lecco, Lodi, Pavia, Sondrio,
Varese, Verbania, Cusio, Ossola
Publications
Borgini A, Tittarelli A, Ricci C, Brtoldi M, De saeger E,
Crosignani P. Personal exposure to pm 2.5 among
high-school students in Milan and background
measurements: The EuroLifeNet study. Atmospheric
Environ. 2011; 45: 4147–51.
van Duijnhoven FJ, Bueno-De-Mesquita HB, Calligaro
M, Jenab M, Pischon T, Jansen EH, Frohlich J, Ayyobi A,
Overvad K, Toft-Petersen AP, Tjønneland A, Hansen L,
Boutron-Ruault MC, Clavel-Chapelon F, Cottet V, Palli
D, Tagliabue G, et al. Blood lipid and lipoprotein
concentrations and colorectal cancer risk in the
European Prospective Investigation into Cancer and
Nutrition. Gut. 2011; 60(8): 1094-102.
Contributions
Paolo Crosignani is member of the Editorial Board of
“Giornale Italiano di Medicina del Lavoro” and of
“Epidemiologia e Prevenzione”.
61
PREVENTIVE AND PREDICTIVE
MEDICINE DEPARTMENT
DIRECTOR OF DEPARTMENT
Franco Berrino (until 30 April)
Marco A. Pierotti (Interim 1st May)
UNITS
EPIDEMIOLOGY AND PREVENTION
Franco Berrino (until 30 April)
Marco A. Pierotti (Interim 1st May)
NUTRITIONAL EPIDEMIOLOGY
Vittorio Krogh
EVALUATIVE EPIDEMIOLOGY
Gemma Gatta
ANALYTICAL EPIDEMIOLOGY
Milena Sant
MEDICAL GENETICS
Siranoush Manoukian
HEREDITARY DIGESTIVE TRACT
TUMORS
Lucio Bertario
MOLECULAR BASIS OF GENETIC
RISK AND GENETIC TESTING
Paolo Radice
MOLECULAR BASIS OF GENETIC
RISK, POLYGENIC MODELS
Tommaso Dragani
The Department focuses primarily on epidemiological and translational
research. This comprises knowledge of lifestyle and genetic risk factors in
order to take preventive action (i.e. from prediction to prevention), and
knowledge of inequalities in cancer prevention and treatment for carrying out
corrective actions. Our research relies on extensive interaction between
researchers in the fields of basic experimental science, epidemiology, genetics,
and clinical medicine.
The priorities of the Department are:
• promotion of healthy diet and lifestyle: to proceed from large cohort
studies in which the INT has been actively involved for more than 20 years, to
dietary intervention studies targeting the general population, high-risk
subgroups, and cancer patients to minimize the risk of recurrence (facilities
include a hormonal laboratory, a teaching kitchen, and a synergic garden)
• environmental and occupational risk factors: this research is moving from
standard epidemiological designs to the systematic monitoring of occupational
risk through the linkage of cancer registry data and occupational history files,
in addition to forming stronger collaborations with the public agencies that are
responsible for occupational and environmental surveillance in order to establish specific preventive actions
• hereditary cancer prevention in high-risk families: to go beyond clinical surveillance and prophylactic surgery, and promote research on environmental
and lifestyle factors as well as genetic characteristics that may affect the penetrance of hereditary cancer genes
• in the field of low penetrance cancer genes and polygenic inheritance: to
classify the complex genetics of risk and prognosis of lung and breast cancer
• inequalities in survival and cure rates of cancer patients: from the systematic
description of cancer incidence, prevalence and survival, to research on the
interpretation of survival differences between and within countries, and
advance actions to minimize such inequalities.
62
epidemiology and prevention
The Unit has two main research activities:
1) dietary and life-style intervention trials aimed at the
prevention and recurrence of breast cancer (BC), and
2) observational studies on the relationship between
metabolic and endocrine parameters and the incidence
of BC and BC recurrences.
The main ongoing study is the DIANA (DIet and
ANdrogens)-5 project, a randomized controlled trial to
test the efficacy of dietary change and physical activity to
prevent or delay the development of recurrences in BC
patients estimated to be at high risk based on hormonal
or metabolic profiles. Study design: a) recruitment of
2000 patients aged 35-70, operated for BC in the last 5
years, without recurrences, in 12 collaborative centers in
different Italian regions (Lombardy, Piedmont, Emilia,
Abruzzo, Campania, Basilicata, and Sicily); b) randomization in a control group that receives only general lifestyle
recommendations for cancer prevention and in an intervention group that is helped to change through periodic
meeting, kitchen, fitness courses, and common meals, with
decreasing intensity over 5 years; c) follow-up the cohort
for 5 years; analysis by intention-to-treat and by compliance score. By December 2011, 1424 patients were
randomized.
Further studies include:
• A prospective study on several thousand BC patients
admitted to INT for primary surgical treatment to test
the prognostic role of androgens in BC progression. A
biological bank of fasting blood samples collected at the
time of diagnosis is available for BC research.
• A pilot trial of the effects of caloric restriction and
metformin, a caloric restriction mimetic drug, for prevention of BC in 400 peri-or postmenopausal women with
anthropometric or metabolic traits of metabolic
syndrome. Factorial design: metformin versus placebo
(double-blind) and dietary intervention with kitchen
courses and common meals versus dietary recommendations only. The main objective of the trial is to clarify the
metabolic and endocrine effects of calorie restriction, and
the epigenetic mechanisms that mediate such an effect.
Keywords: diet, breast cancer, metformin
HEAD
Franco Berrino, MD (until 30 April)
Marco A. Pierotti, PhD (Interim 1 May)
RESEARCH STAFF
Maria Gaetana Di Mauro, MD
Patrizia Pasanisi, MD, MSc
Anna Villarini, Biol Sci D
Elisabetta Venturelli, Biol Sci D
Giuliana Gargano, Biol Sci D
Eleonora Bruno, MSc
PSYCHOLOGIST
Manuela Bellegotti
Milena Raimondi
DIETICIAN
Daniela Del Sette Cerulli
TECHNICIAN
Adalberto Cavalleri
Paola Consorti, Curtosi Patrizia, Maria
Grazia Guerrini, Maria Larossa
CONSULTANT
Franco Berrino, MD (from 1st May)
RELEVANT NOTES
Publications
Pasanisi P, Bruno E, Venturelli E, Manoukian S, Barile
M, Peissel B, De Giacomi C, Bonanni B, Berrino J,
Berrino F. Serum levels of IGF-I and BRCA
penetrance: a case control study in breast cancer
families. Fam Cancer. 2011; 10: 521-8.
Bakken K, Fournier A, Lund E, Waaseth M,
Dumeaux V, Clavel-Chapelon F, Fabre A, Hémon B,
Rinaldi S, Chajes V, Slimani N, Allen NE, Reeves GK,
Bingham S, Khaw KT, Olsen A, Tjønneland A,
Rodriguez L, Sánchez MJ, Etxezarreta PA, Ardanaz
E, Tormo MJ, Peeters PH, van Gils CH, Steffen A,
Schulz M, Chang-Claude J, Kaaks R, Tumino R, Gallo
V, Norat T, Riboli E, Panico S, Masala G, González
CA, Berrino F. Menopausal hormone therapy and
breast cancer risk: impact of different treatments.
The European Prospective Investigation into
Cancer and Nutrition. Int J Cancer. 2011; 128: 144156.
63
nutritional epidemiology
The Nutritional Epidemiology Unit is involved in large
prospective studies on the association between diet, hormones, nutrition, lifestyle, genetic factors, and cancer risk.
The EPIC study (http://epic.iarc.fr) was designed to investigate the relationships between diet, lifestyle, genetic, and
environmental factors and the incidence of cancer and
other chronic disease in 10 European countries. The main
published results of 2011 are: smoking, heavy alcohol consumption, and obesity contributed to sizeable fractions of
hepatocellular carcinoma burden; in western Europe, a
significant proportion of cancer cases are attributable to
alcohol consumption, especially consumption higher than
the recommended upper limits; high concentrations of
serum HDL are associated with a decreased risk of colon
cancer; high levels of glycated hemoglobin are associated
with an increased risk of pancreatic cancer; heavy alcohol
consumption is associated with an increased risk of intestinal-type non-cardia gastric cancer; presence in the
serum of specific immunoglobulin E is associated with
decreased risk of glioma.
The ORDET study, one of the first prospective European
studies on the role of hORmones and DiET in the etiology of cancer, was organized within the Epidemiology
Units of the INT. The main published results of 2011 are:
elevated serum glucose and HOMA-IR are associated
with increased breast cancer risk, in particular n women
diagnosed after 55 years, for which elevated SHBG levels
are associated with a reduced risk; women who drank
more than 13 g alcohol per day had lower survival than
non-drinkers. The ORDET study is participating in the
“Pooling project on circulating level of vitamin D in breast
and colorectal cancer”, a collaborative project that
involves major European and North American cohort
studies coordinated by Harvard University and funded by
NIH. In 2011, the researchers have been involved in the
preparation of data for statistical analysis.
Keywords: prospective studies, diet, hormones
HEAD
Vittorio Krogh, MD MS
RESEARCH STAFF
Claudia Agnoli, Nutrition Tech, ScD, MSc
Sara Grioni, Nutrition Tech, BSc
Maria Valeria Pala, Agronomy D, PhD
Sabina Sieri, Biol Sci D, PhD
Alberto Evangelista, Follow-up and Database
Manager, BSc
RELEVANT NOTES
Collaborations
Epidemiology of endometrial cancer consortium
(E2C2).
Endogenous Hormones and Breast Cancer
Collaborative Group.
The Pooling Project of Prospective Studies of Diet
and Cancer.
The Pooling Project on circulating level of vitamin
D in Breast and Colorectal Cancer.
IDEFICS Consortium. International Lung Cancer
Consortium.
Publications
Schütze M, Boeing H, Pischon T, Rehm J, Kehoe T,
Gmel G, Olsen A, Tjønneland AM, Dahm CC,
Overvad K, Clavel-Chapelon F, Boutron-Ruault MC,
Trichopoulou A, Benetou V, Zylis D, Kaaks R,
Rohrmann S, Palli D, Berrino F, Tumino R, Vineis P,
Rodríguez L, Agudo A, Sánchez MJ, Dorronsoro M,
Chirlaque MD, Barricarte A, Peeters PH, van Gils
CH, Khaw KT, Wareham N, Allen NE, Key TJ,
Boffetta P, Slimani N, Jenab M, Romaguera D, Wark
PA, Riboli E, Bergmann MM. Alcohol attributable
burden of incidence of cancer in eight European
countries based on results from prospective
cohort study. BMJ. 2011; 342:d1584.
Trichopoulos D, Bamia C, Lagiou P, Fedirko V, Trepo
E, Jenab M, Pischon T, Nöthlings U, Overved K,
Tjønneland A, Outzen M, Clavel-Chapelon F, Kaaks
R, Lukanova A, Boeing H, Aleksandrova K, Benetou
V, Zylis D, Palli D, Pala V, Panico S, Tumino R,
Sacerdote C, Bueno-De-Mesquita HB, Van Kranen
HJ, Peeters PH, Lund E, Quirós JR, González CA,
Sanchez Perez MJ, Navarro C, Dorronsoro M,
Barricarte A, Lindkvist B, Regnér S, Werner M,
Hallmans G, Khaw KT, Wareham N, Key T, Romieu I,
Chuang SC, Murphy N, Boffetta P, Trichopoulou A,
Riboli E. Hepatocellular carcinoma risk factors and
disease burden in a European cohort: a nested
case-control study. J Natl Cancer Inst. 2011;
103(22): 1686-95.
Contributions
Vittorio Krogh is a member of the editorial board
of the International Journal of Public Health.
64
evaluative epidemiology
The Unit is principally involved in assessing the burden of
cancer in populations, focusing on rare cancers and
tumors diagnosed in children, adolescents, and young
adults (AYA). The project Surveillance of Rare Cancers in
Europe (RARECARE) estimated the incidence,
prevalence, survival, and mortality of rare cancers and
published a series of articles in the European Journal of
Cancer. In collaboration with the ESO and the ESMO, the
first training course on rare solid cancers was organized
in Stresa (March 2011). A further important result of
RARECARE was the estimation of cancer prevalence in
Europe for common cancers, and a publication is in
preparation.
The project “Prostate cancer survival patients in Italy”
funded by the AIRC aims at interpreting survival differences within Italy with the application of cure survival
models. The project is part of the Prostate Program of
the INT. The project Rare Cancers in Italy: surveillance
and evaluation of the access to diagnosis and treatment
(RITA2) aims at: providing updated cancer burden indicators in Italy, describing diagnosis and treatment pathways
for rare cancers, and designing a study for the reciprocal
validation of the Rete Tumori Rari (RTR) and cancer registries data. In the context of this project, discussion
started with the RTR and dedicated high resolution
studies on mesothelioma long-term survival,
neuroendocrine tumors, and testicular cancers have been
designed in collaboration with experts of the INT and
cancer registries.
The Unit is updating the Italian estimations of incidence,
mortality, and prevalence for major cancer sites. A monographic number of the journal Tumori will be ready by the
end of 2012. The project, supported by the CCM and
ACC, is in collaboration with the ISS. From the EUROCARE study, a new indicator of outcome was estimated
for childhood and AYA lymphoid leukemia (ALL), namely
the proportion of cured patients. A paper is in preparation presenting the results from ALL across European
countries.
Keywords: rare cancers, childhood cancer, cancer burden in
population
HEAD
Gemma Gatta, MD
RESEARCH STAFF
Annalisa Trama, MD, PhD
Roberto Foschi, Math D, MSc
Francesca Rabito, Rossana Berruti
RELEVANT NOTES
Collaborations
National collaborations:
In the frame work of the project Rare Cancers in
Italy: surveillance and evaluation of the access to
diagnosis and treatment (RITA2), this Unit
collaborate with the Italian Association of Cancer
Registries (AIRTUM), with the clinical rare cancers
network (Rete Tumori Rari) coordinated by Dr.
Paolo Casali, with the Istituto Superiore di Sanità
(ISS) and the Federazione Italiana delle Associazioni
di Volontariato in Oncologia (FAVO).
Collaborations have been established with Dr.
Filippo de Braud and Dr. Vincenzo Mazzaferro to
study neuroendocrine tumors, and with Dr. Ugo
Pastorino, Dr. Marina Garassino, and Prof. Giuseppe
Pelosi to study mesothelioma. Within the prostate
cancer survival patients in Italy, this Unit
collaborates with the Prostate program of the INT,
with 8 population-based Italian cancer registries
(Varese, Trento, Bolzano, Reggio Emilia, Genoa,
Latina, Naples, and Ragusa) and with the ISS.
International collaborations:
Thanks to the new project on rare cancers
(Information network on rare cancers RARECARENet) supported in the context of the
Second Program of Community Action in the Field
of Health (2008-2013) of the EU, this Unit has
collaborations with several European partners
(University of Edinburgh, Comprehensive Cancer
Centre in The Netherlands, Institut de
Cancérologie Gustave Roussy, National Oncology
Hospital in Bulgaria, National Cancer Registry in
Ireland, Finland and Slovenia), with the European
Cancer Patient Coalition (ECPC), with major
scientific societies (ESSO, ESMO and ECCO), with
the portal for rare diseases in Europe (Orphanet),
and with the European initiative Rare Cancer
Europe. In the framework of the European
Partnership for Action Against Cancer (EPAAC),
this Unit works closely with different European
experts with the aim to contribute to the
reduction of cancer burden in Europe.
Publications
Gatta G, van der Zwan JM, Casali PG, Siesling S, Dei
Tos AP, Kunkler I, Otter R, Licitra L, Mallone S, Tavilla
A, Trama A, Capocaccia R; RARECARE working
group. Rare cancers are not so rare: The rare
cancer burden in Europe. Eur J Cancer. 2011; 47:
2493-511.
Contributions
Maura Massimino, Felice Giangaspero, Maria Luisa
Garrè, Lorenza Gandola, Geraldina Poggi, Veronica
Biassoni, Gemma Gatta, Stefan Rutkowski
Collaboration for the recommendations for Wilms
tumor in adults.
START chapter on Childhood medulloblastoma.
Critical Reviews in Oncology/Hematology. 2011;
79: 65-83.
Segers H, van den Heuvel-Eibrink MM, Coppes MJ,
Aitchison M, Bergeron C, de Camargo B, Dome JS,
Grundy P, Gatta G, Graf N, Grundy P, Kalapurakal
JA, de Kraker J, Perlman EJ, Reinhard H, Spreafico F,
Vujanic G, Warwick AB, Pritchard-Jones K; The
SIOP-RTSG and the COG-Renal Tumour
Committee. Management of adults with Wilms’
tumor: recommendations based on international
consensus. Expert Rev Anticancer Ther. 2011;
11(7): 1107-15.
65
analytical epidemiology
The main activity of the unit consists in the analysis of
cancer survival and in the interpretation of differences
across countries and over time, within the framework of
the EUROCARE (European CAncer REgistry based
project on survival and care of cancer patients) project, a
collaborative effort started in the 1990s and now at its
5th round, centralizing survival data from 113 European
cancer registries. To date, the project has produced 4
monographs and numerous scientific publications. The
unit coordinates the EUROCARE scientific activities and
secretariat and, in collaboration with the Istituto
Superiore di Sanità, Rome, contributes to data management and statistical analyses. The unit is responsible for
data collection, management, and analyses of the EUROCARE high resolution (HR) studies, designed to explain
the reasons for the survival differences across regions and
over time. The cancer registries participating in EUROCARE HR collect detailed clinical information on tumor
stage, diagnostic exams, tumor gene expression,
treatment, follow-up, and comorbidity factors influencing
survival. The HR studies describe, compare, and monitor
HEAD
Milena Sant, MD
RESEARCH STAFF
Pamela Minicozzi, Mathematics D, MSc
PHD STUDENTS
Carmen Tereanu, MD
Paolo Bonaiuti, Mathematics D, MSc
Chiara Margutti
patterns of cancer care across European
countries/regions, developing indicators of best practice,
and analyzing their dissemination in current clinical practice. Presently, studies are in course on breast, colorectal,
lung cancer, lymphoma, and melanoma. The Unit is
responsible for HAEMACARE, a project aimed to investigate epidemiological and clinical indicators for
hematological neoplasms in Europe. The unit collaborates
with the CONCORD project (worldwide study on
cancer survival) led by Prof. MP Coleman, LSHTM,
London, UK. Dr. Sant is project leader of the EPAAC
(European Partnership Against Cancer Action) Work
Package 4 (Health information), whose major aim is to
unify the epidemiologic data produced by population
cancer registries in a European Cancer Information
System. In addition to population-based studies, the unit
participates in a clinical study based at INT investigating
the prognostic influence of tumor characteristics and
metabolic factors on breast cancer prognosis.
Keywords: survival, patterns of care, cancer registries
RELEVANT NOTES
Collaborations
ISS. Centro Nazionale di Epidemiologia,
Sorveglianza e Promozione della Salute IARC
International Agency for Research on Cancer
LSHTM London School of Hygene and Tropical
medicine
AIRTUM Associazione italiana dei registri tumori;
FRANCIM France-cancer-incidence et mortalité;
ENCR European Network of Cancer Registries;
ICBP International cancer Benchmark Project, UK;
EUROCOURSE Europe Against Cancer:
Optimisation of the Use of Registries for Scientific
Excellence in Research
EUROCHIP European Cancer Health Indicator
Project EU Joint Research Centre, Ispra
Publications
Marcos-Gragera R, Allemani C, Tereanu C, De
Angelis R, Capocaccia R, Maynadie M, Luminari S,
Ferretti S, Johannesen TB, Sankila R, KarjalainenLindsberg ML, Simonetti A, Martos MC, Raphaël M,
Giraldo P, Sant M; HAEMACARE Working Group.
Survival of European patients diagnosed with
lymphoid neoplasms in 2000-2002: results of the
HAEMACARE project. Haematologica. 2011;
96(5): 720-8.
66
medical genetics
The consolidated activity of the Medical Genetics Unit
offers genetic counseling for several hereditary predispositions to cancer syndromes. The main focus of the Unit is
the study of hereditary breast and ovarian cancer
(HBOC) syndrome, in addition to other inherited predispositions to cancer such as Li-Fraumeni syndrome and
familial melanoma. The principal goal of the Unit is to
identify individuals at genetically increased risk of cancer
in order to offer a targeted clinical management by providing an integrated and multidisciplinary health care
service. More than 7200 individuals belonging to about
3500 different HBOC families have been identified and
characterized. When available, all relevant data has been
collected in the Medical Genetics HBOC database
(including more than 1000 BRCA1 and BRCA2 gene carriers from over 540 families). Moreover, about 620
healthy and 550 affected patients are regularly followed in
collaboration with other INT Units. All clinical, genetic,
and molecular data of individuals belonging to HBOC
families is constantly updated. For all patients treated at
INT and followed by the Medical Genetics Unit, tumor
specimens and blood samples are routinely collected.
The availability of familial, molecular, clinical, and pathological data, as well as biological specimens, is essential for
the following studies:
• genetic characterization of HBOC: gene penetrance,
survival, disease features, as well as environmental risk
factor modifiers and tumor characteristics
• long-term efficacy, health and psychological impact of
clinical and instrumental surveillance, risk reducing
options and treatment in HBOC individuals
• biological and clinical significance of BRCA gene mutations of unknown risk
• genomic and transcriptome analyses for the identification of modifier risk factors and new genes involved in
genetic predisposition to HBOC
Keywords: hereditary breast and ovarian cancer, cancer predisposition
syndrome, familial and hereditary cancer
HEAD
Siranoush Manoukian, MD, PhD
CLINICAL RESEARCH STAFF
Bernard Peissel, MD, PhD
Gaia Roversi, MD, PhD
DATA MANAGER
Daniela Zaffaroni, Biol Sci D, PhD
RESIDENTS
Elisa Cattaneo, MD
Giulia Melloni, MD
Caterina Spina, Alex Sandra Dos
Santos Masioli
RELEVANT NOTES
Publications
Collaborations
Manoukian S, Peissel B, Frigerio S, Lecis D, Bartkova
J, Roversi G, Radice P, Bartek J, Delia D. Two new
CHEK2 germ-line variants detected in breast
cancer/sarcoma families negative for BRCA1,
BRCA2, and TP53 gene mutations. Breast Cancer
Res Treat. 2011; 130(1): 207-15.
Breast Cancer Consortium (BCAC) - Consortium
of Investigators of Modifiers of BRCA1/2 (CIMBA)
Medical Genetics, Department of Medicine,
Surgery and Dentistry, University of Milan
Hereditary Breast Cancer Clinical Study Group Department of Oncology, A.O. Sacco and A.O.
Fatebenefratelli (development of a model for the
identification and management of women at high
genetic risk for breast cancer - PI: Manoukian)
Istituto Superiore Sanità (ISS), Rome - Department
of Oncology, A.O. Sacco and A.O. Fatebenefratelli
(development of a model for the identification and
management of women at high genetic risk for
breast cancer)
Cancer Research Institute, Genoa (IST) and Cancer
Institute Regina Elena, Rome (IFO) in collaboration
with Psychological Unit of INT
Yang XR, Chang-Claude J, Goode EL, et al.
Associations of breast cancer risk factors with
tumor subtypes: A pooled analysis from the breast
cancer association consortium studies. J Natl
Cancer Inst. 2011; 103(3): 250-63.
Sardanelli F, Podo F, Santoro F, Manoukian S,
Bergonzi S, Trecate G, Vergnaghi D, Federico M,
Cortesi L, Corcione S, Morassut S, Di Maggio C,
Cilotti A, Martincich L, Calabrese M, Zuiani C,
Preda L, Bonanni B, Carbonaro LA, Contegiacomo
A, Panizza P, Di Cesare E, Savarese A, Crecco M,
Turchetti D, Tonutti M, Belli P, Maschio AD; for the
High Breast Cancer Risk Italian 1 (HIBCRIT-1)
Study. Multicenter surveillance of women at high
genetic breast cancer risk using mammography,
ultrasonography, and contrast-enhanced magnetic
resonance imaging (the high breast cancer risk
Italian 1 study): final results. Invest Radiol. 2011;
46(2): 94-105.
Contributions
Scientific Committee of the National Italian
Network for the Surveillance of the high genetic
risk women (Ministry of Health and Istituto
Superiore Sanità, Rome)
Members of Italian Society of Human Genetics
(S.I.G.U.) and SIGU-Oncological Medical Genetics
group
67
molecular basis of genetic risk, polygenic models
During 2011, our research Unit continued its studies on
genetic susceptibility to lung cancer. In particular, we carried out a case-only genome-wide association study
(GWAS) using a 620,901 single-nucleotide polymorphism
(SNP) array in a first series of 600 lung adenocarcinoma
(ADCA) patients and in a replication series of 317 lung
ADCA patients to identify SNPs associated with clinical
stage. We observed the strongest statistical association
with rs10278557 (P = 1.1 x 10-5), located in the
mesenchyme homeobox 2 (MEOX2) gene, and our
results pointed to the role of germ line variations
involving multiple loci in modulating clinical stage and,
therefore, prognosis in lung ADCA patients. We have also
characterized the mechanism underlying the tumor suppressor activity of the MFSD2A gene, and found that a
5’-region polymorphism modulates promoter activity of
this gene, potentially affecting MFSD2A mRNA levels in
normal lung and in lung tumors. We carried out meta-
and pooled analyses of the FGFR4 Gly388Arg polymorphism as a cancer prognostic factor, observing a role for
the variant in modulating outcome in different types of
cancer, thus offering to clinicians a new marker to predict
predisposition to poor survival in cancer patients. Finally,
we carried out a pharmacogenomic study on the
response to opioids for cancer pain in a European series
of 1008 cancer patients by testing 1 million SNPs. Our
results indicated that a SNP panel including eight SNPs,
with rs12948783, upstream of the RHBDF2 gene,
showing the best statistical association (P = 8.1 x 10-9),
was significantly associated with pain relief, and may provide a new tool for personalized therapy of cancer pain.
Functional annotation analysis of SNP-tagged genes suggested the involvement of genes acting on processes of
the neurologic system.
Keywords: genetic susceptibility, pharmacogenomics, polymorphisms
HEAD
Tommaso A. Dragani, PhD
RESEARCH STAFF
Giacomo Manenti, PhD
POSTDOCTORAL FELLOWS
Antonella Galvan, PhD
Sara Noci, PhD
Elisa Frullanti, PhD
Francesca Colombo, PhD
PHD STUDENT
Alice Dassano, Biol Sci D
TECHNICIANS
Felicia S. Falvella, PhD
Angela Pettinicchio
Silvia Portincasa
RELEVANT NOTES
Collaborations
opioid therapy response for cancer pain. Clin
Cancer Res. 2011; 17: 4581-7.
European Pharmacogenetic Opioid Study (EPOS)
consortium, Norwegian University of Science and
Technology (NTNU), Trondheim, Norway.
Frullanti E, Galvan A, Falvella FS, Manenti G,
Colombo F, Vannelli A, Incarbone M, Alloisio M,
Nosotti M, Santambrogio L, Gonzalez-Neira A,
Pastorino U, Dragani TA. Multiple genetic loci
modulate lung adenocarcinoma clinical staging. Clin
Cancer Res. 2011; 17: 2410-6.
Publications
Contributions
Galvan A, Skorpen F, Klepstad P, Knudsen AK,
Fladvad T, Falvella FS, Pigni A, Brunelli C, Caraceni
A, Kaasa S, Dragani TA. Multiple Loci modulate
Frullanti E: Second Level Master in Medical
Statistics and Statistical Methods for Epidemiology.
University of Milan.
Dr. Olga Ibanez, Butantan Institute, Sao Paulo,
Brazil.
68
molecular basis of genetic risk and genetic testing
This research unit is devoted to the identification and
characterization of genetic elements associated with predisposition to cancer and cancer progression. Our studies
are mainly focused on breast carcinoma and Wilms tumor
(WT).
The main achievements in 2011 are as follows.
• Following the discovery that PALB2 constitutional
mutations predispose to both breast and pancreatic carcinomas, we screened 62 hereditary breast cancer cases
negative for BRCA gene mutations (BRCAX) and with a
personal and/or familial history of pancreatic cancer. The
frequency of identified pathogenic mutations (4.8%) was
not significantly different from that (2.1%) we observed in
BRCAX cases unselected for association with other
cancer types.
• A putative polymorphism (rs12975333) in the miR125 microRNA, previously reported in association with
increased breast cancer risk, was genotyped in 3145
BRCAX cases and 4114 controls from Italy, Spain,
Germany, and Australia. None of the examined samples
carried the analyzed variant, ruling out its role in breast
cancer predisposition in the investigated populations.
• The occurrence of specific telomere maintenance
mechanisms (TMMs) was investigated in 34 WTs.
Alternative lengthening of telomeres (ALT) was detected
as the sole TMM in 5 samples and in association with
telomerase activity (TA) in 6 samples; 17 samples exhibited TA only and in 6 cases no TMM was found. This is the
first evidence of the presence of ALT in WT, which was
found to be the only TMM supporting tumor development in a subset of cases.
• The genetic effects induced by the RPF-1 protein,
encoded by the WT-related POU6F2 gene, was investigated using a genome-wide approach. Protein-DNA
interactions were validated by band-shift assay of putative
consensus sequences and functionally characterized on
promoters cloned into reporter vectors. Several regulators of embryonic kidney development were found
directly modulated by RPF-1, suggesting a role for this
factor in kidney morphogenesis.
Keywords: cancer genetics, familial breast cancer, Wilms tumor
HEAD
Paolo Radice, Biol Sci D
RESEARCH STAFF
Daniela Perotti, PhD
Laura Caleca, PhD
Mara Colombo, PhD
Giovanna De Vecchi, Biol Sci D
Antonio Fiorino, Biol Sci D
Paolo Peterlongo, PhD*
Carla B. Ripamonti, MD
PHD STUDENT
Irene Catucci, Med Biotech D*
FELLOWS
Claudia Foglia, Biol Sci D
Sara Ciceri, Med Biotech D
TECHNICIAN
Patrizia Mondini
Silvia Grassi
*c/o FIRC Institute of Molecular Oncology Foundation
(IFOM)
RELEVANT NOTES
Collaborations
Fondazione Istituto FIRC di Oncologia Molecolare,
Milan Italy
Network Italiano Tumori Eredo-Famigliari (INTEF) P. Radice, co-coordinator
CONsorzio degli Studi ITaliani sul Tumore
Ereditario alla Mammella (CONSIT TEAM) - P.
Radice, coordinator
Evidence-based Network for the Interpretation of
Germline Mutant Alleles (ENIGMA) - P. Radice,
steering committee member
Associazione Italiana di Ematologia ed Oncologia
Pediatrica (AIEOP) - D. Perotti, Wilms tumor
working group steering committee member
Breast Cancer Consortium (BCAC)
Consortium of Investigators of Modifiers of
BRCA1/2 (CIMBA)
Institut Catala de Oncologia, Barcelona, Spain
Department of Human Genetics, Leiden University
Medical Center, Leiden, The Netherlands
Queensland Institute of Medical Research,
Brisbane, Queensland, Australia
Publications
Peterlongo P, Catucci I, Pasquini G, Verderio P,
Peissel B, Barile M, Varesco L, Riboni M, Fortuzzi S,
Manoukian S, Radice P. PALB2 germline mutations
in familial breast cancer cases with personal and
family history of pancreatic cancer. Breast Cancer
Res Treat. 2011; 126:
825-8.
Venturini L, Daidone MG, Motta R, Collini P,
Spreafico F, Terenziani M, Piva L, Radice P, Perotti D,
Zaffaroni N. Telomere maintenance in Wilms
tumors: First evidence for the presence of
alternative lengthening of telomeres mechanism.
Genes Chromosomes Cancer. 2011; 50: 823-9.
69
hereditary digestive tract tumors
The Unit of Hereditary Digestive Tract Tumors is devoted
to the counselling, molecular testing, and clinical management of individuals with genetic predisposition to the
major hereditary syndromes of gastrointestinal cancer.
These include Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC), familial adenomatous
polyposis (FAP) and its phenotypic variant attenuated
FAP, Peutz-Jeghers Syndrome, and hereditary gastric
cancer.
Individuals with evidence of hereditary susceptibility to
cancer are counseled and informed about personal risk
and that of their relatives. Depending of the fulfillment of
defined criteria, individuals who receive genetic
counseling are offered the possibility to undergo molecular testing for identification of specific genetic
alteration(s) that may be associated with the increased
risk of cancer in their families. These criteria include personal and family history of cancer, presence of specific
clinical phenotypes, and tumor characteristics. The genes
presently screened on a routine basis include: MLH1,
MSH2, MSH6, and PMS2, cumulatively referred to as
DNA mismatch repair (MMR) genes [HNPCC]; APC and
MUTYH [FAP and attenuated FAP]; LKB1 [Peutz-Jeghers
Syndrome], and CDK1 [gastric cancer].
All tests are performed at the diagnostic laboratory
located at IFOM (FIRC Institute of Molecular Oncology)
in collaboration with the DNA Sequencing Unit of the
Cogentech Consortium at the IFOM-IEO campus. During
2011, more than 300 individuals were screened for
germline mutations in cancer predisposing genes. This
diagnostic activity is integrated by several research programs (LILT, Rome; PIO, Bari). At the preclinical level, they
are focused on the identification of genetic markers
responsible for familial aggregations that test negative by
the above described molecular screenings or that influence cancer risk in mutation carriers.
Keywords: hereditary cancer, colorectal tumor, polyposis
HEAD
Lucio Bertario, MD
RESEARCH STAFF
Paola Sala, Biol Sci D
Stefano Signoroni, Biol Sci D
Mariangela Di Ceglie
Ornella Galuppo
RELEVANT NOTES
Collaborations
randomised controlled trial. Lancet. 2011; 378:
2081-7.
InTEF (Network Nazionale Italiano Tumori EredoFamigliari)
Vitellaro M, Bonfanti G, Sala P, Poiasina E, Barisella
M, Signoroni S, Mancini A, Bertario L. Laparoscopic
colectomy and restorative proctocolectomy for
familial adenomatous polyposis. Surg Endosc. 2011;
25: 1866-75.
Publications
Contributions
Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein
G, Olschwang S, Eccles D, Evans DG, Maher ER,
Bertario L, Bisgaard ML, Dunlop MG, Ho JWC,
Hodgson SV, Lindblom A, Lubinski J, Morrison PJ,
Murday V, Ramesar R, Side L, et al. Long-term effect
of aspirin on cancer risk in carriers of hereditary
colorectal cancer: an analysis from the CAPP2
Lucio Bertario, coordinator of the collaborative
group for the elaboration of guidelines for clinical
management of familial adematous polyposis,
Lombardy Region.
Mallorca European Group for the Hereditary
Colorectal Cancer
Lucio Bertario, president of AIFEG Association
(Associazione Italiana per lo Studio della Familiarità
ed Ereditarietà dei Tumori Gastrointestinali)
71
EXPERIMENTAL ONCOLOGY
AND MOLECULAR MEDICINE
DEPARTMENT
phone: +39 02 2390 2238
[email protected]
UNITS
IMMUNOBIOLOGY OF HUMAN
TUMORS
Andrea Anichini
MOLECULAR THERAPIES
Silvana Canevari
MOLECULAR IMMUNOLOGY
Mario P. Colombo
BIOMARKERS
MOLECULAR MECHANISMS OF
CELL CYCLE CONTROL
Domenico Delia
MOLECULAR MECHANISMS
Angela Greco
IMMUNOTHERAPY OF HUMAN
TUMORS
Licia Rivoltini
TUMOR GENOMICS
Gabriella Sozzi
MOLECULAR TARGETING
Elda Tagliabue
MOLECULAR PHARMACOLOGY
Nadia Zaffaroni
The Department of Experimental Oncology and Molecular Medicine
(DOSMM) includes 10 Research Units dedicated to preclinical investigations.
The primary goal of the Department is to serve as an important conduit
through which new discoveries are applied to cancer diagnosis, prognosis, and
treatment. This is fostered by a collaborative environment and a strong interaction among physician and basic scientists working in different disciplines.
During 2011, DOSMM acted as an interactive platform fostering
collaborations among preclinical investigators and with INT Clinical Departments on topics of common interest, such as the identification and validation
of circulating molecular markers as new tools for early detection and risk
assessment, study of tumor-microenvironment related changes, and the underlying molecular mechanisms using both animal models and patient samples,
which have been awarded by national and international grant support.
DOSMM supports investigators with state-of-the-art core facilities, with
shared instrumentation and trained specialists.
The following resources are available.
• Immunohistochemistry (technical specialists: Lorena Ventura and Lucia
Gioiosa): histological and cytological processing, including tissue microarrays, by
a wide range of histological techniques, immunohistochemistry, in situ
hybridization, and autoradiography.
• Cell imaging facility (Technical Specialist: Patrizia Casalini, Biol Sci D): provides access to a BioRad Radiance 2000 laser confocal microscope allowing
for a wide range of fluorescent dye use, sequential and simultaneous 3 channel
bright field image collection, and live cell imaging.
• Flow cytometry and cell sorting (Technical Specialist: Gabriella Abolafio;
Research Fellow: Andrea Vecchi, Biol Sci D): using state-of-the-art flow cytometric instrumentation, and software analysis.
• Microbiology (Technical Specialist: Maria Teresa Radice): core services
include preparation/analysis of a) competent bacteria, media, agar plates, and
72
other reagents; b) bacterial transformation and miniprep; c) medium/large
scale plasmid DNA; d) BAC and YAC DNA; e) culture/induction of bacteria for
purification of recombinant proteins, freezing and storage of recombinant plasmids and transformed bacteria, database management.
• DNA sequencing (Technical Specialist: Donata Penso): this facility provides
DOSMM Units as well as Units of other Departments with computer-readable
sequences and fragment analysis of DNA templates, processing samples on
ABI 3100 and 3130 capillary genetic analyzers.
• Functional genomics and Bioinformatics (see a detailed description on
page 146)
• Proteomics/mass spectrometry laboratory (see a detailed description on
page 147)
• Tissue and cell repository (see a detailed description on page 145)
• Laboratory animal facility
Administrative team: Grazia Barp, Grazia Convertino, Simona Galluzzi, Ester Grande, Silvia Grassi,
Laura Mameli, Silvia Portincasa, Luisa Rivetta, Daniela Silva, Laura Zanesi, Cristina Zanini.
This team facilitates the activity of the Department by providing administrative support to research
unit leaders and core facilities, coordinating the activities of graduate students and fellows, handling
purchasing requests for laboratory consumables, and finance administration.
Laboratory Management Team: Enrico Ronchi, Domenico Di Fazio, Angelo Labori, Salvatore Venturino.
This team plays an essential role to support the research units within the Department for
maintenance of instrumentation, and management and supervision of areas for cryopreservation of
stored tissues/cells/cell extracts and reagents. In addition, the team – in association with the
administrative team - also oversees a cost-effective and efficient centralized system of ordering and
stock control for the most widely used items.
Supporting Personnel: Antonietta Calcagno, Linda Cimaglia, Antonio Illuminato, Agata Mancuso, Luisa
Mona, David Penni, Gisella Rivadossi, Pasquale Russo, Claudio Santagostini.
73
immunobiology of human tumors
The main goals of the research unit are:
• to understand how the adaptive immune response
that develops in neoplastic patients, or that promoted by
immunotherapy, can contribute to control of tumor
growth;
• to identify new molecular targets to overcome tumor
resistance to cell death;
• to define the roles in tumor biology of activated tyrosine kinase receptors (RTK) expressed in melanoma;
• to dissect the role of the tumor-host interaction in
promoting cancer development and progression.
The main projects during 2011 have focused on: a) mechanisms of immune response promoted by
immunotherapy in melanoma patients. b) Prognostic significance of immune-related markers associated with
hematopoietic stem cell transplantation in pediatric solid
tumors. c) Identification of new therapeutic targets in
melanoma to overcome tumor resistance to
programmed cell death induced by pro-apoptotic drugs
and target-specific inhibitors. d) Identification of
melanoma subsets defined by RTK expression and signaling pathway profiling.
The main results of 2011 included: a) evidence that promotion of T cell infiltration and maturation, in neoplastic
lesions of melanoma patients, is a main mechanism of
action of immunotherapy based on the anti-CTLA-4
monoclonal antibody ipilimumab; b) identification of a
new subset of cutaneous melanomas defined by expression of the RTK AXL and role of this RTK in melanoma
migration and invasion; c) identification of the inhibitor of
apoptosis Apollon as a main regulator of melanoma
resistance to cell death by cytotoxic drugs, MEK and
BRAF-specific inhibitors, as well as to soluble or
membrane-TRAIL; d) identification of NFATc2 transcription factor as a new potential therapeutic target in
melanoma.
Keywords: melanoma, tumor immunity, microenvironment
HEAD
Andrea Anichini, Biol Sci D
RESEARCH STAFF
Marialuisa Sensi, Biol Sci D
Roberta Mortarini, Biol Sci D
FELLOWS
Valentina E. Perotti
Giulia Grazia
POSTDOCTORAL FELLOW
Elena Tassi
TECHNICIANS
Paola L. Baldassari, Ilaria Bersani, Alessandra
Molla, Gabriella Nicolini, Claudia Vegetti
RELEVANT NOTES
Collaborations
ISS, Rome
JS, Anichini A. T-cell activation and maturation at
tumor site associated with objective response to
ipilimumab in metastatic melanoma. J Clin Oncol.
2011; 29: e783-8.
Dr. P. Allavena, Istituto Clinico Humanitas, Milan
Sensi M, Catani M, Castellano G, Nicolini G, Alciato
F, Tragni G, De Santis G, Bersani I, Avanzi G,
Tomassetti A, Canevari S, Anichini A. Human
cutaneous melanomas lacking MITF and
melanocyte differentiation antigens express a
functional Axl receptor kinase. J Invest Dermatol.
2011; 131: 2448-57.
Prof. B. Venerando, Università degli Studi di Milano
Contributions
Dr. P.F. Ferrucci, Istituto Europeo di Oncologia,
Milan
Andrea Anichini, Editorial Boards: Cancer
Immunology Immunotherapy, The International
Journal of Biological Markers, Tumori.
Dr. Riccardo Dolcetti, C.R.O., Aviano
Dr. Ennio Carbone, Università degli Studi di
Catanzaro “Magna Graecia”
Dr. R. Falcioni, Istituto Nazionale Tumori “Regina
Elena”, Rome
Publications
Del Vecchio M, Mortarini R, Tragni G, Di Guardo L,
Bersani I, Di Tolla G, Agustoni F, Colonna V, Weber
74
molecular therapies
Through a multidisciplinary approach and integrated functional/analytical methodologies, the Unit aims to: gain
insight in the molecular events involved in the tumor progression; identify and validate new potential targets and
prognostic/predictive markers; to develop and validate
new diagnostic/therapeutic strategies targeting ovarian
and prostate carcinoma. The majority of the Unit projects
are possible thanks to fruitful interactions with other
Units of DOSMM, Gynecological Oncology, Prostate Program, Nuclear Medicine, and Anatomic Pathology. The
research group is also involved in numerous national and
international collaborations.
Major results achieved in the area of characterization of
molecular events involved in cancer progression. We
defined the role of key enzymes of the choline metabolic
pathway in cervical cancer tumor initiating cells; by means
of specific RNA interference achieved a detailed knowledge of the biology underlying the sustained
expression/activity of ChoK-alpha in ovarian carcinoma;
contributed to the characterization of a subset of
melanomas expressing Axl and endowed with high invasive potential; identified a new signaling transduction
pathway, downstream to EGFR activation, characterized
by a FAK phosphorylated form concentrated at mitotic
spindle.
In the area of new prognostic/predictive markers for
ovarian carcinoma we: demonstrated that down-modulation of a miRNA cluster on chrXq27.3 is associated with
shorter time to relapse and that forced overexpression of
these miRNAs resensitized cells to cisplatin cytotoxicity;
contributed to the identification of the prognostic role of
stathmin in p53 mutated advanced stage cases. In the
area of therapeutic approaches with antibody-based
reagents we demonstrated that, in preclinical models, a
human anti-folate receptor fragment in dimer format was
able to strongly accrete 131I to ovarian carcinoma cells
and cure treated animals.
Keywords: translational medicine, molecular mechanisms of tumor
progression, antibody-based therapy
HEAD
Silvana Canevari, Biol Sci D
RESEARCH STAFF
Fabio Benigni, Biol Sci D (from May 2011)
Marina Bagnoli, Biol Sci D
Mariangela Figini, Biol Sci D
Delia Mezzanzanica, Biol Sci D
Antonella Tomassetti, Pharmacol Sci D
Alberto Zacchetti, Vet D (until April 2011)
FELLOWS
Chiara Alberti, Biol Sci D
Davide Bernareggi, Biotech Sci D
Ileana Bortolomai, Biol Sci D
Barbara Frigerio, Biol Sci D
Anna Granata, Biol Sci D
Roberta Nicoletti, Med Biotech D (from May
2011)
Patrizia Pinciroli, Biol Sci D
Katia Rea, Med Biotech D
Alessandro Satta, Vet Biotech D
TECHNICIANS
Paola Alberti, Renata Ferri, Elena Luison
RELEVANT NOTES
Collaborations
National Collaborations: Dr Silvano Ferrini, IST
Genoa; Prof. Marco Colombatti, University of
Verona; Dr. Franca Podo and Dr. Egidio Iorio, ISS,
Rome; Dr. Sandro Pignata on behalf of the MITO
group, Ist. Pascale, Naples; Dr. Massimo Libra,
University of Catania; Dr. Gustavo Baldassarre,
CRO, Aviano; Dr. Teresa Pellegrino, CNR Lecce and
ITT, Genoa; Dr. Laura Belvisi, University of Milan
International Collaborations: Dr. Nathalie Jacobs,
CNR, Liege, Belgium; Drs. Sophia Karagiannis and
Hannah Gould, King’s College, London, UK; Dr.
Zaver Bhujwalla, Johns Hopkins University,
Baltimore, USA; Dr Daniel Powell, University of
Pennsylvania, USA
Publications
Alberti C, Pinciroli P, Valeri B, Ferri R, Ditto A,
Umezawa K, Sensi M, Canevari S, Tomassetti A.
Ligand-dependent EGFR activation induces the coexpression of IL-6 and PAI-1 via the NFkB pathway
in advanced-stage epithelial ovarian cancer.
Oncogene. 2011; doi: .1038/onc.2011.572.
Bagnoli M, De Cecco L, Granata A, Nicoletti R,
Marchesi E, Alberti P, Valeri B, Libra M, Barbareschi
M, Raspagliesi F, Mezzanzanica D, Canevari S.
Identification of a chrXq27.3 microRNA cluster
associated with early relapse in advanced stage
ovarian cancer patients. Oncotarget. 2011; 2: 126578.
Contributions
Editorial Board: Silvana Canevari, Cancer
Immunology Immunotherapy
75
molecular immunology
We study the complex interplay among cells of the
immune system, the extracellular matrix, and transforming
tissues.
• We have studied the role of mast cells (MCs) in
prostate tumor development, starting from the observation that, in prostate tumors from both tumor-prone
TRAMP mice and human patients, MCs are specifically
enriched and degranulated in areas of well-differentiated
(WD) adenocarcinoma (AC), but not around poorly differentiated (PD) foci coexisting in the same tumors. We
derived novel cell lines, representative of WD and PD
variants, and by pharmacologically stabilizing or genetically
ablating MCs in recipient mice, demonstrated that MC
promote WD AC growth, but are dispensable for PD
tumors. WD tumors rely on MCs for MMP-9 provision, as
reconstitution of MC-deficient mice with wt but not
MMP-9-/- MCs was sufficient to promote their growth,
whereas PD tumors, consistently with epithelial-to-mesenchymal transition, are MMP-9 self-competent. Such a
dual source of MMP-9 was confirmed in human tumors,
suggesting that MCs could be a good target for early
stage prostate cancer. Nevertheless, testing whether MC
targeting could block or delay tumorigenesis in tumorprone TRAMP mice, we observed a high incidence of
early and aggressive tumors, characterized by a neuroendocrine (NE) signature and c-Kit expression. These data
underscore the contribution of MCs in tumor progression and uncover a new, opposite role of MCs in
protecting against the occurrence of aggressive NE variants in prostate cancer.
• Fibrosis results from inflammatory tissue damage and
impaired regeneration. In the context of bleomycininduced pulmonary fibrosis we demonstrated that the
matricellular protein SPARC distinctly regulates inflammation and collagen deposition depending on its cellular
origin.
Keywords: mast cells, SPARC/osteonectin, tumor microenvironment
HEAD
Mario P. Colombo, Biol Sci D
RESEARCH STAFF
Silvia Miotti, Biol Sci D
Claudia Chiodoni, Biol Sci D
Sabina Sangaletti, PhD, Biol Sci D
Agniezka Chronowska, PhD
Paola Pittoni, PhD
Caterina Vitali, PhD
Giorgio Mauri, Med Biotech D
FELLOW
Andrea Tomirotti, Med Biotech D
PHD STUDENTS
Alessia Burocchi, Biol Sci D
Alessandra Santangelo, Biol Sci D
Alice Rigoni, Biol Sci D
Ilaria Torselli, Biol Sci D
TECHNICIANS
Ivano Arioli, Barbara Cappetti, Ileana Facetti,
Mariella Parenza, Claudia Bassani, Laura
Botti, Biol Sci D, Chiara Ratti
RELEVANT NOTES
Collaborations
Claudio Tripodo, Univerity of Palermo
Katia Scotlandi, Istituto Ortopedico Rizzoli, Bologna
Sangaletii S, Tripodo C, Cappetti B, Casalini P,
Chiodoni C, Piconese P, Santangelo A, Parenza M,
Arioli I, Miotti S, Colombo MP. SPARC Oppositely
regulates inflammation and fibrosis in bleomycininduced lung damage. Am J Pathol. 2011; 179:
3000-10.
Alessandra Carè, Istituto Superiore di Sanità, Rome
Contributions
Publications
Pittoni P, Tripodo C, Piconese S, Mauri G, Parenza
M, Rigoni A, Sangaletti S, Colombo M.P. Mast cell
targeting hampers prostate adenocarcinoma
development but promotes the occurrence of
highly malignant neuroendocrine cancers. Cancer
Res. 2011; 71: 5987-97.
Mario P. Colombo is Senior Editor of Cancer
Research and Associate Editor of Cancer
Immunology Immunotherapy and
Oncoimmunology
76
biomarkers
Research in this Unit is aimed towards identification, validation and targeting of cancer-related biomarkers
relevant on cancer progression, with a focus in 2011 on
breast cancer to investigate: The subtype-dependent
prognostic relevance of an interferon metagene in nodenegative tumors: to identify a signature - beyond the
classical risk factors - associated with metastatization, we
profiled a comparable (for clinicopathologic features)
series of ER-positive tumors from women with early
relapse in distant sites and from women who remained
disease-free for a longer time, and we considered differentially expressed (DE) metagenes rather than single DE
genes. A metagene containing interferon-induced genes
(IFN metagene) was DE (P=0.029) as a function of
metastasis occurrence. The validation of these results on
publicly available larger datasets showed the association
of the IFN metagene with poorer prognosis in luminal
(P=0.012), but with a better prognosis (P=0.0014) in
ERBB2+ tumors. The combined consideration of IFN and
T-cell metagenes indicated a complex interaction in all
the molecular subsets except for basal tumors (whose
unfavorable outcome was independent of both
metagenes), thus confirming the importance of analyzing
prognostic variables separately within molecular subtypes.
Gene expression profiling (GEP) of circulating tumor cells
(CTC): CTCs might represent an easy-accessible “liquid
biopsy” whose transcriptional characterization likely
allows identification of pathways involved in metastatic
dissemination and to obtain clinically-relevant information.
We are currently: i) capturing CTCs by antibodies against
EpCAM and MUC-1 and by evaluating the expression of
epithelial-mesenchymal-transition and stemness-related
markers, which markedly improved CTC detection rate;
ii) assessing the feasibility of GEP by developing a protocol to profile the expression of 29,000 genes by the
DASL approach in as few as 50 CTCs; iii) validating these
approaches within neo-adjuvant settings.
Keywords: breast cancer, biomolecular profile, cancer stem cells
HEAD
Maria Grazia Daidone, Biol Sci D, PhD
RESEARCH STAFF
Vera Cappelletti, Biol Sci D
Silvia Veneroni, Biol Sci D
Raffaella Villa, Biol Sci D
Valentina Appierto, Biol Sci D, PhD
Graziella Cimino Reale, Biol Sci D, PhD
Daniela Sia, Med Biotech D, PhD
PHD STUDENTS
Maurizio Callari, Med Biotech D
Valeria Musella, Med Biotech D
Lorenza Venturini, Biol Sci D
FELLOWS
Eleonora Di Buduo, Med Biotech D
Emanuela Fina, Biol Sci D
Guido Santilli, Med Biotech D
Paola Tiberio, Biol Sci D
Sara Toffanin, Med Biotech D
TECHNICIANS
Cinzia De Marco, Lucia Gioiosa, Patrizia
Miodini, Biol Sci D, Rosita Motta
RELEVANT NOTES
Collaborations
Paolo Ciana, University of Milan, Italy; Giannino Del
Sal, University of Trieste, Italy; Maurizio D’Incalci
(IRFMN, Milan), within the framework of the
project NEPENTE, financed by the Lombardy
Region; Silvia Giordano, University of Turin and
IRCC Candiolo, Italy; Josep M. Llovet, Hospital
Clinic (Barcelona, Spain) and Mount Sinai School of
Medicine (New York, USA), within the frame of the
HCC Consortium; Angelo Paradiso, within the
framework of a research project on biobanking
supported by ACC, the Italian Alliance against
Cancer; Gaio Paradossi, University of Tor Vergata,
Rome, Italy; Pier Giuseppe Pelicci (IEO), within the
framework of a research project supported by
ACC, the Italian Alliance against Cancer; Stefano
Piccolo, University of Padua, Italy; Daniela Pistillo,
Istituto Clinico Humanitas, within the framework of
a CCM project supported by the Italian Ministry of
Health; EATRIS Consortium, European Community
funded project to foster translational research and
IATRIS Consortium, Italian initiative for translational
studies coordinated by ISS, the Italian Health
Institute EurocanPlatform, European Platform for
Translational Cancer Research, FP7 HEALTH
European Collaborative Project “SIGHT - Systems
for in situ theranostic using of micro-particles
triggered by ultra-sound”, FP6 HEALTH European
Collaborative Project “3 MICRON - Three
modality contrast imaging using multi-functionalised
microballoons”, FP7 HEALTH Genomnia (s.r.l.):
Next generation sequencing on single cell samples
Publications
Callari M, Cappelletti V, De Cecco L, Musella V,
Miodini P, Veneroni S, Gariboldi M, Pierotti MA,
Daidone MG. Gene expression analysis reveals a
different transcriptomic landscape in female and
male breast cancer. Breast Cancer Res Treat. 2011;
127: 601-10.
Cordenonsi M, Zanconato F, Azzolin L, Forcato M,
Rosato A, Frasson C, Inui M, Montagner M, Parenti
AR, Poletti A, Daidone MG, Dupont S, Basso G,
Bicciato S, Piccolo S. The Hippo transducer TAZ
confers cancer stem cell-related traits on breast
cancer cells. Cell. 2011; 147: 759-72.
Contributions
Maria Grazia Daidone is Member of the TechnicalScientific Committee of AIRC, the Italian
Association for Cancer Research and Member of
the Scientific Committee of the Italian School of
Senology (SIS)
Maria Grazia Daidone is Chairperson of the
PathoBiology Group of the EORTC (European
Organization for Research and Treatment of
Cancer) and Member of the EORTC Translational
Research Division M.G. Daidone is co-editor of the
International Journal of Biological Markers and
Member of the Editorial Board of BMC Cancer
and Cell Proliferation
77
molecular mechanisms of cell cycle control
Dissection of the molecular events underlying the ATM-CHK2
dependent DNA damage response and role in genomic stability. One of the components of the DNA damage
response (DDR) we have recently identified and characterized is DBC1 (Deleted in Breast Cancer-1), a putative
tumor suppressor involved in apoptosis, transcription regulation, and histone modification. DBC1 is a potent
inhibitor of SIRT1 deacetylase, a regulator of p53-dependent apoptosis induced by genotoxic stress. We have
found that upon DNA damage, DBC1 is phosphorylated
on thr454 by ATM and ATR kinases, and that this previously unknown modification of DBC1 is involved in the
physical interaction and inhibition of SIRT1. Moreover,
phosphorylation of DBC1-T454 leads to the dissociation
of SIRT1-p53 complex, thereby increasing p53 acetylation
and p53-dependent cell death. Our findings thus further
extend the mechanisms of DDR connected with the
ATM/ATR-dependent regulation of the SIRT1/p53 apoptotic axis.
Development of pro-apoptotic SMAC-mimetic compounds
with anticancer activity. The ongoing collaboration with
scientists of the University of Milan on the
structural/functional analysis and design of pro-apoptotic
small SMAC-mimetics has lead to the development of
new monomeric and dimeric compounds with increased
affinity for the BIR3 and BIR3 domains of IAPs (inhibitors
of apoptosis proteins) and tumor cell killing at nanomolar
concentrations. One of these drug-like SMAC-mimetics,
SMAC83, is currently being investigated for its in vivo
activity, alone or in combination with soluble TRAIL or
CD34+ hemopoietic stem cells expressing membrane
TRAIL, against human tumors engrafted in mice.
Keywords: DNA damage, cell cycle checkpoints, apoptosis
HEAD
Domenico Delia, Biol Sci D
Giacomo Buscemi, PhD
Benjamin Nachimuthu, PhD
Laura Zannini, PhD
PHD STUDENTS
Annalisa Conti, BSc
Elena Fusar-Poli, BSc
Daniele Lecis, BSc
FELLOW
Luigi Carlessi, BSc
TECHNICIAN
Enrico Fontanella
RELEVANT NOTES
Collaborations
Profs. Martino Bolognesi and Pierfausto Seneci,
University of Milan
Prof. Henning Walczak , Imperial College, London,
UK
Prof. Shuki Mizutani, Tokyo Dental and Medical
University, Japan
Publications
Manoukian S, Peissel B, Frigerio S, Lecis D, Bartkova
J, Roversi G, Radice P, Bartek J, Delia D. Two new
CHEK2 germ-line variants detected in breast
cancer/sarcoma families negative for BRCA1,
BRCA2, and TP53 gene mutations. Breast Cancer
Res Treat. 2011; 130: 207-15.
De Amicis A, Piane M, Ferrari F, Fanciulli M, Delia
D, Chessa L. Role of senataxin in DNA damage
and telomeric stability. DNA Repair (Amst). 2011;
10: 199-209.
Contributions
Patent: “New homo- and heterodimeric SMAC
mimetic compounds as apoptosis inducers”.
PCT/IB2012/000297
78
molecular mechanisms
The Unit is involved in studies of the molecular mechanisms of thyroid carcinogenesis, with particular interest in
papillary thyroid carcinoma (PTC), the most frequent thyroid neoplasia. The final goal of ongoing studies is the
identification of markers useful for early detection, prognosis, and follow up, as well as novel therapeutic targets.
Towards this end, the Unit employs several different
approaches including generation of in vitro models of thyroid carcinogenesis using tumor derived cell lines and
human primary thyrocytes; analysis of the role of selected
pathways and molecules; mRNA and microRNA expression analysis; characterization of a thyroid tumor case
collection, used both for discovery and validation studies.
The results achieved during 2011 are related to:
• Relevance in thyroid carcinogenesis of oncogeneinduced senescence (OIS), a novel mechanism proposed
as a barrier to cancer, by the demonstration OIS restrains
thyroid tumor progression, as it is present in early phase,
indolent tumor papillary thyroid microcarcinoma.
• Identification of miRNAs modulated by RET/PTC1, and
demonstration that RET/PTC1 may up-regulate MET
expression through miR199a.
• Demonstration through functional studies that the
RET-K666E mutation, detected in a MTC patient, is oncogenic, and that its transforming activity is enhanced by the
in cis G691S polymorphism.
• Demonstration that DUSP6/MKP3, a feedback negative
regulator of ERK1/2 pathway, is over-expressed at the
mRNA and protein levels in both papillary and poorly
differentiated thyroid carcinoma and may have a protumorigenic role in thyroid carcinogenesis.
• Identification of genetic determinants controlling the
progression of MTC by using a mouse model (in collaboration with Polygenic Inheritance Unit).
The Unit has also contributed to a study showing that
mutations of RAS or BRAF gene confer resistance to imatinib in GIST carrying imatinib-sensitive c-Kit mutations.
Keywords: thyroid carcinoma, oncogenes, functional studies
HEAD
Maria Angela Greco, Biol Sci D
RESEARCH STAFF
Maria Grazia Borrello, Biol Sci D
Claudia Miranda, Biol Sci D
Debora Degl’Innocenti, Biol Sci D
PHD STUDENTS
Maria Grazia Vizioli, Biotech Med D
Maria Chiara Anania, Biol Sci D
Mara Mazzoni, Biol Sci D
Paola Romeo, Biotech Med D
Emanuela Minna, Biol Sci D
TECHNICIANS
Sonia Pagliardini, Maria Grazia Rizzetti
RELEVANT NOTES
Università degli Studi di Milano
Collaborations
Laura Fugazzola Endocrine Unit, Fondazione IRCCS
Ca’ Granda, Università degli Studi di Milano
Clara V. Alvarez, IDIS, Neoplasia and Endocrine
Differentiation, Department of Physiology, CIMUS,
School of Medicine, University of Santiago de
Compostela USC, Spain
Paola Allavena Dep Immunology and Inflammation,
IRCCS Humanitas Clinical Institute
Daniel Peeper Division of Molecular Genetics, The
Netherlands Cancer Institute, Amsterdam
Enrico Radaelli Dipartimento di Patologia
Veterinaria, Facoltà di Veterinaria, Università degli
Studi di Milano
Jesus Gil, MRC Imperial College, London
Erminio Giavini, Elena Menegola, Functional and
Reproductive Biology, Dipartimento di Biologia,
Borrello MG, Aiello A, Peissel B, Rizzetti MG,
Mondellini P, Degl’Innocenti D, Catalano V, Gobbo
M, Collini P, Bongarzone I, Pierotti MA, Greco A,
Publications
and Seregni E. Functional characterization of the
MTC-associated germ line RET-K666E mutation:
evidence of oncogenic potential enhanced by the
G691S polymorphism. Endocrine Related Cancer.
2011; 18(4): 519-27.
Vizioli MG, Possik PA, Tarantino E, Meissl K, Borrello
MG, Miranda C, Anania MC, Pagliardini S, Seregni E,
Pierotti MA, Pilotti S, Peeper DS, and Greco A.
Evidence of oncogene-induced senescence in
thyroid carcinogenesis. Endocr Relat Cancer. 2011;
18(6): 743-57.
79
immunotherapy of human tumors
Clinical development of new immune-related cancer
therapies: we continued to enroll melanoma and
prostate carcinoma patients, in collaboration with the
Melanoma Surgery, Prostate Program, and Medical Oncology, in phase II trials based on anti-CTLA4 Ab+
chemotherapy (NIBIT-M1), cancer vaccines with recombinant tumor antigens (PRAME and NY-Eso1) or peptides
(Prostavax), and BRAF/MEK inhibitors. Blood and tumor
biopsies were collected for subsequent immunomonitoring. Additionally, we monitored immunoregulatory
pathways (myeloid-derived suppressor cells –MDSC-,
Treg, cytokine/chemokine profiling) in blood, serum, saliva
and tumor biopsies of sarcoma as well as head and neck
cancer patients undergoing conventional or targeted therapies.
Studies on cancer-related immune regulatory
pathways: we focused on MDSC and Treg, finding a
mRNA/miRNA signature involving IL-6 / HIF1-α / TGF-β
related patterns in MDSC from melanoma patients. We
also assessed the impact of metabolic microenvironment
conditions, observing that low pH induces MDSC accumulation and T cell anergy, while pH regulating drugs
mediate recovery of tumor immunity. We further studied
tumor exosomes either as an immunosuppressive pathway or as a strategy for specific drug delivery.
Molecular studies on melanoma progression markers:
we analyzed gene expression and microRNA profiling in
sentinel lymph node biopsy (SNB), finding that positive
SNB from patients with regional node involvement and
poor prognosis at 5 years display distinct immune-related
transcriptional patterns. Mutated BRAF as a circulating
molecular marker for disease progression was analyzes in
melanoma lesions and in plasma of melanoma patients,
observing that 70% patients have circulating BRAFV600E
DNA.
Keywords: immunotherapy, myeloid-derived suppressor cells,
exosomes
HEAD OF UNIT
Licia Rivoltini, MD
RESEARCH STAFF
Chiara Castelli, Biol Sci D
Veronica B. Huber, MD
Monica Rodolfo, Biol Sci D
Maria Carmela Careri, MD
Gianluca Cutolo, MD
DATA MANAGER
Marco Asioli, Paola Frati
PHD STUDENTS
Chiara Camisaschi, Michela Perego, Marcella
Tazzari, Elisabetta Vergani
Annamaria De Filippo, Biol Sci D
Paola Filipazzi, Biol Sci D
Viviana Vallacchi, Biotec Sci D
TECHNICIANS
Valeria Beretta, Agata Cova, Paola Deho, Simona
Frigerio, Francesca Rini,
Paola Squarcina
RESEARCH NURSES
Felicetta Giardino, Gianluigi Rigamonti
RELEVANT NOTES
Collaborations
Active collaboration with members of the Italian
Network for Tumor Bio-Immunotherapy (NIBIT),
Italian Melanoma Intergroup (IMI), International
Melanoma Working Group (IMWG), International
Society for Biological and Cellular Therapy (ISBTC).
Collaborations with Istituto Superiore di Sanità (Dr.
S. Fais), University of Siena (Dr. M.Maio), University
of Milan (Dr. L. Guerrini), University of Genoa (Dr.
G. Bianchi Scarrà), Istituto Pascale (Dr. P. Ascierto),
University of Heidelberg (Dr. V. Umansky), National
Cancer Institute (Dr. F Marincola), University of
Charleston (Dr. M. Nishimura), University of Tokyo
(Dr. Y. Kawakami), Karolinska Institute (Dr. S.
Caramuta, A. De Milito), Faculte de Pharmacie of
Chatenay-Malabry (Dr. F. Triebel), Université
Catholique de Louvain (Dr. S. Lukas) and Ludwig
Cancer Institute Brussels (Dr. P. Coulie); Nodality
(Dr. Alessandra Cesano, San Francisco, USA.
Publications
Vergani E, Vallacchi V, Frigerio S, Deho P, Mondellini
P, Perego P, Cassinelli G, Lanzi C, Testi MA, Rivoltini
L, Bongarzone I, Rodolfo M. Identification of MET
and SRC activation in melanoma cell lines showing
primary resistance to PLX4032. Neoplasia. 2011;
13(12): 1132-42.
Butterfield LH, Palucka AK, Britten CM, Dhodapkar
MV, Håkansson L, Janetzki S, Kawakami Y, Kleen TO,
Lee PP, Maccalli C, Maecker HT, Maino VC, Maio M,
Malyguine A, Masucci G, Pawelec G, Potter DM,
Rivoltini L, Salazar LG, Schendel DJ, Slingluff CL Jr,
Song W, Stroncek DF, Tahara H, Thurin M, Trinchieri
G, van Der Burg SH, Whiteside TL, Wigginton JM,
Marincola F, Khleif S, Fox BA, Disis ML.
Recommendations from the iSBTc-SITC/FDA/NCI
Workshop on Immunotherapy Biomarkers. Clin
Cancer Res. 2011; 17(10): 3064-76.
Contributions
Patent on the Immunomodulating use of PPI
Masters on Melanoma (IMI), Masters on Tumor
Biotherapy (NIBIT)
Editorial Board of Journal of Immunotherapy
National guidelines on Immunomonitoring (NIBIT)
National Guidelines in Melanoma Treatment
(contribution)
ACC Melanoma Guidelines
INT-Educa Courses; FAD Courses on Tumor
Vaccines.
80
tumor genomics
The main field of interest of the Tumor Genomics Unit is
the biological and molecular characterization of lung cancer and the development of genetic signatures in tissues
and biological fluids useful for early detection of lung cancer and to establish novel therapeutic approaches. Our
past and current approaches for biomarker discovery in
lung cancer are mainly focused on the identification of
molecular changes in biological fluids collected by noninvasive procedures, such as sputum and plasma. In
particular, we have focused on miRNAs circulating in
plasma as biomarkers of invasive lung disease and
validated those able to identify aggressive lung cancer
before its clinical appearance in order to define molecular
predictors of high-risk disease. We investigated the
miRNA profiles of lung tumors, normal tissues, and
plasma samples from cases identified in two independent
spiral-CT screening trials with extensive follow-up where
multiple plasma samples, collected before radiological disease detection were available. We identified specific
miRNA signatures in plasma samples collected up to two
years before cancer detection by spiral-CT. We also
defined a signature that discriminates subjects according
to aggressiveness of their future tumors, and in particular
the occurrence of early metastatic but spiral-CT invisible
lung tumors or small spiral-CT detected lesions with
aggressive potential. Interestingly, the plasma signature
associated with tumor aggressiveness seemed related
with miRNA expression not only in tumor, but also in
normal lung tissue from patients (Boeri M. et al., Proc
Natl Acad Sci USA. 2011; Sozzi G. et al., Cell Cycle. 2011).
Very recently, we validated the performance of plasma
miRNA signatures in an extended series of 51 patients
and 100 individual controls belonging to the MILD
screening trial at the INT, proving the strength of our signatures in the prediction of lung cancer development and
in the classification of the disease aggressiveness.
Keywords: lung cancer, microRNA, cancer stem cells
HEAD
Gabriella Sozzi, PhD
RESEARCH STAFF
Luca Roz, Pharm Sci D
Francesca Andriani, Pharm Sci D
Patrizia Gasparini, Biol sci D
Carla Verri, Biol Sci D
Massimo Moro, PhD
Giulia Bertolini, Med Biotech D
PHD STUDENT
Mattia Boeri, Biotech D
TECHNICIANS
Davide Conte, Federica Facchinetti, Roberto
Caserini, Michela Grassi
RELEVANT NOTES
Publications
Collaborations
Boeri M, Verri C, Conte D, Roz L, Modena P,
Facchinetti F, Calabrò E, Croce CM, Pastorino U,
Sozzi G. MicroRNA signatures in tissues and
plasma predict development and prognosis of
computed tomography detected lung cancer. Proc
Natl Acad Sci USA. 2011; 108(9): 3713-8.
PET Unit, HSR, Milan (Dr. F. Fazio, Dr. R. Moresco);
CERMS, A.O.U. San Giovanni Battista, Turin (Prof. R.
Ferracini)
Dr. F. Pezzella, Oxford University, UK; Prof. C.M.
Croce, OSUMC, Columbus (USA)
Chemores consortium (FP6, European Community); Curelung consortium (FP7, European Community)
Sozzi G, Pastorino U, Croce CM. MicroRNAs and
lung cancer: from markers to targets. Cell Cycle.
2011; 10(13): 2045-6.
Contributions
CBS member (Comitato Borse Studio) AIRC-FIRC
Scientific Committee Societa’ Italiana di
Cancerologia (SIC)
Scientific Committee “Fondazione Edo Tempia”,
Biella, Italy
Scientific Advisory Board American-Italian Cancer
Foundation (AICF)
Selection Committee Pezcoller-AACR award 2011
Editorial Board: Lung Cancer Steering Committee
of the European project “Chemores”( VI sharedcost RTD action Patent: Italian and US provisional
“MICRO-RNA BIOMARKERS AND METHODS
OF USING SAME” (Inventors G. Sozzi, M. Boeri, U.
Pastorino)
81
molecular targeting
We aim to gain insight into the molecular pathways relevant for progression and response to therapy of breast
carcinomas, especially those with HER2 overexpression
and triple-negative (TN) features. During 2011, we completed two observational studies carried out, respectively,
in HER2-positive breast carcinoma patients treated with
trastuzumab-based therapy in a metastatic and an adjuvant setting. In the metastatic study, 272 patients under
trastuzumab treatment during 2000-2001 who
progressed after first-line trastuzumab treatment showed
clinically and statistically significant benefits from continued trastuzumab treatment in both RECIST responder
and non-responder patients. Analysis in the adjuvant setting, which included 1012 patients treated with
trastuzumab between 2005 and 2009 in 42 Italian hospitals, showed that trastuzumab is differentially-protective
depending on the site of metastasis; in fact, in addition to
the well-known CNS relapses, bone metastases were also
resistant to the antibody treatment in our retrospective
series. Excluding these two sites, protection by
trastuzumab was more than 70% in all other distant
metastases, suggesting that the overall 50% protection
rate observed in trials is not equally distributed among
different anatomical sites. Our analysis of TN breast carcinomas demonstrated that these tumor cells contribute
directly to the tumor vasculature through endothelial cell
differentiation and that the wound-healing process promotes tumor cell progression through specific activation
of PDGFR and VEGFR and their downstream pathways.
Accordingly, targeting of PDGFR and VEGFR significantly
impaired growth of TN breast carcinoma xenografts.
Keywords: breast carcinoma, targeted therapy, HER2
HEAD
Elda Tagliabue, Biol Sci D
RESEARCH STAFF
Manuela Campiglio, Biol Sci D
Rosaria Orlandi, Biol Sci D (membership of
DOSMM Functional Genomics Facility)
Serenella M. Pupa, Biol Sci D
FELLOWS
Valentina Ciravolo, Biotech Sci D
Gaia C. Ghedini, Biotech Sci D
Alessandra Meini, Biol Sci D
Ilaria Plantamura, Biol Sci D
Manuela Ratti, Biol Sci D
Francesca Ripamonti, Biotech Sci D
Tiziana Triulzi, Biotech Sci D (AIRC)
Marilena V. Iorio, Biotech Sci D
Francesca Bianchi, Biotech Sci D (AIRC)
PHD STUDENTS
Claudia Piovan, Biol Sci D
Marianna Sasso, Biol Sci D
TECHNICIANS
Pierangela Aiello, Patrizia Casalini
(responsible for DOSMM imaging facility),
Cristina A. Ghirelli
CONSULTANTS
Sylvie Ménard, Biol Sci D
Marco Sandri, Stat Sci D
RELEVANT NOTES
Collaborations
Augusto Amici, Genetic Immunization Lab., Dept of
Molecular, Cellular and Animal Biology, Univ. of
Camerino; Manuela Iezzi, Lab. di ImmunoOncologia, CeSi, Chieti Scalo; Claudio Tripodo,
Sezione di Anatomia Patologica, Policlinico
Universitario P. Giaccone, Palermo; Rossella
Canese, Dept. of Cell Biology and Neurosciences,
Istituto Superiore di Sanità, Rome; Egidio Iorio,
Dept. of Cell Biology and Neurosciences, Istituto
Superiore di Sanità, Rome; Jiong Wu, Cancer
Hospital, Fudan University, Shanghai
treatment: evidence from a retrospective study.
Breast Cancer ResTreat. 2011; 128: 147-54.
Publications
Tagliabue E, Campiglio M, Pupa SM, Balsari A,
Ménard S. The HER2 world: better treatment
selection for better outcome. J Natl Cancer Inst
Monogr. 2011; 2011: 82-5.
Campiglio M, Bufalino R, Sandri M, Ferri E, Aiello
RA, De Matteis A, Mottolese M, De Placido S,
Querzoli P, Jirillo A, Bottini A, Fantini M, Bonetti A,
Pedani F, Mauri M, Molino A, Ferro A, Pupa SM,
Sasso M, Ménard S, Balsari A, Tagliabue E, on behalf
of the Demetra Group. Increased overall survival
independent of RECIST response in metastatic
breast cancer patients continuing trastuzumab
Contributions
Elda Tagliabue is on the Editorial Boards of The
Breast and the Chinese Journal of Clinicians
82
molecular pharmacology
Novel therapeutic targets. The confirmation that not
only telomeric G-quadruplexes (G4) but also G4 present
in gene promoters represent valuable therapeutic targets
was obtained exposing telomerase-negative and -positive
tumor cells to hybrid G4 ligand-alkylating agents. Cytotoxic activity was mainly ascribable to the induction of
telomeric dysfunction (TRF2 and POT1 displacement) in
telomerase-negative cells, and to the inhibition of telomerase activity, caused by interference with G4 structures
present in the promoters of c-myc and hTERT genes in
telomerase-positive cells.
Mechanisms of drug resistance. The characterization of
cellular changes associated with resistance to
topoisomerase I inhibitors indicated that tyrosyl-DNA
phosphodiesterase 1, whose expression is increased in
resistant variants, can account per se for mild levels of
resistance to the new camptothecin gimatecan. However,
the enzyme strongly cooperates with BRCA1 and
XRCC1 to repair drug-mediated DNA damage.
New drug combinations. In a human model of RET-driHEAD
Nadia Zaffaroni, Biol Sci D, PhD
RESEARCH STAFF
Marco Folini, Biol Sci D, PhD
Cinzia Lanzi, Biol Sci D
Paola M.C. Perego, Biol Sci D, PhD
Rosanna Supino, Biol Sci D
Giovanni L. Beretta, Biol Sci D, PhD
Giuliana Cassinelli, Pharm D, PhD
Michelandrea De Cesare, Vet D
Paolo Gandellini, Biotech Sci D, PhD
Laura Gatti, Biol Sci D, PhD
Chiara Giommarelli, Pharm D, PhD
Marzia Pennati, Biol Sci D, PhD
FELLOWS
Erika Borghini, Biol Sci D
Anna Casamichele, Biol Sci D
Denis Cominetti, Biol Sci D
Valentina Profumo, Biotech Sci D
Valentina M. Zuco, Biol Sci D
PHD STUDENTS
Giacomo Cossa, Biotech Sci D
Alessia Lopergolo, Biotech Sci D
TECHNICIANS
Nives Carenini, Elisa Campi, Elisabetta
Corna, Laura Dal Bo, Enrica M. Favini, Maria
Stella Tinelli, Monica Tortoreto
CONSULTANT
Franco Zunino, Biol Sci D
ven medullary thyroid carcinoma, the combination of cisplatin and sunitinib resulted in in vitro synergistic
interaction and increased in vivo antitumor activity due to
the enhancement of both intrinsic and extrinsic apoptotic
pathway activation mediated by Ret targeting.
Preclinical development of new anticancer agents. The
new camptothecin namitecan showed a promising therapeutic profile in a panel of pediatric sarcoma models,
including bone and soft-tissue tumors. Favorable drug
pharmacokinetics and ability to inhibit angiogenesis
appear as major determinants of antitumor activity.
miRNA-based therapeutic approaches. We
demonstrated that, in the context of a network involving
p63, miR-205 is able to control the deposition of laminin332 in normal prostate cells, and that therapeutic
replacement of this miRNA in prostate cancer cells can
restore basement membrane deposition and 3D organization into normal-like acini.
Keywords: therapeutic targets, drug resistance, preclinical drug
development
RELEVANT NOTES
Collaborations
Prof. P. Chiarugi, University of Florence; Dr. L.
Fugazzola, Fondazione Policlinico IRCCS, Milan;
Prof. M. Magnani, University of Urbino; Prof. M.
Palumbo, University of Padua; Prof. E. Scanziani,
University of Milan. Prof. D.A. Altieri, The Wistar
Institute Cancer Centre, Philidelphia (PA); Prof. F.
Caruso, University of Melbourne (Australia); Prof.
S.B. Howell, University of San Diego (CA); Prof.
N.W. Keith, University of Glasgow (UK); Dr. S.
Linder, Karolinska Institute, Stockholm, (Sweden);
Prof. R.R. Reddel, Children’s Medical Research
Institute, Sydney (Australia); Dr I. Vlodavsky, The
Bruce Rappaport Faculty of Medicine, Haifa
(Israel).
Favini E, Zaffaroni N, Zunino F, Lanzi C. Interplay
between Ret and Fap-1 regulates CD95-mediated
apoptosis in medullary thyroid cancer cells.
Biochem Pharmacol. 2011; 82: 778-88.
Becker AL, Orlotti NI, Folini M, Cavalieri F, Zelikin
AN, Johnston AP, Zaffaroni N, Caruso F. Redoxactive polymer microcapsules for the delivery of a
survivin-specific siRNA in prostate cancer cells.
ACS Nano. 2011; 5: 1335-44.
Contributions
Editorial board: Critical Reviews in
Oncology/Hematology, European Journal of
Cancer, BMC Cancer, Journal of Chemotherapy,
Apoptosis, Critical Reviews in Oncogenesis (Nadia
Zaffaroni)
Publications
International Journal of Oncology, ISRN
Biochemistry (Paola Perego)
Nicolini V, Cassinelli G, Cuccuru G, Bongarzone I,
Petrangolini G, Tortoreto M, Mondellini P, Casalini P,
Anti-Cancer Agents in Medicinal Chemistry, ISRN
Oncology (Marco Folini)
85
PATHOLOGY AND LABORATORY
MEDICINE DEPARTMENT
Giuseppe Pelosi
Professor of Pathology
University of Milan
+39 02 2390 3017
[email protected]
UNITS
ANATOMIC PATHOLOGY 1
Maria Luisa Carcangiu
ANATOMIC PATHOLOGY 2 AND 3
Giuseppe Pelosi
EXPERIMENTAL MOLECULAR
PATHOLOGY LABORATORY
(part of Anatomic Pathology 3)
Silvana Pilotti
SIMT - IMMUNOHEMATOLOGY AND
TRANSFUSION MEDICINE
Fernando Ravagnani
LABORATORY MEDICINE
Daniele Morelli
The mission of the Department is to provide accurate diagnoses and information of prognostic and therapeutic value to clinicians. The activities of Surgical
Pathology, Diagnostic Molecular Pathology, Cytopathology, and Autopsy Pathology are carried out in the three Anatomic Pathology Units, while biological
tests/microbiological investigations and blood collection, screening, processing,
storage, and distribution are carried out at the Laboratory Medicine Unit and
SIMT-Hematological Transfusion Service, respectively. The activities are
performed using conventional and state-of-the-art techniques, and all laboratories are quality certified (ISO9001; 2000, confirmed in 2008 until 2015). The
Pathology Department is also involved in two Institutional activities:
• Human frozen tumor tissue bank (see Shared Research Resources page
145). The frozen tumor tissue bank of INT is a systematic collection that looks
much like a project-driven collection, but is not restricted to a specific organ
or disease type.
• Telepathology. In order to acquire uniform high quality in pathologic diagnostics and to rapidly spread knowledge related to cancer research, a Virtual
Pathology group is being developed in Italy. It is composed of pathologists
working in the seven Italian Cancer Institutes within the national ACC project.
The programs of the ACC Virtual Pathology Institution include consensus sessions, quality control, educational activities, second opinion, and research.
86
anatomic pathology units 1, 2 and 3
In 2011, the clinical activity of Anatomic Pathology Units
1, 2 & 3 included 31,331 histologic and 21,300 cytologic
pathologic reports, all carried out according to internationally shared classification schemes. The spectrum of the
diverse tumor types has comprised skin tumors (including
melanomas), lymphoproliferative disorders, male
genitourinary tract tumors, non-neuroendocrine gastrointestinal tumors, thoracic and mediastinal lesions,
endocrine tumors (including thyroid, adrenal glands, gastroenteropancreatic tract and lung), soft tissue tumors,
head and neck tumors, pediatric malignancies, gynecologic
and breast tumors, and malignancies from unknown primary sites.
Most pathological reports were supplied with extensive
pheno-genotyping for diagnosis, indicating predictive
and/or prognostic factors and personalization of the best
care according to criteria of therapeutic pathology. About
50,000 immunohistochemical reactions, over 5000 special
stains, and 4145 genetic reports were carried out in 2011
for characterization of malignancies, with particular reference to lymphoproliferative disorders and pediatric,
thoracic, soft tissue, neuroendocrine, head and neck,
breast and gynecologic tumors, including the immunohistochemical evaluation of estrogen and progesterone
receptors and Her-2/neu in breast cancer, the assessment
of the status of several genes for tailored therapy (for
example, Her-2/neu, EGFR, CD117, PDGFRA/B, VEGFR,
ALK or TP53) or characterization of malignancies from
unknown primary sites.
Keywords: diagnosis, prognosis, prediction
DIAGNOSTIC ACTIVITY OF ANATOMIC PATHOLOGY UNITS 1,2 & 3 IN 2011
Type of Report
Number
HISTOLOGICAL (TOTAL 31,331)
Surgical pathology specimens
Biopsy samples
Frozen section examinations
Sentinel lymph nodes
Consultation for second opinion
10,062
8362
2830
700
2980
CYTOLOGICAL (TOTAL 21,300)
Fine needle aspiration biopsy or extravaginal cytology samples
Conventional PAP tests
PAP tests from screening programs
HEAD
Maria Luisa Carcangiu, MD: Anatomic
Pathology Unit 1
Giuseppe Pelosi, MD: Anatomic Pathology
Unit 2 & 3
Silvana Pilotti, MD: Experimental Molecular
Pathology Laboratory (part of Anatomic
Pathology 3)
Marta Barisella, MD; Antonello Domenico
Cabras, MD; Paola Collini, MD; Maurizio
Colecchia, MD; Alessandra Fabbri, MD; Flavia
Melotti, MD; Massimo Milione, MD; Biagio
Paolini, MD; Alessandro Pellegrinelli, MD;
Pasquale Quattrone, MD; Gabrina Tragni,
MD; Barbara Valeri, MD; Antonella Aiello, Biol
Sci D; Annunziata Gloghini, Biol Sci D;
Federica Perrone, Biol Sci D; Carla Riva, Biol
Sci D (Coordinator of Cytopathology);
Mario Ruggeri, Biol Sci D; Elena Tamborini,
Biol Sci D; Adele Testi, Biol Sci D.
FELLOWS
Nicoletta Di Mari, MD (until July 2011);
Valentina Galimberti, Biol Sci D (until
November 2011); Ambra Gualemi, Biol Sci D;
Mr. Emanuele Procacci
Elena De Paoli, Biol Sci D
RESIDENTS
Chiara Volpi, Biol Sci D
STAFF TECHNICIANS
Claudia Alphandery (cytotechnologist); Maria
Grazia Bonora; Renata Borchini; Rita
Antonella Carminati; Alessandra Chinosi;
Marilena Colantuono; Silvia Colombo
(cytotechnologist); Daniela De Bari;
Francesca Dominoni (chief technician and
department coordinator); Alessandra Elli;
Maria Grazia Facciorusso; Elena Fomiatti;
Angelo Gaito; Daniela Galbiati; Morena
Gobbo; Rosangela Intorre; Teresa Labella;
Matteo Marcuzzo; Alessia Mietta; Marzia
Mietta; Loretta Missiato; Maria Luisa
Moiraghi; Margherita Mondini; Paola Murè;
Marta Orsenigo; Desirè Parimbelli; Katia
Ponzoni (cytotechnologist); Silvia Redaelli;
Gianni Roncato (photographer) Carla Scalia;
Manuela Scuro; Consiglia Sgura.
Patrizia Cangioli; Margherita Cariglia; Maria
Teresa Codecasa; Maria Cristina Di
Bartolomeo; Roberto Ferrari; Mariangela
2980
9404
8595
Girotti (fellow); Maria Morelli; Alda Tosi;
Enrica Colzani (volunteer)
HEALTHCARE ASSISTANTS
Paolo Castioni; Cosima Ciccarese; Massimo
Festa; Paola Tonielli; Anna Urbano.
RESEARCH STAFF (EXPERIMENTAL
MOLECULAR PATHOLOGY LABORATORY)
Fabio Bozzi, Biol Sci D; Tiziana Negri, Biol Sci
D; Gian Paolo Dagrada, Biol Sci D (since
December 2011)
FELLOWS (EXPERIMENTAL MOLECULAR
PATHOLOGY LABORATORY)
Claudia Bertan, Biol Sci D; Silvia Brich, Biol
Sci D; Elisa Ciulla: Biol Sci student; Elena
Conca, Biol Sci D; Barbara Cortelazzi, Biol
Sci D; Andrea Lampis, Biol Sci D; Valentina
Mauro, Biol Sci D; Eva Tarantino, Biol Sci D
87
There is also a Laboratory of Molecular Pathology, both
diagnostic and experimental, for extensive molecular testing, which is equipped with most up-to-date instruments
and hosted under Anatomic Pathology Unit 3. Most
pathologic reports have been supplied with extensive
pheno-genotyping for diagnosis, determining predictive
and/or prognostic factors, and personalization of the best
patient care according to the criteria of therapeutic
pathology. Most diagnoses were rendered in 2011 within
7 days from patient admission. Major efforts have been
made in the Laboratory of Experimental Pathology to set
up methodologies able to extend the study of the network of receptor tyrosine kinase signalling to extracellular
matrix components on surgical specimens, and to address
the role of autophagy/quiescence/senescence in the
development of drug resistance using established primary
cell cultures after validation on available stable cell lines.
Keywords: therapeutic pathology, immunohistochemistry, molecular
assay
DIAGNOSTIC ACTIVITY OF THE MOLECULAR PATHOLOGY LABORATORY IN 2011
Type of Analysis
Number
Mutational analysis (BRAF, EGFR, K-RAS, KIT, PDGFRA/B, TP53,
Beta-catenin, microsatellite, HER2, NRAS, PI3K, RET)
1156
FISH + CISH
1792
Clonality tests
111
Cytogenetic assessments
271
ISH (EBER + HPV)
168
Total
3498
RELEVANT NOTES
Collaborations
Antonella Aiello, Biol Sci D, Department of
Experimental Oncology, Fondazione IRCCS Istituto
Nazionale dei Tumori: Identification of new
prognostic markers and therapeutic strategies in
medullary thyroid cancer. Project funded by
Fondazione G. Berlucchi per la Ricerca sul Cancro
(2011-2013)
Marta Barisella, MD ISG (Italian Sarcoma Group)
Paola Collini, MD Participation in the Pathology
panel of the Italian Association of Pediatric
Ematology and Oncology (AIEOP), of the Societé
Italienne de Oncologie Pédiatrique and Italian
Sarcoma Group (ISG)
Maurizio Colecchia, MD Italy-USA Oncoproteomic
Project (in collaboration with Istituto Superiore di
Sanità) for tissues to be saved over time at room
temperature (kidney and breast tumors); Project
SIURO PRIAS (inside the Programma Prostata):
check of histologic requirements of low risk
prostatic tumors to include patients in a survey
protocol; Italian Society of Urology (SIU) Hospital
Urologist Association (AURO)
Alessandro Pellegrinelli, MD Hepato-Oncology: A
multidisciplinary approach for an emerging
specialty. The Pathologist’s role; “Ricerca
Traslazionale su Marcatori Molecolari in Pazienti
Operati di Carcinoma Gastrico ed inclusi nel
Protocollo Clinico di Terapia Adiuvante (I.T.A.C.A.S)”. Project supported by AIRC. (Dr. Pellegrinelli,
Dr. Di Bartolomeo)
Giuseppe Pelosi, MD Italian Group of
Pleuropulmonary Pathology (GIPP) Pathologist
Panel member of the International Academy for
the Study of Lung Cancer (IASLC) International
Association of Cytology (IAC) Member (MIAC),
USA Pulmonary Pathology Society (PPS) Member,
USA
Silvana Pilotti, MD Sabrina Pricl, Molecular
Simulation Engineering Laboratory, DI3, University
of Trieste. Maurizio D’Incalci, Oncology
Department, Istituto di Ricerche Farmacologiche
Mario Negri, Milano.
Annunziata Gloghini, Biol Sci D Proteomic analysis
of PEL (Giuliano Elia - Conway Institute for
Biomolecular and Biomedical Research, Conway
Institute for Biomolecular and Biomedical Research,
University College Dublin); Genomic
characterization of NHL in immunosuppressed
patients (F. Bertoni - Oncology Institute of
Southern Switzerland (IOSI); functional studies on
lymphomas (A. Carbone, A. Aldinucci, De Re V –
CRO Aviano); Molecular characterization of HIVassociated lymphomas (G. Gaidano, D. Capello Università del Piemonte Orientale Amedeo
Avogadro); Biomarkers for targeted therapies in
lymphomas (A. Younes – MD Anderson Cancer
Center, Houston, USA)
Elena Tamborini, Biol Sci D Prof. G. Kroemer and
Prof. Zitvogel, INSERM Paris (regarding the
expression of SNPS in GIST)
Publications
Zappasodi R, Bongarzone I, Ghedini GC, Castagnoli
L, Cabras AD, Messina A, Tortoreto M, Tripodo C,
Magni M, Carlo-Stella C, Gianni AM, Pupa SM, Di
Nicola M. Serological identification of HSP105 as a
novel non-Hodgkin lymphoma therapeutic target.
Blood. 2011; 118: 4421-30.
Seregni E. Functional characterization of the MTCassociated germline RET-K666E mutation: evidence
of oncogenic potential enhanced by the G691S
polymorphism. Endocr Relat Cancer. 2011; 18(4):
519-27.
Pierotti MA, Tamborini E, Negri T, Pricl S, Pilotti S.
Targeted therapy in GIST: in silico modeling for
prediction of resistance. Nat Rev Clin Oncol. 2011;
8(3): 161-70.
Alberti C, Pinciroli P, Valeri B, Ferri R, Ditto A,
Umezawa K, Sensi M, Canevari S, Tomassetti A.
Ligand-dependent EGFR activation induces the coexpression of IL-6 and PAI-1 via the NFkB pathway
in advanced-stage epithelial ovarian cancer.
Oncogene 2011; Dec 12. doi:
10.1038/onc.2011.572.
Granata R, Miceli R, Orlandi E, Perrone F, Cortelazzi
B, Franceschini M, Locati L, Bossi P, Begamini C,
Mirabile A, Mariani L, Scaramellini G, Potepan P,
Quattrone P, Licitra L. Tumor stage, human
papillomavirus and smoking status affect the
survival of patients with oropharyngeal cancer: an
italian validation study. Ann Oncol (2011).
Dileo P, Pricl S, Tamborini E, Negri T, Stacchiotti S,
Gronchi A, Posocco P, Laurini E, Coco P, Fumagalli E,
Casali PG, Pilotti S. Imatinib response in two GIST
patients carrying two hitherto functionally
uncharacterized PDGFRA mutations: an imaging,
biochemical and molecular modeling study. Int J
Cancer. 2011; 128(4):983-90.
Contributions
Massimo Milione, MD: Linee guida GIPAD:
Microscopic esophagitis and Barrett’s esophagus:
the histology report
Maria Luisa Carcangiu, MD: Editorial Board,
International Journal of Gynecological Pathology
Maurizio Colecchia, MD: Editorial Board,
Pathologica
Giuseppe Pelosi, MD: Associate Editor, International
Journal of Surgical Pathology Editorial Board,
Virchows Archiv Editorial Board, Pathologica
88
SIMT, immunohematology and transfusion medicine
The Unit is responsible for laboratory diagnosis as well as
for donation, testing, processing, preservation, storage,
distribution, and transfusion safety of blood components.
Clinical work and laboratory testing are always in implementation according to European and American
technologies and standards. Other activities are: immunohematology, virology diagnosis (serological and
molecular), HLA typing of patients and donors
(related/unrelated), hematologic diagnosis, and therapeutic apheresis. The latter activity is particularly focused on
peripheral blood stem cell (PBSC) harvesting for autologous and allogeneic stem cell transplantation and
therapeutic procedures such as extracorporeal photopheresis (ECP). In 2011, the apheresis team concluded
the feasibility study for autologous PBSC collection with
Spectra Optia-MNC Protocol generation II and is now
validating the use of this apheresis device for routine use.
The Radio Frequency Identification project (RFID) for a
total traceability and enhanced safety of the transfusion
HEAD
Fernando Ravagnani, MD
Flavio Arienti, MD
Annalisa Birolini, MD
Paola Coluccia, MD
Paola D. Faccini, MD
Laura R. Terranova, MD
Claudia Lombardo, Biol Sci D
Arabella Mazzocchi, Biol Sci D
FELLOW
Francesca Taverna, Biol Sci D
Orietta C. Polisena, Elide Spinelli, Maria C.
Zanetti, Giovanni Veronese
TECHNICIANS
Mario Avella, Cinzia L. Biasuz, Alvaro
Bompadre, Laura M. Bonizzoni, Antonella
Falanga, Daniela Ferrari, Marina Galbiati,
Annamaria Gorla, Silvia Larghi, Roberto
Losa, Antonia Morleo, Ernestina Pigliafreddo,
Lara Pusterla, Roberta Serpi, Lorena Sfreddo,
Barbara Strada, Tiziano P. Tattanelli, Ornella
Zanaboni
NURSES
Donata Bertolesi, Roberta Colombo, Marisa
Dentella, Filomena Fedele, Rita Fiorito,
Cristina I. Lasala, Monica Pedretti, Carmela
Santolla
Antonella Atzeni, Carmela Gizzi, Maria A.
Somma, Maria Tamburriello
process through electronic matches (item identification,
data transfer, and possibility to implement workflow management rules) obliging healthcare workers to follow the
implemented procedures has been applied in most clinical contexts of the INT, improving the efficiency and
safety of the transfusion process. In collaboration with
Medical Oncology Units, we are evaluating the serum levels of CC thymus and activation-related chemokine
(TARC) in Hodgkin’s lymphoma patients to prospectively
investigate the prognostic role of this chemokine in disease outcome. The production of platelet gel and its
clinical application was increased, and 9 patients treated
with good results. Specimens of lung cancer and nontumor lung tissue were examined for the presence of
HPV DNA. We also improved the PCA3 score analysis, a
new sensitive and specific molecular marker for prostate
cancer. The test was performed on 125 urine samples.
Keywords: transfusion medicine, HLA, virology
RELEVANT NOTES
Collaborations
European Institute of Oncology;
L. Sacco Hospital, Fondazione IRCCS Istituto
Neurologico Besta
Publications
Peterlongo P, Caleca L, Cattaneo E, Ravagnani F,
Bianchi T, Galastri L, Bernard L, Ficarazzi F, Dall’olio
V, Marme F, Langheinz A, Sohn C, Burwinkel B,
Giles GG, Baglietto L, Severi G, Odefrey FA,
Southey MC, Osorio A, Fernández F, Alonso MR,
Benítez J, Barile M, Peissel B, Manoukian S, Radice P.
The rs12975333 variant in the miR-125a and
breast cancer risk in Germany, Italy, Australia and
Spain. J Med Genet. 2011; 48(10): 703-4.
89
laboratory medicine
Laboratory Medicine performs biological tests and microbiological investigations that contribute to the diagnosis,
prognosis, and monitoring of oncologic patients submitted to conventional and experimental therapies. In 2011,
about 1,750,000 examinations were performed, an
increase of almost 3% over the previous year. The reliability of the results is guaranteed by maintaining high quality
standards, which are constantly monitored by national
and international External Quality Assessment (EQA).
Much attention has been paid to the choice of appropriate technologies and to the continuous improvement of
technical and scientific knowledge of the medical and sci-
HEAD
Daniele Morelli, Biol Sci D
Mariachiara Bonini, Biol Sci D
Eutilia Conte, Biol Sci D
Antonio Mastroianni, Biol Sci D
Roberta Rossi, Biol Sci D
Loredana Simoni, MD
Giovanna Viola, Biol Sci D
TECHNICIANS
Giuseppina Ballabio, Rosella Bonfanti, Chiara
Brusati, Maria Rosa Carati, Maria Rosa
Cattaneo, Maria V. Corengia, Teresa Fontana,
Carlo Maggi, Roberta Marchetti, Valerio
Motta, Giuseppa Perrucci, Pia S. M. Picco,
Marco Ranzani, Nicola Salvatore, Federica
Sozzani
Santa Zingone
entific staff. Moreover, the Unit tests new technologies
and analytical methodologies and transfers scientific
know-how relative to the clinical laboratory to professionals and students.
The Unit is also involved in evaluation of the diagnostic
potential of new tests and technologies and in the search
for innovative organizational solutions. The Unit is
engaged in support activity for several clinical trials conducted at the INT and is involved in the project
“Personalized Treatment of Sarcomas”.
Keywords: clinical chemistry, hematology, microbiology
91
SURGERY DEPARTMENT
Ugo Pastorino
+39 02 2390 2906
[email protected]
UNITS
GASTROINTESTINAL, HEPATO
PANCREATOBILIARY SURGERY, AND
LIVER TRANSPLANTATION
Vincenzo Mazzaferro
COLORECTAL SURGERY
Ermanno Leo
BREAST SURGERY
Roberto Agresti
MELANOMA AND SARCOMA
Mario Santinami
DIAGNOSTIC ENDOSCOPY AND
ENDOSCOPIC SURGERY
Emanuele Meroni
OTOLARYNGOLOGY SURGERY
Gabriele Scaramellini
GYNECOLOGIC ONCOLOGY
Francesco Raspagliesi
THORACIC SURGERY
Ugo Pastorino
PLASTIC AND RECONSTRUCTIVE
SURGERY
Maurizio B. Nava
UROLOGIC SURGERY
Roberto Salvioni
PEDIATRIC SURGERY
Luigi Piva
LASER THERAPY
Anna Colombetti
DAY SURGERY
Aldo Bono
The Department of Surgery is composed of 10 surgical divisions and three
departmental units, organized for homogeneity of performance, with 240 inpatient beds and 14 outpatient beds. The Department treats oncological
diseases that affect all areas of the body except for the brain, providing elective and emergency surgical activity, in ordinary inpatient and day hospital
regimens, and specialistic oupatient activity for diagnosis and follow-up. Routine clinical activity ensures a high standard of care for all surgically-treated
patients, providing conservative surgery (organ/function preserving or minimally invasive) for early stage disease and combined treatment modalities for
advanced disease.
Surgery Department
92
gastrointestinal, hepatopancreatobiliary surgery, and liver transplantation
Activity is focused on improvement of the standard of
care and clinical research of primary and secondary
tumors affecting the liver, biliary system, pancreas, and
gastrointestinal tract. In the particular setting of hepatooncology, our unit can offer a complete panel of the most
up-to-date therapeutic options for liver cancer that
includes liver transplantation, minimally-invasive and computer-assisted surgery, transarterial chemoembolization
and radioembolization, percutaneous and laparoscopic
tumor ablation, and use of molecular targeted therapies.
A multidisciplinary approach is applied on a routine basis
thanks to the presence of gastroenterologists in the unit
and the close collaboration with the other specialties
(radiology, oncology, nuclear medicine and other surgical
units). The Liver Transplant Program is mainly focused on
oncological indications and plays a leading role worldwide
in defining the best indications for liver transplantation for
cancer. More than 60% of patients are offered therapies
within prospective clinical trials. Patient care and support
are at the highest standard with 800 admissions and 400
major surgical procedures/year, among which treatment
of colorectal liver metastases and hepatocarcinoma represent the leading group.
A permanent laboratory staff at the INT direct expression of the hepatobiliary clinical Unit will complete the
program of the Consortium on Translational Research on
HEAD
Vincenzo Mazzaferro, MD
Carlo Battiston MD, staff surgeon; Sherrie Bhoori MD, hepatogastoenterologist; Jorgelina C. Coppa MD, staff surgeon;
Christian Cotsoglou MD, staff surgeon; Alessandro Germini
MD, staff surgeon; Vincenzo Mazzaferro MD, Head of Unit;
Andrea Pulvirenti MD, staff surgeon; Enrico Regalia MD, staff
surgeon; Raffaele Romito MD, staff surgeon; Marcello Schiavo
MD, staff surgeon; Carlo Ferruccio Sposito MD, consultant
surgeon
RESEARCH STAFF
Maria Flores Reyes, MD
Sottotetti Elisa, MD
Raffaella Reati, MD
RESIDENTS
Marco Angelo Bogini, MD
Davide Citterio, MD
Cecilia Muscarà, MD
Marco Nencioni, MD
Matteo Origi, MD
Elisa Giavari and Francesco Roncacci, Unit Secretariat; Daniela
Guarneri and Nela Zito, Scientific Secretariat;
Simona G. Marchesi (Data manager)
NURSES
Paola Serafin (head nurse), Adriana Blanco, Salvatore Bonafede,
Annateresa Bugada, Milda Di Giacomo, Angela Mihaela Farcas,
Stefania Fici, Francesca Maiorano, Giuseppe Marena, Antonella
Masiello, Monica Mitarotonda, Nadia Nicoletti, Patrizia Perotto
Ghi, Patrizia Rota, Rossina Sitta, Stefania Sperandio, Cristina
Stracquadaini, Patrizia Valentini, Luigi Zarrella
Nicoletta Damiani, Rosa De Felice, Mariangela Lopriore,
Annamaria Pancari, Angela Restaini, Enza Spina, Anna Vecchio
Liver Tumors already active in the two sister labs at
Barcelona and New York. As a part of the Institutional
research at the INT, the liver tumor translational lab will
have access to all technological platforms and technical
devices described in the Shared Research Resorces.
In addition, clinical technologies are routinely used in the
management of patients. The pre-operative assessment
uses the Myrian software that allows 3D reconstruction
of the vascular anatomy of the patient and calculation of
the volume of the remnant liver after intervention. We
use the LIMON system to perform the indocyanine green
retention test to calculate liver function. Laparoscopic
procedures are performed in a dedicated operative room
in which all devices are integrated and can be controlled
by the surgeon through a touch screen. All technologies
are at the highest level: ultrasonic and radio-frequency
dissectors, bipolar vessel sealers, radiofrequency and
microwave needles for tumor ablation, high definition
video cameras, and monitors. We perform ultrasoundguided surgery and ablation with the newest ultrasound
machines with or without contrast enhancement, using
intraoperative and laparoscopic probes. The unit is a pioneer in computer-assisted liver surgery. This is performed
using an ultrasound navigation system that allows localization of tumors deep in the liver that would not otherwise
be visible through conventional ultrasound.
RELEVANT NOTES
Collaborations
Barcelona Clinic Liver Cancer Group,
Barcelona, Spain; Liver Unit of the Mt. Sinai
School of Medicine , New York USA;
Harvard Broad and Dana-Farber Institute,
Boston, USA; ENETS Program; University
of Geneva, Switzerland; University of
Milan, Gastroenterology and Surgery;
Nord-Italia Transplant (NITp), Milan
Publications
Villanueva A, Hoshida Y, Battiston C, Tovar
V, Sia D, Alsinet C, Cornella H, Liberzon A,
Kobayashi M, Kumada H, Thung SN, Bruix J,
Newell P, April C, Fan JB, Roayaie S,
Mazzaferro V, Schwartz ME, Llovet JM.
Combining clinical, pathology, and gene
expression data to predict recurrence of
hepatocellular carcinoma.
Gastroenterology. 2011; 140(5):
1501-12.
Toffanin S, Hoshida Y, Lachenmayer A,
Villanueva A, Cabellos L, Minguez B, Savic
R, Ward SC, Thung S, Chiang DY, Alsinet C,
Tovar V, Roayaie S, Schwartz M, Bruix J,
Waxman S, Friedman S, Golub T,
Mazzaferro V, Llovet JM. MicroRNA-based
classification of hepatocellular carcinoma
and oncogenic role of miR-517a.
Gastroenterology. 2011; 140(5):
1618-28.
Mazzaferro V, Majno P. Principles for the
best multidisciplinary meetings. Lancet
Oncology. 2011; 12(4): 323-5.
Contributions
II Level Master on Organ Transplantation
Medicine, University of Milan-Bicocca
Dr. Mazzaferro: Professor of Surgery
(contract) and Director of Training Center
for the University of Milan (post-graduate
residency program) and the Italian
Association of Hospital Surgeons (Scuola
Nazionale di Chirurgia Epatica
dell’Associazione Chirurghi Ospedalieri
Italiani)
Dr. Mazzaferro: Scientific Director of
Radioembolization Courses, Milan, Italy
Dr. Mazzaferro: Associate Editor of Journal
of Hepatology and member of the
Editorial Board of Hepatology, Lancet
Oncology, and Liver Transplantation
Dr. Mazzaferro: Expert for EASL
(European Association for the Study of the
Liver): EASL-EORTC Clinical Guidelines of
Hepatocellular Carcinoma
Dr. Mazzaferro: Head GEP-NET Center of
excellence
93
colorectal surgery
The Unit is specialized in surgery of cancers of the colon
and rectum, and maintains an elevated surgical standard
and quality similar to other major European reference
centers. In particular, over the years, the Unit has acquired
an extremely high expertise in the treatment of tumors
of the distal rectum, and has developed conservative
HEAD
Ermanno Leo, MD
Luigi Battaglia, MD
Filiberto Belli, MD
Giuliano Bonfanti, MD
Alessandro Cesa Bianchi, MD
Francesco Gallino, MD
Marco Vitellaro, MD
RESIDENTS
Michele Droz Dit Busset
Marcello Guaglio
Gaia Pietropaolo
Vincenzo Pruiti
Roberta Aceto
NURSES
Katia Masala (head of nurses), Rosalia Aloe,
Maria Paola Augello, Placida Battaglia, Fabiana
Bettoni, Lucia Caracciolo, Rut Cittadin,
Angela Colamonaco, Alonso Manuel,
Magdalena Marica Melis, Antonio Micello,
Vanessa Neri, Maria Palma, Riccardo Vacca,
Mirtha Ybazeta Ramos
Isabella Damasi, Nunzia Di Perna, Fabio
Lizzano, Maria Petrosina
techniques that avoid extensive resection and definitive
colostomy. Another area of expertise is in treatment of
local recurrences of rectal cancer: in selected patients,
highly-specialized intervention can allow achievement of
radical excision even in previously recurrent tumors.
Keywords: colon, rectum, cancer, surgery, colorectal cancer
RELEVANT NOTES
Publications
Battaglia L, Vannelli A, Belli F, Rampa M, Milione M,
Gasparini P, Leo E. Giant condyloma acuminatum of
the anorectum: successful radical surgery with anal
reconstruction. Tumori. 2011; 97(6): 805-7.
Contributions
Regional referent for guidelines for treatment of
rectal cancer.
Surgery Department
94
breast surgery
The clinical activity of the Unit includes all aspects of
breast cancer treatment: diagnosis, primary and adjuvant
therapy, and follow up. Treatment is performed by multidisciplinary teams involving several other Units and
Departments. The results from a randomized clinical trial
comparing axillary dissection with observation in patients
aged >65 years with T1N0 breast cancer has been
accepted in Annals of Surgery. Moreover, we have investigated in a consecutive series of elderly breast cancer
patients without palpable axillary nodes whether biological markers may predict axillary relapse and breast cancer
mortality. The paper is under review. Another randomized
clinical trial aiming at the development of integrated therapeutic strategies to reduce surgical morbidity in the
treatment of T1N0 breast cancer is ready for publication.
In a joint study with the MRI Unit, we have evaluated the
ability of MRI to show the extent and location of the
tumor in a breast surgical specimen by ex vivo MRI. The
paper is under review. A pilot study is in progress comparing FDG-PET with sentinel lymph node biopsy for
staging of regional lymph nodes, followed a previous
experience in the use of PET in preoperative evaluation
of axillary lymph nodes. Enhanced understanding of the
pathogenesis of breast cancer coupled with growing interest in improved esthetic results led to investigation of
skin-sparing and nipple-sparing mastectomy as a potential
modification to conventional mastectomy. In the last three
years, we performed over 400 NAC sparing mastectomies.
In cooperation with the Medical Genetics Unit, an
approach tailored for women at high genetic risk has
been developed. During genetic counseling, genetic risk
estimation is performed to allow a personalized program
including available preventive options and treatments. Furthermore, patient risk stratification allows classification of
patients and tumors.
Keywords: breast cancer, surgical treatment, axillary management
HEAD
Roberto Agresti, MD
Silvia Bohm, MD
Alberto Rudy Conti, MD
Cristina Ferraris, MD
Massimiliano Gennaro, MD
Maria Ilaria Grosso, MD
Gabriele Martelli, MD
Cristina Pellitteri, MD
Domenico Piromalli, MD
FELLOWS
Mario Rampa, MD
Ilaria Maugeri, MD
Angela Allegri
NURSES
Irene Alessandrini, Giovanni Cavaliere,
Myria Paola Conti, Stefano Licata, Bruna
Nuscis, Maria Carla Puddu, Michele
Rossello, Gelsomina Sasso, Francesco
Antonio Spagnolo, Liliane Venafra
Maria Caterina Fadda, Luigi Magnifico,
Caterina Pianu
RELEVANT NOTES
Publications
Martelli G, Miceli R, Daidone MG, Vetrella G,
Cerrotta AM, Piromalli D, Agresti R. Axillary
dissection versus no axillary dissection in elderly
patients with breast cancer and no palpable axillary
nodes: results after 15 years of follow up. Ann Surg
Oncol 2011; 18: 125-33.
Secreto G, Meneghini E, Venturelli E, Cogliati P,
Agresti R, Ferraris C, Gion M, Zancan M, Fabricio
AS, Berrino F, Cavalleri A, Micheli A. Circulating sex
postmenopausal breast cancer patients. A crosssectional study. Int J biol Markers. 2011; 26: 241-6.
Contributions
Roberto Agresti: editorial board of The Scientific
World Journal
95
melanoma and sarcoma
Melanoma During 2011, more than 550 melanoma
patients were treated by major surgery. More than
15,000 patients were seen in the outpatient clinic and
1000 were treated by minor surgery; a unit database,
containing more than 4000 patients in the last 10 years,
has been managed.
Sarcoma Our Institution is a referral center for soft tissue
sarcomas of the extremities and trunk, as well as
retroperitoneal sarcomas, GIST, and axial bone sarcomas.
In 2011, we carried out 342 major operations for new
patients and 24 operations for patients already treated at
our institution in the past and presenting for a locoregional recurrence. We saw 850 new patients in
consultation and performed routine follow-up visit for
over 3000 cases. We also chaired the surgical section of
the Italian Network on Rare Tumors, performing weekly
second opinion through the network.
Peritoneal Cancers The clinical and scientific activities are
oriented to the study and treatment of primary and sec-
ondary peritoneal tumors, and primarily for two rare diseases: malignant peritoneal mesothelioma (MPM) and
pseudomyxoma peritonei (PMP). An additional field of
interest is represented by peritoneal carcinomatosis.
These disease entities are clinically managed in
accordance with our institutional and ROL diagnostic and
therapeutic guidelines, within a multidisciplinary clinical
team involving the surgeons of our unit with medical
oncologists, pathologists, and experimental oncologists.
Considering the resources available, only a limited group
of patients with peritoneal cancer and selected to receive
combined treatment, are currently treated at our institution. Most patients are referred to other centers where
the procedure is available in accordance with the logistic
requirements of the patients themselves. In the period
under review, a total of 23 interventions of CRS and
HIPEC were performed at our institution for MPM
(n=12), PMP (n=10), or other peritoneal carcinomatosis
(n=1).
Keywords: melanoma, sarcoma, peritoneal cancers
HEAD
Mario Santinami, MD
Melanoma
Andrea Maurichi, MD
Daniele Moglia, MD
Roberto Patuzzo, MD
Roberta Ruggeri, MD
Surgery of Sarcoma
Alessandro Gronchi, MD
(Director)
Dario Baratti, MD
Chiara Colombo, MD
Marcello Deraco, MD
Marco Fiore, MD
RESEARCH STAFF
Federica Crippa, MD
Shigeki Kusamura, MD
Elena Tolomio, MD
RESIDENTS
Giulia Baffa, MD
Ilaria Mattavelli, MD
RELEVANT NOTES
Publications
Gronchi A, Miceli R, Colombo C, Collini P,
Stacchiotti S, Olmi P, Mariani L, Bertulli R, Fiore M,
Casali PG. Primary Extremity Soft Tissue Sarcoma:
outcome improvement over time at a single
institution. Ann Oncol. 2011; 22(7):
1675-81.
Gronchi A and Pollock RE. Surgery in
retroperitoneal soft tissue sarcoma: a call for a
consensus between Europe and North America.
Ann Surg Oncol. 2011; 18: 2107-10.
Deraco M, Elias D, Glehen O, Helms W, Sugarbaker
P.H. Verwaal V. Peritoneal Surface Malignancy
Cancer Principles and Practice of Oncology. Ed. IX
2011 Editors: De Vita, Hellman and Rosemberg.
Yan TD, Deraco M, Elias D, Glehen O, Levine EA,
Moran BJ, Morris DL, Chua TC, Piso P, Sugarbaker
PH; Peritoneal Surface Oncology Group. A novel
tumor-node-metastasis (TNM) staging system of
diffuse malignant peritoneal mesothelioma using
outcome analysis of a multi-institutional database.
Cancer. 2011; 117(9): 1855-63.
Contributions
Melanoma Deputy President of SICO (Società
Italiana Chirurgia Oncologica)
Editorial board and reviewer: Annals of Surgery,
Dermatology Research and Practice, European
Journal of Dermatology, European Journal Surgical
Carlotta Tinti, MD
Stefano Radaelli, MD
Antonella Vescera
CLINICAL TRIALS
COORDINATOR
Annabella Di Florio
Giovanna Lomartire (Head,
responsible quality Dept. of
Surgery), Nicola Abatangelo,
Annamaria Biondo, Sonia
Cappellini, Annarita Carluccio,
Alessio Cremonesi, Nello
Curatolo, Loridana Marino,
Elda Neira, Erica Panigada,
Giusy Pede, Esther Reinoso
Crespo, Claudia Sonzogni,
Monica Ullio, Addolorata Volpe,
Roberta Allenza, Antonella
Comasicchio, Floarea Dorca,
Silvana Mirante
Oncology, Journal Investigative Dermatology,
Oncology, Surgical Oncology, World Journal of
Clinical Pediatrics, World Journal of Dermatology,
World Journal Surgical Oncology, Tumori, Sarcoma
Member of: Sarcoma Task Force European Society
for Medical Oncology (ESMO); Connective Tissue
Oncology Society board of directors (CTOS);
International Committee of the Society of Surgical
Oncology (SSO)
Secretary of EORTC Soft Tissue and Bone
Sarcoma Group; Chairman of Italian Sarcoma
Group (ISG) Soft Tissue Sarcoma committee;
Associate Editor of Sarcoma Journal; Sarcoma
Section Editor for Annals of Surgical Oncology
Surgery Department
96
diagnostic endoscopy and endoscopic surgery
The activities of this multidisciplinary endoscopy Unit
include diagnostic and therapeutic procedures of the gastrointestinal, biliopancreatic, respiratory, and urinary
tracts. The Unit is particularly committed to cancer prevention and early cancer diagnosis and treatment. A
special effort is dedicated to the Regional Colorectal
Cancer Screening Program as well as to endoscopic surveillance of patients affected with familial adenomatous
polyposis (FAP) or Lynch syndrome. Detection and staging of early cancer is potentiated by the use of advanced
diagnostic technologies, such as wireless capsule
endoscopy (WCE) for the study of small intestine and
endoscopic ultrasonography (EUS) for the study of gastrointestinal tract and biliopancreatic malignancies. The
Unit is a core partner of the institutional GastroEntero
Pancratic NeuroEndocrine Tumors (GEP-NET) Center,
according to ENETS guidelines. The Endoscopy Unit is
also a referral Center within the Lombardy Region for
endoscopic treatment of a pre-cancerous esophageal
condition, such as Barrett’s esophagus, using endoscopic
radiofrequency ablation (RFA). With regard to advanced
cancers, endoscopic palliative therapy is routinely
provided using argon plasma electrocoagulation, laser
photocoagulation, and stenting for tracheobronchial,
esophageal, duodenal, and colorectal malignancies.
Keywords: cancer prevention, endoscopic diagnosis, endoscopic
therapy
HEAD
Emanuele Meroni, MD
Giovanni Ballardini, MD
Giuseppe Calarco, MD
Gianfranco Di Felice, MD
Massimo Falsitta, MD
Andrea Mancini, MD
NURSES
Vittorio Mauro (head nurse); Francesco
Bottani, Raffaele Calò, Roberto Fiocco
Daniele Lo Curcio, Francesca Mannai,
Giovanni Sammartino, Raffaele Quagliolo
TECHNICIANS
Silvia Cara, Rosanna Loi, Salvatore Morfeo
Concetta Di Quattro
Annamaria Mercuri
RELEVANT NOTES
Publications
Collaborations
Rotondano G, Bianco MA, Buffoli F, Gizzi G, Tessari
F, Cipolletta L on behalf of the FLIN investigators.
The Cooperative Italian FLIN Study Group:
prevalence and clinico-pathological features of
colorectal laterally spreading tumors. Endoscopy.
2011; 43: 856-61.
A fruitful collaboration with the Fondazione
IRCCS Istituto Neurologico Carlo Besta is ongoing
for treatment of symptoms related to neurological
disorders (neurologic dysphagia, Parkinson’s
disease).
In 2011, collaboration started with Politecnico
University and Experimental Oncology
Department of INT for preclinical research in the
biomedical field and for developing new diagnostic
tools.
Libro Bianco della Gastroenterologia Italiana, 2011
Contributions
Dr Meroni is a member of the review board of
Gastrointestinal Endoscopy and World Journal of
Gastrointestinal Endoscopy.
In 2011, Dr Meroni also contributed to the
Guidelines of the Regional Oncological Network.
97
otolaryngology surgery
The Division is highly specialized in the treatment of
benign and malignant tumors of the head and neck area.
In our Unit, state-of-the-art surgical treatment for
patients with head and neck tumors is guaranteed by
experts from across disciplines: otolaryngologists and
maxillofacial surgeons. Another key point is thyroid surgery, performed under the appointment of a
multidisciplinary team including specialists in endocrinology and nuclear medicine. We are focused on
quality-of-life issues such as retaining the patient’s ability
to speak and swallow, maintaining a normal appearance,
and minimizing the functional outcome of surgical treatments. In this light, we are using tools for
minimally-invasive surgery such as rigid endoscopy, new
sources of light, and imaging for diagnosis and treatment
of cavity cancers. We have developed a multidisciplinary
team including specialists in radiation oncology, medical
oncology, radiology, pathology, plastic and reconstructive
surgery, neurosurgery, dental and maxillofacial prosthetics,
nutrition, and pain management. Weekly multidisciplinary
meetings ensure that each patient receives the adequate
and customized treatment, as well as rehabilitation and
prevention services, tailored to his/her needs. Preclinical
research is conducted in collaboration with medical
oncologists, pathologists, molecular biologists, and
endocrinologists on prognostic features and molecular
targets of head and neck cancer. The office of outpatient
oral precancerous lesions deals with diagnosis and conservative treatment of oral lesions and our attention is
focused on HPV-related lesions and the cancerogenetic
role of this virus.
Keywords: head neck cancer, organ preservation, multidisciplinary
approach
HEAD
Gabriele Scaramellini, MD
STAFF MEMBERS
Roberto Bianchi, MD
Sarah Colombo, MD
Letizia M. C. Ferraro, MD
Walter Fontanella, MD
Paolo Formillo, MD
Marco Guzzo, MD
Tullio M. Ibba, MD, PhD
Franco Mattavelli, MD
Natalia R. E. Pizzi, MD
Madia Pompilio, MD
Stefano Riccio, MD
NURSES
Giovanna V. Bello, Petronilla D’agostino,
Angelo Di Caro, Giorgio Fumi, Giorgio
Inverni, Vincenzo Mandurino, Rosita Manna,
Marta Marsella, Laura Ongari, Daniele
Pezzera, Francesca Pisano, Federica
Prudenzano, Raffaella Repetto, Maura
Rimoldi, Maria Stefania Selva, Vincenzo Spanò
(coordinator)
Sabrina Zazzera
TECHNICIANS
Pablita Endaya, Vincenzo Marotta, Erick Papa,
Immacolata Pedico
RELEVANT NOTES
Collaborations
Otolaryngology residency program, University of
Milan; Maxillo-facial residency program, University
of Milan; “Miguel Hernandez de Elche” State
University of Alicante (Spain): theoretical and
hands-on head and neck dissection course for
young surgeons
Fellowship: “management and treatment of head
and neck tumors”
Publications
Guzzo M, Ferraro L, Rezzonico S, Ibba T, Bianchi R,
Fontanella W, Scaramellini G. Open organ
preservation surgery of the larynx: Experience of
Istituto Nazionale Tumori of Milan. Head Neck.
2011; 33: 673-8.
Sultan I, Rodriguez-Galindo C, Al-Sharabati S,
Guzzo M, Casanova M, Ferrari A. Salivary gland
carcinomas in children and adolescents: a
population-based study, with comparison to adult
cases. Head Neck 2011; 33: 1476-81.
Contributions
ROL (rete oncologica lombarda) guidelines on
adult head and neck cancers
Surgery Department
98
otolaryngology surgery
Maxillo-Facial Surgery (Gabriele Scaramellini, MD)
In the Unit a state-of-the-art surgical treatment for
patients with head and neck tumors is guaranteed by
experts from across disciplines: head and neck surgeons,
neurosurgeons, plastic surgeons, and dentists. This team of
specialists treats patients with tumors of skull base,
paranasal sinus, oral cavity, pharynx, salivary glands,
melanomas, non-melanoma skin cancers, sarcomas of the
soft tissue and bone, and orbital and ocular adnexal
malignancies. Our surgical team works together with
medical oncologists and radiation oncologists to optimize
functional outcome and provide the highest level of care.
In particular, we have extensive experience in skull base
and paranasal sinus tumors and in complex reconstruction of surgical defects of head and neck using free
microvascular flaps, having the largest series in Italy for
both. In 2011, we focused on:
RELEVANT NOTES
Collaborations
The Unit actively cooperates with the
Neurosurgery Unit of the Fondazione IRCCS
Istituto Neurologico C. Besta of Milan and the
Maxillo-Facial Surgery Unit of the S. Anna Hospital
of Como.
Publications
Cantu G, Solero CL, Miceli R, Mattana F, Riccio S,
Colombo S, Pompilio M, Lombardo G, Formillo P,
Quattrone P. Anterior craniofacial resection for
malignant paranasal tumors: a monoinstitutional
experience of 366 cases. Head Neck. 2012; 34(1):
78-87.
• the use of customized stereolithographic models in
bone reconstruction; this method is used to obtain the
most effective cosmetic and functional long-term results.
• ozone-therapy followed by conservative surgery for
the treatment of BRONJ.
• intraoperative rehabilitation after resection of the
maxilla by using a prefabricated dental obturator.
• development of endoscopic sinus surgery.
During the year, we also carried out a study about the
possible role of polymorphisms in xenobiotic metabolizing enzymes as a determinant for the degree of
susceptibility to intestinal type adenocarcinomas (FRAC)
and participated in the development of regional guidelines for management.
Licitra L, Perrone F, Tamborini E, Bertola L, Ghirelli
C, Negri T, Orsenigo M, Filipazzi P, Pastore E,
Pompilio M, Bossi P, Locati LD, Cantu’ G,
Scaramellini G, Pilotti S, Tagliabue E. Role of EGFR
family receptors in proliferation of squamous
carcinoma cells induced by wound healing fluids of
head and neck cancer patients. Ann Oncol. 2011;
22(8): 1886-93.
Cantu G, Solero CL, Mariani L, Lo Vullo S, Riccio S,
Colombo S, Pompilio M, Perrone F, Formillo P,
Quattrone P. Intestinal type adenocarcinoma of the
ethmoid sinus in wood and leather workers: a
retrospective study of 153 cases. Head Neck.
2011; 33(4): 535-42.
Thyroid Surgery (Franco Mattavelli, MD)
The Unit is focused on the diagnosis and treatment of
thyroid and parathyroid gland diseases in cooperation
with specialists in endocrinology, nuclear medicine, radiology, and pathology. Each patient is evaluated by a
multidisciplinary team and receives appropriate surgical
and non-surgical treatment according to Institutional
guidelines. Special care is reserved to the treatment of
multiple endocrine neoplasia and pediatric malignancies
of the thyroid gland. Furthermore, the Unit is specialized
in the surgical treatment of parathyroid glands disease,
using the intraoperative parathormone monitoring. In
2011, we studied the possible role of circulating miRNA
as a prognostic factor in papillary thyroid cancer in cooperation with Molecular Mechanisms Unit.
99
gynecologic oncology
The clinical activity of the Unit covers all aspects of gynecological surgery and medical oncology. The Unit deals
mainly with primary and secondary tumors of the female
genital tract. The activities of staff members are dedicated
to clinical practice, research, and teaching (3 tumor
boards weekly, international meetings; 3 surgical master
courses yearly). Gynecologic Oncology is mainly focused
on: first entry gynecological oncological evaluation; familial
cancer; abnormal pap-test and 1st and 2nd level
colposcopy; HPV multidisciplinary office; 1st and 2nd level
US; hysteroscopy; follow-up. All surgical and medical treatments are coordinated on a weekly basis meeting by a
multidisciplinary team involving surgeons, medical oncologists, pathologists, and radiotherapists. The research
activity of the group concerns clinical studies from basic
science to clinical research. In collaboration with the
Experimental Oncology Department and Molecular Medicine, we carried out several studies on gene expression,
folate receptor levels, and apoptosis in ovarian carcinoma.
Studies on the detection of stem cells in normal ovaries
HEAD
Francesco Raspagliesi, MD
Antonino Ditto, MD
Rosanna Fontanelli, MD
Barbara Grijuela, MD
Francesco Hanozet, MD (1/10/2011 out)
Marina Merola, MD
Domenica Lo Russo, MD (1/11/2011 in)
Eugenio Solima, MD
Gianbattista Spatti, MD
Bernardina Stefanon, MD
Flavia Zanaboni, MD
FELLOWS
Massimo Gabbanini, MD
Valentina Guadalupi, MD
Stefano Ramondino, MD
RESIDENT
Fabio Martinelli, MD
Cinzia Marretta
Rosella Zennoni
NURSES
Lorenzina Greco, Eva Guitti, Marianela P.
Maienza, Agnese Manganoni, Marianna
Miranda, Rosanna P. Penasa, Maria R. T.
Pichardo, Ylenia Ponti, Giuseppa M. Serravillo,
Patrizia A. Valente, Viviana Villa, Stefania
Labori, Concetta Brugaletta, Claudio Oppido,
Paolo Re, Rosita Bianco, Masha Kintaba
TECHNICIANS
Michele Iannelli, Simona Tuiu, Rosa Farro,
Laura Somma, Alessia Formicola, Cecilia
Muzzupappa
and ovarian cancer to preserve the endocrine potential in
ovarian cancer patients by selecting new drugs against
these cells are ongoing. Clinical research aimed to evaluate the efficacy of chemotherapeutic agents in ovarian
cancer, cervical cancer, and uterine sarcoma. Active collaboration in international and national multicenter
controlled clinical studies in both medical and surgical
protocols is ongoing. In the management of gynecological
cancer, our standards of care reproduce international
guidelines. To improve the prognosis of early stage cancer,
several studies are ongoing on the efficacy and safety of
laparoscopic techniques in gynecological oncology. We
extended the concept of mini-invasiveness to laparotomy
to reduce the complications of radical hysterectomy. As a
result of our commitment in gynecological oncology, the
peri-operative morbidity, mortality and postoperative
hospital stay in our Unit are excellent compared to the
international standards for gynecologic surgery.
Keywords: gynecological surgery, chemotherapy, research
RELEVANT NOTES
Collaborations
MITO collaborative group; MANGO collaborative
group; ESGO group Università degli Studi and
Politecnico, Milan; Department of Gynecological
Oncology, University of Turin, Mauriziano Hospital
Publications
Cibula D, Abu-Rustum NR, Benedetti-Panici P,
Köhler C, Raspagliesi F, Querleu D, Morrow CP.
New classification system of radical hysterectomy:
emphasis on a three-dimensional anatomic
template for parametrial resection. Gynecol Oncol.
2011; 122(2): 264-8.
Ditto A, Martinelli F, Mattana F, Reato C, Solima E,
Carcangiu M, Haeusler E, Mariani L, Raspagliesi F.
Class III nerve-sparing radical hysterectomy versus
standard class III radical hysterectomy: an
observational study. Ann Surg Oncol. 2011; 18(12):
3469-78.
Contributions
Three advanced forums in Gynecological
Oncology with live surgery.
Surgery Department
100
thoracic surgery
The mission of the Thoracic Surgery Unit is to provide
high-standard clinical care and scientific research by continous improvement of processes and bed-side application
of evidence-based medicine. Furthermore, traslational
research allows patients to benefit from advanced multimodality strategies as soon as positive results are
obtained from preclinical trials. Clinical activities cover all
aspects of thoracic oncology, focusing on pulmonary,
mediastinal, chest wall, and esophageal tumors. In the
management of lung cancer, the mainstay of surgical treatment is maximal functional sparing. All patients undergo
muscle-sparing thoracotomy, avoiding any muscular section. Lung-sparing procedures (bronchoplasty and/or
angioplasty) are adopted to avoid the removal of the
entire lung, when possible. A clinical randomized trial is
ongoing, searching for the best drainage strategy to limit
postoperative air leak (airINTrial). In the domain of secondary lung tumors, the Thoracic Surgery Unit
cooperates with different INT Units (mainly with Oncology, Pediatric Oncology and Sarcoma Units), performing
standard metastasectomy by innovative parenchyma-sparRELEVANT NOTES
Collaborations
University of Milan, Thoracic Surgery and General
Surgery; University of Parma, Department of
Clinical Science; Section of Radiology, Mario Negri
Institute, Milan; General Epidemiology Istituto
Superiore di Sanità, Rome; San Raffaele, Milan;
Humanitas Cancer Center, Milan; San Gerardo,
Monza; University of Ohio US, Human Cancer
Genetics; University of Oxford UK, Tumor
Pathology; International Agency for Research on
Cancer (IARC) Lyon FR, Infection and Cancer
Epidemiology
Publications
Girotti P, Leo F, Bravi F, Tavecchio L, Spano A,
Cortinovis U, Nava M, Pastorino U. The “rib-like”
technique for surgical treatment of sternal tumors:
ing procedures (thulium laser + stem cells application).
Extended resections are proposed when an acceptable
postoperative impairment of the quality of life can be
expected. Innovative techniques for tridimensional chest
wall reconstruction have been developed (rib-like technique), permitting appropriate reconstruction even in
case of removal of an entire hemithorax. In mediastinal
surgery, superior vena cava (SVC) replacement is
performed by procedures not requiring SVC cross-clamping, avoiding intraoperative hemodynamic instability.
Pleuro-pneumonectomy is proposed in limited malignant
mesothelioma, after induction chemotherapy. In more
advanced disease, a trial will be started in 2012 to measure the advantage of pleurectomy/decortication after
chemotherapy in terms of disease-free survival and quality of life, compared to chemotherapy only (PASS trial).
Esophageal surgery is performed in cooperation with different Units (Otorhinolaryngology, GastrointestinalPancreatic Liver Surgery, Endoscopy).
Keywords: lung cancer, secondary lung tumors, thoracic oncology
lessons learned from 101 consecutive cases. Ann
Thorac Surg. 2011; 92(4): 1208-15.
Boeri M, Verri C, Conte D, Roz L, Modena P,
Facchinetti F, Calabrò E, Croce CM, Pastorino U,
Sozzi G. MicroRNA signatures in tissues and
plasma predict development and prognosis of
computed tomography detected lung cancer. Proc
Natl Acad Sci USA. 2011; 108(9): 3713-8.
Contributions
Patent: miRNA (BIOVITAS New York, US); Editorial
Board: Scientific reviewer for: Annals of Oncology,
Annals of Thoracic Surgery, British Journal of
Cancer, European Journal of Cancer, International
Journal of Cancer, Lung Cancer, Respiration, Thorax,
Tumori, European Journal of Cardio-Thoracic
Surgery. Associate Editor of the Journal of the
National Cancer Institute.
HEAD
Ugo Pastorino, MD
Barbara Conti, MD
Vincenzo Delledonne, MD
Riccardo Giovannetti, MD
Francesco Leo, MD
Paolo Scanagatta, MD
Luca D. Tavecchio, MD
FELLOWS
Filippo Acerbis, MD
Giuseppe Garofalo, MD
Emilia Anna Polimeno, MD
PHD STUDENTS
Leonardo Duranti, MD
Simone Furia, MD
RESIDENTS
Lara Girelli, MD
Luca Turati, MD
NURSES
Federica Pirovano, Brice Atiomeguim,
Francesco Auletta, Marcella Bernardo, Laura
De Porras, Payà Yesica Del Rio Mendez,
Margherita Fersurella, Fabrizio Lupo, Hilda A.
Martinez, Daniele Marino, Maria L.
Quitadamo, Anna M. Panareo, Antonio
Pantano, Antonella Prete, Antonino Proto,
Simona Ugolini
TECHNICIANS
Vincenzo Dellaquila, Nekpen Eguavoen,
Antonietta G. Fantilli, Jose Salinas Montoya,
Pamela K. Soto Fernandez
Tiziana Negri
RESEARCH STAFF
Elena Bertocchi, Anna Maria Calanca, Caludio
Jacomelli, Carolina Ninni, Paola Suatoni
EXTERNAL COLLABORATORS
Elisa Bonati, Benedetta Finamore, Barbara
Puricelli, Valentina Rosato, Marta Rossi,
Nicola Sverzellati
101
plastic and reconstructive surgery
Reconstructive surgical procedures are related to demolitive breast and head and neck surgery, soft-tissue tumors,
chest-wall surgery, and other types of aggressive oncologic surgeries, as well as surgical treatment and repair of
skin cancer. Oncoplastic surgery represents a new standard for reconstructive procedures after tumor excision.
Plastic procedures related to breast cancer surgery
account for the main workload, and fat and implant
hybrid breast reconstruction is planned and started concurrently with breast ablation. Fat cell transplantation
allows implant-based reconstruction in some cases even
after tissue damage by radiotherapy. In patients who are
not candidates for hybrid breast implant insertion, reconstruction is carried out with flaps. Both DIEP and free
flaps have been used for delayed or immediate breast
reconstruction, after ablation of large soft tissue tumors,
and in reconstruction after head and neck demolitions.
Cohesive gel breast implants together with fat cell transplantation and microsurgery represent the highest
standard in reconstructive surgery. Fat tissue transplantation using fat cells together with adipose-derived fat cells
and platelet-rich plasma allow us to regenerate damaged
tissue. Oncoplastic surgery is actually the main activity of
the unit and the core of its clinical and experimental
investigations.
Keywords: plastic, oncoplastic-breast-skin-surgery, microsurgery, fat
cell transplantation
HEAD
Maurizio B. Nava, MD
Umberto Cortinovis, MD
Joseph Ottolenghi, MD
Angela E. Pennati, MD
Egidio Riggio, MD
Andrea Spano, MD
Novella Bruno, MD
Manuela Forti, MD
Pierfrancesco Cadenelli, MD
Luisa Morandi
NURSES
Maria Saracino (Head), Samantha F. Castelli,
Cinzia Gentilini, Giusppe L’Abbate, Marisa
Labò, Giovanna Melia, Caterina Pireddu,
Irene Rossi, Raffaella Tupputi
TECHNICIANS
Raffaella Cagnazzo, Nadia Casati, Provvidenza
Peci, Nomi Ibazeta Ramos, Iolanda Panipucci
RELEVANT NOTES
Collaborations
We continue collaboration with the Department
of Experimental Oncology and Molecular Medicine
to evaluate the stem cell activity of injected fat
cells.
Clinical Trials: EORTC, quality of life after Breast
reconstruction, Suri-2 for breast reconstruction,
Oncoplastic Workflow, to be validated with other
three centers.
Publications
Folli S, Curcio A, Buggi F, Mingozzi M, Lelli D,
Barbieri C, Asioli S, Nava MB, Falcini F. Improved
sub-areolar breast tissue removal in nipple-sparing
mastectomy using hydrodissection. Breast. 2012;
21(2): 190-3.
Nava MB, Pennati AE, Lozza L, Spano A, Zambetti
M, Catanuto C. Outcome of different timings of
radiotherapy in implant-based breast
reconstructions. Plast Reconstr Surg 2011; 128(2):
353-9.
Contributions
In 2011, enrollment for clinical trials continued and
new clinical studies and experimental investigations
have been started. Collaboration with the
Politecnico University, Bioengineering Unit and the
University of Catania are still active.
Surgery Department
102
urologic surgery
Urothelial cancer A study with pazopanib in relapsing
urothelial cancer closed enrollment on July 2011. Very
impressive responses were achieved. Concomitant trials
were planned, in particular a phase II study with the monoclonal antibody against the TGF-β receptor ALK1 was
accepted for funding and support within the Rete Oncologica Lombarda (ROL). Two other clinical trials are
ongoing: a clinical study with sorafenib and chemotherapy
in the neoadjuvant setting and another randomized phase
II study of vinflunine and gemcitabine versus vinflunine
and carboplatin as first-line therapy for cisplatin unfit
patients.
Testicular cancer The observational study on the quality
of life of patients undergoing retroperitoneal lymph-node
dissection (RPLND) as primary treatment for clinical
stage I disease continued enrolling during 2011. Preliminary data show a general increase in FACT-G QoL scale
scores from baseline to follow-up evaluations. Current
optimization of laparoscopic RPLND shows that the
treatment has an acceptably low-morbidity, which can
actually duplicate the historical oncologic results of open
RPLND. A project aimed at re-evaluating the expression
of CD30 antigen in residual masses yielding viable cancer
after chemotherapy was started in late 2011. The objective of this project was to establish the basis for a phase II
study with the immunoconjugated anti-CD30 monoclonal
antibody (SGN-35, brentuximab) in the setting of
metastatic and chemotherapy resistant disease. The phase
II study of tandem high-dose chemotherapy for relapsing
germ cell tumors continued enrolling throughout the
year.
Penile cancer We pursued the multimodal project for
clinically node-positive squamous cell carcinoma of the
penis aimed at evaluating the activity of neoadjuvant TPF
chemotherapy followed by lymph-node dissection after
primary tumor control that incorporates the use of
PET/CT for both staging and response evaluation prior to
surgery.
Kidney cancer We extended the indications for
nephron-sparing surgery. A new multidisciplinary
approach with controlled intraoperative hypotension is
currently under investigation in order to minimize renal
damage.
Keywords: genitourinary cancer, multidisciplinary, mininvasive therapy
International Consortium on RPLND International
Germ Cell Tumors Cooperative Group (G3)
Necchi A, Nicolai N, Colecchia M, Catanzaro M,
Torelli T, Piva L, Salvioni R. Proof of activity of antiepidermal growth factor receptor-targeted therapy
for relapsed squamous cell carcinoma of the penis.
J Clin Oncol. 2011; 29(22): e650-2.
Publications
Contributions
Nicolai N, Colecchia M, Biasoni D, Catanzaro M,
Stagni S, Torelli T, Necchi A, Piva L, Milani A, Salvioni
R. Concordance and prediction ability of original
and reviewed vascular invasion and other
prognostic parameters of clinical stage I
nonseminomatous germ cell testicular tumors after
retroperitoneal lymph node dissection. J Urol.
2011; 186(4): 1298-302.
In late 2011, we actively participated at the 3rd
European Consensus Conference on Diagnosis
and Treatment of Germ Cell Cancer aimed at
updating the European guidelines on the disease.
Further collaborative projects on retrospective
case-series within the international network are
planned. Currently, we are members of
International agencies involved in definition of
Guidelines in this field.
RELEVANT NOTES
Collaborations
HEAD
Roberto Salvioni, MD
Davide Biasoni, MD
Mario A. Catanzaro, MD
Angelo Milani, MD
Nicola Nicolai, MD (Head, Testicular Cancer Surgery
Unit)
Luigi Piva, MD (Head, Pediatric Surgery Unit)
Silvia Stagni, MD
Tullio Torelli, MD
Andrea Necchi, MD (Faculty, Department of
Medical Oncology, Medical Oncology Unit 2)
Patrizia Giannatempo, MD (Resident, Department
of Medical Oncology, Medical Oncology Unit 2)
Daniele Raggi, MD (Fellow, University of Milan
School of Medicine)
NURSES
Graziella Russo (Coordinator), Maria L.
Cennamo, Anna M. Cercaci, Zino Ferro,
Maria R. Leo, Francesca Marelli, Giovanni
Mazzilli, Lucia Mesiano, Arturo Monetta,
Valentina Musarò, Giuseppa Napoli, Veronica
P. Rojas, Maria Silva, Annalisa Simone
Maria G. Bodini
TECHNICIANS
Antonio Bonelli, Elena Cristiani, Isabella
Vurchio, Olimpia Liberatore De La Cruz
Velesmoro Rocio Del Pilar
103
pediatric surgery
The Unit collaborates with pediatric oncologists and provides a high standard of treatment for the most frequent
solid - non central nervous system - tumors observed in
children and adolescents. The role of surgery is
established according to ongoing European treatment
protocols. During 2011, the following surgical interventions were carried out. Wilms tumor: 15 surgeries on
patients enrolled in the TW 2003 AIEOP (Associazione
Italiana Ematologia Oncologia Pediatrica) study, 10
nephrectomies, 2 partial bilateral kidney excisions, and 4
partial monolateral kidney excisions. Neuroblastoma: 5
surgeries. Germ cell tumors/gynecological and andrological procedures: 2 orchiectomies, 2 surgeries on patients
with germ cell tumors, 2 partial scrotectomies, 2 testis
transpositions, and 4 urological procedures. Soft tissue
sarcomas and rare tumors: surgery on soft tissue sarco-
HEAD
Luigi Piva, MD
mas was performed in collaboration with the Melanoma
and Sarcoma Unit: 17 soft tissue tumors and 5 cutaneous
lesions. Cranio-maxillofacial tumors: in this type of tumor,
surgeries are performed in cooperation with the ORL
Division: 1 total thyroidectomies, 2 hemi-thyroidectomies,
1 parotidectomy, and 5 facial surgeries. Lung metastases:
surgeries are performed in cooperation with Thoracic
Surgery Unit: 7 metastasectomies and 6 patients underwent thoracotomy for different diseases. In collaboration
with the Colorectal Unit, 4 colectomies through
laparoscopy were performed and 2 closing ileostomies.
Breast procedures: 1 excision nodule and 2 partial breast
exeresis. Finally, 14 surgical biopsies were necessary for 6
sarcoma, 5 lymphoadenopathies, and 4 for
ganglioneuroma, renal tumor, and neuroblastoma.
Keywords: renal tumors, pediatric sarcoma, multidisciplinary teams
Surgery Department
104
laser therapy
The Unit is dedicated to diseases where laser therapy is
the first or only treatment choice and features high quality instrumentation including four lasers for a total of 20
wavelengths. This allows both conservative and ablative
therapies. Selective photothermolysis laser treatment is
performed for keloids, pigmented and vascular lesions,
and the laser ablation technique is used for mucosal and
skin cancer lesions requiring histological evaluation.
Treated lesions can be conveniently classified into 5
groups:
Tumor lesions: skin carcinomas, melanoma in-transit
metastases, cutaneous and mucosal localizations of
Kaposi’s sarcoma, precancerous lesions such as actinic keratosis
Vascular lesions: flat-type congenital capillary angiodysplasia, angiomas, and venous lymphatic angiodysplasia
Nevi: giant melanocytic nevi
Traumatic and post-burn hypertrophic scars and
keloids
Cutaneous localizations originating from complex syn-
dromes, such as adenomas in tuberous sclerosis,
angiodysplasias related to Sturge-Weber syndrome, neurofibroma, and cafe-au-lait spots in neurofibromatosis
(with the INT serving as national referral center for this
disease).Compared with previous years, an increasing rate
of tumoral and vascular diseases and complex syndromes
was observed. During 2011, we performed 2000 treatments of laser therapy: 1400 of these procedures were in
an ambulatory setting.
Keywords: laser therapy, skin cancer, angiodysplasia
HEAD
Anna Colombetti, MD
Roberto Grillo, MD
Mario Z. Raso, MD
ADMINISTRATIVE
Aceto M. Rosaria
NURSE
Maria Saracino (Coordinator), Emilia
D’Arrigo
Domenica Lo Prete
RELEVANT NOTES
Relevant technologies
The instrumentation of the Laser Unit includes
four lasers for a total of 20 wavelengths: mode
fiber, QS, pulsed light (IPL), and a CO2 laser for
both conservative and ablative therapies.
Collaborations
Diagnosis, follow-up, clinical and laser procedures,
were performed with the Melanoma and Sarcoma
Unit for the treatment of melanoma in-transit
metastases. In collaboration with the Radiology
Unit, congenital and acquired vascular lesions are
diagnosed and followed. The general clinical
management of patients affected by
neurofibromatosis is ensured by the Medical
Genetic Unit of the Fondazione IRCCS Policlinico
of Milan.
In collaboration with the Department of
Anesthesiology, 80 pediatric patients affected by
giant nevi, post-burn scars, hemangiomas, and
congenital vascular pathologies were treated with
laser procedures under general anesthesia.
105
day surgery
The Unit is devoted to surgical procedures performed in
day hospital and ambulatory settings. The Unit includes 10
beds, 2 operating rooms for various surgical activities, and
one operating room for laser surgery. The clinical activity
covers many aspects of oncologic surgery, and in particular includes the treatment of the different neoplastic
lesions involving skin, soft tissues, and breast, as well
lesions in gynecological, urological and head and neck
areas. The activity involves physicians of the Department
of Surgery, sometimes working in cooperation. During the
year 2011, about 4900 operations were performed. Of
these, nearly 2800 were performed in a day hospital setting, whereas 2100 patients underwent outpatient
surgery. Nearly 4380 interventions were performed
under local anesthesia, while 520 were performed under
sedo-analgesia or general anesthesia. These procedures
were assisted by anesthesiologists from the Intensive
Care Unit. In addition to normal surgical activity, other
special procedures were performed such as
electrochemotherapy of secondary skin tumors (in collaboration with the Melanoma and Sarcoma Unit) and fat
injection or lipostructure with the Coleman technique to
lessen local skin and subcutaneous damage (in collaboration with the Plastic and Reconstructive Unit. Clinical
research activity is, at present, mainly performed in collaboration with the Melanoma and Sarcoma Unit. The aim of
this activity is to better define the initial clinical features of
early melanoma to allow curative limited surgery.
Keywords: day surgery, ambulatory surgery, early melanoma
HEAD
Aldo Bono, MD
Maria R. Bignamini, Anna Corella, Loredana
Orezzi
NURSES
Giovanna R. Colaci, Mariangela Lena, Mara D.
Luisoni, Pina P. Mele, Anna Picciallo, Marina
Zocchi
Guglielmina Riccio, Franca Atzeni, Antonella
Bordoni,
RELEVANT NOTES
Publications
Bono A, Tolomio E, Carbone A, Moglia D, Crippa
F, Tomatis S, Santinami M. Small nodular
melanoma: the beginning of a life-threatening
lesion. A clinical study on 11 cases. Tumori. 2011;
97: 35-38.
Contributions
Editorial Board of Tumori.
Reviewer activity of Archives of Dermatology,
Melanoma Research, and Tumori.
107
MEDICAL ONCOLOGY
DEPARTMENT
Paolo Corradini
Professor of Hematology
University of Milan
+39 02 2390 2950
[email protected]
UNITS
HEMATOLOGY AND ALLOGENEIC
BONE MARROW
TRANSPLANTATION (ETMO)
Paolo Corradini
MEDICAL ONCOLOGY 1
Filippo de Braud
(since August 1st)
MEDICAL ONCOLOGY 2
Alessandro M. Gianni
PEDIATRIC ONCOLOGY
Maura Massimino
ADULT SARCOMA MEDICAL
TREATMENT
Paolo G. Casali
HEAD AND NECK CANCER
MEDICAL ONCOLOGY
Lisa Licitra
MEDICAL DAY HOSPITAL
Roberto Buzzoni
The Department consists of clinical medical Units (81 beds), one centralized
day hospital (28 beds), 22 outpatient rooms, and a laboratory area for clinical
cell manipulation, flow cytometry, clinical pharmacology, and molecular biology.
The routine clinical activity is focused on the treatment of adult and pediatric
patients with solid tumors and hematologic malignancies. Several clinical programs are active, which range from conventional chemotherapy to phase I
studies to the transplantation of hematopoietic cells.
The Department is organized in Units which are in charge of different aspects
of cancer research and treatment.
• Medical Oncology 1: gastrointestinal and lung tumors, melanoma, renal, and
prostate cancers and breast carcinomas; treatment and development of new
drugs
• Medical Oncology 2: preclinical and clinical activities mainly in the field of
malignant lymphomas and germ cell tumors
• Pediatric Oncology: pediatric patients with solid cancers
• Hematology and Allogeneic Bone Marrow Transplantation: treatment of
hematologic malignancies and allogeneic transplantation.
• Adult Sarcoma Medical Treatment: clinical research activities in sarcomas
and peritoneal mesothelioma
• Head and Neck Cancer Medical Oncology: clinical activity in head and neck
carcinomas
• The Medical Day Hospital deals with adult patients referred by the clinical
Units of the Department; diagnosis, treatment, and follow-up neuroendocrine
tumors
• The Cardiology/Pneumology and Psychology Units cover all aspects of
patients in their specific setting (see Shared Resources page 139).
108
hematology and allogeneic bone marrow transplantation (ETMO)
The ETMO Unit coordinates and takes part in several
clinical trials testing new combinations of drugs and monoclonal antibodies for the treatment of lymphoid and
myeloid malignancies with the aim of enhancing antitumor activity while reducing toxic effects. Several new
trials have been started:
• a Phase III randomized trial comparing the efficacy of
G-CHOP versus R-CHOP in previously untreated
patients with CD20-positive DLBCL;
• a randomized phase III study to compare bortezomib,
melphalan, prednisone (VMP) with high dose melphalan
followed by bortezomib, lenalidomide, dexamethasone
(VRD) consolidation, and lenalidomide maintenance in
patients with newly-diagnosed multiple myeloma;
• Phase I study of a new protein kinase C inhibitor in
patients with CD79-mutant diffuse large B-cell lymphoma.
The Unit has also focused on:
• a phase I/II study of pomalidomide, cyclophosphamide,
and prednisone (PCP) in patients with multiple myeloma
relapsed and/or refractory to lenalidomide;
HEAD
Paolo Corradini, MD
Anna Dodero, MD
Vittorio Montefusco, MD
Lucia Farina, MD
Jacopo Mariotti, MD
RESEARCH STAFF
Cristiana Carniti, PhD
CLINICAL FELLOWS
Francesco Spina, MD, PhD
Mara Morelli, MD
Cecilia Olivares, MD
RESIDENTS
Serena Dalto, MD
Alberto Mussetti, MD
Luisa Roncari, MD
Antonio Vendramin, Biol Sci D, PhD
PHD STUDENTS
Anisa Bermema, Biol Sci D
Silvia Gimondi, Biol Sci D
DATA MANAGERS
Liana Bevilacqua, Debora Degl’Innocenti
Marialuisa Longhi, Elena Maggioni
NURSES
Giorgia Gobbi, Rosa Abate, Sonia Citro,
Letteria Consolo, Riccardo De Stefano,
David Guiote Pertierra, Donatella Luongo,
Simona Mazzella, Elisabetta Martinell,
Francesco Murana, Rita Russo, Leonardo
Orsini, Rita Sciancalepore, Serafina
Tomasicchio, Giuseppe Torregrossa, Anna
Vernone
Carmelo Fede, Evelina Palella, Jose Noboa
Velasco, Nunzio Bovello
• a phase III trial for multiple myeloma patients at first
relapse aimed at comparing the activity of a regimen
including either bortezomib or lenalinomide combined
with cyclophosphamide and dexamethasone. The study
includes a biological portion aimed at the evaluation of
simple biomarkers that may be useful to predict long
term response in the relapse setting.
Other research projects include phenotypic, functional
and molecular characterization of post-transplant T-cell
and B-cell recovery to elucidate the kinetics of the
immune reconstitution after stem cell transplantation,
prospective analysis of the plasma miRNA profile of allografted patients to identify markers predictive of acute
GVHD (aGVHD), onset analysis of the effects of myeloidderived suppressor cells (MDSCs), dose contained in the
graft on the incidence of GVHD use of a mouse model
of peripheral T-cell lymphomas (PTCLs), and test in vivo
the activity of new drugs and drug combinations.
Keywords: lymphoma, transplantation, myeloma
RELEVANT NOTES
Publications
Barosi G, Bosi A, Abbracchio MP, Danesi R,
Genezzani A, Corradini P, Pane F, Tura S. Key
concepts and critical issues on epoetin and
filgrastim biosimilars. A position paper from the
Italian Society of Hematology, Italian Society of
Experimental Hematology, and Italian Group for
Bone Marrow Transplantation. Haematologica.
2011; 96: 937-42.
Corradini P, Sarina B, Farina L. Allogeneic
transplantation for Hodgkin’s lymphoma. Br J
Haematol. 2011; 152: 261-72.
Thiel U, Wawer A, Wolf P, Badoglio M, Santucci A,
Klingebiel T, Basu O, Borkhardt A, Laws HJ, Kodera
Y, Yoshimi A, Peters C, Ladenstein R, Pession A,
Prete A, Urban EC, Schwinger W, Bordigoni P,
Salmon A, Diaz MA, Corradini P. et al. No
improvement of survival with reduced- versus
high-intensity conditioning for allogeneic stem cell
transplants in Ewing tumor patients. Ann Oncol.
2011; 22: 1614-21.
109
medical oncology 1
In 2011, the previous two Divisions of Medical Oncology
managing most solid tumors were merged under the
direction of Dr Filippo de Braud since August 1, as it was
when Gianni Bonadonna was leading Medical Oncology
in our Institute. Our mission is to improve clinical care
and outcomes of medical treatment of cancer through
multidisciplinary management, personalized medicine, and
development of new drugs and strategies. A major effort
has been made to restore the infrastructure for inpatient
care and renew the clinical research structure.
Major areas of interest are:
• Translational research on prognostic and/or predictive
biomarkers in most solid tumors (upper and lower gastrointestinal tract, non-small cell lung cancer, malignant
pleural mesothelioma, and thymoma).
• New generation targeted therapy and immunotherapy
for malignant melanoma.
• Adjuvant and systemic treatment of patients affected
by renal cell carcinoma and the management of castration-resistant prostate cancer using new therapeutic
approaches.
• The identification and selection of different subsets of
HEAD
Filippo de Braud, MD
Bianchi Giulia Valeria, MD
Buzzoni Roberto, MD
Capri Giuseppe, MD
Celio Luigi, MD
Cresta Sara, MD
Del Vecchio Michele, MD
Di Bartolomeo Maria, MD
Garassino Marina, MD
Mariani Gabriella, MD
Moliterni Angela, MD
Procopio Giuseppe, MD
Zilembo Nicoletta, MD
Platania Marco, MD
Elena Verzoni, MD
Milena Vitali, MD
Damian Silvia, MD
De Benedictis Elena, MD
Di Guardo Lorenza, MD
Dotti K. Fiorella, MD
Mariani Paola, MD
Pietrantonio Filippo, MD
Pusceddu Sara, MD
RESEARCH STAFF
Antonia A. Martinetti, Biol Sci D
RESIDENTS
Agustoni Francesco, MD; Biondani Pamela,
MD; Dazzani M. Chiara, MD; Gevorgyan
Arpine, MD; Parati M. Chiara, MD; Puma
Elisa, MD; Ricchini Francesca, MD; Sica
Lorenzo, MD; Tessari Anna, MD; Testa
Isabella, MD
Barbara Formisano, Giuseppa Iannaci,
Susanna Maggi
DATA MANAGER
Sinno Valentina, Alessandra Siliprandi
breast cancer patients to be treated differently according
to the molecular profile of their disease (i.e. integrating
targeted therapies with standard chemotherapy or with
hormone treatment).
• Active involvement in research on antiemetic drugs.
• A unit fully dedicated to new drug development
(phase I and Ib studies) and the promotion of
translational research projects. In this regard, we propose
not only to develop treatments using new molecular
compounds, but also to investigate new therapeutic
strategies.
The facilities available at Medical Oncology include a 22
bed inpatient ward, a day hospital area, 9 consulting
rooms (one of which is dedicated to consultations and
first-admittance visits), and a research laboratory for pharmacokinetic and pharmacodynamic evaluation of new
treatments. In 2011, the Unit carried out 37,387 clinical
visits, 458 consultations to patients at first access; 2 phase
I, 6 phase II, and 5 phase III trials were activated in the last
quarter of 2011.
Keywords: patient care, new drug development, personalized medicine
RELEVANT NOTES
Collaborations
The clinical research activities stem from the
productive collaboration with different institutes
and cooperative groups. OM1 has a long-standing
collaboration with the Breast Cancer Working
Group of the Michelangelo Foundation aimed at
the conduct and the coordination of Phase II/III
trials in operable breast cancer or metastatic
disease. The collaboration with the Southern
Europe New Drugs Organization is focused on
Phase I and early Phase II studies in breast cancer
and all solid tumor types.
Publications
Del Vecchio M, Mortarini R, Tragni G, Di Guardo
L, Borsani I, Di Tolla G, Agustoni F, Colonna V,
Weber JS, Anichini A. T-cell activation and
maturation at tumor site associated with
objective response to ipilimumab in metastatic
melanoma. J Clin Oncol. 2011; 29: e783-8.
Procopio G, Guadalupi V, Giganti MA, Mariani L,
Salvioni R, Nicolai N, Capone F, Valdagni R, Bajetta
E. Low dose of ketoconazole in patients with
prostate adenocarcinoma resistant to
pharmacological castration. BJU Int. 2011; 108:
223-7.
Contributions
The Unit, together with other important
members of the multidisciplinary team, was asked
by ROL (Rete Oncologica Lombarda) to update
national guidelines. Prof. de Braud and Dr. Del
Vecchio were involved in drafting the
MELANOMA guidelines (AIOM).
110
medical oncology 2
Medical Oncology 2 Unit carries out both preclinical and
clinical translational research in a variety of fields, including hematopoietic stem cells, immunotherapy, autologous
stem cell transplantation (ASCT), and targeted therapies.
The Unit includes four areas (a 12-bed inpatient ward; a
day hospital facility; an outpatient clinic with three consulting rooms; a cell processing laboratory) and provides
care mainly for patients with non-Hodgkin lymphomas
(NHL), Hodgkin lymphoma (HL), multiple myeloma, and
selected patients with high-risk germ cell testicular
tumors. During 2011, an average of 150 patients were
treated as inpatients, resulting in a total of 500
admissions, and 35 patients received ASCT. A total of
1500 treatments were administered in day hospital. An
average of 300 new outpatients requested examination.
The activity of the cell processing laboratory consisted of
1100 CD34+ cell monitoring and 220 stem cell cryopreservations.
The following phase II and III studies have been launched
from our Unit:
HEAD
Alessandro M. Gianni, MD
Liliana F. Devizzi, MD
Massimo A. Di Nicola, MD
Anna Guidetti, MD
Michele Magni, MD
Paola Matteucci, MD
Simonetta Viviani, MD
RESEARCH STAFF
Alessandra Canavè, PhD
Giusi Ruggero, Fellow
Roberta Zappasodi, PhD
Maria Luisa Longhi
FELLOWS
Luca Bergamaschi, MD
Annamaria Marte, MD
Emanuela Paternò, MD
NURSES
Caterina Asprella, Stefania Bevacqua, Matteo
Biondelli, Rita Boffa, Salvatore Capuano,
Letizia De Palma, Elisea Ferrante, Veronica
Fuccio, Santina Marafioti, Giovanna Miceli,
Andrea Mulas, Immacolata Navarra, Chiara
Paternoster, Lucia Saracino, Giuseppina
Tomassini, Daniela Trentin
Antonietta M. Maglione, Agnese Lasala,
Loredana Costa, Mauro L.Pedretti, Antonella
Di Perna
TECHNICIANS
Paolo D. Longoni, Marco Milanesi
• phase III study comparing rituximab-ABVD and ABVD
followed by involved-field radiotherapy in early-stage HL
• phase II trial evaluating ofatumumab, bendamustine, and
dexamethasone in elderly patients with mantle cell NHL
• phase II trials investigating efficacy and safety of epigenetic and targeted therapies in relapsed/refractory
lymphomas.
A randomized phase III trial in advanced stage HL
patients receiving ABVD or BEACOPP as first-line
chemotherapy has been concluded and its results have
been published in the New England Journal of Medicine.
Two randomized phase III clinical studies comparing standard- and high-dose chemotherapy in aggressive NHL
and chronic lymphocytic leukemia have been concluded.
In the preclinical area, we identified HSP105 as a novel
NHL tumor antigen whose expression was higher in
aggressive NHL. Studies in mice suggest inhibiting HSP105
could help treat B cell NHL. Developing new antiHSP105 therapeutic monoclonal antibodies is ongoing.
Keywords: lymphoproliferative disease, stem cell transplantation,
immunotherapy
RELEVANT NOTES
Collaborations
Istituto Superiore di Sanità (ISS), Rome, Italy;
Cancer Centers of Federazione Italiana Linfomi
(FIL); Istituto di Ematologia “Seragnoli”, University
of Bologna, Italy; Department of Hematology,
University of Turin, Italy; MD Anderson Cancer
Center, Houston, Texas, USA
Publications
Viviani S, Zinzani PL, Rambaldi A, Brusamolino E,
Levis A, Bonfante V, Vitolo U, Pulsoni A, Liberati AM,
Specchia G, Valagussa P, Rossi A, Zaja F, Pogliani EM,
Pregno P, Gotti M, Gallamini A, Rota Scalabrini D,
Bonadonna G, Gianni AM; Michelangelo
Foundation; Gruppo Italiano di Terapie Innovative
nei Linfomi; Intergruppo Italiano Linfomi. ABVD
versus BEACOPP for Hodgkin’s lymphoma when
high-dose salvage is planned. N Engl J Med. 2011;
365: 203-12.
Blood. 2011; 118: 4421-30.
111
pediatric oncology
Brain tumors. The Division is the national coordinator
for trials in localized medulloblastoma that are in the
pipeline. Coordination continues for the second national
study on ependymoma (129 patients) for the European
protocol.
Brain stem gliomas. A pilot study with concomitant
radiotherapy, anti-EGFR nimotuzumab and vinorelbine has
accrued 21 patients demonstrating an improvement with
previous results in PFS and OS.
Neuroblastoma. The Division has the national coordination of the pan-European protocol for high-risk
neuroblastoma; over 370 Italian patients have been
enrolled so far (51 by our unit).
Wilms tumor. The Division chairs the national Working
Group for clinical and biological studies, and also chairs
the relapse program.
Soft-tissue sarcomas. Accrual for the EpSSG trials (cocoordinated by one of us) is ongoing: 2010 patients from
16 different countries, 212 from our center, the highest
accrual.
Rare childhood tumors. The Division co-coordinates a
national-scale cooperative project for the most uncomHEAD
Maura Massimino, MD
Michela Casanova, MD
Graziella Cefalo (until September 30)
Andrea Ferrari, MD
Roberto Luksch, MD
Cristina Meazza, MD
Daniela Polastri, MD
Filippo Spreafico, MD
Monica Terenziani, MD
RESEARCH STAFF
Veronica Biassoni, MD
Serena Catania, MD
Cristina Meazza, MD
Marta Podda, MD
Elisabetta Schiavello, MD
Marco Vajna de Pava, MD
Carlo Alfredo Clerici, MD psychologist
Barbara Giacon, psychologist
Fabio Simonetti, MD
Francesca Favini, resident
Paola Gorgoglione, Gabriella Vighi
DATA MANAGERS
Luna Boschetti, Chiara Secco
mon pediatric cancers. Since the project started, 600
patients have been enrolled (one third from our center).
A European Network has been established on rare
tumors, called EXPeRT (European Cooperative Study
Group on Pediatric Rare Tumors): a member of our center co-coordinates the group.
Bone tumors. A new protocol for localized limb osteosarcoma has been launched, including mifamurtide for
adverse biological features.
Germ-cell malignancies. The Unit is the national coordinator for this trial.
New drugs. A phase 1 “first-in-child” trial with LDE225
(anti-SMO) and two front-line randomized trials in
metastatic sarcoma and high-grade glioma with
bevacizumab.
Board member of Pan-European Network for Care of
Survivors after Childhood and Adolescent Cancer (PanCare) Adolescents. Our center leads the AIEOP national
Working Group. A Youth Project has been recently
launched by our Unit.
Keywords: international trials, new drugs, adolescents
TECHNICIANS
Elena Barzanò
SOCIAL WORKERS
Giovanna Casiraghi, Michela Rapetti
TEACHERS
Stefania Benedetti, Franca Bertola, Cinzia
Cassanelli
EDUCATORS
Antonia Biasi, Manuela Farina, Maria
Cremona, Andrea Gazzi, Angelo Prati,
Delia Rimoldi
NURSES
Mariangela Armiraglio (head nurse), Cecilia
Alberti, Giulia Antonacci, Iris Baranella,
Morena Berti, Daniela Bruno, Cristina
Comelli, Patrizia Conti, Domenica Costeri,
Lucia Curelli, Ruggero Fauro, Marta Ferrante,
Carmelo Fiorello, Giuseppe Forzini, Marinella
Gaidolfi, Rossana Ghezzi, Laura Lottaroli,
Simone Macchi, Rossana Marra, Manuela
Oriani, Elisa Procopio, Silvana Saverino, Elisa
Triglia
Annamaria Bilanzuoli, Gisella Cancedda, Rita
Carulli, Silvana Celauro, Rita Marina Tamburo,
Stella Uzzardi
RELEVANT NOTES
Collaborations
AIEOP (Associazione Italiana di Ematologia
Oncologia Pediatrica); SIOP (International Society
for Pediatric Oncology) COG (Children
Oncology Group) ISG (Italian Sarcoma Group)
Publications
Chosen among the over 30 already published:
Ferrari A, Miceli R, Rey A, Oberlin O, Orbach D,
Brennan B, Mariani L, Carli M, Bisogno G,
Cecchetto G, De Salvo GL, Casanova M,
Vannoesel MM, Kelsey A, Stevens MC, Devidas M,
Pappo AS, Spunt SL. Non-metastatic unresected
paediatric non-rhabdomyosarcoma soft tissue
sarcomas: results of a pooled analysis from United
States and European groups. Eur J Cancer. 2011;
47: 724-31.
Massimino M, Gandola L, Barra S, Giangaspero F,
Casali C, Potepan P, Di Rocco C, Nozza P, Collini P,
Viscardi E, Bertin D, Biassoni V, Cama A, Milanaccio
C, Modena P, Balter R, Tamburrini G, Peretta P,
Mascarin M, Scarzello G, Fidani P, Milano GM, Sardi
I, Genitori L, Garrè ML. Infant ependymoma in a
10-year AIEOP (Associazione Italiana Ematologia
Oncologia Pediatrica) experience with omitted or
deferred radiotherapy. Int J Radiat Oncol Biol
Phys. 2011; 80: 807-14.
Contributions
Eupolis Master for Hospital Management (M.
Massimino) Editor of the book: D. Schneider, I.
Brecht, T. Olson, A. Ferrari. Rare tumors in children
and adolescents. Springer (with many
contributors in the Unit).
112
adult sarcoma medical treatment
This Medical Oncology Unit deals with adult patients with
sarcomas and peritoneal mesothelioma within the institutional Multidisciplinary Sarcoma Group.
In 2011, the Unit had more than 450 inpatient admissions
and over 5000 outpatient visits, with more than 1000 new
sarcoma patients seen. About 600 new sarcoma patients
were clinically shared with other Italian centers through the
Italian Network on Rare Cancers (RTR), a project aimed at
distantly sharing cases of adult patients with rare solid cancers to improve the quality of care and reduce patient
migration.
The Unit has always had a strong focus on networking. In
addition to coordinating the national project of RTR, it
coordinates the rare cancer area of the Rete Oncologica
Lombarda (ROL), the cancer network of Lombardy
Region. The Unit also submitted a project to create a virtual center on mesenchymal neoplasms in collaboration
with RTR and ROL by joining some centers in the Milan
area. From 2012, this should result in a highly strengthened
sarcoma facility in the Milan area, with the potential of
serving as one of the main reference centers for sarcomas
in Europe.
The Unit was involved in driving the update of the ESMO
Clinical Guidelines on STS and GIST and the Clinical
Guidelines on Sarcomas and Rare Tumors within the
Regional Cancer Network. Clinical research activities
2011 RELEVANT NOTES
Publications
Casali PG, Sanfilippo R. Uterine sarcomas: a
multidisciplinary challenge. Eur J Cancer 2011; 47
Suppl 3: S326-7.
Casali PG. Medical oncology: the long-awaited prize
of recognition. Ann Oncol. 2011;22(8):1695-7.
Stacchiotti S, Casali PG. Systemic therapy options
for unresectable and metastatic chordomas. Curr
Oncol Rep. 2011; 13: 323-30.
Stacchiotti S, Palassini E, Sanfilippo R,Vincenzi B, Arena
MG, Bochicchio AM, De Rosa P, Nuzzo A,Turano S,
Morosi C, Dei Tos AP, Pilotti S, Casali PG. Gemcitabine in advanced angiosarcoma: a retrospective case
series analysis from the Italian Rare Cancer Network.
Ann Oncol. 2012; 23(2): 501-8.
included the participation in 37 prospective clinical studies
on sarcomas, with 60 patients enrolled in 2011. Among
others, the Unit was the first enrolling center in the international trial on regorafenib in advanced pre-treated GIST;
it coordinates the medical therapy of the Italian Sarcoma
Group trial on neoadjuvant histology-driven chemotherapy
of high-risk soft tissue sarcomas; it coordinates a study in
imatinib resistant-chordomas on imatinib + everolimus.
In 2011, among others, the Unit published significant contributions to further understand the role of trabectedin
and sunitinib in soft tissue sarcomas. It co-signed the general report of the RARECARE project, which finalized a
clinically and epidemiologically sound definition of “rare
cancers”, also providing a “list” of them, with incidence,
prevalence, and survival data in Europe. It co-signed the
report of an important retrospective
clinical/molecular/pathologic study on the natural history of
GIST. Other significant scientific papers were accepted and
are due for publication in 2012, among others with regard
to: a Phase 2 study on imatinib in chordoma, which the
Unit coordinated after first reporting the efficacy of this
targeted therapy in such a rare disease; the Italian Sarcoma
Group trial on 3 vs. 5 cycles of neoadjuvant chemotherapy
in high-risk soft tissue sarcomas; other reports on the histology-driven approach to soft tissue sarcomas.
Keywords: adult sarcoma, GIST, rare cancers
Italiano A, Laurand A, Laroche A, Casali P, Sanfilippo
R, Le Cesne A, Judson I, Blay JY, Ray-Coquard I, Bui
B, Coindre JM, Nieto A, Tercero JC, Jimeno J, Robert
J, Pourquier P. ERCC5/XPG, ERCC1, and BRCA1
gene status and clinical benefit of trabectedin in
patients with soft tissue sarcoma. Cancer. 2011;
117(15): 3445-56.
Stacchiotti S, Negri T, Zaffaroni N, Palassini E,
Morosi C, Brich S, Conca E, Bozzi F, Cassinelli G,
Gronchi A, Casali PG, Pilotti S. Sunitinib in
advanced alveolar soft part sarcoma: evidence of a
direct antitumor effect. Ann Oncol. 2011; 22(7):
1682-90.
Sanfilippo R, Miceli R, Grosso F, Fiore M, Puma E,
Pennacchioli E, Barisella M, Sangalli C, Mariani L,
Casali PG, Gronchi A. Myxofibrosarcoma:
Prognostic Factors and Survival in a Series of
Patients Treated at a Single Institution. Ann Surg
Oncol. 2011; 18: 720-5.
Contributions
Paolo G. Casali is: Member of the Executive Board
of the European Society for Medical Oncology
(ESMO) as Chair of the Public Policy Committee;
Member of the Sarcoma Faculty of the European
Society for Medical Oncology (ESMO); Member of
the Policy Committee of the European Cancer
Organization (ECCO); Secretary of the Italian
Sarcoma Group; Member of the EORTC Soft
Tissue and Bone Sarcoma Group; Coordinator of
the Italian Network on Rare Tumors; Member of
the Regional Oncology Commission, Regione
Lombardia, Italy; Coordinator of the Rare Cancer
Group of the Lombardia Oncology Network;
Editor in chief of Clinical Sarcoma Research
(http://www.clinicalsarcomaresearch.com)
HEAD
Paolo G. Casali, MD
Rossella Bertulli, MD; Beatrice De Troia, MD;
Elena Fumagalli, MD; Michela Libertini, MD;
Andrea Marrari, MD; Elena Palassini, MD;
Roberta Sanfilippo, MD; Silvia Stacchiotti, MD
RESIDENTS
Mauro Rossitto, MD
DATA MANAGERS
Camilla Cassani, PhD; Cinzia Molendini, PhD
ADMINISTRATIVES
Stefania Cimbari, PhD; Anabela Di Giovanni,
PhD; Paola Esposti; Elisabetta Prati, PhD
Data managers and administrative staff are shared with
the Head and Neck Cancer Medical Oncology Unit
113
head and neck cancer medical oncology
The Unit performed the following clinical activities in
2011: 474 inpatient admissions, 75 day hospital
admissions, and 3723 outpatient visits. In 2011, the following clinical trials were conducted: five studies were
opened with 58 patients enrolled; five trials on thyroid
cancer, nine on squamous head and neck cancer, one on
salivary gland tumor, and one on basal cell carcinoma
were active. The Unit was also involved in the establishment of the oncological network in Lombardy (ROL) for
head and neck cancers.
Keywords: head and neck cancer, medical oncology, clinical research
HEAD
Lisa Licitra, MD
Cristiana Bergamini, MD
Paolo Bossi, MD
Laura Locati, MD
Aurora Mirabile, MD
RESIDENTS
Roberta Granata, MD
Carlo Resteghini, MD
Martina Imbimbo, MD
Data managers and administrative staff are shared with
the Adult Sarcoma Medical Treatment Unit
RELEVANT NOTES
Collaborations
Lisa Licitra is a member of the board of the
EORTC and chair-elect of the Head & Neck
EORTC group
The Unit coordinates the START project.
Publications
Bossi P, Orlandi E, Bergamini C, Locati LD, Granata
R, Mirabile A, Parolini D, Franceschini M, Fallai C,
Olmi P, Quattrone P, Potepan P, Gloghini A, Miceli R,
Mattana F, Scaramellini G, Licitra L. Docetaxel,
cisplatin and 5-fluorouracil-based induction
chemotherapy followed by intensity-modulated
radiotherapy concurrent with cisplatin in locally
advanced EBV-related nasopharyngeal cancer. Ann
Oncol. 2011; 22(11): 2495-500.
Contributions
Granata R, Miceli R, Orlandi E, Perrone F, Cortelazzi
B, Franceschini M, Locati LD, Bossi P, Bergamini C,
Mirabile A, Mariani L, Olmi P, Scaramellini G,
Potepan P, Quattrone P, Ang KK, Licitra L. Tumor
stage, human papillomavirus and smoking status
affect the survival of patients with oropharyngeal
cancer: an Italian validation study. Ann Oncol. 2011
Dec 21.
The Unit is responsible for the production and
updating of guidelines for head and neck cancer.
Lisa Licitra is:
Associate Editor, Annals of Oncology
Chair Head and Neck faculty for ESMO
114
medical day hospital
The Day Hospital and Oncologic Outpatient Therapy
Unit (MDH) treats adult patients referred by different
clinical Units of the Department. The complexity of some
oncologic medical treatments and the increasing number
of medical trials frequently require close observation during treatment and one day hospitalization. Treatments are
prepared by specialized nurses who dilute therapeutic
agents in a protected area equipped with two air flow
cabinets, and administer them under the supervision of
MDH physicians. A separate section is dedicated to short
duration regimens or biological therapies by infusion
pump systems and management of central venous
catheters. Special care is given to management and prevention of emesis, diarrhea, extravasation of cytotoxic
drugs, and acute drug reactions for which a project about
pharmacovigilance (FARMAONCO) is ongoing. The referent physician of this regional project is Dr. Ferrari since
2009. The acute adverse effects are reported, with the
help of Dr. Fanetti, in a database. A room in the outpatient clinic is dedicated to diagnosis, treatment, and
follow-up in patients diagnosed with neuroendocrine
tumors (NET) and a database with all NET cases
followed in our Institution is ongoing with the collaboration of Dr. Damato. Our Institution has been certified as a
Center of Excellence by the European Society Neuroendocrine Tumors.
In 2011, the activity of MDH consisted in approximately
21,500 procedures (monthly average activity of 1800).
51% of these procedures were short therapies, 36% long
therapies, 4% treatments requiring admission, and 9%
were medical procedures (i.e. CVC medications, lumbar
puncture, bone marrow biopsy). The cancer types treated
were breast cancer (35%), gastrointestinal cancer (20%),
hematologic malignancies (23%), melanoma (6%), lung
cancer (8%), head and neck cancer (2.5%), sarcomas
(1.5%), and other tumors (3%). Moreover, about 100
adverse drug reactions were reported during the year.
Keywords: medical procedures, adverse drug reactions,
neuroendocrine tumors
HEAD
Roberto Buzzoni, MD
Laura A.M. Ferrari, MD
CLINICAL FELLOWS
Giuseppe Fanetti, MD
Angela Damato, MD
Anna R. Cabiddu
Antonella Bifano
NURSES
Deborah Zordan (head nurse), Chiara
Bernasconi, Domenica Comberiati, Lucia
D’Agnessa (pharmacy), Laura Di Vico,
Claudia Facchinetti, Anna Frisario, Lucia
Giordano, Francesca Maffione, Elena Nuti,
Maria Paolillo, Maria N. Pisanu, Stefania
Russo, Elena Sala (pharmacy), Laura Sala,
Sonia Sanapo, Pietrina Sanna
Vincenzina Arnone, Fabio Di Bartolo, Lucia
A. Di Murro, Maria Rosa Forte, Anna Maria
Meloni, Rita Trovato
RELEVANT NOTES
Contributions
Publications
Roberto Buzzoni is a member of the Editorial
Board of Tumori
Platania M, Agustoni F, Formisano B, Vitali M,
Ducceschi M, Pietrantonio F, Zilembo N,
Gelsomino F, Pusceddu S, Buzzoni R. Clinical
retrospective analysis of erlotinib in the treatment
of elderly patients with advanced non-small cell
lung cancer. Target Oncol. 2011; 6(3): 181-6.
Procopio G, Verzoni E, Iacovelli R, Guadalupi V,
Gelsomino F, Buzzoni R. Targeted therapies used
sequentially in metastatic renal cell cancer: overall
results from a large experience. Expert Rev
Anticancer Ther. 2011; 11(11): 1631-40.
The Unit is in part responsible for the production
and updating of NET guidelines of the ROL
Clinical Guidelines
Roberto Buzzoni in center coordinator, ENET
center of excellence (Milan)
Laura A.M. Ferrari is a member of the Commission
“Dirigenza Medica” of Milan Medical Association
Laura A.M. Ferrari is INT Referent Member at
“Dipartimento Oncologico Milanese”
117
ANESTHESIA, INTENSIVE CARE,
PAIN THERAPY, AND PALLIATIVE
CARE DEPARTMENT
Martin Langer
Professor of Anesthesiology
University of Milan
+39 02 2390 2139
[email protected]
UNITS
CLINICAL ANESTHESIA
Martin Langer
INTENSIVE CARE
Myriam Favaro
PALLIATIVE CARE, PAIN THERAPY,
AND REHABILITATION
Augusto T. Caraceni
SUPPORTIVE CARE IN CANCER
Carla I. Ripamonti
CLINICAL NUTRITION
Cecilia Gavazzi
The department has 4 main missions:
1) Perioperative medicine
2) Treatment of chronic pain and supportive care in cancer patients
3) Palliative care and terminal support in the hospice and in-home care for
patients with advanced cancer after failure of aggressive treatments
4) Safety in the hospital.
The Department has a key position in the hospital, and is involved in the medical and surgical treatment of cancer patients with very close collaboration
with surgeons, medical oncologists, and pediatricians, in addition to
radiologists, for many different interventional treatments.
A very relevant innovation in 2011 is the establishment of the Master Course
(Master Universitario di II° livello) of the University of Milan in Palliative Medicine, one of the first active in Italy, which primarily involves our specialists in
palliative care, but also many other physicians at the Institute.
Anesthesia, Intensive Care, Pain Therapy, and Palliative Care Department
118
clinical anesthesia
The INT runs a very intense surgical program, and the
Anesthesia Team must care for challenging surgical procedures such as liver transplantation, major liver resection,
peritonectomy-HIPEC, and resection of tumors in the
thorax and retroperitoneum. The hospital is also a referral
center for solid tumors in pediatric patients, and anesthesiologists are involved not only in the operating room
(OR), but also have to care for many other procedures
such as long-term central venous catheter placement and
anesthesia for diagnostics and radiotherapy. In spite of a
relevant shortage of OR nurses, we maintained the previous planning of surgical activity with 73 hours/week and
more than 100% utilization of planned time. Quality
improvement programs during 2011 were focused on
patient safety (the check list and the TIME-OUT procedure) and care for acute, postoperative pain.
Patient-controlled analgesia is provided for about 40-50%
of patients with major surgery, epidural analgesia with
elastomeric pumps in 20-25%, while continuous
HEAD
Martin Langer, MD
Mario Ammatuna MD, Maria Grazia Bonalumi
MD, Anna Cardani MD, Roberta Casirani MD,
Pasqualina Costanzo MD, Ilaria Donati MD,
Luca Fumagalli MD, Edward Arturo Haeusler
MD, Antonio Maucione MD, Silvana
Migliavacca MD, Lucia Miradoli MD, Federico
Piccioni MD, Andrea Poli MD; Giacomino
Rebuffoni MD, Giuseppe Rigillo MD, Mara G.
Roberto MD, Emiliano Tognoli MD,
Alessandro Zanon MD
RESIDENTS
Camilla dell’Acqua MD, Valentina Colosio
MD, Marco Carbonara MD, Giuliana Motta
MD Giada Donà MD, Camilla L’Acqua MD,
Marco Carbonara MD, Rosalia Paternò MD,
Marta Negri MD, Ilaria Rivetti MD, Sara
Mirandola MD
Stefania Bettinardi, Fiorina Cantisani
NURSES
Romano Castellari (head nurse), Teresina
Altana, Anchora Elisabetta, Stefania S.
Andreoli, Laura Elisabetta Anselmi, Marina
Balbi, Marco Balconi, Silvana Bertoli,
Gabriella Bianchessi, Renata Bordonali,
Rossella Brambilla, Debora Buenaventura
Boada, Julia D. Burgos Baena, Claudia
Calderara, Antolella Chiesa, Hipolito V. Otani,
Liviu D Corbu, Maria B. Corbu, Matrona De
Felice, Maria Della Croce, Simonetta Delrio,
Andrea Dibiase, Maria A. DiTano, Marina
intravenous opioid infusion by an elastomeric pump is the
treatment chosen for the remaining 30-40%. The pain
team visits patients at 3-4 days after surgery and tailors
treatment as necessary. The acute postoperative pain
project and the results obtained won the prestigious
prize “Premio Nazionale Nottola – Mario Luzi, 2011”.
Our training program for residents in the Anesthesia and
Intensive Care Program at the University of Milan is well
established and allows 5-7 young doctors yearly to
become familiar with clinical anesthesia and pain therapy.
The projects founded by the 5% contributions of the
Fondazione (the acute pain team and the central venous
catheter project) are ongoing with satisfactory results.
Two research projects, led by Dr. Tognoli (on the possible
opioid sparing effect of ketamine and methadone) and
Dr. Piccioni (on postoperative residual curarization) are
still enrolling patients.
Keywords: anesthesia, palliative care, supportive care
Djokic, Luca G. Falcone, Federica Fiorini,
Claudio Gasparro, Angelo Giannuzzi,
Rosanna Giumbo, Marcella Gozzo, Mara G.
Longo, Ezio Luzzi, Margherita A. Marzo, Anna
Rita Mazzotta, Annamaria Morricella,
Antonella Nieddu, Cosmina V. Noti, Barbara
Ottonello, Lucia Orru, Maria R. Pezone,
Cecilia Pifarotti, Flavia F. C. Ravasi, Manuela
Riva, Stefania Ronca, Maria A. Jolanda Rosso,
Massimo Sanseverino, Salvatore Santucciu,
Sara Sciamanna, Paola Striglia, Ioan Marius
Tere, George F. Titi, Adriana Valentini, Filippo
Venezia, Mirella A. Zaninelli, Silvia Zanotto.
Rosa Maria Benvenuto, Pierangela Carrino,
Denise de Bastiani, Annuccia Delrio, Miriam
Faccini, Antonio Labori, Anna Lorenti, Maria
Maestri, Stefania Massella, Monica
Mastrogiovanni, Maria C. Pirrotta, Maria C.
Pisasale, Elisabetta Saccaggi, Elena Scotti,
Carmelo Scrofani, Rosa Selvati, Rosa M.
Tirone
TECHNICIANS
Maria Irene Cipolletta, Giovanni Di Bari,
Gerardo Gizzi, Gianbattista Grazioli, Monica
Mastrogiacomo, Luca Pedone
2011 RELEVANT NOTES
Collaborations
University of Milan: Istituto di Anestesiologia,
Terapia Intensiva e Scienze Dermatologiche;
Scuola di Specialità in Anestesia e Rianimazione.
Publications
E.A.Haeusler: Il paziente sottoposto a chirurgia
polmonare in “Il monitoraggio delle funzioni vitali
nel perioperatorio non cardochirurgico” a cura di
B. Allaria e M. Dei Poli. Springer Verlag Italia, 2011
ISBN 978-88-470-1722-1 DOI 10.1007/978-88470-1723-8, pg 257-271.
Bertolini G, Rossi C, Crespi D, Finazzi S,
Morandotti M, Rossi S, Peta M, Langer M, Poole D.
Is influenza A(H1N1) pneumonia more severe
than other community-acquired pneumonias?
Results of the GiViTI survey of 155 Italian ICUs.
Intensive Care Med. 2011; 37(11): 1746-55.
Contributions
Martin Langer is Director of the Master Course in
Palliative Medicine (Master Universitario di II
livello Medicina Palliativa)
119
intensive care
Monitoring and surveillance of high-risk surgical patients
in the immediate postoperative period and intensive
treatment of patients with life-threatening postoperative
complications or organ failure of different origins is the
mission of the Intensive Care Unit (ICU). The Unit is
equipped with 6 ICU beds, and in 2011 admitted 581
patients (80% after scheduled surgery) for 1467 overall
treatment days. Two physicians during the day and one at
night are available, with the nurses of the ICU, for emergencies in the Institute, counseling for critically-ill patients
in different wards, and blood gas and point-of-care analyses for all patients. 452 central venous catheters, both as
elective and as emergency procedures, were placed by
ICU physicians; we also started a program for the longterm catheter positioning (39 Groshong and 9 Port a
Cath catheters). Liver function was investigated by DDG
in 31 patients, mainly preoperatively, before major liver
resections. Percutaneous tracheotomies (“Griggs”and
“Percutwist”), were performed in 8 patients on prolonged
HEAD
Myriam Favaro, MD
Valerio Costagli, MD
Fortunato D’Elia, MD
Marco Faustini, MD
Renato Manzi, MD
Laura Persiani, MD
Maurillia Rizzi, MD
Edda Merola, MD
NURSES
M. Savioli, M. Gasparini, R. Di Nino, A.
Simonetti, F. Filippazzo, S. Alcamo, A. Casali,
S. Sirigu, S. Romero Lemos, E. Lonetti, M.
Zoanni, M. Boccola, A. Cofone, L. Morsenti,
F. Montalto, R.Santini, A. Ferraresi
G. Montecalvo, E. Zedda, R. Zicconi,
C. Garzon
mechanical ventilation. We continued to treat patients
with failing liver function and hyperbilirubinemia with
extracorporeal “plasma-adsorption-perfusion” during 40
sessions. We started a new activity in the surgical day
hospital: sedo-analgesia in patients scheduled for limited
resections of breast cancer (288 patients) and we
adopted sedo-analgesia even for patients with metastatic
melanoma (228 patients), gynecologic cancer (387
patients) and in plastic surgery (259 patients). This ICU
has been chosen as Italian party leader in the Clean Care
Project of the WHO finalized to optimize patient safety in
hospital. We are also participating in a new national study
(ALBIOS) on the efficacy of albumin administration for
volume replacement in patients with severe sepsis or
septic shock, and since 2008 we adhere to the
MARGHERITA project aimed at quality improvement
coordinated by the GiViTI network at the Mario Negri
Institute.
Keywords: monitoring, emergency procedures, surgical day hospital
120
palliative care, pain therapy, and rehabilitation
The clinical and research program reflects the two-fold
mission of the unit, namely palliative care and rehabilitation. The program is multidisciplinary and multiprofessional including the control of physical symptoms,
psychological and social support and the alleviation of
existential suffering with early integration with antineoplastic interventions for incurable cancer. Cancer
Rehabilitation provides interventions that are appropriate
for the recovery of acute and chronic consequences of
surgery, radiation-therapy, and medical treatments as well
as to support the complications of advanced cancer. In
2011, the following results highlight the quantitative
aspects of the clinical activity: 197 inpatient unit (Hospice)
admissions, 2136 day-hospital admissions, 32,703 outpatient clinic treatments, 12,185 inpatients consults, and 1
home care (hospital at home) admission. The research
program in 2011 continued the activity of the European
Palliative Care Research Center (PRC) founded as a collaborative between our unit and the Cancer department
at the University of Science and Technology in Trondheim
(Norway).
The following research projects are concluded, ongoing
or initiated:
• European Palliative Cancer Care Symptom Study
(EPCCS)
• Pain assessment and classification, international consensus, systematic reviews, and empirical research
• Cancer pain opioid guidelines revision in collaboration
with the European Association for Palliative Care
• Opioid pharmacogenetic study identified multiple
genetic loci modulating individual pain response to opioids
• A multicenter national trial on cancer pain with 4 different opioids in collaboration with the Mario Negri
Institute. This trial combines the assessment of genetic
material.
• A phase II trial on methylnaltrexone for opioidinduced constipation (concluded)
• Systematic review on hydration and nutrition within
OPCARE (7th EU framework)
• National multicenter cluster randomized trial on Liverpool Care Pathway
Keywords: cancer pain, palliative care, rehabilitation
HEAD
Augusto T. Caraceni, MD
Augusta Balzarini, MD
Fulvia A. Gariboldi, MD
Cinzia A. Martini, MD
Luigi Saita, MD
Ernesto Zecca, MD
RESEARCH STAFF
Paola Bracchi, MD
Cinzia Brunelli, ScD
Tiziana Campa, MD
Laura Campanello, PhyD
Marco Carminati
Gianluigi Cislaghi
Daniela G.M. Ermolli, MD
Elena Fagnoni, MD
Nausika Gusella, PsyD
Andrea Magni, MD
Alessandra Pigni, MD
Carmela P. Sigari, MD
Fabio Simonetti, MD
PHYSICAL THERAPISTS
Livia I. E. Bedodi, Maria G. Blandini, Chiara
Bottani, Simona Breggiè, Paola Campanini, Lucia
M. Cavallini, Anna B. Cotza, Liviana Craba,
Heike Feddersen, Cinzia A. Ficcarelli, Donato F.
Ficchì, Alida M. E. Grossi, Chiara Piazza, Patrizia
Placucci, Raffaella Sensi, Beatrice Simoncini
NURSES
Barbara Acquisto, Maria Chiara Allemano,
Giuseppe Baiguini, Claudio Baratella, Barbara
Benegiamo, Sara Bianchi, Giuseppina
Bottigliero, Rosa A. Candigliota, Angela
Carugati, Olmina Di Florio, Massimo Di
Francesco, Floriana Dimo, Vincenzina Ferraro,
Elsa R. Lovo, Anna M. Mazzucchelli, Rosa
Olivieri, Nives Porta, Edoardo Rossetti, Arianna
Rossi, Elisabetta Volpato
Raffaela Diaferio, Maria Rosaria Lia, Nataliya
Maksymova, Cristina Marras, Anna Mastroianni,
Teresa Natali, Teresa Pace, Nicola Paternoster
Emanuela Brusati, Loredana D’Urso, Loredana
R. Illuminato
TECHNICIANS
Maria Libera Cipolletti, Martinelli Brunella
RELEVANT NOTES
Collaborations
Istituto di ricerche farmacologiche Mario Negri, Milan;
Department of cancer and molecular biology Norwegian
University of Science and Technology, Trondheim, Norway;
Istituto Nazionale Tumori di Genova (IST); European
Association for Palliative Care Research Network St
Christopher’s Hospice London
Publications
Caraceni A, Pigni A, Brunelli C. Is oral morphine still the first
choice opioid for moderate to severe cancer pain? A
systematic review within the European Palliative Care
Research Collaborative Guidelines Project. Palliat Med. 2011;
25: 402-9.
Galvan A, Skorpen F, Klepstad P, Knudsen AK, Fladvad T,
Falvella FS, Pigni A, Brunelli C, Caraceni A, Kaasa S, Dragani
TA. Multiple loci modulate opioid therapy response for
cancer pain. Clin Cancer Res. 2011; 17: 4581-7.
Contributions
Editorial board of Journal of pain and symptom management,
Minerva Anestesiologica
High specialization course in oncological lymphology
Università degli Studi di Milano
121
supportive care in cancer
The Unit (out-patient and Day Hospital settings) has clinical, educational, and research objectives aimed at the
assessment, treatment, and study of prevention and treatment of side effects or toxicity resulting from cancer
therapy as well as in the cure of emotional, social, and
spiritual patient needs through GLOBAL CARE of
patients starting from diagnosis. The primary purpose is
to support, through an integrated and ancillary activity,
the work of each specialist and to implement supportive
medical therapy for the patient during the entire period
of cancer treatment to ensure the physical well being of
the patient and improve adherence to treatment protocols in terms of dose-intensity and dosing intervals.
Moreover, the Unit provides real-time answers to oncological emergencies by treating patients suffering from
iatrogenic toxicity. An additional objective is to give support to family, survivors, and personnel involved in daily
care. The treatments carried out are compliant with the
guidelines of the WHO, MASCC, ESMO, and AIOM. We
work in integration with INT Units and administer the
following therapies: hydration, electrolytes, diuretics,
steroids, octreotide, glutathione, transfusions, antivirals,
antifungals, antibiotics, analgesics, IV nutrition (not TPN),
IV bisphosphonates, iron immunoglobulins, and antiemetics. All patients are regularly assessed for the presence
and intensity of physical and psychological symptoms, and
spiritual and social needs. They have the support of a
chaplain and/or social worker and/or psychologists during
the infusion of drugs. The clinical activity was significant in
2011: visits (3182); Day Hospital patients (1360); infusions
as out-patient regimen (1972); transfusions (501); IV bisphosphonates (zoledronic acid) (722).
Keywords: supportive care, oncological treatments, bone health
HEAD
Carla Ripamonti, MD
Maria Adelaide, MD
Stefania Boldini, MD
NURSES
Pietro Toma, Maria Albertina Sorgato,
Rosanna Scarpa
Chiarina Pireddu, Volunteers, Anna Aquilini, Anna
Cremonesi, Adriana Cremagnani, Ivana Zaglio,
Antonella Puntieri, Renata Nobili, Fulvia
Sangermani
RELEVANT NOTES
Publications
Collaborations
Ripamonti C, Bandieri E, Roila F, on behalf of the
ESMO Guidelines Working Group. Management of
cancer pain: ESMO Clinical Practice Guidelines. Ann
Oncol 2011; 22 (Suppl 6): 69-77.
WHO, ESMO, Multinational Association of
Supportive Care in Cancer (MASCC), AIFA,
Department of Clinical Pharmacology and
Epidemiology, Consorzio Mario Negri Sud, Santa
Maria Imbaro (Chieti); Societa’ Italiana di
Osteoncologia (ISO), Associazione Malati
Oncologici Nove Comuni Modenesi Area Nord
(AMO), Department of Oncology, Hematology
and Respiratory Diseases, Azienda Ospedaliera
Universitaria, University of Modena and Reggio
Emilia, Italy; Psychology Unit, Center for
Oncological Rehabilitation-CERION of Florence;
Clinical Epidemiology Unit, ISPO-Institute for the
Study and Prevention of Cancer, Florence;
Department of Psychology University of Milano
Bicocca; CeVEAS, WHO Collaborating Centre,
Modena; Liguria Regional Coordination of Palliative
Care, (IST), Genova; Palliative Care Unit ASL BiBiella; Campus Biomedico Roma; University of
Verona (Specialties of Internal MedicineRheumatology and Oncology); Istituto Scientifico
Romagnolo; University of Turin (Specialization in
oncology)
Ripamonti C, Cislaghi E, Mariani L, Maniezzo M.
Efficacy and safety of medical ozone (O(3))
delivered in oil suspension applications for the
treatment of osteonecrosis in patients with bone
metastases treated with bisphosphonates:
Preliminary results of a phase I-II study. Oral Oncol
2011; 47: 185-90.
Ripamonti C, Valle A, Acerbis F, Pessi MA, Prandi C.
[Project “Hospital without pain”: analysis of the
Italian situation before the law 38]. Assist Inferm Ric
2011; 30: 95-9.
Contributions
Updated guidelines on the use of Bisphosphonates
in Bone Metastases for the Associazione Italiana di
Oncologia Medica (AIOM)
ESMO guidelines “Management of cancer pain:
ESMO Clinical Practice Guidelines” 2011. Adviser
in the working group for the preparation and the
development of the WHO Guidelines for
pharmacological treatment of persisting pain in
children with medical illnesses
Re-elected ESMO Faculty Member Educational
Committee Supportive and Palliative Care
Re-elected Italian Member of the Palliative Care
Working Group of the European Society Medical
Oncology (ESMO PCWG)
Re-elected Italian Member of Directors of the
International Association Hospice Palliative Care
(IAHPC)
Re-elected ESMO Media Ambassador for Pain
Therapy and Supportive Care topic
Cherny N, Catane R, Chasen M, Grigorescu A-C,
Hassan AA, Kloke M, Olver I, Ozyilkan O, Pohl G,
Ripamonti C, et al. A guide for patients with
advanced cancer. Getting the most out of your
oncologist. Edited by the Members of ESMO
Palliative Care Working Group. ESMO press 2011
www.esmo.org/patients/.
Member of the psychosocial and spiritual Working
Group Multinational Association Supportive Care
in Cancer (MASCC)
122
clinical nutrition
Malnutrition is a well-known negative factor in the final
prognosis of cancer patients as it reduces tolerance to
oncological treatment, increases morbidity and mortality,
and deteriorates the quality of life; nutritional intervention
should be considered throughout all the different phases
of oncologic therapy, from diagnosis and during surgery,
to chemotherapy and radiotherapy. Prevention and early
treatment of malnutrition are the main goals of the structure. In accordance with the recommendations of the
European Society of Clinical Nutrition, nutritional screening is undertaken in all patients with a high risk of
malnutrition, i.e. patients affected by gastrointestinal cancer, candidates for major surgery, and those affected by
head and neck cancer and candidate for combined
chemotherapy and radiotherapy. Patients affected by any
form of malnutrition are included in a comprehensive
nutrition program, which consists of nutritional status
monitoring and personalized nutrition therapy mainly
with artificial nutrition, both enteral and parenteral, nutritional counseling, and diet therapy. For those patients who
need prolonged periods of artificial nutrition, specific
training is performed by specialized nurses, logistic procedures are organized, and patients are discharged on
home artificial nutrition. In 2011, 424 inpatients were
included in a nutrition program and 2520 days of nutrition therapy were administered during hospitalization; 92
patients were discharged on home artificial nutrition.
Keywords: nutritional status, malnutrition, nutrition therapy
HEAD
Cecilia Gavazzi, MD
Alessandro Sironi, MD
Giovanna Pinelli, MD
RESIDENTS
Nicoletta Guanziroli, MD
Silvia Mercuro, MD
FELLOW
Jessica Lops
NURSES
Riva Lorena, Carmen Maiorana, Franca
Filicieri, Anna Armonti
Silvia Colatruglio
RELEVANT NOTES
Collaborations
Italian Society for Artificial Nutrition and
Metabolism
European Society for Parenteral and Enteral
Nutrition
Publications
Gavazzi C, Colatruglio S, Sironi A, Mazzaferro V,
Miceli R. Importance of early nutritional screening
in patients with gastric cancer. Br J Nutr. 2011; 106:
1773-8.
Pironi L, Joly F, Forbes A, Colomb V, Lyszkowska M,
Baxter J, Gabe S, Hèbuterne X, Gambarara M,
Gottrand F, Cuerda C, Thul P, Messing B, Goulet O,
Staun M, Van Gossum A, Gavazzi C. Home artificial
nutrition & chronic intestinal failure working group
of the European Society for Clinical Nutrition and
Metabolism (ESPEN). Long-term follow-up of
patients on home parenteral nutrition in Europe:
Implications for intestinal transplantation. Gut.
2011; 60: 17-25.
Contributions
Scientific Coordinator of international meeting
“Nutrition and oncology towards integration”
125
DIAGNOSTIC IMAGING
AND RADIOTHERAPY DEPARTMENT
Emilio Bombardieri
+39 02 2390 2220
[email protected]
UNITS
RADIOLOGY AND DIAGNOSTIC
IMAGING 1
Daniele Vergnaghi
IMAGING 2
Alfonso V. Marchianò
INTRALESIONAL TREATMENT
Francesco Garbagnati
IMAGING 3
AND BREAST IMAGING UNIT
Silvana Bergonzi
(retired December 2011)
Pietro Panizza
(present)
DIAGNOSTIC AND
INTERVENTIONAL
GASTROENTEROLOGY
Guido Cozzi
NUCLEAR MEDICINE
Emilio Bombardieri
CLINICAL PET
Flavio Crippa
NUCLEAR MEDICINE THERAPY AND
ENDOCRINOLOGY
Ettore Seregni
RADIOTHERAPY 1
Riccardo Valdagni
RADIOTHERAPY 2
Carlo Fallai
MEDICAL PHYSICS
Giancarlo Zonca
The Department of Diagnostic Imaging and Radiotherapy is a large multidisciplinary structure including different modalities for Diagnostic Imaging and
Radiotherapy. Three Radiologic Imaging Units RD1, RD2, and RD3, are dedicated to cancer diagnosis. RD1 carries out conventional radiologic tests
(X-rays) and magnetic resonance imaging (MRI); RD2 performs breast cancer
diagnosis (mammography, US, radioguided biopsies) and radiological tests for
the gastrointestinal tract; RD3 is dedicated to computed tomography (CT),
angiography, interventional radiology, and intralesional treatments. The Nuclear
Medicine Unit visualizes tumors by single photon emission tomography
(SPECT), planar examinations, and positron emission tomography (PET/CT). In
this Unit there are also: a section for radiochemistry with a 17 MeV cyclotron;
a section with protected beds dedicated to radiometabolic therapy, a radioisotope laboratory for radioimmunometric (IRMA) tests, and a clinic for
outpatients with endocrine disease. The external beam radiotherapy (3D conformal radiation therapy, intensity modulated radiotherapy (IMRT), Rapid Arc,
and 2D conventional radiotherapy) is the main activity of the Unit of Radiotherapy 1 (RT1). The activity of Unit of Radiotherapy 2 (RT2), in addition to
some applications of external beam radiotherapy, is focused on the high dose
rate brachytherapy (HDR-BT) and on the combination of chemo-radiotherapy
using a facility with 8 beds in 4 shielded rooms. A Medical Physics Unit supports Units RT1 and RT2 in planning radiotherapy treatments and dosimetric
calculations. This Units also take care of quality controls performed on the
instrumentation for diagnostic imaging.
126
radiology and diagnostic imaging 1
In 2011, RD1 carried out 12,039 MRI scans. MRI play a
fundamental role in cancer diagnosis in all anatomical districts. Moreover, in case of oncological treatments, it can
be essential in detecting tumor response or in distinguishing fibrotic tissue from disease relapse. Besides
morphological evaluation combined with the use of a
contrast medium, over the past year two emerging diagnostic functional tools, namely DWI and DCE, have been
widely improved to implement diagnostic interpretation.
Specific attention has been devoted to improve prostate
cancer staging by combined analysis of endorectal MRI
and magnetic resonance spectroscopy (endoMRI/MRSI).
Significant development has also been attained in the
analysis of colorectal cancer. Diagnosis and staging of
breast cancer also achieved a significant implementation,
especially in young patients and in those with high genetic
risk. Whole body MRI and whole body DWI have also
demonstrated their utility in detecting skeletal metastasis
in a single examination and in evaluating their degree of
aggressiveness. MRSI and DWI also provide a favorable
impact for diagnosis and follow-up of pediatric brain
tumors. MRI has been applied to evaluation of prosthetic
implants where it can be the only reliable tool to detect
rupture and to define intra or extra capsular modality of
the damage. Furthermore, thanks to its multiplanarity and
high contrast resolution, MRI can also detect silicone
migration within muscle fibers and lymphatic stations.
Keywords: MRI, functional imaging, diffusion imaging
HEAD
Daniele Vergnaghi, MD
Alberto Laffranchi, MD
Antonella Messina, MD
Paolo Potepan, MD
Giovanna Trecate, MD
Davide Scaramuzza, MD
Sonia Leone, Angelina Laganà, Giulia Melis
TECHNICIANS
Valeria Tosi, Nicola Pulerà, Annunziata
Gaetano, Cinzia Fossaceca, Tina
Mastrostefano, Antonella Laturra, Luca
Musumeci, Carmelina Pannone, Maurizio
Zattoni
NURSE
Loredana Palella
RELEVANT NOTES
Collaborations
Multicentric surveillance of women at high genetic
risk for breast cancer, in collaboration with Istituto
Superiore di Sanità in Rome. This collaboration
allowed to proceed with more than one round of
enrolment for breast cancer screening thus
improving MRI accuracy in anticipating cancer
detection. The results of this work have been
published in recent papers.
Breast cancer study in collaboration with the
Breast Unit to plan surgical treatment when
conventional examination are suspect for
multifocality to evaluate the extension of DCIS and
ILC.
Prostate project based on endorectal MRI and
magnetic resonance spectroscopic imaging
combined with DCE and DWI MRI.
Department of Biomedical Engineering of
Politecnico of Milan to develop new software
devoted to computer-aided diagnosis and follow-
up of whole body and head and neck MRI
examinations.
EORTC for the development of European MRI,
DCE-MRI, and DWI protocols in Phase II
chemotherapy studies.
Cortesi L, Corcione S, Morassut S, Di Maggio C,
Cilotti A, Martincich L, Calabrese M, Zuiani C,
Preda L, Bonanni B, Carbonaro LA, Contegiacomo
A, Panizza P, Di Cesare E, Savarese A, Crecco M,
Turchetti D, Tonutti M, Belli P, Maschio AD; for the
High Breast Cancer Risk Italian 1 (HIBCRIT-1)
Study. Multicenter surveillance of women at high
genetic breast cancer risk using mammography,
ultrasonography, and contrast-enhanced magnetic
resonance imaging (the High Breast Cancer Risk
Italian 1 Study): Final Results. Invest Radiol. 2011;
46(2): 94-105.
Publications
Contributions
Massimino M, Solero CL, Garrè ML, Biassoni V,
Cama A, Genitori L, Di Rocco C, Sardi I, Viscardi E,
Modena P, Potepan P, Barra S, Scarzello G, Galassi E,
Giangaspero F, Antonelli M, Gandola L. Secondlook surgery for ependymoma: the Italian
experience. J Neurosurg Pediatr. 2011; 8(3): 24650.
Collaboration with SIOP and Pediatric Oncology
Unit for the development of European guidelines &
protocols for diagnosis and follow-up of Brain MRI
pediatric brain tumors.
ISBE (Imaging Science and Biomedical Engineering)
in a project for evaluation of DCE-MRI in rectal
cancer.
SIOP and Pediatric Oncology Unit and
development of European protocols for diagnosis
and follow-up of brain MRI pediatric brain tumors.
Sardanelli F, Podo F, Santoro F, Manoukian S,
Bergonzi S, Trecate G, Vergnaghi D, Federico M,
Collaboration with EORTC for European
guidelines & protocols on head & neck cancer to
assess early response with DCE-DWI MRI.
127
Diagnostic oncology and interventional-oriented radiology represent the core activity of the Unit. Inpatients and
outpatients undergo a diagnostic work-up that includes
different steps of patient management: primary cancer
diagnosis, staging, follow-up, and monitoring after surgery,
chemotherapy, and radiotherapy. The lung cancer screening program (MILD) with “low dose” spiral CT continued
in 2011. We performed over 2000 low-dose spiral CT
exams, and we are currently testing a system of
computer-aided detection (CAD) of pulmonary nodules.
Two CT scanners, both provided with faster multi-slice
scanning capabilities are available, and about 22,000 diagnostic examinations per year and an extensive number of
interventional radiological procedures are carried out. All
types of percutaneous biopsies are currently performed
in our patients. Interventional radiology activities include
long-term venous central catheter placement, embolization, and chemoembolization for regional cancer
treatment. Intralesional radiofrequency ablation based
HEAD
Alfonso V. Marchianò, MD
Francesco Garbagnati, MD
Enrico Civelli, MD
Giuseppe Di Tolla, MD
Laura F. Frigerio, MD
Rodolfo Lanocita, MD
Carlo Morosi, MD
Carlo Spreafico, MD
Giovanni Capone, Giuliana Manzoni, Ornella
Venegoni
TECHNICIANS
Pietro Basile, Marilena Barbiero, Maria
Ferrarello, Roberto Gallo, Giuseppina
Gentile, Roberto Nioi, Antonio Perchinunno,
Geremia Porcelli, Salvatore Romaniello,
Luciana Tanzini, Vanni Tirella
NURSES
Pietro Ciccarese, Laura Fagnani, Roberta
Populin, Marinella Porceddu
RELEVANT NOTES
Publications
Use of a retrievable vena cava filter with lowintensity anticoagulation for prevention of
pulmonary embolism in patients with cancer: an
observational study in 106 cases. J Vasc Interv
Radiol. 2011; 22(9): 1312-9.
CT-guided percutaneous cryoablation of renal
masses in selected patients. La Radiologia Medica.
2011. Oct 21.
methods, such as chemo-interventional procedures consisting in local-regional drug delivery for malignancies of
the liver, head and neck, pelvis and limbs, have been successfully performed. An international multicentric study
on the treatment of inoperable hepatocellular carcinoma
with intra-arterial injection of yttrium-90 radiolabeled
microspheres is ongoing in collaboration with Units of
Nuclear Medicine and Gastrointestinal and Hepatopancreatobiliary Surgery and liver Transplantation. The Unit
has also developed an original experience of
percutaneous cryoblation in selected patients with small
renal tumors. During 2011, over 1000 vascular diagnostic
procedures, 500 vascular and non-vascular interventional
procedures, over 550 long-term venous central catheters,
and 600 percutaneous biopsies in various body districts
were performed.
Keywords: interventional radiology, multidetector computed
tomography, image-guided biopsy
128
Intralesional Treatment (Francesco Garbagnati, MD)
In the Radiological Department, since 2005, a specific
Unit for mini-invasive intralesional treatment with percutaneous thermal ablation procedures (RF, microwave,
etc.) was founded. At our Institute in the late 1980s,
(1988 - 1989), percutaneous radiofrequency treatment
was carried out with pioneering research and recently
obtained scientific recognition at international levels. Since
1990, we have treated more than 1400 patients mainly
with liver cancer, but also kidney, lung, and bone lesions.
The Unit works within the Radio-Diagnostic Service
Department of Radiology utilizing radiological interventional treatment procedures for centering and treatment
follow up.
In HCC and liver metastases with a diameter greater than
3.5 cm, we studied the possibility of radiofrequency
RELEVANT NOTES
Collaborations
Royal Marsden Hospital, London
Fondazione IRCCS Policlinico San Matteo, Pavia
University of Milan
hyperthermia combined with the arterial stop flow procedure to achieve maximum effectiveness with minimal
invasiveness. (Treatment in local anesthesia and one-day
surgery). This procedure has also been officially accepted
and codified by the Italian Society of Interventional Radiology. We also treated liver metastases, inoperable lung
cancer, supra renal and renal cancer, and painful bone
metastasis that were unresponsive to pain control with
conventional therapies. In collaboration with the
Fondazione IRCCS Policlinico San Matteo (Pavia), we are
studying a minimally-invasive system to destroy tumors
with different tissue characteristics using very thin probes
and with the possibility of single electrode insertion even
in large tumors.
Keywords: radiofrequency, percutaneous thermoablation, tumor
thermoablation
129
This Diagnostic Radiology is composed of two Units: the
Breast Imaging Unit and the Diagnostic and Interventional
Gastroenterology Unit. The two Units share technicians,
while clinical research staff have specific duties in each Unit.
HEAD
Silvana Bergonzi, MD
Breast Imaging
Claudio Ferranti, MD
Monica Marchesini, MD
Gianfranco Scaperrotta, MD
Laura Suman, MD
Diagnostic and Interventional Gastroenterology
Monica Salvetti, MD
Marco Milella, MD
TECHNICIANS
Folini Cristina (Coordinator), Colombo Luisa,
Dedei Luciana, Depedri Enrico, Lanzillotti
Luca, Mannella Maria Pia, Sala Stefania, Tavola
Anna
NURSES
Dolores Mauro, Ferruccio Mirella
Breast Imaging Unit (Silvana Bergonzi, MD, until 30
November 2011)
The Breast Imaging Unit has all the diagnostic and interventional tools which are necessary in a comprehensive
cancer center, where patients from any referral come in
search of reassurance to not have cancer, as well as early
diagnosis and proper treatment in the case that lesions
are present. Breast imaging consists mostly in clinical
mammography and breast ultrasound studies on symptomatic or treated patients as well as on asymptomatic
women with the aim of prevention. We also participate in
a program of surveillance for high-risk patients and BRCA
mutation carriers.
Interventional examinations are directed to preoperative
localization of non-palpable lesions and to assessment of
breast masses or microcalcifications by core-needle biopsies (CNB) or vacuum-assisted biopsies (VAB) with
ultrasonographic or stereotactic guidance. These interventions are basic elements of a multidisciplinary approach
Diagnostic and Interventional Gastroenterology (Guido
Cozzi, MD)
The clinical activity of the Unit continues to be mainly
oriented towards diagnostic and interventional radiology
of the digestive and biliary tracts and diagnostic and interventional US applications. A total of 11,795 examinations
were carried out by the Unit, with a decrease of 9.4%, for
plain films of the chest, (due to the new organization of
the Radiological Units), together with US examination. In
2011, 2831 contrastographic examinations of the digestive and urinary tract were performed, with an increase
of 3.5%. In this diagnostic field, according to the past
trend, examinations of functional disorders of the digestive tract increased, increased to 715 (+9%). Biliary and
gastroenteric interventional procedures were performed
in patients with different biliopancreatic or gastrointestinal
diseases. In the biliary field, definitive jaundice palliation
with drainages or stents, curative dilatation of cicatricial
to provide assistance for surgical planning. In 2011, about
14,000 mammographic examinations and 9300 breast
ultrasound studies were performed, in addition to 400
second opinion consultations. Moreover, 850 conventional
radiodiagnostic examinations on inpatients were carried
out. About 1550 interventional procedures were
performed on patients with suspicious breast findings, and
respectively, 620 preoperative targeting of non-palpable
lesions and 930 imaging-guided breast biopsies (CNB +
VAB).
In 2011, the breast lesion excision system (BLES) was
implemented, consisting in a biopsy device that acquires a
unique intact specimen instead of multiple samples such
as VAB, and preliminary results have been presented. During 2011, new mammographic equipment performing 3D
examinations (digital breast tomosynthesis) was installed,
allowing better confidence in mammographic interpretation and increasing sensitivity for detection of breast
cancer.
stenoses, drainage of fistulas, transluminal biopsies, and
other less common maneuvers were routinely
performed. In the gastrointestinal field, in addition to
treatment of complications (transluminal drainage of fluid
collections, dilatation of cicatricial stenoses) IP played a
basic role in nutritional support (percutaneous gastrostomy, positioning of feeding tubes, stenting of inoperable
stenoses). It must be emphasized that a substantial part
of all these interventional procedures must be performed
as promptly as possible, requiring exceptional organization. Overall, 633 interventional procedures were
performed in the Unit, with a decrease of 5.5% compared
to 2010. During 2011, 5176 US examinations were performed. In the context of the INT “Progetto Tiroide”, in
cooperation with the multidisciplinary outpatient service
of thyroid disease, 2422 neck US examinations, most for
monitoring thyroid nodules, were performed.
Keywords: biliary interventional radiology, gastroenteric interventional
radiology, thyroid biopsy
130
nuclear medicine
This structure is a modern division including different
integrated sections dedicated both to the diagnosis and
radiometabolic therapy of cancer. Other important goals
are to develop novel radiopharmaceuticals and manage
patients with endocrine diseases. The most important
areas of activity are: 1) a diagnostic Unit based on
gamma-emitting radiopharmaceuticals (SPECT Unit); 2) a
diagnostic Unit based on positron-emitting radiopharmaceuticals (PET Unit); 3) a therapy Unit for radiometabolic
therapy; 4) radiochemistry laboratories with a 17 MeV
cyclotron equipped for the production of PET and
SPECT tracers and radiopharmaceuticals for therapy; 5) a
laboratory for preclinical studies equipped with a
microPET; 6) a biochemistry laboratory for IRMA and
RIA tests; 7) a clinical endocrinology Unit for studying
endocrine cancer patients. Some of the most important
achievements of the programs carried out are: a) clinical
studies of SPECT and PET tests and their validation as a
tool for targeting tumors; b) validation of some radiola-
HEAD
Emilio Bombardieri, MD
Alessandra Alessi, MD
Gianluca Aliberti, MD
Anna Bogni, Biol Sci D
Maria R. Castellani, MD
Carlo Chiesa, Physicist
Flavio Crippa, MD
Vinicio De Sanctis, Engineer
Marco Maccauro, MD
Eva Orunesu, MD
Claudio Pascali, Radiochemist
Gianluca Serafini, MD
Ettore Seregni, MD
RESEARCH STAFF
Angela Coliva (Chemist), Claudio Cucchi
(Chemist), Luca Laera, Chemist, Greta
Maiocchi (Chemist)
Barbara Padovano, MD
Federica Pallotti, MD
TECHNICIANS
Monica Testoni (Coordinator), Grazia
Aprigliano, Danilo Baratella, Davide Bassani,
Gianercico Cucchetti, Carlotta Edera, Maria
Di Francesco, Pietro Di Nuzzi, Martino
Faedi, Rita Filieri, Deborah Mansi, Giovanni
Nido, Rossana Pavesi, Biagio Perrone, Matteo
Regazzoni, Lidia Spano, Roberto Segreti
NURSES
Rita Sicari (Coordinator), Cristina De
Somma, Carmela Fallacara, Calogero Oliveri,
Aurelio Scarabelli
Annaluisa De Simone Sorrentino
(Coordinator), Isabella Flauto, Valentina
Fracchiolla, Rosangela Ghilardi, Patrizia
Gobbi
beled oncotropic tracers as a prognostic index of tumors
in terms of characterization in vivo and early response; c)
the discovery of a original procedure for synthesis of the
PET tracer F18-FLT (patent PCT WO 2008/146316A); d)
the validation of a new methodology to visualize pelvic
lymph nodes in patients with gynecological cancer by lymphoscintigraphy after peri-tumoral injection of
99mTc-labeled microspheres; e) successful treatment of
hepatocarcinomas by intra-arterial radioembolization
with Y-90 microspheres; f) irradiation of NET tumors by
tandem treatment with somatostatin analogues radiolabeled with dual radioisotopes (Y-90 and Lu-177); g) the
optimization of radiometabolic therapy (thyroid cancer,
neuroblastoma, neuroendocrine tumors,
hepatocarcinoma and lymphoma) by a pre-therapy dosimetric approach to enhance the dose of irradiation
delivered to cancer mass.
Keywords: nuclear medicine diagnosis, nuclear medicine therapy,
radiopharmaceuticals
RELEVANT NOTES
Collaborations
Seregni E, Padovano B, Coliva A, Zecca E,
Bombardieri E. State of the art of palliative therapy.
Q J Nucl Med Mol Imaging. 2011; 55: 411-9.
EANM, European Association of Nuclear Medicine
(Vienna)
Contributions
IAEA, International Association of Atomic Energy
(Vienna)
Associate Editor: Quarterly Journal of Nuclear
Medicine and Molecular Imaging Minerva Medica
(Turin)
Publications
Editorial Board of European Journal of Nuclear
Medicine and Molecular Imaging, Springer
(Heidelberg)
Lopci E, Chiti A., Castellani M.R., Pepe G.,
Antunovic L, Fanti S, E. Bombardieri. Matched pairs
dosimetry: 124I/131I mIBG and 124I/131I and
86Y/90Y antibodies. Eur J Nucl Med Mol Imaging.
2011; 38: 28-40.
131
nuclear medicine
Clinical PET (Crippa Flavio, MD)
Routine activity is focused on FDG imaging for staging,
therapy monitoring, and follow-up in almost all types of
solid tumors and onco-hematologic malignancies. 11Cmethionine to study gliomas and FLT (fluorothymidine) is
under clinical validation. In 2011, clinical research was
mainly focused on the following topics. FDG-PET in
locally advanced rectal cancer submitted to neoadjuvant
chemoradiotherapy with the aim to evaluate whether
tumor FDG uptake can predict pCR. PET is performed at
baseline, 2 weeks after treatment initiation, and 6 weeks
after therapy completion. The results are compared with
post-surgical histology. Thirty patients have been studied
and the results will be submitted for publication. FDGPET to monitor pazopanib monotherapy in
relapsed/refractory urothelial cancer. PET scans are
planned at baseline and 4 weeks thereafter. They are
compared with conventional imaging and clinical
outcome. Preliminary results have been already submitted
(ASCO 2011), and definitive results will be submitted for
publication. FLT-PET in locally advanced breast cancer
submitted to pre-surgical neoadjuvant treatment. The aim
is to evaluate whether tumor FLT uptake can predict
pCR. Fifteen patients will be evaluated with PET at baseline, after 1-2 cycles, and at the conclusion of therapy.
Results will be compared to post-surgical histology. In collaboration with the Experimental Oncology and
Molecular Medicine and Nuclear Medicine Department
of San Rafaelle Hospital in Milan, a microPET study has
been carried out in rats with a breast cancer model
(MDA-BB-468) treated with taxol. Tumor response was
evaluated with FDG and FLT at baseline and 2 weeks
after treatment initiation. Tracer uptake has been compared with tumor volume during the study. Preliminary
results show a reduction of FDG/FLT uptake in responder
rats and an increase in non-responder rats. The definitive
results will submitted for publication.
Keywords: PET/CT, metabolic imaging, therapy monitoring
RELEVANT NOTES
Collaborations
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan
Neuro-Oncologia Unit, Department of Neuroscienze,
Università e A.U.O. San Giovanni Battista, Turin
Nuclear Medicine Therapy And Endocrinology (Ettore
Seregni, MD)
The activities of the Unit cover three main areas involved
in routine and experimental procedures: nuclear medicine
therapy, radiosotope laboratory, and an endocrinology
outpatient clinic. Regarding the former, two main studies
are of interest. The first is “Treatment with tandem
[90Y]DOTA-TATE and [177Lu]DOTA-TATE of neuroendocrine tumors refractory to conventional therapy”. To
date, 44 patients have entered the study. Clinical results
are available for the first group of 26 patients. A complete
response was observed in 2 patients (8%), partial
response in 9 (35%), stable disease in 11 (42%), and disease progression occurred in 4 patients (15%). The
overall objective tumor response rate was 42%. The
median overall survival at 24 months was 78%, and the
median progression-free survival (PFS) was 25 months.
Global PFS at 24 months was 52%. The second study is
“Efficacy of endoarterial treatment with 90Ymicrospheres in hepatocellular carcinoma”. To date, 153
treatments have been performed. A phase II study on the
RELEVANT NOTES
Publications
Seregni E, Padovano B, Coliva A, Zecca E,
Bombardieri E. State of the art of palliative therapy.
Q J Nucl Med Mol Imaging. 2011; 55: 411-9.
first 58 treatments on 52 patients has been conducted.
This demonstrated the relevance of a dosimetry-based
approach. In fact, non-responding lesions had a median
dose of 199 Gy, while responding lesions of 431 Gy.
Regarding the area of endocrinology, the study “Growth
hormone (GH) replacement therapy in surviving patients
with primary pediatric brain tumors (PBT)” is reported.
More than 700 patients with PBT were screened for GH
deficit (GHD), which was found in 110 cases. In all but 5
children, growth recovery was observed after treatment.
Improvement of bone mineral density was also attained
and improvement in neuropsychological performances
due to GH therapy was seen. Disease recurrence was
found in 7 patients, a relapse rate lower than in non-GH
treated patients. This study demonstrated that GH
replacement therapy is safe and effective in the correction of GH deficiency and in improving quality of life of
patients with PBT.
Keywords: nuclear medicine therapy, endocrine oncology,
neuroendocrine tumors
polymorphism. Endocr Relat Cancer. 2011; 18: 51927.
Contributions
Core partner as Endocrinologist of the certified
ENETS Center of Excellence European Expert in
the definition of consensus on “Follow-up in
patients with differentiated thyroid cancer with
antibody interference in thyroglobulin
measurement” (Berlin, Germany, November 2011)
132
radiotherapy 1
Clinical research of Radiotherapy Oncology 1 is aimed at
optimizing radiotherapic treatments for patients with
breast cancer, genitourinary cancers, gastrointestinal cancers, lung cancer, bone and soft tissue sarcomas,
lymphomas, and pediatric cancers treated at our Institution according to national and international protocols. The
multidisciplinary management represents a priority to
deliver high quality therapies to cancer patients. Therefore, all staff members are actively involved in
multidisciplinary case discussions for cancer patients at all
stages, from diagnosis to follow-up. In close collaboration
with the Medical Physics Unit, particular attention and
effort are dedicated to validate new technologies in each
specific clinical setting. Radiation Oncology 1 participates
in the clinical and preclinical activities of the Prostate
Cancer (PC) Program of the INT. Two staff members, one
clinical research member and one resident, are in the PC
clinical team and take part in multidisciplinary clinical
HEAD
Riccardo Valdagni, MD
Nice Bedini, MD
Anna Di Russo, MD
Lorenza Gandola, MD
Laura Lozza, MD
Claudia Sangalli, MD
Fulvia Soncini, MD
Francesca Valvo, MD
Sergio Villa, MD
FELLOWS
Simona Fantini, MD
Marzia Franceschini, MD
Mulugeta Haile Techlemichael, MD
RESEARCH STAFF
Barbara Avuzzi, MD
Emilia Pecori, MD
RESIDENTS
Chiara Chiruzzi, MD
Sara Morlino, MD
TECHNOLOGISTS
Franca Gaetano (Coordinator), Claudio
Boccadamo, Giuseppina Bonanno,
Alberto Buzzetti, Carmelo Campolo,
Federica Caputo, Gabriele Carabelli,
Pasquale Contessa, Lucio Donatone,
Rosa Fortunato, Sarah Frasca, Emanuela
Gatti, Manuela Guerra, Antonio
Spartano, Francesca Spartano, Carla
Valenti, Luca Zappa
NURSES
Pasquale Brunacci, Emanuela Visentin
Grazia Arpaia, Manuel Cornelli, Cristina
Terenghi, Sebastiano Sicilia
Donatella Orlandi, Patrizia Riva
activities (first examinations, second opinions, follow-ups
of patients on active surveillance or watchful waiting), in
the active surveillance protocols, in Monday clinical case
discussions and in monthly CME events (Grand Rounds).
They also collaborated in writing and updating the PC
institutional guidelines. Radiation Oncology 1 is also
proactive in preclinical and translational research. Topics
of interest are prediction of acute and late rectal toxicity
after high dose radiotherapy, correlation between plasma
levels of inflammatory markers and radiation induced
acute and late toxicity, prediction of erectile dysfunction
and genitourinary toxicity following radiotherapy, quality
of life in irradiated patients (DUE-01 protocol), and validation of a vaccine combination for hormone-naïve or
refractory patients with biochemical recurrence.
Keywords: radiation oncology, clinical and translational research,
quality assurance and toxicity prediction
RELEVANT NOTES
Publications
Collaborations
Rancati T, Fiorino C, Fellin C, Vavassori V, Cagna E,
Casanova Borca, V, Girelli G, Menegotti L, Monti AF,
Tortoreto F, Delle Canne S, Valdagni R. Inclusion of
clinical risk factors into NTCP modelling of late
rectal toxicity after high dose radiotherapy for
prostate cancer. Radiother Oncol 2011; 100 (1):
124-30.
AIRO (Associazione Italiana di Radioterapia
Oncologica) ESTRO (European Society for
Radiotherapy and Oncology) EORTC (European
Organisation for Research and Treatment of
Cancer)
Claudia Sangalli was appointed National Radiation
Oncologist Coordinator for EORTC Trial “A phase
III randomized study of preoperative radiotherapy
plus surgery versus surgery alone for patients with
Retroperitoneal Sarcomas”
ESMO (European Society for Medical Oncology)
ESO (European School of Oncology) EU (Europa
Uomo) PRIAS (Prostate cancer Research
International: Active Surveillance)
SIUrO (Società Italiana Urologia Oncologica)
Sanfilippo R, Miceli R, Grosso F, Fiore M, Puma E,
Pennacchioli E, Barisella M, Sangalli C, Mariani L,
Casali PG, Gronchi A. Myxofibrosarcoma:
prognostic factors and survival in a series of
patients treated at a single institution. Ann Surg
Oncol 2011; 18(3): 720-25.
Contributions
Riccardo Valdagni is member of the Editorial Board
of the International Journal of Radiation Oncology
Biology Physics, and participated in the Consensus
Conference to update the clinical
recommendations of ESMO in prostate cancer.
133
radiotherapy 1
Radiotherapy of Digestive Tract Tumors (Francesca
Valvo, MD )
The goal of the Unit is to offer the best chance of cure to
patients with locally-advanced cancer of the esophagus
and rectum through a neoadjuvant combined radiochemotherapy approach, in the attempt to achieve a
complete pathological response that represents an important positive prognostic factor in terms of local as well as
distant control regardless of clinical stage. For patients
with anal cancer, curative radiochemotherapy is employed
with a high rate of local control and organ preservation.
RELEVANT NOTES
Collaborations
AIRO (Associazione Italiana Radioterapia
Oncologica) Working Group on Gastrointestinal
Cancer
GAT (Gruppo di Appropriatezza Terapeutica
regionale for Rectal Cancer Surgery)
Postoperative radiochemotherapy is employed in locally
advanced (pT3 or pN+) gastric and pancreatic
neoplasms. Personalized treatment plans are elaborated
for each patient, and volumetric intensity modulated
radiotherapy is usually adopted to reduce acute and late
side effects. An ongoing study of our multidisciplinary
team is evaluating the effectiveness of revaluation with
FdG-Pet during neaodjuvant radiation treatment as a predictive tool for outcome in patients with rectal cancer.
Keywords: gastrointestinal cancers, combined treatments, organ
preservation
ESTRO (European Society for Radiotherapy and
Oncology):
Online Course tutor: Evidence and Research in
Rectal Cancer
Contributions
AIOM (Associazione Italiana Oncologia Medica)
Rectal Cancer Guideline
Radiotherapy of Breast Tumors (Laura Lozza, MD)
In 2011, about 500 patients received conventional adjuvant radiotherapy (3D conformal or IMRT) after
conservative breast surgery or mastectomy. Therapeutic
programs were discussed in a multidisciplinary setting
with the Breast Surgery Unit and Medical Oncology staff.
Women aged ≥70 years were given a hypofractionated
regimen (42.4 Gy, 16 fractions/3 weeks) with optimal
compliance, low toxicity, and excellent/good cosmetic
results in the majority of patients. Active collaboration
with the Plastic and Reconstructive Surgery Unit allowed
offering patients submitted to breast reconstruction tis-
sue expanders or prosthesis and the best timing for radiation. An experimental study together with the Medical
Physics Unit of our Institute and the Bioengineering
Department of the Politecnico of Milan, structural modifications after radiotherapy in different silicon implants
were investigated and the publication of its results is
imminent. To help patients understand the technical procedures in breast radiotherapy and to improve clinical
information, an audiovisual tool was created by medical,
physical, and technical staff.
Keywords: breast radiotherapy, hypofractionated radiotherapy, implant
radiotherapy
RELEVANT NOTES
Contributions
Collaborations
EDITORIAL BOARD for Attualità in Senologia:
Breast Radiotherapy Literature Review.
AIRO: Associazione Italiana Radioterapia
Oncologica
Publications
Nava MB, Pennati AE, Lozza L, Spano A, Zambetti
M, Catanuto G. Outcome of different timings of
radiotherapy in implant-based breast
reconstructions. Plast Reconstr Surg. 2011; 128:
353-9.
Guidelines AIRO (Associazione Italiana
Radioterapia Oncologica) Breast Radiotherapy
Guidelines Upgrade
134
radiotherapy 1
Pediatric Radiotherapy (Lorenza Gandola, MD; Clinical
Research Staff on private grant: Emilia Pecori, MD)
Clinical research activity is focused on improving the therapeutic index of radiotherapy for childhood cancers with
the aim of optimizing cure while reducing long-term
iatrogenic sequelae that is so critical in the pediatric population. This goal is pursued through a strict
multidisciplinary approach, the development and adoption of institutional, national, and international treatment
programs representing the best up-to-date knowledge in
the field of pediatric oncology, and validating the new
available technologies for the irradiation of children. The
Unit coordinates the AIEOP “Radiotherapy Working
Group”, is responsible for radiation therapy of two
national protocol on ependymoma (129 children
enrolled) and Wilms’ tumor (more than 300 patients
enrolled), and co-chairs the SIOP Europe “Brain Tumor
Committee”. It is also actively involved in developing new
therapeutic strategies as a member of the AIEOP “Cen-
RELEVANT NOTES
Collaborations
AIEOP: Associazione Italiana Ematologia Oncologia
Pediatrica
SIOP: Société Internationale d’Oncologie
Pédiatrique
ISG: Italian Sarcoma Group
Publications
Massimino M, Gandola L, Barra S, Giangaspero F,
Casali C, Potepan P, Di Rocco C, Nozza P, Collini P,
Viscardi E, Bertin D, Biassoni V, Cama A, Milanaccio
C, Modena P, Balter R, Tamburrini G, Peretta P,
tral Nervous System Tumors, Bone Tumors, Renal Tumors,
Neuroblastoma Working Groups” and SIOP “PNET and
Ependymoma Working Groups”. In particular, within the
SIOP Ependymoma Working group, the Unit is the lead
radiotherapy center for a forthcoming European Study.
On a national basis, the Unit is a reference center for
radiation therapy of children treated in other hospitals
with limited specific expertise or lacking particular facilities such as anesthesiology support. In 2011, thanks to an
original idea of two members of the technical staff, the
Unit published a picture book entitled “The cat that lost
its tail”, which is a fairy tale to explain radiotherapy to
children: the effectiveness of the book as a therapeutic
tool to improve pediatric compliance to radiotherapy
procedures, also reducing requirements for general anesthesia, is under evaluation in collaboration with the
psychologist team of the Pediatric Oncology Unit.
Keywords: pediatric radiotherapy, quality of life, multidisciplinary
treatments
Mascarin M, Scarzello G, Fidani P, Milano GM, Sardi
I, Genitori L, Garrè ML. Infant ependymoma in a
10-years AIEOP experience with omitted or
deferred radiotherapy. Int J Radiat Oncol Biol Phys.
2011; 80(3): 807-14.
Ferrari S, Sundby Hall K, Luksch R, Tienghi A, Wiebe
T, Fagiolo F, Alvegard TA, Brach Del Prever A,
Tamburini A, Alberghini M, Gandola L, Mercuri M,
Capanna R, Mapelli S, Prete A, Carli M, Picci P,
Barbieri E, Bacci G, Smeland S. Non-metastatic
Ewing family tumors: high-dose chemotherapy with
stem cell rescue in poor responders patients.
Results of the Italian Sarcoma Group/Scandinavian
Sarcoma Group III protocol. Ann Oncol. 2011;
22(5): 65-71.
135
radiotherapy 2
Radiation Therapy Unit 2 (RT2) is composed of outpatient and inpatient sections. The activity of RT2 is focused
on the irradiation of head and neck cancer, gynecologic
cancer, and brain metastases. In 2011, 382 patients underwent 431 treatments mainly delivered with 3D-CRT or
IMRT/Rapidarc (83% of all cases). 152 treatments were
performed for patients affected with head and neck cancer (35%), and 91 treatments, for patients affected with
gynecologic cancer (21%). High-dose rate brachytherapy
(HDR BCT) is given as endocavitary treatment in uterine
cancers, as endoluminal BCT in biliary tract cancers, and
as interstitial BCT in prostate cancer with HDR equipment (Selectron®). During 2011, 54 patients were
treated with 176 fractions and 167 treatment plans.
Prostate cancer HDR brachytherapy, as monotherapy (28
Gy in 2 fractions) or as a boost, was delivered in 25
cases. Overall, 369 patients were referred to RT2 during
2011 with a mean hospital stay of 7 days. In an inpatient
setting, combination chemoradiotherapy treatments are
also performed, mainly in gynecologic, ano-rectal, and
head and neck cancers. 231 chemotherapy sessions were
given during 2011. Supportive care for acute and, more
infrequently, late radiotherapy-related complications is
given as well. RT2 cooperates with the Radiology Diagnostic Units for the care of patients undergoing
chemo-embolization, intra-arterial chemotherapy, biliary
tract cancer, and other oncologically-targeted interventional procedures requiring hospitalization.
Keywords: head and neck cancer, gynecologic cancer, brachytherapy
HEAD
Carlo Fallai, MD
Annamaria Cerrotta, MD
Ester Orlandi, MD
Silvia Tana, MD
Garcia Monica, MD
NURSING STAFF
Pier Giulio Pezzaglia, Head of nurses, Rosa
Attolino, Antonella Causio, Luigia Cerra,
Antonio Floresta, Alessandro Fragnoli,
Carmen Garcia Cuesta, Olga Gratii,
Alessandra Licata, Antonio Lucenti, Gerlando
Mandracchia, Carmelina Minio, Marisa De
Carli
Angela Abatangelo, Vincenzo Caradonna,
Brenilda Marlene Fuentes Delgado, Giuseppe
Gaglio, Claudia Soave, Dario Tonelli
TECHNICIANS
Ciro Pintaudi (Head of Radiation Therapists),
Sergio Bavusi, Paolo D’Agnese, Carmelo Di
Marco, Dayana Pignata, Piera Fusar Poli
RELEVANT NOTES
Collaborations
Members of the staff are active in various scientific
societies in addition to the Cooperative Study
Group of the AIRO (Associazione Italiana
Radioterapia Oncologica);
AIRO Head & Neck Group; AIRO Brachytherapy
Group; AIRB (Associazione Italiana di
Radiobiologia);
ESTRO (European Society Therapeutic Radiation
Oncology);
EORTC Head & Neck cancer Group; ASTRO
(American Society Therapeutic Radiation
Oncology);
SIOG (Società Internazionale Oncologia
Geriatrica);
MARCH Collaborative Group; Gynecologic Cancer
Intergroup.
AIRO-L (Gruppo regionale AIRO Lombardia):
Membership in the Directive Board. Italian Germ
Cell Group: Membership in the Directive Board.
Publications
Mongioj V, Orlandi E, Palazzi M, Deponti E, Marzia F,
Stucchi C, Sangalli C, Fallai C, Zonca G, Olmi P,
Pignoli E. Set-up errors analyses in IMRT
treatments for nasopharyngeal carcinoma to
evaluate time trends, PTV and PRV margins. Acta
Oncol. 2011; 50: 61-71.
Martelli G, Miceli R, Daidone MG, Vetrella G,
Cerrotta AM, Piromalli D, Agresti R. Axillary
dissection versus no axillary dissection in elderly
patients with breast cancer and no palpable axillary
nodes: results after 15 years of follow-up. Ann Surg
Oncol. 2011; 18: 125-33.
Contributions
Staff members participated in the development of
the ROL (Rete Oncologica Lombarda)
Guidelines in head & neck tumors, geriatric
oncology, and gynecologic oncology, and
participation in the development of EAU
(European Association of Urology) Guidelines for
penile cancer.
136
medical physics
The Unit is involved in diagnosis and treatment of cancer
patients. The main activities are planning of radiation
treatments using either external radiation beams or
radioactive sources for high dose rate brachytherapy
(HDR BRT), and the accurate measurements of the radiation output from radiation sources employed in
radiotherapy. During 2011, the Medical Physics Unit was
engaged in the following research in the field of applied
medical physics. In HDR-BRT, new miniaturised detectors
for on-line in vivo dosimetry were investigated. In cooperation with the Universities of Milan and Wollongong,
(Australia), the application to HDR BRT of innovative
MOSFET detectors was optimized, whereas with the University of Milan-Bicocca a new scintillation detector was
developed and studied. In cooperation with Politecnico di
Milano, a study was performed to evaluate the possible
effects of conventional radiotherapy treatment on
implanted silicon breast prostheses. Morphological variations were studied using CT images and mechanical
characterization of the external implant shell and its internal gel content. A method for the management of
respiratory motion during irradiation was implemented
for use in lung cancer radiotherapy treatments. This
method allows synchronization of the acquisition of CT
images and of the following treatment dose delivery with
a selected interval of the respiratory cycle (gate). The
impact of respiratory motion on dose delivered with and
without the respiratory gating system was investigated for
different radiotherapy techniques. As part of the multidisciplinary Prostate Program group, research was
performed to develop new radiobiological algorithms
based on non-linear models to predict acute and late
toxicity following high dose prostate radiotherapy. The
study on the role of the native fluorescence in the diagnosis of colorectal cancer proceeded.
Keywords: respiratory gating system, high dose rate brachytherapy,
neural network
HEAD
Giancarlo Zonca, Physics D
Marta R. Borroni, Physics D
Mauro Carrara, Physics D
Valeria Mongioj, Physics D
Emanuele Pignoli, Physics D
Claudio G. Stucchi, Physics D
Stefano Tomatis, Physics D
FELLOW
Manuela Lualdi, Physics D
RESIDENTS
Tommaso Giandini, Physics D
Silvia Meroni, Physics D
TECHNICIANS
Vito Cosentino, Elena C. Fraigola, Luca C.
Marrone, Ester Mazzarella, Dario Postè
Giuseppina Esposito
RELEVANT NOTES
Publications
Collaborations
Mongioj V. Orlandi E, Palazzi M, Deponti E, Marzia F,
Stucchi C, Sangalli C, Fallai C, Zonca G, Olmi P,
Pignoli E. Set-up errors analyses in IMRT
treatments for nasopharyngeal carcinoma to
valuate time trends, PTV and PRV margins. Acta
Oncol. 2011; 50: 61-71.
Physics Department of the University of Milan
National Institute of Nuclear Physics of Milan,
University of Milan-Bicocca Centre for Medical
Radiation Physics
University of Wollongong, Australia
Politecnico di Milano
139
SHARED RESEARCH RESOURCES
Cardiology
Tobacco Control
Clinical Psychology
Medical Statistics, Biometry, and Bioinformatics
Tissue Bank
Functional Genomics Core Facility
Cancer Proteomics-Molecular Mechanisms
Shared Research Resources
140
cardiology
The Cardiology Unit carries out activity mainly concerning the preoperative evaluation of surgical patients, tightly
collaborating with anesthesiologists, thoracic and abdominal surgeons in order to reduce preoperative risk and
manage complications. Meanwhile, evaluation and consultation support is also carried out for patients of Besta
Neurological Institute. The Cardiology Unit, among its
main obligations, performs general cardiological evalua-
tion of all candidates for chemo-radiotherapy treatment,
with the aim of monitoring potential cardiovascular toxicity related to antineoplastic treatments: early recognition,
diagnosis, and therapy Several Phase II and Phase III clinical studies have been carried out during 2011, with
regular, mandatory, cardiological surveillance for possible
cardiotoxicity of new experimental drugs.
Keywords: preoperative evaluation, cardiotoxicity, experimental drugs
surveillance
HEAD
Patrizia Piotti, MD
Carlo Materazzo, MD
Enzo Viggiano, MD
Costanza Mantovani, MD
Patrizia Greco, MD
POSTDOCTORAL FELLOW
Ivan Moschetti, MD
NURSES
Sabrina Barrotta, Graziella Borlenghi, Rosella
Murru, Luisa Sala, Maria Nunziata Depetro
Maria Grazia Marchetti, Rosanna Villani
RELEVANT NOTES
Collaborations
Patrizia Piotti was an invited supervisor at
Symphosium Cardio-Oncologia: Follow-up
ecocardiografico in soggetti trattati con
chemioterapia: interrompere? Quando? XV
Congresso Nazionale Ecocardiografia 2011, Naples,
14-16 April 2011. Carlo Materazzo, Teacher of the
ECM course “Le indicazioni cliniche e
l’appropriatezza delle richieste: Valutazione clinica
del dosaggo delle troponine convenzionali e ad alta
sensibilità” IRCCS Foundation Neurologic Institute
C Besta. Milan, 25 Nov 2011. Patrizia Piotti and
Carlo Materazzo: Co-founding members of
Echocardio-Oncology Group of Italian
Cardiovascular Echocardiography Society (SIEC),
established in March 2010
Publications
Boccardi L.,Cardinale D., Civelli M., Lestuzzi C.,
Materazzo C., Maurea N., Monte I., Oliva S., Piotti
P., Quattrocchi G., Rossi E., Toglia G., Gruppo di
Studio di Ecocardio-Oncologia della Società Italiana
di Ecografia Cardiovascolare (SIEC), Coordinatore :
Prof Pezzano A. (SIEC Milano): Approccio
Cardiologico al paziente sottoposto a trattamento
antitumorale. Documento primo. J Cardiovasc
Echography. 2011; 21: 31-41. Di Salvo G., Di Bello
V., Salustri A., Antonini Canterin F., La Carrubba S.,
Materazzo C., Badano L., Caso P., Pezzano A.,
Calabrò R., Carerj S., on behalf of the Research
Group of the Italian Society of Cardiovascular
Echography (SIEC). The prognostic value of early
left ventricular longitudinal systolic dysfunction in
asymptomatic subjects with cardiovascular risk
factors. Clin Cardiol. 2011; 34: 500-6. Di Salvo G.,
Di Bello V., Salustri A., Antonini-Canterin F., La
Carrubba S., Materazzo C., Badano L., Caso P.,
Pezzano A., Calabrò R., Carerj S., on behalf of the
Research Group of the Italian Society of
Cardiovascular Echography (SIEC). Early left
ventricular longitudinal systolic dysfunction and
cardiovascular risk factors in 1,371 asymptomatic
subjects with normal ejection fraction: a tissue
Doppler study. Echocardiography 2011; 28: 26875.
141
tobacco control
Clinical activity of the Tobacco Control Unit (TCU) is
devoted to smoking cessation (SC) programs: in 11 years
of activity, the Unit was able to enroll 2200 smokers with
an average cessation or reduction of 40%, in agreement
with guideline data. At the end of 2011
pharmacogenomic study of smoking cessation was initiated in smokers treated with antismoking therapies. A
remarkable proportion of clinical activity (10%) is
devoted to the health of passive smokers. In 2006 we
started a comprehensive project aimed to offer to all
inpatient smokers minimal advice and a SC program. To
date we have interviewed about 500 patients. Educational
activities of TCU address to smoking policy at the workplace, to educational programs in schools, and to lobby
activities against tobacco smoke. TCU helped 20 companies in the implementation of a smoke-free workplace,
while 40 schools are engaged in educational anti-smoking
programs for children and teachers. Educational activities
in schools is still a major activity of the TCU; in fact, during
HEAD
Roberto Boffi, MD
EXTERNAL CONSULTANTS
Paolo Pozzi, MD
Giovanni Invernizzi, MD
Ario Alberto Ruprecht
Elena Munarini, PsyD
Chiara Marabelli, PsyD
Micaela Lina, PsyD
this school year it started the project “La scuola della
salute” in collaboration with MIUR and Chiamamilano to
promote healthy lifestyles among young people. We are
also teaching smoking cessation and tobacco marketing
to degree programs in medicine, nursing, and pharmacy
of the University of Milan since 2003. Another important
project was initiated in collaboration with Local Health
Authorities (Assessorato alla Salute del Comune di
Milano) and AFM S.p.A. to bring in 5 community pharmacies in Milan with new antismoking centers. For this
purpose, 15 hours of training for 10 selected pharmacists,
2 for every pharmacy, edited by TCU, has been
performed. Because of the educational importance of
explaining the environmental health risks linked to
tobacco smoke, a research laboratory section for the
study of ETS was implemented in 2001. The laboratory
implemented several innovative research programs with a
number of scientific articles published.
Keywords: smoking cessation, prevention, tobacco research
RELEVANT NOTES
Collaborations
Società Italiana di Medicina Generale Dipartimento
di Prevenzione Regione Veneto Respiratory Unit,
Brompton Hospital, London, UK South Western
University, Los Angeles, USA Cornell University,
New York, USA
Publications
Mazza R., Lina M., Invernizzi G., Pierotti M., De
Marco C., Borreani C., Boffi R. The gap between
tobacco treatment guidelines, health service
organization, and clinical practice in comprehensive
cancer centres. J Oncol. 2011; 2011: 145617. De
Marco C., Invernizzi G., Miceli R., Mariani L., Villarini
A., Munarini E., Mazza R., Boffi R. Breast change
perception in women after smoking cessation. A
pilot study. Tumori. 2011; 97: 672-5.
Contributions
Consensus document: Il tabagismo in Italia Interventi per la smoking-cessation: il ruolo della
farmacoterapia (Istituto Superiore di Sanità 2011)
http://www.iss.it/fumo/publ/cont.php?id=263&lang=1&tipo
=19
142
clinical psychology
The Clinical Psychology Unit addresses the psychological
and social aspects of patients with cancer. PsychOncology
looks at the whole range of mental and emotional issues
related to cancer, in the context of the patient’s life
before, during, and after diagnosis and treatment. Helping
clinicians to know when patients need emotional support
is another part of PsychOncology’s mission. The clinical
activity includes: psychological assessment, individual psychological counseling, short psychotherapies, family
therapies, and psycho-educational groups. During 2011,
the following psycho-educational groups were carried
out: a) the Ulysses program, which involves patients and
their relatives in educational and psychological support
groups; b) stress management training and relaxation
imagery groups; c) touch therapy groups; d) meaning oriented groups. “Ambulatorio Giocoparola” created with
the aim to give ill parents a support in the communica-
tion with their children about the disease, continued its
activity. Collaboration with other Clinical Units on specific
issues includes: • Multidisciplinary clinical project to support cancer patients undergoing liver transplant in
collaboration with the Transplantation Unit. • Multidisciplinary clinical project to support decision-making in
BRCA1/2 carriers in collaboration with Medical Genetics
Unit • Clinical decision making counseling, psychological
support, and psycho-sexual counseling for prostate cancer patients in collaboration with Prostate Program • The
multidisciplinary smoking cessation project for inpatients
in collaboration with the Tobacco Control Unit. The
research activity of the Unit is mainly oriented to the
evaluation of subjective impact of cancer and treatments
on patients’ quality of life and the psychosocial aspects
related to the different phases of oncological disease.
Keywords: psychoncology, psychological support, quality of life
HEAD
Claudia Borreani, Psy D
Marco Bosisio, Psy D
Margherita Greco, Psy D
Micaela B. Lina, Psy D
Luciana Murru, Psy D
Patrizia Trimigno, Psy D
Laura Gangeri, PsycoPedagogist
Silvia Bettega, Social Worker
FELLOW
Elisabetta Bianchi, PsyD
STATISTICIAN
Cinzia Brunelli
Teresa Maria Cariglia
RELEVANT NOTES
Collaborations
Dipartimento di Psicologia dell’Università degli
Studi di Milano-Bicocca. Istituto per lo Studio e la
Prevenzione Oncologica (ISPO), Florence Unità di
Neuro Epidemiologia Fondazione IRCCS Istituto
Neurologico C. Besta, Milan
Publications
Mazza R, Lina M, Invernizzi G, Pierotti M, De Marco
C, Borreani C, Boffi R. The gap between tobacco
treatment guidelines, health service organization,
and clinical practice in comprehensive cancer
centres. J Oncol. 2011; 2011: 145617. Borreani C,
Giordano A, Falautano M, Lugaresi A, Martinelli V,
Granella F, Tortorella C, Plasmati I, Radaelli M,
Farina D, Bella ED, Bianchi E, Acquarone
N,Miccinesi G, Solari A; on behalf of the SIMS-Trial
group. Experience of an information aid for newly
diagnosed multiple sclerosis patients: a qualitative
study on the SIMS-Trial. Health Expect. 2011 Nov
1. doi:10.1111/j.1369-7625.2011.00736.x.
143
medical statistics, biometry, and bioinformatics
The Medical Statistics Biometry and Bioinformatics Unit
(MSBB) provides quantitative support to development of
the research activity of INT. Moreover, MSBB bridges collaborative relationships with other national or
international research groups. The INT group activity is
governed by the convention with the University of Milan.
Areas of method development and application pertinent
to MSBB activity include assay development and quality
control, predictive models for diagnosis and prognosis,
plan and design of observational or randomized studies,
data management and study monitoring, and techniques
to report and interpret the results of clinical studies. The
main topics in epidemiological research are the relationships between dietary habits and risk of cancer, to
implement innovative statistical multivariate models in the
analysis of dietary data, and to develop predictive models
for cancer risk. Biostatistics for Oriented Basic Research
and Quality Control (Paolo Verderio) The team applies
statistical methods to different phases of the biomarker
development process in oncology. Specifically, it provides
implementation and statistical analysis of quality control
studies for tumor biomarkers and in vitro-diagnostic
tools; studies for the evaluation of inherited diseases in
oncology; studies for setting up and validation of biological assays; studies of preclinical pharmacology and studies
for testing new molecular detection strategies based on
innovative technologies.
Biostatistics for Bioinformatics and Translational Research
(Elia M. Biganzoli) The team follows the transfer of basic
preclinical research to the clinical setting, resorting to
quantitative approaches for the assessment of the impact
of new technologies in oncology, according to cost-benefit principles and sustainability perspectives. Collaborative
projects are related to the comparison of different highthroughput and next generation sequencing platforms for
RNA analysis, qRT-PCR, and high throughput assays in
cancer.
Keywords: risk prediction methods, high dimensional data methods,
oncological biomarkers
HEAD
Adriano Decarli, PhD
RESEARCH STAFF
Elia Biganzoli, PhD
Sara Pizzamiglio, MSC
Paolo Verderio, Biol Sci D, PhD
Maria Chiara Piano
Ilaria Ardoino, PhD
Matteo Malvezzi, PhD
PHD STUDENTS
Nicola Bassani
Annalisa Orenti
FELLOW
Chiara Maura Ciniselli, MSC
RELEVANT NOTES
Collaborations
International Agency for Research in Cancer
(IARC), Lyon, France Biostatistics Branch, National
Cancer Institute, Bethesda, USA Molecular and
Nutritional Epidemiology Unit , ISPO Florence, Italy
ISS-ACC Bioinformatics Oncology Network
RNBIO INNS Biopattern Special Interest Group
Italian Network for Quality Assessment of Tumor
Biomarkers (INQAT) SPIDIA – European Project 7th FP: Standardisation and improvement of
generic pre-analytical tools and procedures for in
vitro diagnostics PIO project - Italian Ministry of
Health:Analytical and clinical validation of new
biomarkers for early diagnosis: the Network, the
resources, the methodology, the QC, the analysis of
data. AB Analitica s.r.l.: Programma di verifica
esterna di qualità (VEQ) in biologia molecolare
AIRC projects : “Novel approaches for the
assessment of the functional effects of unclassified
variants in BRCA genes”; Translating innovation
into colorectal cancer control”. Ricerca Finalizzata
2009 : “Cerebrospinal fluid proteome from Central
Nervous System pediatric tumors: patient related
pattern” Collaborations with the following national
and international working groups: CIMBA, EFCC,
SIBIOC,ROL
Publications
Casarsa C, Bassani N, Ambrogi F, Zabucchi G,
Boracchi P, Biganzoli E, Coradini D. Epithelial-tomesenchymal transition, cell polarity and
stemness-associated features in malignant pleural
mesothelioma. Cancer Lett. 2011; 302: 136-43.
Catucci I, Verderio P, Pizzamiglio S, Manoukian S,
Peissel B, Zaffaroni D, Roversi G, Ripamonti CB,
Pasini B, Barile M, Viel A, Giannini G, Papi L, Varesco
L, Martayan A, Riboni M, Volorio S, Radice P,
Peterlongo P. The CASP8 rs3834129
polymorphism and breast cancer risk in BRCA1
mutation carriers. Breast Cancer Res Treat. 2011;
125: 855-60. Petracci E., Decarli A., Schairer C.,
Pfeiffer R.M., Pee D, Masala G, Palli D., Gail M.H. Risk
Factor Modification and Projections of Absolute
Breast Cancer Risk. J Natl Can Inst. 2011; 103:
1037-48.
Contributions
Paolo Verderio is member of the Editorial Board of
the Journal of Clinical Oncology. Paolo Verderio
and Sara Pizzamiglio are members of the “Società
Italiana di Statistica Medica ed Epidemiologia
Clinica” (SISMEC). Elia Biganzoli is member of the
Editorial Board of Source Code in Biology and
Medicine. He was the chairman of the international
conference Computational Intelligence for
Bioinformatics and Biostatistics CIBB 2011 in
Gargnano del Garda. Adriano Decarli is member of
the Epidemiology Working Group of the
International Society of Clinical Biostatistics (ISCB),
President of the Biometric Society (Italian Region).
AD and EB are members of the Organizing
Commettee of International Biometric Society
Congress (Florence, 2014)
medical statistics, biometry, and bioinformatics
An overall number of 126 projects were run (mainly in
the areas of surgical, medical or hematologic oncology), of
which 80 were activated during the year. A total of 17
articles were published.
Keywords: biostatistics, study design, data analysis
HEAD
Luigi Mariani, MD, PhD
RESEARCH STAFF
Rosalba Miceli, PhD
TECHNICIAN
Salvatore Lo Vullo, BSc
Maria Chiara Piano
RELEVANT NOTES
Publications
Mazzaferro V., Bhoori S., Sposito C., Bongini M., Langer
M., Miceli R., Mariani L. Milan criteria in liver
transplantation for HCC: an evidence-based analysis on
15 years of experience. Liver Transplant. 2011; 17(S2):
44-57. Scarpi E., Maltoni M., Miceli R., Mariani L.,
Caraceni A., Amadori D., Nanni O. Survival prediction
for terminally ill cancer patients: revision of the palliative
prognostic score with incorporation of delirium.
Oncologist. 2011; 16: 1793-9.
144
145
tissue bank
Since 2002, the Tissue Bank Facility of the INT has been
dedicated to the collection and distribution of neoplastic,
preneoplastic, and normal tissues from human subjects
for research projects. This resource is a project of INT
Scientific Directorate, with day-to-day staff supervision
provided by personnel from the Departments of Pathology and Experimental Oncology & Molecular Medicine.
The activities are overseen by an interdepartment advisory committee, which also evaluates and approves
research projects depending on the availability of tissue
specimens. Adopting TUBAFROST procedures, although
slightly modified to comply with local conditions, the INT
Tissue Bank stores frozen samples (primary and metastatic lesions, with corresponding normal tissues) and
contributes specimens to more than 30 specific research
projects dealing with breast, ovarian, lung, head and neck,
thyroid, colorectal, endometrial, and renal cancers, in addition to soft tissue sarcomas, melanoma, and pediatric
tumors.
All patients/subjects sign an informed consent document
(approved by the Independent Ethics Committee and
filed in the patients’ record) to donate the leftover
tissue/biological specimens after diagnostic procedures
have been completed for future studies at the INT Tissue
Bank. It is a one-time general consent using a two step
decision simplifying procedure, that might allow patients
to control the use of their samples and foster important
researches. At the time of surgical and/or medical procedures, patients are told how samples and health
information will be obtained, what risks future research
uses pose to them, and whether the research will have
any impact on their clinical care. They can choose
whether their samples and associated information may or
DIRECTORS
Giuseppe Pelosi, MD
Maria Grazia Daidone, Biol Sci D, PhD
RESEARCH STAFF
Silvia Veneroni, Biol Sci D
TECHNICIANS
Francesco Pastore
Gloria Morandi
may not be used for future research, relying on an Independent Ethics Committee for the approval of biologically
and/or clinically relevant studies. Otherwise, patients will
be contacted repeatedly to provide study specific authorization for the use of biological samples and associated
personal information. Guidelines have been proposed to
define responsibilities for Tissue Bank management, policies, and procedures to protect patient confidentiality and
privacy, and establish priorities for specimen distribution.
A survey carried out on about 3000 inform consent
forms showed that reliable and consistent responses
were obtained in 80% of the cases: 95& of the patients
support the future research use of their biological samples, with a request to be repeatedly contacted in only
3% of the cases.
In collaboration with the INT Division of Information
Technology an integrated data base is now under implementation to link information related to biospecimens to
pathologic diagnosis, minimum clinical data set, and follow-up and to allow a dynamic and user-friendly interface
for pre-clinical and clinical studies.
In 2011, the INT Tissue Bank stored frozen specimens
from 1190 new cases. Investigations are currently ongoing
to assess the routine feasibility of a formalin-free sample
collection method based on a 4°C under-vacuum preservation of tissue specimens from surgical removal to
processing for sampling and biobanking and its reliability
in preserving RNA integrity, gene expression, phosphoproteomic and metabolomic profiles. Pre-processing
conditions between surgery and freezing of samples
appear to have a strong impact on sample quality and
should be considered as a mandatory variable to control
for clinical implications of inadequate tissue handling.
146
functional genomics and bioinformatics core facility
The activities of the Functional Genomics and Bioinformatics core facility are based on wet analyses performed
using the Illumina and Agilent platforms and
computational analyses using dedicated workstations. The
research group comprises full time personnel involved in
wet analyses and personnel dedicating part of their institutional activity to computational analysis of wet and in
silico data.
The core facility takes care of: study design; RNA and
DNA extraction and quality controls; all the labeling and
hybridization methodologies required for high quality
analysis; data processing and normalization. Full computational analyses are performed using Software open
source (such as R-Bioconductor, BRB, GSEA, MAGIA) and
dedicated licenses (such as IPA for candidate protein
interactions, Gene Spring, Genomic Workbench). Computational biofunctional interpretation of promising
biomarkers are based on: Correlation Analysis, Gene
Ontology, Gene Set Enrichment Analysis, and Prediction
of miRNA targets.
During 2011, more than 2000 samples arising from
experimental and clinical studies were analyzed for: whole
genome expression; Illumina DASL (cDNA-mediated
annealing, selection, extension and ligation) assay; miRNA
whole expression.
Furthermore, the core facility staff: set-up specific
methodologies for efficient extraction and quality control
of nucleic acids from archival materials such as
heparinated plasma and formalin fixed paraffin embedded
samples; made methodological comparison of different
miRNA platforms; elaborated in silico analyses using publicly available datasets; participated to the information and
formation of the personnel with dedicated seminars.
HEAD
Silvana Canevari, Bio Sci D
RESEARCH STAFF
Marina Bagnoli, Biol Sci D,
Vera Cappelletti, Biol Sci D
Loris De Cecco, Biol Sci D
Rosaria Orlandi, Biol Sci D
Maria Luisa Sensi, Biol Sci D
Maurizio Callari, Biotech D, Bioinformatician
Gaetano De Feo, Biol Sci D
Matteo Dugo, Biotech D, Bioinformatician
Patrizia Pinciroli, Biol Sci D
TECHNICIANS
Edoardo Marchesi
Donata Penso
RELEVANT NOTES
Collaborations
Dr Giovanna Chiorino, Fondazione Edo ed Elvo
Tempia, Biella
Dr Silvano Ferrini, IST Genova
Publications
Bagnoli M, De Cecco L, Granata A, Nicoletti R,
Marchesi E, Alberti P, Valeri B, Libra M, Barbareschi
M, Raspagliesi F, Mezzanzanica D, Canevari S.
Identification of a chrXq27.3 microRNA cluster
associated with early relapse in advanced stage
ovarian cancer patients. Oncotarget. 2011
Dec;2(12):1265-78.
Sommariva M, De Cecco L, De Cesare M,
Sfondrini L, Ménard S, Melani C, Delia D, Zaffaroni
N, Pratesi G, Uva V, Tagliabue E, Balsari A. TLR9
agonists oppositely modulate DNA repair genes in
tumor versus immune cells and enhance
chemotherapy effects. Cancer Res. 2011 Oct
15;71(20):6382-90.
147
cancer proteomics - molecular mechanisms
The laboratory continues to develop progressive methods for the discovery of biomarkers. These
developments include evaluation of proteins for quantitative studies, methods to measure proteins in cell lines,
tissue biopsies, and dual tissue/biofluid analysis for more
confident biomarker discovery.
Our main interest is the tumor microenvironment
because of its role in growth and metastasis. The tumor
microenvironment can be defined as the insoluble elements of the extracellular matrix, the stroma with its
cellular elements such as fibroblasts and immune cells and
the fluid phase of dissolved substances. Traditionally the
focus has been on the stroma and the cellular elements
of the tumor, whereas we focus on the fluid phase that
may be thought as a “misconsidered component of the
internal milieu of a solid tumor”.
Mass spectrometry techniques combined with bioinformatics allow detection, identification and quantification of
numerous peptides and proteins in biological samples.
This offers new avenues for detection of tumor-specific
biomarkers may be important for detection of risk, early
disease and response to treatment. Other sources used
for biomarkers are cerebrospinal fluid and urine that can
be sampled noninvasively and in addition to
plasma/serum.
Ongoing projects:
• regulation of iron metabolism in breast cancer
• renal cancer stratification for anticancer strategies
• signaling pathway profiling of colorectal cancer liver
metastases for targeted therapy
• cerebrospinal fluid proteome from central nervous
system pediatric tumors: patient-related patterns.
Keywords: mass spectrometry, cancer biomarkers, human fluids,
signaling pathways, targeted therapy
HEAD
Italia Bongarzone, Biol Sci D
Caccia Dario, Biotech D, PhD
Elena Vaghi, Biotech D, PhD
Ruben Magni, Biotech D, PhD
TECHNICIAN
Maida De Bortoli
RELEVANT NOTES
Technologies
1-D and 2-D electrophoretic protein separations,
DIGE technology,
MALDI-TOF mass spectrometry (Voyager DESTR), and SELDI-TOF technology (PCS 4000)
Collaborations
Istituto Superiore di Sanità
Istituto Nazionale per la Ricerca sul Cancro (IST),
Genoa
IRCCS Ospedale Oncologico, Bari
IRCCS S. Maria Nuova, Reggio Emilia
Applied Biology at the University of Brescia
George Mason University, Center for Applied
Proteomics and
Molecular Medicine, Virginia, USA
Laboratori d'Investigació UdL/HUAV Dept.
Medicina Experimental
Universitat de Lleida, Spain
Publications
Vergani E, Vallacchi V, Frigerio S, Deho P, Mondellini
P, Perego P, Cassinelli G, Lanzi C, Testi MA, Rivoltini
L, Bongarzone I, Rodolfo M. Identification of MET
and SRC activation in melanoma cell lines showing
primary resistance to PLX4032. Neoplasia. 2011
Dec;13(12):1132-42.
Da Riva L, Bozzi F, Mondellini P, Miccichè F,
Fumagalli E, Vaghi E, Tarantino E, Huber V, Gronchi
A, Tamborini E, Pierotti MA, Pilotti S, Bongarzone I.
Proteomic detection of a large amount of SCGF
in the stroma of GISTs after imatinib therapy. J
Transl Med. 2011 Sep 23;9:158.
Blood. 2011 Oct 20;118(16):4421-30.
Caccia D, Zanetti Domingues L, Miccichè F, De
Bortoli M, Carniti C, Mondellini P, Bongarzone I.
Secretome compartment is a valuable source of
biomarkers for cancer-relevant pathways. J
Proteome Res. 2011 Sep 2;10(9):4196-207.
Miccichè F, Da Riva L, Fabbi M, Pilotti S, Mondellini
P, Ferrini S, Canevari S, Pierotti MA, Bongarzone I.
Activated leukocyte cell adhesion molecule
expression and shedding in thyroid tumors. PLoS
One. 2011 Feb 22;6(2):e17141.
Nicolini V, Cassinelli G, Cuccuru G, Bongarzone I,
Petrangolini G, Tortoreto M, Mondellini P, Casalini P,
Favini E, Zaffaroni N, Zunino F, Lanzi C. Interplay
between Ret and Fap-1 regulates CD95-mediated
apoptosis in medullary thyroid cancer cells.
Biochem Pharmacol. 2011 Oct 1;82(7):778-88.
Mondellini P, Degl'Innocenti D, Catalano V, Gobbo
polymorphism. Endocr Relat Cancer. 2011 Jul
25;18(4):519-27.
Garrisi VM, Bongarzone I, Mangia A, Cremona M,
De Bortoli M, Vaghi E, Galetta D, Pastorino U,
Quaranta M, Abbate I, Paradiso A. Characterization
of a serum protein pattern from NSCLC patients
treated with Gefitinib. Clin Biochem. 2011
Jul;44(10-11):936-40.
148
EDUCATION AND TRAINING
INT is strongly committed to educating future research scientists and clinicians and is directly engaged in quality education and training. INT offers a wide range of educational activities for clinical and experimental researchers at different stages of their professional experience. PhD studentships, postdoctoral research fellowships, graduate student training,
medical residency training, psychology and social work training, as well as continuing medical
education are all included in the portfolio of educational opportunities offered to staff and
external participants.
Invited lectures, seminars, and workshops in a variety of research disciplines related to cancer are regularly arranged.
Participants in education and training programs are encouraged to attend also the interdepartmental journal clubs, clinical case discussions, and grand rounds as well as other multidisciplinary activities aimed to create interspecialistic knowledge.
ACADEMIC PROGRAMS
INT provides education and training at various levels, including undergraduate, graduate as
well as postgraduate medical and biotechnology students, physicians, nursing students, and
nurses. On the basis of formal agreements with the University of Milan, INT hosts the
Chairs of Medical Oncology (Prof Alessandro M. Gianni), Hematology (Prof Paolo
Corradini), Medical Statistics and Biometry (Prof Adriano Decarli), Anesthesiology (Prof
Martin Langer), and Pathology (Prof Giuseppe Pelosi). A number of staff members have a
joint appointment as professors at the University of Milan and contribute to the regular
curriculum at this University. INT hosts the “Postgraduate School in Oncology”, the
“Postgraduate Medical School in Pathology”, and the 3-year degree in “Nursing Sciences” of
the University of Milan. Additionally, INT participates in the degree in “Biotechnology and
Molecular Medicine in Oncology”, as well as in two PhD programs of the University of
Milan (“Hematology” and “Medical Biotechnology”).
DOCTORAL (PHD) TRAINING PROGRAM AT INT
The INT is an Affiliated Research Centre of the Open University, Milton Keynes, UK, providing a PhD Program in Life and Biomolecular Sciences. The program run at INT meets the
requirements of the Quality Assurance Agency (QAA) for Higher Education Code of
Practice INT provides direct support for these training positions and offers
fellowship/grants to European Community postgraduate students holding a degree in
Medicine, Biological Sciences or Pharmacy.
Students are involved in several activities, including induction courses, generic skills training,
journal club meetings, and seminars. At present, 19 students are carrying out their training
and working on their research projects.
In 2011, 8 students were awarded a PhD degree: Giulia Bertolini, Francesca Bianchi, Ileana
Bortolomai, Francesca Colombo, Elisabetta Crippa, Elisa Frullanti, Marianna Perego, and
Roberta Zappasodi.
149
MASTERS
• Academic Master in Epidemiology. This is a joint appointment
with the Università di Torino, ISI Foundation and INT Division of
Etiologic Epidemiology and Prevention.
• Master in Rectal Surgery. INT and ARECO (Association for
the European Research in Surgical Oncology) offer a Rectal
Surgery Master for medical doctors with a surgery degree.
• Academic Course in Oncologic Lymphology. The course is
designed for physicians and students graduating in lymphology and
oncologic lymphology. The Division of Palliative Care, Pain Therapy,
and Rehabilitation is the scientific coordinator and is in charge of
the educational activities, referred to the Medical Faculty of the
Università degli Studi di Milano.
• Master of Palliative Medicine for Nurses. Under the direction
of the Università degli Studi di Milano and in collaboration with
INT, this academic course trains graduated nurses to provide palliative care to patients with cancer.
• A number of lecturers from INT contribute to the Advanced
Master Course in Palliative Cares offered by the Università degli
Studi di Milano.
• Master in Medical Statistics and Statistical Methods for
Epidemiological Research. MSSME is aimed for graduate with
Medicine, Biological Sciences, Physics or Statistics degree.
A postgraduate course in biostatistics is also provided.
Postgraduate students are often directly involved in research projects coordinated by MSBB members
OTHER COURSES
PHD STUDENTS
AND THEIR RESEARCH TOPICS
Alessia Burocchi
Modulation of regulatory T cell suppression in
tumors through OX40
Maria Chiara Anania
Role of genes differentially expressed in
thyroid carcinogenesis
Maria Grazia Vizioli
Role of oncogene-induced senescence and DNA
damage response in thyroid carcinogenesis
Giacomo Cossa
Modulation of sensitivity to platinum
compounds in ovarian carcinoma cell systems
Mattia Boeri
Exploring the role of microRNA in early lung
cancer
Irene Catucci
Identification of low penetrance alleles, genetic
modifiers, and mutation analysis in familial
breast cancer cases
Claudia Piovan
MicroRNAs in breast tissue biology and
disease: involvement in development and
tumorigenesis
Alessandra Santangelo
SPARC, a matricellular protein that protects
tumors from therapy
Marianna Sasso
Biomarkers of aggressive phenotype in triple
negative breast cancer
The Pathology Department is involved in the training programs of
the Postgraduate Medical Schools of Pathology, Endocrinology, and
Respiratory Medicine (University of Milan) and of the Soft Tissue
Pathology, Postgraduate School of Pathology (Insubria University
of Varese).
Alfonso Passafaro
Role of SPARC in inflammation and cancer
The Anesthesia Department is involved in the training program
and residency of the Postgraduate School for Anesthesia and
Intensive Care, hosts a number of residents/students, and organizes part of the formal teaching in the program of the postgraduate course of the Medical School - University of Milan. Residents
in Anesthesia and Intensive Care, Cardiology, Nutritional Support
(University of Milan and Milano-Bicocca) work within all the Units
of the Department.
Davide Bernareggi
Conversion of AFRA Fab into a fully human
monoclonal antibody to design a suitable
reagent for therapy.
Many Staff Members have teaching positions or are tutors in postgraduate medical schools or in national/international master programs in Supportive Cancer Care, in Organization, Management
and Care in Hospice and in INT Nursing School.
Within the Surgery Department, the Division of Colorectal
Surgery is affiliated with the General Surgery Residency Programs
of Milano-Bicocca and Pavia Universities; the Division of
Gastrointestinal and Hepatopancreatobiliary Surgery and Liver
Alice Rigoni
Mast cells at the interface between external
challenges and immune regulation in colitis
and colorectal cancer
Daniele Lecis
Inhibitors of apoptosis proteins (IAPs) as
targets for anti-cancer treatment
Ilaria Torselli
Matricellular proteins in osteosarcoma
development and progression
Gaia Ghedini
Role of D16HER2 splice variant in response to
drugs targeting HER2 receptor
Sara Ciceri
Molecular characterisation of Wilms tumor
Education and Training
150
Transplantation is a training center for the University of Milan and the Italian College of
Surgeons and is chosen for clinical fellowships by many visiting clinicians and surgeons every
year. In the area of clinical and training activities, the Plastic and Reconstructive Surgery Unit
holds weekly and 3-monthly surgery courses for Italian and foreign surgeons. The
Gynecologic Oncology Division is chosen for clinical fellowships by many visiting surgeons
from Italy and other countries every year. It also organizes a biennial international meeting,
and a gynecologic oncology course with more than 50 participants three times a year. The
Otorhinolaringology Surgery Division has close links with the University, and is involved in
postgraduate teaching and supervising of junior medical staff. In collaboration with the
Human Morphology Department of the University of Milan, this Division activated two research doctoral degrees to develop a new non-invasive method to evaluate the functionality of the mimetic musculature after iatrogenic damage to the facial nerve. The Division also
collaborates with the Otorhinolaryngoiatric School of Specialization of the University of
Milan, hosting students for practical training and organizing lessons and courses. The
Thoracic Surgery Division collaborates with the General Surgery and Thoracic Surgery
School of Specialization of the University of Milan, hosting students for practical training.
Many postdoctoral fellows attend the Melanoma and Sarcoma Division that collaborates
actively with several medical universities. The Senology Division collaborates with the
University of Milan to teaching and research projects.
The Medical Staff of the Diagnostic Imaging and Radiotherapy Department is involved in
educational activities cooperating with the University of Milan and Milano-Bicocca in the
Radiology, Radiotherapy, and Medical Oncology Specialization Schools, in the “Clinical
Application of Nuclear Medicine”, Nuclear Medicine School of Specialization. The
Radiotherapy Unit also provides tutoring of radiography and radiation technician students.
CONTINUING MEDICAL EDUCATION PROGRAM
The educational and training program promotes professional, cultural, and human growth of
INT employees. During 2011, the INT ECM Provider has proposed 170 events in the main
areas (clinical governance, learning on the job, risks prevention and emergency management, etc.) of ECM-CPD (137 were accredited), attracting the interest and the participation
of resident and visiting health professionals. In particular, the educational initiatives included
in the Business Formation Plan (BFP) have achieved a total amount of 26,452 formative
credits, involving 3013 people.
SEMINARS AND CONFERENCES
JANUARY
Pier Luigi Lollini
(Department of Hematology and Oncology Sciences, University of Bologna, Bologna)
HER-2: mouse, humans and chimeras
Amedeo Columbano
(Medicine and Surgery Faculty, Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari,
Cagliari)
Hippo Pathway and miRNAs: two critical players in HCC development
Enrico Garattini
(Molecular Biology Laboratory, Department of Biochemistry and Molecolar Pharmacology, Istituto di Ricerche Farmacologiche
"Mario Negri", Milan)
RARA gene amplification in HER-2- positive breast cancer: definition of tumor subtype with potential sensitivity to retinoids and
lapatinib combinations
Guido Kroemer
(Institut Gustave Roussy, Villejuif)
Molecular bases of the immunogenicity of cell death: implementations in cancer management and NKp30 isoforms: a novel
biomarker in cancer
151
seminars and conferences
FEBRUARY
Furio Gramatica
(Department Polo Tecnologico, Fondazione Don Carlo Gnocchi ONLUS, Milan)
Nanomedicine: basic principles and applications in oncology
Luisa De Cola
(Westfälische Wilhelms - Universität Münster, Physikalisches Institut and Center for Nanotechnology, Munster)
Nanomaterials for in vitro and in vivo diagnostics
Kristin M. Braun
(Barts & The London School of Medicine and Dentistry, Centre of Cutaneous Research. Blizard Institute of Cell and Molecular
Science, London)
Characterizing the epidermal stem cell compartment
Ian Mackenzie
(Stem Cell Science, Institute for Cell and Molecular Science, Whitechapel, London)
Patterns of stem cell behaviour in head and neck cancers
MARCH
Robert Clarke
(Breast Biology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester)
Stem cells in breast cancer
Giuseppe Giaccone
(Medical Oncology Branch, National Cancer Institute, Bethesda)
Profiling thoracic malignancies
Francesco Pezzella
(Tumor Pathology, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford)
Heat shock proteins deregulation in human cancer and TRAP1/HSP75 case study
APRIL
Alessandro Parodi
(Department of Nanomedicine, School of Medicine, The Methodist Hospital Houston)
Development of a new hybrid polymer-silica nanoparticle platform for cancer treatment through a biomimetic approach
Richard Houlston
(Molecular and Population Genetics, The Institute of Cancer Research, ICR, Sutton Surrey)
What have genome-wide association studies told us about identifying susceptibility to cancer?
Mauro Piacentini
(Department of Biology, Università “Tor Vergata”, Roma)
Ambra1 an essential regulator of autophagy in mammals
Francesco Dazzi
(Stem Cell Biology, Department of Haematology, Imperial College, London)
Mesenchymal stem cells: innate tolerance and tissue repair
Roberto Cerbino (Università degli Studi di Milano) and Bice Chini (Istituto di Neuroscienze del CNR)
Reflective Phantom Interface: a new label-free method for the detection of biomolecular interactions
MAY
Giuseppe Testa
(Laboratory of Stem Cell Epigenetics, European Institute of Oncology; European School of Molecular Medicine. Milano)
Histone methylation in genome programming and reprogramming
Education and Training
152
OCTOBER
Carlos Caldas
(Cancer Medicine, Cambridge University; Breast Cancer Functional Genomics, Cambridge Research Institute)
The landscape of genomic aberrations in breast cancer
Carlos Malpica
(MLP Vision Biotech S.L. European Sales & Marketing, Metabolon Inc., Parque Tecnològico de Madrid. Madrid)
Global Metabolomic analysis applied to cancer research
Alessandra Cesano
(Medical Office, Nodality Inc. - San Francisco, Ca)
Functional Pathway Analysis Using Single Cell Network Profiling: technology and clinical applications in hematological cancer
Cecilia Balbi
(Urological Translational Unit, IST, Genova)
The nuclear matrix as a source of specific biomarkers for prostatic cancer
Valentina Bollati
(Department of Environmental and Occupational Health, Università di Milano, Fondazione IRCCS Cà Granda Ospedale
Maggiore Policlinico, Milan)
Effects of metal-rich particulate matter exposures on microRNAs carried in plasma microvesicles
Christian Unger
(Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield)
Modeling developmental cancer with induced pluripotent stem (iPS) cells
NOVEMBER
Vincenza Dolo
(Clinical Pathology, Post-Graduate School of Clinical Pathology, Master Degree in Health Professions Sciences, Department of
Health Science-School of Medicine, University of L'Aquila. L’Aquila)
Microvesicles and exosomes: different types for different roles or just an overlapping?
Mario Chiariello
(Istituto Toscano Tumori, Core Research Laboratory, Signal Transduction Unit, Siena)
Signaling by the ERK8 MAP kinase: a novel potential target for cancer therapy
Maria Rescigno
(Department of Experimental Oncology, Dendritic Cell Biology and Immunotherapy Unit – IFOM. Milano)
Intestinal immune homeostasis: a very complex affair
DECEMBER
Claudia Desiderio
(Consiglio Nazionale delle Ricerche, Istituto di Chimica del Riconoscimento Molecolare, Roma)
The proteomic analysis of cerebrospinal fluid of pediatric patients with posterior fossa cancer has highlighted the potential role
of LVV- and VV-emorphine-7 as prognostic biomarkers
Stuart Forbes
(Transplantation & Regenerative Medicine, MRC Centre for Regenerative Medicine, The University of Edinburgh)
Stem cells in liver regeneration and therapy
153
Paolo Ciana
(Department of Pharmacological Sciences, Università degli Studi di Milano, Milano)
Molecular imaging and regulation of estrogen receptor activity in breast cancer: a story of SNPs and endocrine responsiveness
Ian James Stratford
(School of Pharmacy and Pharmaceutical Sciences, University of Manchester)
Computation screening of the NCI chemical database reveals a role for the oxidoreductase NQO2 in modulating NFkB
transcriptional activity
Patrizia Paterlini Bréchot
(Faculté de Médecine Necker-Enfants Malades, Paris Cedex)
Christian Bréchot
(Institut Merieux, Lyon)
Isolation and characterization of Circulating Tumor Cells by ISET : Technical aspects and clinical impact
JUNE
Hua Eleanor YU
(Cancer Immunotherapeutics & Tumor Immunology City of Hope, Duarte, CA)
STAT3 in cancer inflammation and immunity
JULY
Davide Rossi
(Division of Hematology, Department of Clinical and Experimental Medicine Amedeo Avogadro, University of Eastern
Piedmont, Novara)
Richter syndrome: from genetics to clinical management
Workshop, “The Methodist Hospital Research Institute”
Speakers: Elvin Blanco, PhD - Research Associate Department of Nanomedicine; Rebecca Hall, PhD - Scientific
Communications; Jason Sakamoto, PhD - Co-Chair, Assistant Member Department of Nanomedicine; Ennio
Tasciotti, PhD - Co-Chair, Associate Member Department of Nanomedicine Scientific, Director of The Spine
Advanced Technology Laboratory and Interim Director of Regenerative Medicine Program
SEPTEMBER
Shuki Mizutani
(Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo)
Clinico-pathological features and dysregulation of DNA damage response network in childhood hemato-oncological diseases
Ciro Isidoro
(Cell Pathology, "Amedeo Avogadro" University, Laboratory of Molecular Pathology Department of Medical Sciences, Novara)
Autophagy, a Potential Target for Prevention and Therapy of Cancer
Rocco Piazza
(Department of Clinical Medicine, Bicocca University, Milano)
High-throughput sequencing approaches for the study and characterization of tumor genomes
Lisa Wiesmüller
(Gynaecological Oncology, Department of Obstetrics and Gynaecology, University of Ulm, Ulm)
The link between DNA repair and breast cancer/susceptibility genes
Chandrika J. Piyathilake
(Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama)
Diet and epigenetic biomarkers
154
PUBLICATIONS
IF 2353.98
1
Agnoli C., Krogh V., Grioni S., Sieri S., Palli
D., Masala G., Sacerdote C., Vineis P., Tumino R., Frasca G., Pala M. V., Berrino F.,
Chiodini P., Mattiello A., Panico S.: A priori-defined dietary patterns are associated with reduced risk of stroke in a large
italian cohort. J Nutr 2011; 141: 15521558 [IF 4.295]
2
Ahrens W., Bammann K., Siani A.,
Buchecker K., De Henauw S., Iacoviello L.,
Henbestreit A., Krogh V., Lissner L., Marild
S., Moreno L.A., Pitsiladis Y.P., Reisch L.,
Tornaritis M., Veidebaum T., Pigeot I., on
behalf of the IDEFICS Consortium: The
IDEFICS cohort: design, characteristics
and participation in the baseline survey.
Int J Obes 2011; 35 (Suppl. 1): 3-15 [IF
5.125]
3
Aleksandrova K., Boeing H., Jenab M.,
Bueno-de-Mesquita H.B., Jansen E., van
Duijnhoven F.J., Fedirko V., Rinaldi S.,
Romieu I., Riboli E., Romanaguerra D.,
Overvad K., Ostergaard J.N., Olsen A.,
Tjønneland A., Boutron-Ruault M.C.,
Clavel-Chapelon F., Morois S., Masala G.,
Agnoli C., Panico S., et al.: Metabolic syndrome and risks of colon and rectal cancer: the European prospective
investigation into cancer and nutrition
study. Cancer Prev Res 2011; 4: 18731883 [IF 4.978]
4
Allemani C., Berrino F., Krogh V., Sieri S.,
Pupa S., Tagliabue E., Tagliabue G., Sant M.:
Do prediagnostic drinking habits influence breast cancer survival? Tumori
2011; 97: 142-148 [IF 1.014]
5
Amato E., Barbi S., Malpeli G., Bersani S.,
Pelosi G., Capelli P., Scarpa A.: Chromosome 3p alterations in pancreatic endocrine neoplasia. Virchows Arch 2011;
458: 39-45 [IF 2.336]
6
Anania M. C., Sensi M.L., Radaelli E., Miranda C., Vizioli M.G., Pagliardini S., Favini
E., Cleris L., Supino R., Formelli F., Borrello
M.G., Pierotti M.A., Greco A.: TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells.
Oncogene 2011; 30: 3011-3023 [IF 7.414]
7
Angelico M., Cillo U., Fagiuoli S., Gasbarrini A., Gavrila C., Marianelli T., Costa A.N.,
Nardi A., Strazzabosco M., Burra P., Agnes
S., Baccarani U., Calise F., Colledan M.,
Cuomo O., De Carlis L., Donataccio M.,
Ettorre G.M., Gerunda G.E., Gridelli B.,
Lupo L., Mazzaferro V., Pinna A., Risaliti A.,
Salizzoni M., Tisone G., Valente U., Rossi
G., Zamboni F., Regalia E., Sposito C., on
behalf of the Liver Match Investigators:
Liver Match, a prospective observational
cohort study on liver transplantation in
Italy: study design and current practice of
donor-recipient matching. Dig Liver Dis
2011; 43: 155-164 [IF 2.805]
8
Antoniou A.C., Kartsonaki C., Sinilnikova
O.M., Soucy P., McGuffog L., Healey S., Lee
A., Peterlongo P., Manoukian S., Peissel
B.G., Zaffaroni D., Cattaneo E., Barile M.,
Pensotti V., Pasini B., Dolcetti R., Giannini
G., Putignano A.L., Varesco L., Radice P.,
Mai P.L., et al.: Common alleles at 6q25.1
and 1p11.2 are associated with breast
cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet 2011; 20:
3304-3321 [IF 8.058]
9
Arcaini L., Laszlo D., Rizzi S., Balzarotti M.,
Antoniazzi F., Zilioli V.R., Guggiari E., Farina
L., Todisco E., Bonfichi M., Alamos S.M.,
Rossi G., Martinelli G., Morra E.: Plerixafor
and G-CSF for PBSC mobilization in patients with lymphoma who failed previous
attempts with G-CSF and chemotherapy:
A REL (Rete Ematologica Lombarda) experience. Leuk Res 2011; 35: 712-714 [IF
2.555]
10
Arfe A., Malvezzi M.C., Bertuccio P., Decarli A., La Vecchia C., Negri E.: Cancer
mortality trend analysis in Italy, 19702007. Eur J Cancer Prev 2011; 20: 364374 [IF 2.536]
11
Ascierto P., De Maio E., Bertuzzi S.,
Palmieri G., Halaban R., Hendrix M.,
Kashani-sabet M., Ferrone S., Wang E.,
Cochran A., Rivoltini L., Lee P.P., Fox B.A.,
Kirkwood J.M., Ullmann C.D., Lehmann
F.F., Sznol M., Schwartzentruber D.J., Maio
M., Flaherty K., Galon J., Ribas A., Yang J.,
Stroncek D.F., Mozzillo N., Marincola F.M.:
Future perspectives in melanoma research. Meeting report from the
“Melanoma Research: a bridge NaplesUSA. Naples, December 6th-7 th2010”.
(Review)1 J Transl Med 2011; 9: 32 [IF
3.508]
12
Avolio A.W., Cillo U., Salizzoni M., De
Carlis L., Colledan M., Gerunda G.E., Mazzaferro V., Tisone G., Romagnoli R., Caccamo L., Rossi M., Vitale A., Cucchetti A.,
Lupo L., Gruttadauria S., Nicolotti N.,
Burra P., Gasbarrini A., Agnes S.: On behalf
of the Donor-to-Recipient Italian Liver
Transplant (D2R-ILTx) Study Group.: Balancing Donor and Recipient Risk Factors
in Liver Transplantation: The Value of DMELD With Particular Reference to HCV
Recipients. Am J Transplant 2011; 11:
2724-2736 [IF 6.051]
13
Azar Sharabiani M.T., Vermeulen R., Scoccianti C., Hosnijeh S.F., Minelli L., Sacerdote C., Palli D., Krogh V., Tumino R.,
Chiodini P., Panico S., Vineis P.: Immunologic profile of excessive body weight.
Biomarkers 2011; 16: 243-251 [IF 2.09]
14
Bagnoli M., De Cecco L., Granata A.,
Nicoletti R., Marchesi E., Alberti P., Valeri
B., Libra M., Barbareschi M., Raspagliesi F.,
Mezzanzanica D., Canevari S.: Identification of a chrXq27.3 microRNA cluster
associated with early relapse in advanced
stage ovarian cancer patients. Oncotarget
2011; 2: 1265-1278 [IF 0.176]
15
Bai E., Aiani M.R., Crosignani P.: [OCCAM:
a tool for the workpractice of the units
155
of occupational health, safety and prevention]. Epidemiol Prev 2011; 35: 55-56 [IF
0.636]
16
Bakken K., Fournier A., Lund E., Waaseth
M., Dumeaux V., Clavel-Chapelon F., Fabre
A., Hèmon B., Rinaldi S., Chajes V., Slimani
N., Allen N.E., Reeves G.K., Bingham S.,
Khaw K.T., Olsen A., Tjonneland A., Rodriguez L., Sanchez M.J., Etxezarreta P.A.,
Ardanaz E., Tormo M.J., Peeters P.H., van
Gils C.H., Steffen A., Schulz M., ChangClaude J., Kaaks R., Tumino R., Gallo R.,
Norat T., Riboli E., Panico S., Masala G.,
Gonzalez C.A., Berrino F.: Menopausal
hormone therapy and breast cancer risk:
impact of different treatments. The European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2011; 128:
144-156 [IF 4.926]
17
Balassiano K., Lima S., Jenab M., Overvad
K., Tjonneland A., Boutron-Ruault M.C.,
Clavel- Chapelon F., Canzian F., Kaaks R.,
Boeing H., Meidtner K., Trichopoulou A.,
Laglou P., Vineis P., Panico S., Palli D., Grioni
S., Tumino R., Lund E., Bueno-de-Mesquita
H.B., et al.: Aberrant DNA methylation of
cancer-associated genes in gastric cancer
in the European Prospective Investigation
into Cancer and Nutrition (EPIC-EURGAST). Cancer Lett 2011; 311: 85-95 [IF
4.864]
18
Balic M., Rapp N., Stanzer S., Lin H., Strutz
J., Szkandera J., Daidone M.G., Samonigg
H., Cote R.J., Dandachi N.: Novel immunofluorescence protocol for multimarker assessment of putative
disseminating breast cancer stem cells.
21
28
Baratti D., Kusamura S., Deraco M.: Diffuse malignant peritoneal mesothelioma:
Systematic review of clinical management
and biological research. J Surg Oncol
Beesley J., Johnatty S.E., Chen X., Spurdle
A.B., Peterlongo P., Barile M., Pensotti V.,
Manoukian S., Radice P., Australian Ovarian Cancer Group, Kathleen Cuningham
Consortium for Research, in Familial
Breast Cancer,, Chenevix-Trench G.: No
evidence for an association between the
earwax-associated polymorphism in
ABCC11 and breast cancer risk in Caucasian women. Breast Cancer Res Treat
2011; 103: 822-831 [IF 2.428]
22
Barbareschi M., Cantaloni C., Del Vescovo
V., Cavazza A., Monica V., Carella R., Rossi
G., Morelli L., Cucino A., Silvestri M.,
Tirone G., Pelosi G., Graziano P., Papotti
M., Dalla Palma P., Doglioni C., Denti A.:
Heterogeneity of Large Cell Carcinoma
of the Lung: An Immunophenotypic and
miRNA-Based Analysis. Am J Clin Pathol
2011; 136: 773-782 [IF 2.506]
23
Barisella M., Collini P., Orsenigo M., Aiello
A., Dileo P., Pilotti S.: Myogenic Differentiation in the Ewing Sarcoma Family of Tumors. (Letter) Am J Surg Pathol 2011;
35: 464-465 [IF 4.106]
24
Barosi G., Bosi A., Abbracchio M.P., Danesi
R., Genezzani A., Corradini P., Pane F., Tura
S.: Key concepts and critical issues on
epoetin and filgrastim biosimilars. A position paper from the Italian Society of
Hematology, Italian Society of Experimental Hematology, and Italian Group for
Bone Marrow Transplantation. Haematologica 2011; 96: 937-942 [IF 6.532]
25
Battaglia L., Vannelli A., Belli F., Rampa M.,
Milione M., Gasparini P., Leo E.: Gyant
condyloma acuminant of the anorectum:
successful radical surgery with anal reconstruction. Tumori 2011; 97: 805-807
Appl Immunohistochem Molecul Morphol 2011; 19: 33-40 [IF 1.411]
[IF 1.014]
19
Beck J., Procopio G., Bajetta E., Keilholz U.,
Negrier S., Szczylik C., Bokemeyer C.,
Bracarda S., Richel D.J., Staehler M.,
Strauss U.P., Mersmann S., Burock K., Escudier B.: Final results of the European
Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access
study: a large open-label study in diverse
community settings. Ann Oncol 2011; 22:
26
Baltar V.T., Xun W.W., Chuang S.C., Relton
C., Ueland P.M., Vollset S.E., Midttun O., Johansson M., Slimani N., Jenab M., ClavelChapelon F., Boutron-Ruault M.C.,
Fagherazzi G., Kaaks R., Rohrmann S.,
Boeing H., Weikert C., Bueno-deMesquita H.B., Tagliabue G., et al.: Smoking, Secondhand Smoke, and Cotinine
Levels in a Subset of EPIC Cohort. Can-
1812-1823 [IF 6.452]
cer Epidemiol Biomarkers Prev 2011;
20: 869-875 [IF 3.919]
27
20
Banna G.L., Di Maio M., Follador A.,
Collovà E., Menis J., Novello S., Bria E., Bajetta E., Procopio G., on behalf of ISA CoAuthors: Italian Survey on adjuvant
treatment of non-small cell lung cancer
(ISA). Lung Cancer 2011; 73: 78-88 [IF
3.356]
Becker A.L., Orlotti N.I., Folini M., Cavalieri F., Zelikin A.N., Johnston A.P.R., Zaffaroni N., Caruso F.: Redox-Active Polymer
Microcapsules for the Delivery of a Survivin-Specific siRNA in Prostate Cancer
Cells. ACS Nano 2011; 5: 1335-1344 [IF
9.865]
2011; 126: 235-239 [IF 4.859]
29
Bellardita L., Donegani S., Spatuzzi A.L.,
Valdagni R.: Multidisciplinary Versus Oneon-One Setting: A Qualitative Study of
Clinicians’ Perceptions of Their Relationship With Patients With Prostate Cancer.
J Oncol Pract 2011; 7: e: 1-5
30
Bendinelli B., Masala G., Saieva C., Salvini
S., Calonico C., Sacerdote C., Agnoli C.,
Grioni S., Frasca G., Mattiello A., Chiodini
P., Tumino R., Vineis P., Palli D., Panico S.:
Fruit, vegetables, and olive oil and risk of
coronary heart disease in Italian women:
the EPICOR Study. Am J Clin Nutr 2011;
93: 275-283 [IF 6.606]
31
Benetou V., Orfanos P., Zylis D., Sieri S.,
Contiero P., Tumino M.C., Giurdanella
M.C., Peeters P.H.M., Linseisen J., Nieters
A., Boeing H., Weikert C., Pettersson U.,
Johansson I., Bueno-de- Mesquita H.B.,
Dorronsoro M., Boffetta P., Trichopoulou
A.: Diet and hip fractures among elderly
Europeans in the EPIC cohort. Eur J Clin
Nutr 2011; 65: 132-139 [IF 2.563]
32
Benetou V., Orfanos P., Benetos I.S., Pala
M. V., Evangelista A., Frasca G., Giurdanella
M.C., Peeters P.H.M., var der Schouw Y.T.,
Rohrmann S., Linseisen J., Boeing H.,
Weikert C., Petterson U., Van Guelpen B.,
Bueno-de-Mesquita H.B., Altzibar J., Boffetta P., Trichopoulou A.: Anthropometry,
physical activity and hip fractures in the
elderly. Injury 2011; 42: 188-193 [IF
2.269]
33
Bergmann M.M., Schutze M., Steffen A.,
Boeing H., Halkjaer J., Tjonneland A.,
Travier N., Agudo A., Slimani N., Rinaldi S.,
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Panizza C., Bai E., Oddone E., Scaburri A.,
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Pelosi G., Sonzogni A., Galetta D., Perrone
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Pascali C., Bogni A., Cucchi C., Laera L.,
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Pelosi G.: The new taxonomy of lung adenocarcinoma stemming from a multidisciplinary integrated approach: novel
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Pourhoseingholi M.A., Faghihzadeh S., Hajizadeh E., Gatta G., Zali M.R., Abadi A.R.:
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Prasad K.R., Young R.S., Burra P., Zheng
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Procopio G., Guadalupi V., Giganti M.A.,
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Procopio G., Niger M., Testa I.: Lecture:
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Purdue M.P., Johansson M., Zelenika D.,
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Raijmakers N.J., van Zuylen L., Costantini
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Righi L., Graziano P., Fornari A., Rossi G.,
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Raoul J.L., Sangro B., Forner A., Mazzaferro V., Piscaglia F., Bolondi L., Leoncini R.:
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Rossi D., Rasi S., Di Rocco A., Fabbri A.,
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Rossi S., Miceli R., Messerini L., Bearzi I.,
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Rossi S., Ravetta V., Rosa L., Ghittoni G.,
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Rudman S.M., Josephs D.H., Cambrook
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Ruffini E., Van Raemdonck D., Detterbeck
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van Veldhoven C.M., Khan A.E., Teucher B.,
Rohrmann S., Raaschou-Nielsen O., Tjønneland A., Overvad K., Vigl M., Boeing H.,
Benetou V., Trichopoulou A., Trichopoulos
D., Masala G., Mattiello A., Krogh V., Tumino R., Vermeulen R., et al.: Physical activity and lymphoid neoplasms in the
ers Prev 2011; 20: 1925-1927 [IF 3.919]
431
Viale P., Gesu G., Privitera G., Allaria B.,
Petrosillo N., Zamparini E., Scudeller L.,
Favaro M., Viola G., for the ISABEL Study
Group: Multicenter, prospective surveillance study of Staphylococcus aureus
nasal colonization in 28 Italian intensive
care units: the ISABEL Study. Infect Control Hosp Epidemiol 2011; 32: 193-197
[IF 3.751]
432
Villanueva A., Hoshida Y., Battiston C.,
Tovar V., Sia D., Alsinet C., Cornella H.,
Liberzon A., Kobayashi M., Kumada H.,
Thung S.N., Bruix J., Newell P., April C.,
Fan J.B., Roayaie S., Mazzaferro V.,
Schwartz M.E., Llovet J.M.: Combining
clinical, pathology, and gene expression
data to predict recurrence of hepatocellular carcinoma. Gastroenterology 2011;
140: 1501-1512 [IF 12.032]
433
Vinceti M., Malagoli C., Fiorentini C.,
Longo C., Crespi C.M., Albertini G., Ricci
177
C., Lanzoni A., Reggiani M., Virgili A., Osti
F., Lombardi M., Santini M., Fanti A., Dika
E., Sieri S., Krogh V., Seidenari S., Pellecani
G.: Inverse association between dietary
vitamin D and risk of cutaneous
melanoma in a northern Italy population.
Nutr Cancer 2011; 63: 506-513 [IF
2.553]
434
Vineis P., Chuang S.C., Vaissiere T., Cuenin
C., Ricceri F., The Genair-EPIC Collaborators,, Johansson M., Ueland P., Brennan P.,
Herceg Z., The Genair-EPIC Collaborators:, Pala M. V.: DNA methylation
changes associated with cancer risk factors and blood levels of vitamin metabolites in a prospective study. Epigenetics
2011; 6: 195-201 [IF 4.662]
435
Vitellaro M., Bonfanti G., Sala P., Poiasina
E., Barisella M., Signoroni S., Mancini A.,
Bertario L.: Laparoscopic colectomy and
restorative proctocolectomy for familial
adenomatous polyposis. Surg Endosc
2011; 25: 1866-1875 [IF 3.436]
survival statistics are misleading”: simulation study with National Cancer Registry
data. BMJ 2011; 342: d: 3399 [IF 13.471]
440
Xun W.W., Brenna P., Tjonneland A., Vogel
U., Overvad K., Kaaks R., Canzian F., Boeing H., Trichopoulou A., Oustoglou E.,
Giotaki Z., Johansson M., Palli D., Agnoli
C., Tumino R., Sacerdote C., Panico S., et
al.: Single-nucleotide polymorphisms
(5p15.33, 15q25.1, 6p22.1, 6q27 and
7p15.3) and lung cancer survival in the
Cancer and Nutrition (EPIC). Mutagenesis 2011; 26: 657-666 [IF 3.983]
441
Yan T.D., Deraco M., Elias D., Glehen O.,
Levine E.A., Moran B.J., Morris D.L., Chua
T.C., Piso P., Sugarbaker P.H., Baratti D.,
kusamura S., and Peritoneal Surface Oncology Group: A novel tumor-nodemetastasis (TNM) staging system of
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1855-1863 [IF 5.131]
436
Viviani S., Zinzani P.L., Rambaldi A.,
Brusamolino E., Levis A., Bonfante V., Vitolo U., Pulsoni A., Liberati A.M., Specchia
G., Valagussa P., Rossi A., Zaja F., Pogliani
E.M., Pregno P., Gotti M., Gallamini A.,
Rota-Scalabrini D., Bonadonna G., Gianni
A.M., for the Michelangelo Foundation:
Gruppo Italiano di Terapie Innovative nei
Linfomi; Intergruppo Italiano Linfomi.:
ABVD versus BEACOPP for Hodgkin’s
lymphoma when high-dose salvage is
planned. N Engl J Med 2011; 365: 203-212
[IF 53.486]
437
Vizioli M.G., Possik P.A., Tarantino E., Meissl
K., Borrello M.G., Miranda C., Anania M.
C., Pagliardini S., Seregni E., Pierotti M.A.,
Pilotti S., Peeper D.S., Greco A.: Evidence
of oncogene- induced senescence in thyroid carcinogenesis. Endocr-Relat Cancer
2011; 18: 743-757 [IF 4.432]
438
Vohnout B., Arnout J., Krogh V., Donati
M.B., de Gaetano G., Iacoviello L.: Association between MTHFR C677T genotype
and circulating folate levels irrespective of
folate intake: Data from the IMMIDIET
Project. (Research Letter) Nutrition
2011; 27: 1209-1210 [IF 2.726]
442
Yang X.R., Chang-Claude J., Goode E.L.,
Couch F.J., Manoukian S., Barile M., Radice
P., Hankinson S.E., Hunter D.J., Tamini R., et
al.: Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the breast cancer association
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2011; 103: 250-263 [IF 14.697]
443
Zacchetti A., Martin F., Luison E., Coliva
A., Bombardieri E., Allegretti M., Figini M.,
Canevari S.: Antitumor Effects of a
Human Dimeric Antibody Fragment
131I-AFRA-DFM5.3 in a Mouse Model
for Ovarian Cancer. J Nucl Med 2011; 52:
1938-1946 [IF 7.022]
444
Zamora-Ros R., Knaze V., Lujan-Barroso
L., Slimani N., Romieu I., Fedirko V., Santucci De Magistris M., Ericson U., Amiano
P., Trichopoulou A., Dilis V., Naska A., Engeset D., Skeie G., Cassidy A., Overvad K.,
Peeters P.H.M., Huerta J.M., Sanchez M.J.,
Quiros J.R., Sacerdoce C., Grioni S., Tumino R., et al.: Estimated dietary intakes
of flavonols, flavanones and flavones in
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439
2011; 106: 1915-1925 [IF 3.072]
Woods L., Coleman M.P., Lawrence G.,
Rashbass J., Berrino F., Rachet B.: Evidence
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445
Zamora-Ros R., Knaze V., Luján-Barroso
L., Slimani N., Romieu I., Touillaud M.,
Kaaks R., Teucher B., Mattiello A., Grioni S.,
Crowe F., Boeing H., Förster J., Quirós J.R.,
Molina E., Huerta J.M., Engeset D., Skeie
G., Trichopoulou A., Dilis V., Tsiotas K.,
Peeters P.H., Khaw K.T., Wareham N.,
Bueno-de-Mesquita B., Ocké M.C., Olsen
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Br J Nutr 2011; 106: 1090-1099 [IF
3.072]
446
Zappasodi R., Bongarzone I., Ghedini
G.C., Castagnoli L., Cabras A., Messina A.,
Tortoreto M., Tripodo C., Magni M., Carlo
Stella C., Gianni A.M., Pupa S., Di Nicola
M.: Serological identification of HSP105 as
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[IF 10.558]
447
Zeleniuch-Jacquotte A., Shore R.E.,
Afanasyeva Y., Lukanova A., Sieri S., Koenig
K.L., Idahl A., Krogh V., Liu M., Ohlson N.,
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Hallmans G., Toniolo P., Lundin E.: Postmenopausal circulating levels of 2- and
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448
Zerbi A., Capitanio V., Boninsegna L.,
Pasquali C., Rindi G., Delle Fave G., Del
Chiaro M., Casadei R., Falconi M., Bajetta
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449
Zigon G., Berrino F., Gatta G., Sanchez
M.J., van Dijk B., Francisci S., Allemani C.,
Baili P., Ciampichini R., Ciccolallo L.,
Micheli A., Sant M., Sowe S., Tagliabue G.,
Contiero P., the EUROCARE Working
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population-based study. Ann Oncol 2011;
22: 165-174 [IF 6.452]
450
Zuco V., De Cesare M., Cincinelli R., Nannei R., Pisano C., Zaffaroni N., Zunino F.:
Synergistic Antitumor Effects of Novel
HDAC Inhibitors and Paclitaxel In Vitro
and In Vivo. PLoS ONE 2011; 6: e: 29085
[IF 4.411]
Independent Ethics Committee
178
independent ethics committee
Established in 1973, the institutional Independent Ethics
Committee reviews all new clinical studies submitted by
investigators and approved by the Scientific Institutional
Review Board.
In 2011, 101 new studies received their ethical approval.
In spite of the increase in the number of studies, median
time from submission to discussion was again in the range
of one month (32 days). This was made possible by
intense monthly meetings of a highly dedicated Committee and an optimized pathway for study clearance, which
is carried out in close cooperation with all other relevant
institutional bodies (General and Legal Affairs Unit, Economic and Financial Resource Management Unit, and the
Pharmacy). These tight institutional collaborations resulted
in efficient streamlining of the various scientific and
administrative components of the ethical review process.
During 2011, it was decided to set up a completely new
informatics infrastructure through a software specifically
conceived for support to ethics committees, due to be
installed in 2012. In addition, it was decided to expand
the Committee secretariat by hiring a regulatory affairs
consultant and a statistician devoted to monitoring tasks
(due to be hired in 2012). This should make it possible to
upgrade Committee’s performances in 2012, as long as
the number of studies is due to increase further.
In 2011, the Independent Ethics Committee maintained
its focus on tissue "donation" for biobanking. Following a
consensus document released in 2010, a new draft
informed consent for all institutional patients was finalized
Chairman
Roberto Satolli
Members
Maria Angela Armiraglio
Luigi Cajazzo (until February 2011)
Gianfranco Canti
Francesca Crippa Floriani
Emilio Di Genova (from March 2011)
Paolo Fontana
Marina Garassino
Momcilo Jankovic
Antonio Miadonna
Paolo Spriano
Valter Torri
Rita Vetere
and is currently under discussion with relevant authorities, with a view to shaping it also as a model for other
research institutions in Italy.
It was also decided to launch a project on information of
patients enrolled in clinical trials. The aim is to work out
practical tools for patient information in clinical trials
based on an analysis of ethical and legal requirements on
one side and clinical and psychological needs on the
other. These tools should be acceptable to all the stakeholders (patients, regulators, clinical trial sponsors) and be
clinically and psychologically appropriate. In 2012, some
50-100 patients, properly selected, will be interviewed by
psychologists from the Clinical Psychology Unit, along
with some 20 clinical researchers. A comprehensive
review of available literature will be performed in the
clinical and psychological area. In addition, a comprehensive analysis of ethical and legal requirements will be
carried out. In the next stage of this project (2012-2013),
focus groups will be set up involving all relevant
stakeholders (patients, clinical researchers, general practitioners, psychologists, ethics committees, contract
research organizations, clinical trial sponsors, insurance
companies, regulators, bioethicians, etc.), and data will be
collected and integrated. A multidisciplinary project steering committee is then due to propose practical tools,
with the aim of improving the process of patient information within clinical trials (including formats for informed
consent documents, procedures, quality requirements).
Members ex-officio
Lucio Ascani (until June 2011)
Vito Corrao (from February 2011)
Marco A. Pierotti
Francesco Reitano (until January 2011)
Gabriella Saibene (from July 2011)
Scientific Secretariat
Paolo G. Casali
Bianca M. Francucci
Administratives
Raffaella Didoné
Patrizia Polo
179
ONGOING CLINICAL STUDIES
Study code/Title
Coordinator
Activated
(closed)
Phase
1998
III
Total patients
Patients enrolled in 2011
BREAST CARCINOMA
98/01
Celio L.
24
Closed accrual
Randomized double-blind trial in postmenopausal women with primary breast cancer who have received adjuvant tamoxifen
for 2-3 years, comparing subsequent adjuvant exemestane treatment with further tamoxifen
02/03
Moliterni A.
2002
III
35
Closed accrual
A multicenter, randomized, controlled open-labeled trial of paclitaxel-containing chemotherapy (AT&T) followed by CMF versus
the same chemotherapy plus Herceptin in women with locally advanced breast cancer and HER2/C-ERBB2 overexpression and
amplification, with a parallel observational study of the same chemotherapy regimen alone, in patients with HER2 negative
tumors (or 1+ by immunohistochemistry)
03/32
Berrino F.
2003
Observational
2467
71
Prognostic significance of blood concentrations of testosterone and insulin in women with early breast cancer
04/06
Gianni A.M.
2004
Pilot
4
1
Immunization of patients with locally advanced/metastatic breast and ovary cancer with autologous monocyte-derived dendritic
cells loaded with apoptotic/necrotic autologous tumor cells exposed to heat shock
05/21
Moliterni A.
2005
II
66
Closed accrual
European Cooperative Study of Primary Systemic Therapy in women with operable breast Cancer and T > 2 cm. (ECTO II)
05/68
Bianchi G.
2006
II
7
Closed accrual
A phase II, single arm, multicenter study to evaluate the efficacy and safety of the combination of Omnitarg and Herceptin in
patients with HER2-positive metastatic breast cancer
06/39
Moliterni A.
2006
III
14
Closed accrual
A randomized, open-label, 2-arm, multicentre, phase III study to evaluate the efficacy and safety of bevacizumab in combination
with Trastuzumab/Docetaxel compared with Trastuzumab/Docetaxel alone as first line treatment for patients with HER-2
positive locally recurrent or metastatic breast cancer
07/04
Mariani G.
2007 (06/09/11)
II
8
Closed accrual
A randomized, double-blind, phase II trial of Fulvestran plus Enzastaurin versus Fulvestran plus Placebo in aromatase inhibitor
resistant metastatic breast cancer
07/24
Nava M.
2008
II
57
5
Prevention of postoperative pain by using botulinic toxin in patients candidates to mastectomy and immediate reconstruction
with expander and in patients candidates to additive contralateral mastoplastic in the second reconstructive phase
07/37
Berrino F.
2007
-
1568
336
Randomized trial of diet, physical activity and breast cancer recurrences: the DIANA-5 study
07/43
Mariani G.
2007
IIb
26
Closed accrual
A multinational double-blind, randomized phase IIb cooperative group study evaluating the efficacy and safety of sorafenib
compared to placebo when administered in combination with chemotherapy and/or endocrine therapy in patients with locally
recurrent or metastatic breast cancer
07/47
Bianchi G.
2007
II
28
Closed accrual
A randomized multicentric international phase II study of Herceptin® and docetaxel versus docetaxel in association with
OmnitargTM and Herceptin® versus OmnitargTM and Herceptin® in the treatment of locally advanced HER-2 positive breast
cancer, inflammatory or early breast cancer
Ongoing Clinical Studies
Study code/Title
Coordinator
07/65
Manoukian S.,
Vergnaghi D., Bergonzi S.
Activated
(closed)
2008
Phase
Total patients
Observational
180
106
11
352
33
Italian ISS network for the surveillance of women at high breast cancer risk (ISSIN-HIBCR)
08/18
Moliterni A.
2008
II
Phase II study. Safety of the scheme of adjuvant or primary sequential chemotherapy in operable breast cancer at high risk (AT
x 3 - CMF x 3)
08/65
Bianchi G.
2009
II
5
Closed accrual
A randomized, multicenter, phase II study of the efficacy and safety of trastuzumab-MCC-DM1 vs trastuzumab (Herceptin) and
Docetaxel (Taxotere) in patients with metastatic HER2-positive breast cancer who have not received prior chemotherapy for
metastatic disease
08/76
Berrino F.
2010
III
192
112
Tevere project: primary prevention of breast cancer by diet, physical activity or Metformin assumption
09/07
Gianni A.M.
2009 (01/11/11)
II
36
7
A phase II study to evaluate efficacy and tolerability of Sorafenib for the treatment of post-surgical and post-radiotherapeutic
edema of the superior arm in subjects with breast cancer
09/16
Bianchi G.
2009
III
6
1
A randomized, multicenter, phase III open-label study of the efficacy and safety of trastuzumab-MCC-DM1 vs
capecitabine+lapatinib in patients with HER2-positive locally advanced or metastatic breast cancer who have received prior
trastuzumab-based therapy
09/33
Cresta S.
2010
Ib
6
2
A phase Ib, open label, dose escalation study of the safety and pharmacology of P13-kinase inhibitor GDC-0941 in combination
with paclitaxel and bevacizumab in patients with locally recurrent or metastatic breast cancer
09/63
Bianchi G.
2010
III
8
4
A randomized phase III, double-blind, placebo-controlled multicenter trial of daily everolimus in combination with trastuzumab
and vinorelbine, in pretreated women with HER2/neu over-expressing locally advanced or metastatic breast cancer
09/67
Moliterni A.
2010
II
8
Closed accrual
Multicenter, randomized, open label study evaluating a poly(AFP-ribosio) polymerase-1(PARP-1) inibitor, SAR240550 (BSI-201),
administered twice weekly or weekly, in combination with gemcitabine/carboplatin, in patients with Triple Negative breast
Cancer (mTNBC)
09/68
Raspagliesi F.
2010
III
3
2
A multi-centre, open-label, randomized, two arm phase III trial of bevecizumab plus chemotherapy versus chemotherapy alone
in patients with platinum-resistant, epithelial ovarian, fallopian tube or primary peritoneal cancer
10/35
Bombardieri E.
2010
-
11
10
Evaluation of [18F]FLT-PET/CT in early monitoring of response to primary medical therapy in patients with breast cancer and as
in vivo indicator of cellular proliferation
10/46
Bianchi G.
2011
II
1
1
A multicenter, multinational phase II study to assess the clinical safety and feasibility of T-DM1 sequantially with anthracycline
based chemotherapy, as adjuvant or neoadjuvant therapy for patients with early stage HER2-positive breast cancer
10/51
Nava M.
2011
Observational
12
12
Development of an EORTC breast reconstruction (BRR) module to accompany the EORTC QLQ-C30 and BR23 to
assessquality of life in patients undergoing breast reconstruction
GASTROINTESTINAL CANCERS
04/17
Casali P.
2005
II
22
Closed accrual
A phase II, open-label study of PTK787/ZK222584 in the treatment of metastatic gastrointestinal stromal tumors (GISTs)
resistant to imatinib mesylate
04/28
Procopio G.
2005
III
71
Closed accrual
Open-label randomized, multicenter phase III study of adjuvant chemotherapy in radically resected adenocarcinoma of the
stomach or gastroesophageal junction: comparison of sequential treatment (CPT11 + 5-FU/LV TXT + CDDP versus a 5FU/LV regimen)
181
Study code/Title
Coordinator
Activated
(closed)
Phase
05/33
Buzzoni R.
2005
III
Total patients
38
Closed accrual
A randomized, three arm multinational phase III study to investigate bevacizumab (q3w r q2w) in combination with either
intermittent capecitabine plus oxaliplatin (Xelox) (q3w) or fluorouracil/leucovorin with oxaliplatin (Folfox-4) versus Folfox-4
regimen alone as adjuvant chemotherapy in colon carcinoma: the AVANT study
05/37
Casali P.
2005 (27/05/11)
I
11
Closed accrual
A phase I multicenter, dose escalation study of AMN107 in combination with imatinib on a continuous daily dosing schedule in
adult patients with imatinib-resistant gastrointestinal stromal tumors (GIST)
05/49
Di Bartolomeo M.
2005
II
39
Closed accrual
Capecitabine Time Table and radiotherapy in the adjuvant treatment of cancer of the rectum
06/24
Gavazzi C.
2006
III
55
8
Home Enteral Nutrition in Malnourished Patients after Major Surgery fro Gastrointestinal Malignancy
06/27
Buzzoni R.
2006
II
3
Closed accrual
An open-label, stratified, single-arm phase II study of RAD001 in patients with advanced pancreatic neuroendocrine tumor
(NET) after failure of cytotoxic chemotherapy
06/54
Buzzoni R.
2006
III
1
Closed accrual
Phase III, randomized, double-blind, stratified, comparative, placebo controlled, parallel group, multicentre study to assess the
effect of deep subcutaneous injections of lanreotide autogel 120 mg administered every 28 days on tumour progression free
surivival in patients with non functioning entero-pancreatic endocrine tumour
06/56
Casali P.
2006 (19/12/11)
-
13
Closed accrual
38
Closed accrual
A treatment protocol for patients continuing from a prior SU011248 protocol
06/75
Mazzaferro V.
2006
II
A prospective randomized, open-label trial comparing Sirolimus-containing versus mTOR -inhibitor-free immunosuppression in
patients undergoing liver transplantation for hepatocellular carcinoma
07/09
Regalia E.
2007
-
54
Closed accrual
LIVER MATCH. An Italian multicentric study to evaluate the impact of donor-recipient matching in the outcome of liver
transplantation at short, medium and long term
07/25
Casali P.
2007
Observational
36
Closed accrual
A study of the genetic polymorphisms of patients with gastrointestinal stromal tumors (GIST) and of their predictive value of
clinical activity of tyrosin kinase inhibitors
07/32
Casali P.
2007
Observational
54
Closed accrual
The global observational registry colllecting longitudinal data on advanced GIST patients (GOLD reGISTry)
07/52
Di Bartolomeo M.
2007
III
104
17
A randomized trial investigating the role of FOLFOX-4 regimen duration (3 versus 6 months) and bevacizumab as adjuvant
therapy for patients with stage II/III colon cancer
07/69
Di Bartolomeo M.
2007
III
9
Closed accrual
A double-blind, randomized, multicenter, phase III study of bevacizumab in combination with capecitabine and cisplatin versus
placebo in combination with capecitabine and cisplatin, as first-line therapy in patients with advanced gastric cancer
08/08
Dragani T. Leo E.
2008
-
992
260
Accrual of patients with colorectal cancer and of healthy sisters/brothers for studies on genetic risk factors
08/27
Buzzoni R.
2008
II
21
3
Perioperative treatment with COI-E (capecetabine, oxaliplatin, irinotecan and cetuximab) of liver metastasis of colorectal
carcinoma potentially resectable although at high risk of recurrences
08/38
Mazzaferro V.
2008
III
46
Closed accrual
A phase III randomized, double-blind, placebo-controlled study of sorafenib as adjuvant treatment for hepatocellular carcinoma
after surgical resection or local ablation (STORM)
Study code/Title
Coordinator
08/56
Casali P.
Activated
(closed)
2008 (16/12/11)
Phase
II
Total patients
10
182
Closed accrual
An open-label, multicenter, single-arm study to evaluate the efficacy of nilotinib in adult patients with metastatic or unresectable
gastrointestinal stromal tumors in first line treatment accrual
08/61
Casali P.
2008 (21/11/11)
III
11
Closed accrual
An open label, multicenter, expanded access study of imatinib mesylate in adult patients with GIST in adjuvant setting after R0resection
09/01
Buzzoni R.
2009
III
1
0
Open label extension study of lanreotide autogel 120 mg in patients with non functioning entero-pancreatic endocrine tumour
09/12
Di Bartolomeo M.
2009
II
30
Closed accrual
Capecetabine in combination with oxaliplatin, irinotecan and bevacizumab (COI-B regime) as first.line therapy for metastatic
colorectal cancer: a phase II ITMO study
09/15
Mazzaferro V.
2009 (14/11/11)
II
3
Closed accrual
A phase II randomized, double-blind, placebo-controlled study of sorafenib or placebo in combination with transarterial
chemoembolization (TACE) performed with DC bead and doxorubicin for intermediate stage hepatocellular carcinoma (HCC)
09/21
Casali P.
2009
III
1
1
A randomized, open-label, multicenter phase III study to evaluate the efficacy and safety of nilotinib versus imatinib in adult
patients with unresectable or metastatic gastrointestinal stromal tumors
09/24
Mazzaferro V.
2009
III
6
1
A randomized, double-blind, multicenter phase III study of brivanib plus best supportive care (BSC) versus placebo plus BSC in
subjects with advanced hepatocellular carcinoma (HCC) who have failed or are intolerant to sorafenib
09/31
Casali P.
2009
III
10
1
An open-label, multicenter study to evaluate the efficacy of nilotinib in adult patients with gastrointestinal stromal tumors
resistant to imatinib and sunitinib
09/37
Mazzaferro V.
2009
Observational
28
Closed accrual
Development of programs for weak subjects within the transplant system: optimal use of organs
09/61
Mazzaferro V.
2010
II
2
Closed accrual
An uncontrolled open label multicenter phase II safety study of BAY73-4506 in patients with hepatocellular carcinoma (HCC)
09/79
Casali P.
2010
Observational
51
Closed accrual
Observational study of plasma levels of Imatinib in patients with gastrointestinal stromal tumor
09/80
Mazzaferro V.
2009
III
17
14
Controlled extension of conventional criteria for liver tranplantation in hepatocellular carcinoma (HCC): a prospective
validation study
10/21
Casali P.
2010
II
2
2
A phase II, open label study to evaluate the activity and safety of Everolimus in association to Imatinib in PDGFRA-D842V
unresectable or metastatic gastrointestinal stromal tumours (GISTs) as first line treatment
10/64
Leo E.
2010
-
228
53
10
10
The role of natural fluorescence of plasma in colorectal cancer patients
10/80
Casali P.
2011
III
A randomized, double-blind, placebo-controlled phase III of regorafenib plus best supportive care versus placebo plus best
supportive care for subjects with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has
progressed despite prior treatment with at least imatinib and sunitinib
11/94
Scaramuzza D.
2011
Observational
3
3
Evaluation of diagnostic accuracy of diffusion-weighted magnetic resonance (DW-MRI) and perfusion magnetic resonance
(DCE-MRI) in the dilation of mesorectal lymph nodes in colorectal cancer
183
Study code/Title
Coordinator
Activated
(closed)
Phase
Total patients
2006
II
5
GENITAL APPARATUS
06/34
Procopio G.
Closed accrual
A randomized multicenter phase II trial of Patupilone (EPO906) plus Prednisone versus Docetaxel (Taxotere) plus Prednisone
in patients with metastatic hormone refractory prostate cancer
06/78
Daidone M.G., Salvioni R.
2006 (01/12/11)
Observational
190
Closed accrual
-
224
67
-
7
Analysis of serum protein profiles for the early diagnosis of prostate cancer
07/46
Valdagni R.
2007
Prostate cancer research international: active surveillance (PRIAS)
07/54
Nicolai N.
2008
Identification of Men with a genetic predisposition to Prostate Cancer: Target Screening in BRCA1/2 mutation carriers and
controls - the IMPACTstudy
08/30
Buzzoni R.
2008 (14/07/11)
III
2
A phase III, randomized, placebo-controlled, double-blind study to assess the efficacy and safety of once-daily orally administered
ZD4054 10 mg in non-metastatic hormone-resistant prostate cancer patients
08/54
Zanaboni F. Raspagliesi F.
2008 (31/01/11)
II
55
20
A prospective phase II multicentric study of weekly topotecan and cisplatin (topocis) as neoadjuvant treatment in patients with
locally advanced squamous cervical cancer
09/10
Raspagliesi F.
2009
III
33
18
Carboplatin and Paclitaxel administered every three weeks vs Carboplatin and Paclitaxel administered weekly to patients with
ovary carcinoma: multicentric randomized study
09/11
Raspagliesi F.
2009
-
13
0
TOTEM: a multicentric controlled randomized clinical study between two follow-up regimens with different test intensity in
endometrial cancer treated patients
09/44
Raspagliesi F.
2009
III
2
2
A randomized, double-blind, placebo-controlled, phase III study to assess the efficacy and safety of weekly farletuzumab
(MORAb-003) in combination with carboplatin and taxane in subjects with platinum-sensitive ovarian cancer in first relapsed
09/65
Raspagliesi F.
2010
-
32
23
LION - Lymphadenectomy in ovarian neoplasm An open randomized prospective multicenter-trial . A project of the AGO
Stydy Grop
09/71
Raspagliesi F.
2010
III
2
Closed accrual
A phase III study to evaluate the efficacy and safety of pazopanib monotherapy versus placebo in women who have not
progressed after first line chemotherapy for epithelial ovarian, fallopian tube, or primary peritoneal cancer
10/22
Rivoltini R.
2010
II
24
19
An open label, phase II study of vaccination with surviving peptides emulsified in Montanide ISA 51VG after IMP 321TM
injection in prostate carcinoma patients with biochemical failure
10/38
Salvioni R.
2010
II
17
8
Tandem transplantation of autologous hematopoietic progenitors in relapsed/refractory patients with metastatic germinal
tumors
10/50
Villa S.
2010
Observational
45
320
Multicentric observational study DUE-01: urinary and erectile dysfunction after radical external beam therapy in localized
prostate cancer
10/67
Valdagni R.
2010
Observational
18
18
A prospective evaluation of plasma levels of inflammatory markers in radiotherapy treatment of prostate cancer and
relationship with acute and late rectal toxicity
Study code/Title
Coordinator
11/03
Raspagliesi F.
Activated
(closed)
Phase
Total patients
2011
III
1
184
1
A phase III, randomized, double-blind trial of weekly paclitaxel plus AMG386 or placebo in women with recurrent partially
platinum sensitive or resistant epithelial ovarian, primary peritoneal or fallopian tube cancers
11/11
Raspagliesi F.
2011
Observational
130
130
Breathing analysis by electronic nose for detection of ovarian cancer in general population and in population at risk
11/17
Procopio G.
2011
III
34
34
An open-label study of abiraterone acetate in subjects with metastatic castration-resistant prostate cancer who have progressed
after taxane-based chemotherapy
11/22
Procopio G.
2011
III
6
6
Multicentre, single-arm, open label, clinical trial intended to provide early access to cabazitaxel in patients with metastatic
hormone refractory prostate cancer previously treated with a docetaxel-containing regimen and to document safety of
cabzitaxel in these patients
11/95
Valdagni R.
2011
Observational
1
1
30
Closed accrual
Active surveillance “SA INT”in prostate cancer patients with low progression risk
HEAD & NECK AND THYROID CANCERS
07/42
Licitra L.
2007
II
SAMITAL in the prevention and care of mucositis induced by chemoradiation therapy in the treatment of cervico-facial
neoplasias
08/05
Licitra L.
2008
II
5
Closed accrual
A phase II, randomized trial of chemoradiation with or without Panitumumab in subjects with unresected, locally advanced
squamous cell carcinoma of the head and neck
09/04
Licitra L.
2009
II
11
Closed accrual
Phase II, multicenter, open-label, single arm trial to evaluate the safety and efficacy of oral E7080 in medullary and iodine-131
refractory, unresectable differentiated thyroid cancers, stratified by histology
09/05
Licitra L.
2009
III
9
2
An internationall, randomized, double-blinded, phase III efficacy study of XL184 versus placebo in subjects with unresectable,
locally advanced, or metastatic medullary thyroid cancer
09/52
Licitra L.
2009
I-II
5
5
Open-label, randomized, controlled phase I/II study of cilengitide to evaluate the safety and efficacy of the combination of
different regimens of cilengitide added to cisplatin, 5-FU, and cetuximab in subjects with recurrent/metastatic squamous cell
cancer of the head and neck (ADVANTAGE)
10/02
Licitra L.
2010
II
8
1
Phase II study of Pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma
of the head and neck
10/29
Locati L.
2010
II
31
18
II
5
5
Sorafenib in recurrent and/or metastatic salivary gland carcinomas
10/40
Licitra L.
2010
Phase II study of preoperative TPF chemotherapy in locally advanced resectable oral cavity squamous cell cancer in order to
improve the rate of pathological complete response
10/65
Licitra L.
2011
III
4
4
A double-blind, randomized phase III study evalutating the efficacy and safety of Sorafenib compared to placebo in locally
advanced/metastatic RAI-refractory differentiated thyroid cancer
11/07
Licitra L.
2011
III
8
8
A randomized, international, open-label. Multi-centre, phase III study to assess the effect of a patient outreach program on the
percentage of time patients with locally advanced or metastatic medullary thyroid cancer experience grade 2 or higher adverse
events during the first 12 months of treatment with vandetannib
185
Study code/Title
Coordinator
11/26
Bossi P.
Activated
(closed)
2011
Phase
Observational
Total patients
20
20
Salivary cytokines levels and development of mucositis during radiochemotherapy for head and neck cancer:an observational
study
11/44
Licitra L.
2011
III
1
1
Randomized, double-blind, multicenter two-stage adaptive phase III study of intravenous adnìministration of REOLYSIN
(Reovirus type 3 dearing) in combination with paclitaxel and carboplatin versus the chemotherapy alone in patients with
metastatic or recurrent squamous cell carcinoma of the head and neck who have progressed on or after prior platinum-based
chemotherapy
11/45
Licitra L.
2011
II
3
3
A single arm, open-label, phase II, multicentre study, to assess the safety of vismodegib (GDC-0449) in patients with locally
advanced or metastatic basal cell carcinoma
11/64
Licitra L.
2011
-
10
10
International study of the HPV-etiologic frection for head and neck cancers: retrospective pilot study
HEMATOLOGIC MALIGNANCIES
04/14
Corradini P.
2004
I-II
6
Closed accrual
Rituximab maintenance treatment versus no further after a brief induction therapy with FDN + rituximab in elderly patients
with advanced stage previously untreated follicular lymphoma
04/32
Gianni A.M., Di Nicola M.
2004
Observational
15
3
Prospective observational study in the adult with Burkitt’s lymphoma of a polychemotherapy scheme in use in pediatrics
05/02
Corradini P.
2005
I-II
4
Closed accrual
A multicenter, open-label study of oral melphalan, and CC-5013 (Revlimid) (MPR) as induction therapy in elderly newly
diagnosed multiple myeloma patients
05/34
Gianni A.M., Corradini P.
2005
III
23
4
Multicentric randomized phase III study that compares high-dose chemotherapy with rituximab and autotransplantation of
circulating hemopoietic precursors with CHOP with rituximab administered every 14 days as first-line therapy for patients at
high risk with large B-cell non-Hodgkin’s lymphoma
05/64
Corradini P.
2006 (15/12/11)
III
10
Closed accrual
Randomized comparison of conditioning regimens of reduced intensity containing respectively anti-lymphocyte globulin versus
alemtuzumab in allogeneic transplantation from non-family donors: global study
06/12
Corradini P.
2006
II
12
Closed accrual
A phase II, multicenter study of bortezomib, pegylated liposomal doxorubicin, dexamethasone (PAD) as induction and
melphalan (MEL 100) as transplant, in elderly newly diagnosed multiple myeloma patients
06/13
Corradini P.
2006
III
9
Closed accrual
A phase III, multicenter, randomized open-label study of velcade, melphalan, prednisone and thalidomide (V-MPT) versus
velcade, melphalan, prednisone (V-MP) in elderly untreated multiple myeloma patients
06/14
Corradini P.
2006
III
13
Closed accrual
A phase III, prospective, randomized clinical study with velcade-thalidomide-dexamethasone versus thalidomide-dexamethasone
for previously untreated patients with symptomatic multiple myeloma who are candidates to receive double autologous
transplantation
06/28
Corradini P.
2006
III
4
Closed accrual
15
Closed accrual
Zevalin at myeloablative doses in aggressive lymphomas of elderly patients
06/44
Corradini P.
2006
II
Intensive chemo-immunotherapy as first-line in adult patients with peripheral T-cell lymphoma
Study code/Title
Coordinator
06/45
Corradini P.
Activated
(closed)
2007 (26/07/11)
Phase
Total patients
III
5
186
Closed accrual
A phase IIIb study of MabThera (rituximab) maintenance therapy in patients with follicular Non-Hodgkin’s Lymphoma who have
responded to induction therapy
06/50
Corradini P.
2006
II
12
Closed accrual
A phase II, multicenter study of Melphalan 100 mg/m2 (MEL 100) as transplant, Revlimid and Prednisone (RP) as consolidation
and Revlimid alone as maintenance in elderly newly diagnosed multiple myeloma patients
06/55
Corradini P.
2007
II
12
Bortezomib and Dexamethasone treatment before donor lymphocyte infusions for myeloma patients progressing or relapsing
after allogenetic transplantation of hematophoietic cells (FM-MYEL-06-01)
06/67
Corradini P.
2007
II
3
Closed accrual
A phase II, multi-center, ranodmized, open label study of Velcade, Doxorubicin and Dexamethasone (PAD) vs Thalidomide and
Dexamethasone (TD) in advanced and refractory multiple myeloma patients
07/38
Corradini P.
2007
III
10
4
A multicentric randomized trial in adult patients with acute myelogenous leukemia (AML) to compare: 1) a standard-dose
versus high-dose remission induction regimen, and 2) an autologous blood stem cell transplantation versus an autologous blood
cell-supported multicycle high-dose chemotherapy program,, within a risk-oriented postremission strategy reserving allogeneic
stem cell transplantation for high-risk cases
07/48
Corradini P.
2007
II
12
1
Reduced intensity conditioning with high-dose rituximab followed by allogeneic transplantation of hematopoietic cells for the
treatment of relapsed/refractory B-cell non Hodgkin’s lymphomas
07/55
Corradini P.
2008
II
8
Closed accrual
Treatment with imatinib mesylate (Glivec) of severe chronic scleroderma-like GVHD, refractory to conventional
immunosuppressive therapy
07/63
Corradini P.
2008
Observational
7
0
2008
III
7
Closed accrual
Lombardy registry of HCV positive lymphomas
08/02
A phase III, multicentre, randomized, controlled study to determine the efficacy and safety of lenalidomide, melphalan and
prednisone (MPR) versus melphalan (200 mg/m2) followed by stem cell transplant in newly diagnosed multiple myeloma
subjects
08/14
Corradini P.
2008 (01/05/11)
-
48
A study of the protein profile expression with mass spectrometry (SELDI-TOF) for the identification of prognostic markers in
the plasma of patients with chronic lymphatic leukemia
08/24
Corradini P.
2008
I-II
6
Closed accrual
A phase Ia/II, multi-center, open-label study of HCD122 admnistered intravenously once weekly for four weeks in adult patients
with advanced non-hodgkin’s or Hodgkin’s lymphoma who have progressed after least two prior therapies
08/33
Gianni A.M.
2008
II
36
13
Phase II study of perifosine in combination with sorafenib for refractory/relapsed malignant lymphomas
08/34
Corradini P.
2008
III
3
1
A randomized comparison between conditioning regimens to allogeneic transplant of hemopoietic stem cells containing I.V.
Busulfan (I.V. Bu; Busilvex) with Fludarabin (BUFLU) versus I.V. Busulfan with Cyclophosphamide (BUCY2) in 40-55 years
patients with acute myeloid leukemia (AML) in complete remission
08/49
2008
II
33
8
Multicentre clinical study with early treatment intensification in patients with high-risk Hodgkin lymphoma, identified as FDGPET scan positive after two conventional BVD courses
09/09
2009
III
9
0
Phase III study comparing rituximab-supplemented ABVD (R-ABVD) with ABVD followed by involved-field radiotherapy
(ABVD-RT) in limited-stage (stage I-IIA with no areas of bulk) Hodgkin’s lymphoma
187
Study code/Title
Coordinator
Activated
(closed)
Phase
Total patients
09/13
Corradini P.
2009
II
1
0
Safety and efficacy of lenalidomide as main therapy in patients with newly diagnosed multiple myeloma following a tandem
autologous-allogeneic transplant
09/39
Corradini P.
2009
III
14
3
Phase III intergroup multicentre, randomized, controlled 3 arm parallel group study to determine the efficacy and safety of
lenalidomide in combination with dexamethasone (Rd9 versus melphalan, prednisone and lenalidomide (MPR) versus
cyclophosphamide, prednisone and lenalidomide (CPR) in newly diagnosed multiple myeloma subjects
09/46
Corradini P.
2009
III
11
Closed accrual
A phase III, multicentre, randomized, controlled study to determine the efficacy amd safety of ciclophosphamide, lenalidomide
and dexamethasone (CRD) versus melphalan (200 mg/m2) followed by stem cell transplant in newly diagnosed multiple
myeloma subjects
09/59
Gianni A.M.
2009
I-II
13
4
Phase I/II of desamethasone, ofatumumab and bendamustine (TREANDA) (DOT) as first-line treatment of mantle-cell
lymphoma (MCL) in the elderly
09/69
Corradini P.
2010
III
12
2
A multicenter, randomized, doble-blind, placebo controlled phase III study of panobinostat in combination with bortezomib and
dexamethasone in patients with relapsed multiple myeloma
09/76
Corradini P.
2010
II
4
2
Brief induction chemoimmunotherapy with rituximab + bendamustine + mitoxantrone followed by rituximab in elderly patients
with advanced stage previously unrtreated follicular lymphoma
10/07
Corradini P.
2010
-
3
1
Monitoring of human polyomavirus reactivation in patients with lymphoproliferative disease treated with chemotherapy,
chemotherapy and rituximab, and rituximab
10/12
Corradini P.
2010
I-II
5
3
A phase I/II, multicenter, open label study of pomalidomide cyclophosphamide and prednisone (PCP) in patients with multiple
myeloma relapsed and/or refractory to lenalidomide
10/13
Corradini P.
2010
Observational
8
Closed accrual
II
1
1
Prospective audit on stem cell mobilization in malignant lymphoma
10/27
Di Nicola M.
2010
Randomized phase II trial on primary chemotherapy with high-dose methotrexate and high-dose cytarabine with or without
thiotepa, and with or without rituximab, followed by brain irradiation vs high-dose chemotherapy supported by autologous
stem cells transplantation for immunocompetent patients with newly dignosed primary CNS lymphoma
10/31
Gianni A.M.
2010
III
4
4
A randomized, double-blind, placebo-controlled phase III study of SGN-35 (brentuximab vedotin) and best supportive care
(BSC) versus placebo and BSC in the treatment of patients at high risk of residual Hodgkin lymphoma (HL) following
autologous stem cell transplant (ASCT)
10/43
Devizzi L.
2011
II
2
2
A multicenter phase II study to evaluate the clinical activity and the safety profile of everolimus (RAD001) in marginal zone Bcell lymphomas (MZL)
10/49
Magni M.
2010
Observational
70
0
Outcome of second-line treatment in patients with relapsed follicular lymphoma according to the type of first-line treatment
received
10/57
Corradini P.
2010
III
5
4
A phase III trial comparing bertozomib, cyclofosfamide and dexamethasone versus lenalidomide cyclofosfamide and
dexamethasone in patients with multiple myeloma at first relapse
10/73
Corradini P.
2010
Observational
8
0
Observational study on the incidence of haemorrahagic cystitis (HC) in haematopietic stem cell transplantation (HSCT)
Study code/Title
Coordinator
Activated
(closed)
10/86
Corradini P.
2011
Phase
-
Total patients
1
188
1
Prognosis of patients with relapsed/refractory HL treated with IGEV induction therapy before HDCT with AHSCT
11/13
Devizzi L. Corradini P.
2011
Observational
7
7
2
2
REVEAL- REVlimid Effectiveness of Administration in patients with Lymphoma
11/34
Corradini P.
2011
I
An open-label, single-arm, phase I study of AEB071 (a protein kinase C inhibitor) in patients with CD79-mutant diffuse large Bcell lymphoma
11/37
Corradini P.
2011
II
2
2
A multicenter, open label phase II study of carfilzomib, cyclophosphamide and dexamethasone in newly diagnosed multiple
myeloma patients
LUNG CANCERS
05/53
Pastorino U.
2006
-
4099
2
Spiral CAT, biomarkers and proteomic analysis, associated to a program of primary prevention for the early diagnosis of lung
cancer: randomized study in subjects at high risk: project MILD
07/18
Platania M.
2007
III
5
Closed accrual
II
8
Closed accrual
START - Stimulating Targeted Antigenic Responses To NSCLC
07/22
Zilembo N.
2007
Randomized phase II study of pemetrexed versus pemetrexed and carboplatin as second line chemotherapy in advanced nonsmall cell lung cancer
07/35
Zilembo N.
2007
II
4
Closed accrual
A phase II study of NGR-hTNF administered as single agent every 3 weeks in patients affected by advanced or metastatic
malignant pleural mesothelioma previously treated with no more than one systemic therapeutic regimen
08/28
Zilembo N.
2008
II
5
Closed accrual
Phase II study of the combination of bevacizumab plus pemetrexed and carboplatin as first line therapy in patients with
malignant pleural mesothelioma
08/64
Zilembo N.
2008 (15/07/11)
III
9
Closed accrual
A phase III, randomized, double.blind, placebo-controlled multi-center study of ASA404 in combination with docetaxel in
second-line treatment of patients with advanced or metastatic (stage IIIb/IV) non-small cell lung cancer (NSCLC)
09/27
Zilembo N.
2009
II
31
6
A randomized phase II study with NGR-hTNF in combination with standard chemotherapy regimen vs standard chemotherapy
regimen in non-pretreated patients with advanced non-small cell lung cancer (NSCLC)
09/74
Zilembo N.
2010
III
6
5
A randomized, multicenter, open-label phase III study of gemcitabine-cisplatin chemotherapy plus IMC-11F8 versus gemcitabinecisplatin chemotherapy alone in the first-line treatment of patients with squamous stage IIIb or IV non-small cell lung cancer
(NSCLC)
09/75
Zilembo N.
2010
III
9
1
A randomized, multicenter, open-label phase III study of pemetrexed-cisplatin chemotherapy plus IMC-11F8 versus
pemetrexed-cisplatin chemotherapy alone in the first-line treatment of patients with nonsquamous stage IIIb or IV non-small
cell lung cancer (NSCLC)
10/03
Platania M.
2010
III
4
Closed accrual
A phase III, randomized, double-blind, placebo controlled study of oral talactoferrin in addition to best supportive care in
patients with non-small cell lung cancer who have failed two or more prior treatment regimens
10/10
Zilembo N.
2010
III
2
1
Randomized proteomic stratified phase III study of second line erlotinib versus chemotherapy in patients with inoperable nonsmall cell lung cancer- PROSE Study
189
Study code/Title
Coordinator
10/41
Pastorino U.
Activated
(closed)
Phase
2010
I-II
Total patients
40
18
A prospective randomized phase I/II study on anatomic lung resections using laser, without mechanical suturing devices for
parenchyma and synthetic materials for aerostasis versus standard treatment
10/72
Leo F., Pastorino U.
2011
III
221
221
The airINTrial: a prospective randomized phase III trial of the use of different modalities of pleural aspiration for the
management of breath loss after lung surgical resection
MELANOMA
08/11
Bajetta E.
2008 (05/07/11)
I
9
Closed accrual
A dose-finding study with fotemustine fixed dose in combination with docetaxel in pretreated with metastatic melanoma
08/52
Santinami M.
2009
III
37
16
A double-blind, randomized, placebo-controlled phase III study to assess the efficacy of recMAGE-A3 + AS15 ASCI as adjuvant
therapy in patients with MAGE-A3 positive resected stage III melanoma
08/55
Del Vecchio M.
2008 (20/07/11)
III
8
Closed accrual
A multicenter, randomized, double-blind study of dacarbazine with or without Genasense in chemotheapy naive subjects with
advanced melanoma and low LDH (the AGENDA trial) Del Vecchio M.
2008
09/42
Del Vecchio M.
2009
III
21
Closed accrual
An open label, multicenter, phase III trial of ABI-007 vs dacarbazine in previously untreated patients with metastatic malignant
melanoma
10/06
Del Vecchio M.
2010
III
10
Closed accrual
BRIM 3: a randonized, open-label, controlled, multicenter, phase III study in previuosly untreated patients with unresectable stage
IIIC or stagerIV melanoma with V600E BRAF mutation receiving RO5185426 or dacarbazine
10/25
Santinami M.
2010
I-II
6
6
An open, dose-escalation phase I/II study to assess the safety, immunogenicity and clinical activity of rec-PRAME + AS15
Antigen-specific Cancer Immunotherapeutic as first-line treatment of patients with PRAME-positive metastatic melanoma
10/33
Del Vecchio M.
2010
II
9
9
An open-label, multicenter, randomized, phase Ib/II study of E7080 in combination with dacarbazine versus dacarbazine alone as
first line therapy in patients with stage IV melanoma
10/34
Santinami M.
2010
II
9
9
A phase II single arm study of the combination of Ipilimumaband fotemustine in patients with non-resectable stage III or stage IV
melanoma
11/01
Del Vecchio M.
2011
III
5
5
A phase III randomized, open-label study comparing GSK1120212 to chemotherapy in subjects with advanced or metastatic
BRAFV600E/K mutation-positive melanoma
11/39
Rivoltini L.
2011
Observational
6
6
Identification of circulating microRNAs as potential indicators of progression in metastatic melanoma
11/40
Rivoltini L.
2011
Observational
32
32
10
0
A study of immunomodulatory effect of BRAF and MEK inhibitors in melanoma patients
SARCOMAS
03/31
Casali P.
2003
II-III
EUROpean Bone Over 40 Sarcoma Study. An european treatment protocol for bone-sarcoma in patients older than 40 years
03/45
Gronchi A.
2003
Pilot
41
Pre-operative chemo-radiation therapy in retroperitoneal soft tissue sarcomas (± RT boost)
Closed accrual
Study code/Title
Coordinator
Activated
(closed)
Phase
03/46
Bertulli R.
2004
II
Total patients
21
190
Closed accrual
Ifosfamide at high doses in prolonged continuous infusion by a portable infusion system in soft-tissue sarcomas typical of the
adult in an advanced phase in second/further line chemotherapy
04/01
Bertulli R.
2004
II
15
Closed accrual
Gemcitabine in leiomyosarcoma in an advanced phase in second or further line of chemotherapy
04/20
Corradini P.
2004
II
2
Closed accrual
Transplant of hemopoietic stem cells from family HLA-identical donor after conditioning at reduced intensity in soft tissue
sarcoma in a metastatic phase
05/31
Ferrari A.
2005
III
81
19
122
29
24
2
A protocol for localized non-rhabdomyosarcoma soft tissue sarcoma
05/32
Ferrari A.
2005
III
EpSSG NRSTS 2005. A protocol for localized non-rhabdomyosarcoma soft tissue sarcoma
06/53
Casali P.
2006
II
Trabectedin (ET743) in metastatic or locally advanced cell liposarcoma pretreated with chemotherapy
07/11
Stacchiotti S.
2007
II
10
Closed accrual
1
Closed accrual
Open-label trial of imatinib in patients with desmoid tumor and chondrosarcoma
07/39
Casali P.
2007
II
Phase II, non randomized, open-label, single arm trial of patients with advanced or metastatic osteosarcomas, administered with
pemetrexed (Alimta, 500 mg/m2 by intravenous infusion of 10 minutes)
08/01
Casali P.
2008
Pilot
1
Closed accrual
A pivotal trial to determine the efficacy and safety of AP23573 when administered as maintenance therapy to patients with
metastatic soft-tissue or bone sarcoma
08/22
Casali P.
2008
II
3
Closed accrual
Phase II, non-randomized study of second line tretment with sarafenib (BAY 43-9006) in patients affected by relapsed highgrede osteosarcoma
08/25
Casali P.
2008
III
2
Closed accrual
A multinational, randomized, double-blind placebo controlled study of AVE8062 (25 mg/m2) administered every 3 weeks, in
patients with advanced -stage soft tissue sarcoma treated with cisplatin (75 mg/m2) after failure of antracycline and ifosfamide
chemotherapies
08/45
Casali P.
2008
III
2
1
A randomized, multicenter, phase III trial of Trabectedin (yondelis) versus doxorubicin-based chemotherapy as first-line therapy
in patients with traslocation related sarcomas (TRS)
08/57
Casali P.
2008
III
11
Closed accrual
A randomized double-blind phase III trial of pazopanib versus placebo in patients with soft tissue sarcoma whose disease has
progressed during or following prior therapy
08/62
Casali P.
2008
II
17
3
Open label, multi-center, phase II study denosumab in subject with giant cell tumor of bone
09/58
Casali P.
2009
II
17
8
3
1
Phase II study of lapatinib in EGRF/HER2NEU positive advanced chordoma
09/78
Casali P., Raspagliesi F.
2010
II
A phase II randomized - non comparative - study on the activity of trabectedin or gemcitabine + docetaxel in metastatic or
locally relapsed uterine leiomyosarcoma pretreated with conventional chemotherapy
10/30
Casali P.
2010
II
7
3
Randomized phase II study evaluating two doses of NGR-hTNF administered either as single agent or in combination with
doxoribicin in patients with advanced soft tissue sarcoma (STS)
191
Study code/Title
Coordinator
10/44
Stacchiotti S.
Activated
(closed)
Phase
Total patients
2011
II
9
9
8
8
Phase II study on imatinib in combination with RAD001 in advanced chordoma
10/66
Gronchi A.
2011
II
Localized high-risk soft tissue sarcomas of the extremities and trunk wall in adults: an integrating approach comprising standard
vs histotype-tailored neoadjuvant chemotherapy
10/85
Rivoltini L.
2011
Observational
24
24
Evaluation of the role of immunosuppressive mechanisms in the prognosis and response to treatment with targeted therapy
drugs in sarcoma patients
11/05
Casali P.
2011
-
1
1
Translational study on modulation of gene transcription induced by Trabectedin in patients with myxoid/round cell liposarcoma
11/06
Gronchi A.
2011
Observational
210
210
2011
II
3
3
A retrospecive study of retroperitoneal sarcomas
11/18
Casali P.
A phase II, double-blind placebo-controlled study evalutating the safety and efficacy of IPI-926 in patients with metastatic or
locally advanced (unresectable) chondrosarcoma
11/19
Casali P.
2011
III
1
1
A randomized, open.label, multicenter, phase III study to compare the efficacy and safety of eribulin with dacarbazine in subjects
with soft tissue sarcoma
11/28
Bertulli R.
2011
Observational
2
2
II
3
3
Rabdomiosarcoma of adults. An observational prospective study
11/73
Bertulli R., Luksch R.
2011
ABCB1/P- glycoprotein expression as factor for the biologic stratification of the metastatic osteosarcoma of the extremities: a
prospective study
URINARY APPARATUS
06/38
Procopio G.
2006
II
56
Closed accrual
A randomized open-label multicenter phase II study of first line therapy with Sorafenib in association with IL-2 versus Sorafenib
alone in patients with unresectable and/or metastatic renal cell cancer
07/53
Procopio G.
2007
III
6
1
Sunitinib treatment of renal adjuvant cancer (S-TRAC): a randomized double-blind phase III study of adjuvant sunitinib vs
placebo in subjetcs with high risk RCC
08/41
Procopio G.
2008
II
7
Closed accrual
A randomized, open label, multi-center phase II study to compare bevacizumab plus RAD001 versus interferon alfa-A plus
bevacizumab for the first-line treatment of patients with metastatic clear cell carcinoma of the kidney
08/51
Procopio G.
2008
III
5
Closed accrual
4
2
5
0
Axitinib (AG 013736) as second line therapy for metastatic renal cell cancer: AXIS trial
10/11
Procopio G.
2010
II
Phase II study of sunitinib in metastatic renal cancer with non-clear cell histology
10/52
Salvioni R.
2010
II
A phase II study of neoadjuvant Cisplatin and Gemcitabine plus Sorafenib for patients with transitional cell carcinoma of the
bladder
10/78
Salvioni R.
2011
II
1
1
Randomized phase II study assessing the combination of vinflunine with gemcitabine and vinflunine with carboplatin in patients
ineligible to cisplatin with advanced or metastatic transitional cell carcinoma of the urothelium
Study code/Title
Coordinator
Activated
(closed)
Phase
Total patients
11/09
Procopio G.
2011
III
3
192
3
A randomized, double.blind, placebo-controlled phase III study to evaluate the efficacy and safety of pazopanib as adjuvant
therapy for subjects with localized or locally advanced RCC following nephrectomy
PEDIATRIC TUMORS
95/26
Cefalo G., Luksch R.
1995
II
82
0
Immunotherapy (IL-2 and activated circulating mononucleate cells) and pre- and post-surgical antineoplastic chemotherapy in
the primary treatment of osteosarcoma
01/33
Luksch R.
2001 (30/08/11)
II
31
Closed accrual
Prospective randomized study for the treatment of nonmetastatic osteosarcoma of the extremities
01/40
Luksch R.
2002
III
49
5
400
20
Protocol NB-AR-01: First European Cooperative Study for high-risk neuroblastoma
01/41
Seregni E., Bombardieri E.
2001
Observational
Protocol for evaluation and therapy of the diencephalohypophysial alterations in pediatric patients with cerebral neoplasms
03/12
Massimino M.
2003
Observational
44
3
19
2
Observational
94
15
III
80
8
III
14
Closed accrual
Second protocol for diagnosis and treatment of ependymoma in a pediatric age
03/13
Luksch R.
2003
II
Non-controlled clinical study for the treatment of Ewing’s sarcoma in relapse
03/14
Spreafico F.
2003
Wilms’ tumor: diagnostic-therapeutic protocol AIEOP 2003
03/16
Terenziani M.
2003
Germ cell tumors: diagnostic-therapeutic protocol AIEOP 2003
04/21
Gandola L.
2004
(HIT-SIOP PNET 4. A SIOP and GPOH TRIAL). A prospective randomized controlled trial of hyperfractionated versus
conventionally fractionated radiotherapy in standard-risk medulloblastoma
05/17
Luksch R., Castellani M.R.
2005
II
1
0
Phase II protocol with combined chemotherapy and 131I-MIBG in the treatment of patients with neuroblastoma resistant or in
relapse (I-METCH)
05/26
Luksch R.
2006
Pilot
5
Closed accrual
Ewing’s family tumors at high risk: pilot study comprising a window-therapy with cisplatin, intensive chemotherapy, RT,
consolidation with non-myeloablative immunosuppressive chemotherapy and allotransplant of hemopoietic cells
06/23
Luksch R.
2006
II
7
Closed accrual
35
4
Phase II study of Glivec (Imatinib Mesylate) in patients with advanced neuroblastoma
07/08
Cefalo G.
2007
III
LCH-III. Treatment protocol of the third international study for Langerhan’s cell histiocytosis
07/31
Luksch R.
2007
-
16
4
Guidelines for the treatment of patients with localized resectable neuroblastoma and analysis of prognostic factors
07/36
Casanova M.
2007
II
5
Closed accrual
International randomized study to evaluate the addition of docetaxel to the combination of cisplatin-5-fluorouracil (TCF) vs.
cisplatin-5-fluorouracil (CF) in the induction treatment of nasopharyngeal carcinoma (NPC) in children adolescent
08/13
Casanova M.
2008
II
4
0
Open-label, multi-center, randomized, two stage adaptive design study of the combination of bevacizumab with standard
chemotherapy in minor patients with metastatic rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma or Ewing
sarcoma/soft tissue primitive neuroectdermal tumour
193
Study code/Title
Coordinator
08/17
Cefalo G.
Activated
(closed)
Phase
2008
II
Total patients
13
3
7
3
HL PED 2008 Hodgkin’s lymphoma. A therapeutic protocol for sequels reduction
09/22
Casali P. Luksch R.
2009
III
A phase II study on the efficacy of dose intensification in patients with non-metastatic Ewing’s sarcoma
09/25
Casali P. Luksch R.
2009
II
4
2
Therapeutic protocol with high-dose chemotherapy, radiotherapy, maintenance therapy with low-dose Cyclophosphamide and
anti-COX2 in metastatic Ewing’s sarcoma: ISG/AIEOP study
09/57
Casanova M.
2009
II
7
Closed accrual
Phase II single-arm studies of temozolomide in combination with topotecan in refractory or relapsing neuroblastoma and
opther paediatric solid tumor
11/02
Casanova M.
2011
I
4
4
A phase I study of LDE225 in pediatric patients with recurrent or refractory medulloblastoma or other tumors potentially
dependent on the Hedgehog-signaling pathway
11/47
Cefalo G.
2011
Observational
19
19
Quality of life and personality factors in patients recovered from osteosarcoma in evolutive age towards a deeper
understanding of long-term adaptation
11/55
Casanova M.
2011
III
1
1
A phase III, randomized, double-blind, active comparator-controlled clinical trial, conducted under in house blinding conditions,
to examine the efficacy and safety of aprepitant for the prevention of chemotherapy induced nausea and vomiting (CINV) in
pediatric patients
PALLIATIVE CARE
10/36
Caraceni A.
2011
IV
17
17
An open-label randomized controlled clinical trial to compare the analgesic efficacy of therapeutic strategies with Oxycodone,
Fentanyl and Buprenorphine versus Morphine in patients with cancer-related pain of moderate-severe intensity, since the start
of third-step treatment of the WHO analgesic scale
11/23
Ripamonti C.
2011
Observational
54
54
A no-profit observational, prospective study describing the presence and intensity of nausea, vomiting (N/V), of related
symptoms and of subjective feeling of malaise in patients with the following neoplasms: head and neck , lung (NSCLC/SCLC)
and pleural, urothelial, male genital apparatus (germinal neoplasm, penile spinocellular carcinoma) treated first with
chemotherapy including drugs with high/moderate vomiting risk and in inter cycle phase
MISCELLANEA
02/27
Terenziani M.
2002
Pilot
153
Closed accrual
Program of control in patients subjected to radiotherapy comprising the breast region during infancy and adolescence
05/66
Tagliabue G., Contiero P.
2006
Observational
15666
375
II
10
Closed accrual
Registry of congenital malformations in Lombardy
06/77
Celio L.
2007
Phase II study oh PHA-739358 administered by a 24-Hour IV infusion every 14 days in advanced/metastatic breast, ovary,
colorectal, pancreatic, small cell lung and non-small-cell lung cancer
07/03
Buzzoni R.
2007
III
8
Closed accrual
A randomized, double-blind, placebo controlled, multicenter phase III study in patients with advanced carcinoid tumor receiving
Sandostatin LAR and RAD001 or Sandostatin LAR and placebo
07/07
Laffranchi A.
2010
II
53
50
Calendula cream versus cortisone cream (fluocortolone) for the prevention of cutaneous erythema from breast and ganglion
areas radiation. A comparative randomized phase II study of 60 cases
Study code/Title
Coordinator
07/40
Cresta S.
Activated
(closed)
2007
Phase
I
Total patients
194
23
Closed accrual
61
4
Dose-finding study of Caelix and RAD001 in patients with advanced solid tumors
08/12
Capri G.
2008
Ib
An open-label, safety, pharmacockinetics and pharmacodynamic dose escalation phase Ib study of pazopanib in combination
with epirubicin or doxorubicin in subjects with advanced solid tumors
08/15
Procopio G.
2008
III
13
0
2009
III
5
1
Sorafenib long term extension program (STEP)
08/50
Favaro M.
ALBumin Italian Outcome Sepsis study- ALBIOS STUDY “Efficacy of albumin administration for volume replacement in patients
with severe sepsis or septic shock”
09/06
Buzzoni R.
2009
II
35
Closed accrual
An open label, single arm, phase II study of combination RAD001 and octreotide LAR in patients with advanced
neuroendocrine tumors as fist line treatment
09/08
Tognoli E.
2009
II
60
Methadone for postoperative analgesia after balanced anaesthesia integrated with low dose ketamine S(+)
09/32
Decarli A.
2009
Observational
144
134
Epidemiologic studies on environmental risk factors and their interactions with genetic factors of bladder cancer and sarcomas
09/35
Pastorino U.
2009
-
468
94
Efficay of thermal treatment for respiratory airways in heavy smokers
09/36
Cresta S.
2009 (01/12/11)
I-II
4
Dose-finding study of combination of trabectedin and cisplatin in patients with advanced solid tumors
09/41
Licitra L.
2009
III
36
Closed
accrual
18
Role of Aprepitant in the prevention of delayed vomiting from Cisplatin: a double-blind controlled study
09/47
Cresta S.
2009
I
8
Closed accrual
A phase I, open label, multicenter, study to assess the safety. Tolerability and pharmacology of AZ D2281 in combination with
liposomal doxorubicin (Caelyx) in patients with advanced solid tumors
09/49
Pastorino U.
2009
-
191
24
14
2
Pharmacological prevention with Vareniclin in heavy smokers subjected to screening
09/53
Cresta S.
2009
I
Phase I dose escalation study evaluating the safety and tolerability of PankomabGEX tm in patients with advanced, TA-MUC1
positive solid malignancies who are not longer eligible for standard therapy
09/54
Capri G.
2009
I
10
1
15
Closed accrual
Phase Ib study of CC-5013 and paclitaxel in patients with advanced solid tumors
09/55
Capri G.
2009
I
Phase I dose finding and pharmacokinetic study of daily administrations of the intravenous camptothecin Namitecan (ST1968)
in patients with refractory or recurrent solid tumors
09/72
Corradini P.
2009
Observational
52
Closed accrual
Evaluation of the immune response after anti-flu vaccination against H1N1 pandemic virus in oncologic and hematologic
patients
10/04
Nicolai N.
2010
-
65
34
A prospective evaluation of morbidity parameters and postoperative and medium-term quality of life of patients submitted to
videolaparoscopic vs open retroperitoneal lymphadenectomy
10/32
Cresta S.
2010
I
6
5
Dose-escalation, PK and safety study with single agent CetuGEX in patients with locally advanced and/or metastatic cancer
195
Study code/Title
Coordinator
10/42
Capri G.
Activated
(closed)
2010
Phase
I
Total patients
4
2
An open-label, non-randomized dose escalation, safety and pharmacokinetics phase I study of ombrabulin (AVE8062) in
combination with bevacizumab administered by intravenous infusion every 3 weeks in patients with advanced solid tumors
10/54
Casali P.
2011
II
3
3
Phase II study of nilotinib efficacy in pigmented villo-nodular synovitis/tenosynovial giant cell tumour (PVNS/TGCT)
10/55
Morosi C.
2010
-
15
13
Evaluation of the response according to dimensional and tissue criteria using contrast-enhanced amplifier ultrasonography in
patients with soft tissue sarcomas or gastrointestinal stromal tumors (GIST) after molecular target therapies - CONTICANET
10/68
Ripamonti C.
2010 (01/07/11)
Observational
266
126
Validation in Italian language of the questionnaire “patient dignity inventory” and evaluation of the relationship between
perceived dignity and parameters of physical, emotional, spiritual and religious well-being in patients with solid and hematologic
tumors in active oncological therapy
11/10
Zaffaroni N.
2011
-
2
2
2011
I
4
4
Biotech of prostate cancer
11/56
Guidetti A.
A phase I dose-escalation study of PHA-739358 administered in combination with docetaxel or gemcitabine or bevacizumab or
carboplatin in adult patients with advanced solid tumors, including Hodgkin’s and non-Hodgkin’s lymphoma
11/67
Boffi R.
2011
-
50
Role of genetic profile in the evaluation of the smoker and personalization of anti-smoking therapies
50
196
ONGOING PROJECTS SUPPORTED
BY DIFFERENT ORGANIZATIONS
ALLEANZA CONTRO IL CANCRO – ISTITUTO SUPERIORE DI SANITA’
• Assistance needs in senior adults. Confounding variables in the patient-caregiver relationship
• National Telepathology Network (Teseo)
• National network for clinical trials and GMP structures for tumor biotherapy
• National Network “START project” (State of the Art in Oncology)
• National Italian Network of hereditary/familial tumors: establishment of shared operative tools for assistance and research
• Development of idiotypic vaccines for phase I/II trials of subset-specific immunotherapy of B lymphomas
• Biological combined and target therapies in solid tumors: phase I-II studies
• National network of biobanks in oncology
• New molecules of inflammation: transfer from laboratory to patient bed
• Development of new therapies in skeletal muscle sarcomas: comparison between immunotherapy and target therapy
• National network of tumor registries: indicators and cancer control in Italy
• National Bioinformatics Network in oncology
• National service of information in oncology
• Tumor microenvironment as therapeutic target
• Identification of markers for the prevision of the response to new antitumor drugs (HDAC inhibitors, tyrosine kinase and ionic
pumps)
• Application of chemotherapy to the remodulation of the antitumoral immune response: a study of the "proof of concept" mechanisms in humans
AMERICAN INSTITUTE FOR CANCER RESEARCH (AICR)
• Matricellular SPARC in bone marrow failure and lymphomas
ASSOCIAZIONE BIANCA GARAVAGLIA
• Research activity in pediatric tumors
ASSOCIAZIONE ITALIANA PER LA RICERCA SUL CANCRO
• Comprehensive diagnosis and treatment for intracranial pediatric ependymoma
• Early innovative diagnostic procedures of lung cancer progression
• Identification of genes expressed in human melanoma and regulating antitumor immunity
• Breast carcinoma extracellular matrix and response to therapy
• Molecular markers in lung carcinogenesis for early diagnosis, response to therapy and target identification
• Morphologic criteria and molecular targets in hepatocellular carcinoma: pre-clinical and clinical implications
• Tumor-host interaction affecting immunological and clinical responses in vaccinated colorectal cancer patients
• Anti-CD20antibody before allogeneic transplantation: clinical and biological implications in B-cell lymphomas
• Molecular signatures from paraffin-embedded tissue predicting clinical outcome of breast cancer patients
• Wilms tumor: molecular prognostic markers and candidate genes analyses
• Treatment with tandem 90Y-DOTA-TATE and 177Lu-DOTA-TATE of GEP tumours refractory to conventional therapy
• Identification of potential biopredictors of targeted treatments and monitoring of response/resistance balance
197
• Agonists and antagonists of Toll-like Receptor 9 in oncological experimental models
• Fhit degradation in breast cancer proliferation: a potential target of novel therapeutic strategies
• Identification of therapeutic targets for ovarian cancer by functional genomics and biomolecular analysis
• Extracellular matrix at the intersection between tumor and immune system
• Stemness signature and breast cancer progression:relationship and strategies of interference
• DNA damage responses and Chk2 regulation and interaction with novel targets
• Molecular mechanisms of epithelial thyroid carcinogenesis: role of selected molecules and pathways
• Expression profiling and functional analysis of microRNAs in prostate cancer
• Contribution of drug transporters to resistence to platinum compounds in ovarian cancer patients
• Anti-cancer vaccines in early disease for achieving effective immunological control of tumor progression
• Overcoming drug resistence by modulation of cytotoxic response and protective pathways
• Targeted therapy: disclosing the response limit in Imatinib-treated tumors
• Relationships between FAK signaling, microtubule dynamics and drug response
• Involvement of microRNAs in HER2-and estrogen-mediated pathways in human breast cancer
• Targeting autophagy in cancer therapy
• Melanoma interaction with the microenvironment: role of transcription factors and pro-inflammatory cytokines
• Classification of BRCA1 and BRCA2 alleles: integrating in vitro analyses and multifactorial likelihood models
• Randomized trial of diet, physical activity and breast cancer recurrences: the Diana-5 study
• Molecular and cellular imaging in cancer
• Identification of immunodominant non-Hodgkin lymphoma-restricted antigen(s) as novel biotarget(s) for therapy
• Identification of telomere maintenance mechanism-relatedgenes and miRNAs as prognostic and terapeutic tools
• Translational research on molecular markers in gastric cancer patients treated with adjuvant therapy
• Influence of lung tissue microenvironment on tumorigenesis
• Identification of progression markers for a clinical impact in metastatic melanoma
• Interactions between regulatory T cells and mast cells in cancer
• Altered choline metabolism in ovary cancer: prognostic relevance of choline kinase activity and expression
• Role of the heparanase/heparan sulfate system as a therapeutic target in sarcoma therapy
• Cell therapy with TRAIL-armed, genetically engineered or phenotypically redirected, effectors
• Personalized pain control in cancer care: the contribution of opioid pharmacogenomics
• Prostate cancer survival patients in Italy
• Identification of expression networks as effectors of genetic susceptibility to lung cancer in mice
• Therapeutic pathology: the receptor tyrosin Kinase model
• MicroRNAs in papillary thyroid carcinoma: pathways involved and possible therapeutic targets
• Identification of genetic changes and cellular populations sustaining invasiveness of lung cancer
• miRNA profiles associated to clinical response in ovary cancer: biologic and clinical implications
• Innovative approach for discovery and development of promising targeted agents in head & neck cancer
• New substrates of the ATM-Chk2 signaling axis and function in the DNA damage response pathway
• Matricellular proteins as accomplices in tumor development: homeostatic and immunological roles
• Terapeutic targeting of pathways leading to generation of TGFb+myeloid suppressor cells in melanoma patients
• Distant metastases in early breast cancer: Links with activation of inflammatory and immune response genes
• Integrative genomic analysis of intrahepatic cholangiocarcinoma: implication for clinical management
• Targeting of ALK Kinase activity in neuroblastoma and rhabdomyosarcoma
• Evaluation of biomarkers to predict treatment response in relapsed myeloma
COMPAGNIA DI SAN PAOLO
• Development of an in vitro and in vivo model for the study of lung cancer stem cells to develop selectively target innovative therapeutic approaches
• EPICOR 2 – Study on the risk of coronary heart disease related to behaviour, biological and genetic susceptibility markers in the
EPICOR collaboration in Italy and Europe
Ongoing Projects supported by different organizations
198
• EUROCARE - high resolution collection of clinical data and statistical analysis for the interpretation of the prognostic disparities in
Italy
EUROPEAN COMMISSION
• CONTICANET - CONnective TIssue CAncer NETwork to integrate european experience in adult and children
• IDEFICS - Identification and prevention of Dietary- and lifestyle-induced health EFfects in Children and infantS
• InterAct - Examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes
• CHEMORES - Molecular mechanisms underlying CHEMOtherapy RESistance, therapeutic escape, efficacy and toxicity
• OPCARE9 – Optimizing Cancer Patient Care through the Advancement of Research and Education
• EUROCHIP-III Common Actions
• IMPASHS - Evaluation of the IMPAct of Smoke-free policies in Member States on exposure to second-hand smoke and tobacco consumption
• MAGNIFYCO - MAGnetic Nanocontainers For combined hyperthermia and COntrolled drug release
• SPIDIA - Standardisation and improvement of generic pre-analytical tools and procedures for in vitro diagnostics
• Three modality contrast imaging using multi-functionalized microballons (3MICRON)
• ENVIROGENOMARKERS. Genomic Biomarkers of Environmental Health
• Genomic predictors and oncogenic drivers in hepatocellular carcinoma (HEPTROMIC)
• HSCT and Jak-STAT-Role and Modulation of Jak and STAT signaling in Graft Rejection and Graft versus Host Disease (HSCT and JakSTAT)
• EUROSARC - European clinical trials in rare sarcomas within an integrated translational trial network
• Determining (epi)genetic therapeutic signatures for improving lung cancer prognosis (CURELUNG)
• Transfection Ability and Intracellular Pathway of LbL Nanostructured siRNA Delivery Systems (Nanosirna)
• A European Platform for translational cancer research (Eurocan Platform)
FONDAZIONE CARIPLO
• Identification and biomolecular characterization of cancer stem cells of ovarian cancer for the development of new diagnostic and
therapeutic approaches
• Expression profiles and functional analysis of microRNA in prostate cancer
• Phosphoproteomics of cutaneous melanoma: from biology of cancer stem cells to the identification of new therapeutic targets
• Inhibitors of apoptosis proteins (IAPs) as anticancer therapeutics
• Evaluation of the bone mass and body composition in oncologic pediatric patients
• Modification of gene expression of the sialidases Neu2 and Neu3 in melanoma: identification of new molecular bases for the development of targeted therapies
• Mast cells at the interface between external challenges and immune regulation in colitis and colorectal cancer
• EUROCARE 6 - high resolution collection of clinical data and statistical analysis for the interpretation of the prognostic disparities in
Italy
• The role of religious beliefs/practices and spirituality on life quality and adaptation to disease of oncological patients in advanced
phase of disease
FONDAZIONE GUIDO BERLUCCHI
• The cerebral tumor in children: a help to parent children communication about the disease
• Identification of new prognostic markers and therapeutic strategies in medullary thyroid carcinoma
FONDAZIONE ITALO MONZINO
• Characterization and use of molecular targets for immunobiological therapies in prostate cancer
• Prostate cancer research international active surveillance (PRIAS). Procabio project
ISTITUTO NAZIONALE PER L'ASSICURAZIONE CONTRO GLI INFORTUNI SUL LAVORO
(INAIL)
• The active research of occupational cancer with low etiological fraction by means of routinely available data
199
ISTITUTO SUPERIORE DI SANITA'
• Surveillance of rare cancers in Italy
• Innovative management of patients with diffuse malignant peritoneal mesothelioma: clinical-diagnostic pathway and new therapeutic
targets
• Identification of individual lung cancer risk in heavy smokers by proteomic profile analysis in subjects randomized in two groups (spiral
CT vs observation) (Help-MILD Project)
• Biomarker and Histology Preservative: validation of an innovative fixing agent able to process and maintain tissue samples at room
temperature maintaining the morphological and macromolecular profile
• Phosphoproteomic analysis for the targeted therapy of liver metastases from colorectal carcinoma
LEGA ITALIANA PER LA LOTTA CONTRO I TUMORI
• Psychological evaluation in women with hereditary susceptibility to breast cancer submitted to screening test for BRCA1 and BRCA2
genes
• Lynch syndrome: predictive models of cancer risk and biomarkers for the identification of subjects with germinal mutations in MMR
genes
MINISTERO DELLA SALUTE
• Identification of new therapeutic targets and optimization of resistant tumor
• The effectiveness of the LCP in improving end-of-life care in hospital. A cluster randomised trial
• Regional cancer networks' models comparative assessment and study of their integration
• CAREMORE: joint Community and CAncer REgistry MOdel on Rehabilitation
• Optimization of targeted therapies
• Cancer stem cells, drug resistance and niche in minimal residual disease
• New protocols and targets for the treatment of brain and other solid tumors
• Controlled extension of conventional criteria for liver transplantation in hepatocarcinoma (HCC): a prospective validation study
• Development of programs for weak subjects such as patients waiting kidney transplant for more than 10 years or seropositive subjects (optimal use of organs)
• Analytical and clinical validation of biomarkers for non-invasive early diagnosis of digestive tract carcinoma
• PET Molecular imaging as prognostic and predictor indicator of response to therapy
• Diagnosis and molecular pathogenesis of virus-associated tumors
• Multidimensional Characterization of solid tumors
• Detection of the oncologic disease at early stage
• Research of new prognostic and therapy oriented-biomarkers
• Tumor radioresistance and predictive markers of the response to radiotherapy
• Targeting of tumor - associated myeloid cells
• Validation of new biomarkers: their role in the prognosis and therapy guidance
• Identification of new vaccination strategies for the treatment of limited disease or the prevention of recurrences in patients with solid
tumors
• Targeting tumor-related immunosuppression for new combined approaches for immunotherapy
• Integrated genomic analyses for the identification of genetic markers of breast cancer metastasis
• Surrogate markers of antiangiogenic therapy in triple receptor negative breast cancer
• Cancer prevention: development of evidence-based intervention models
• Multidimensional characterization of human tumors: organizational structure for managing the integrated program and pathologists
network for clinical validation of new tumor markers
• HUCARE - HUmanization of CAncer care in Italy: implementation of evidence-based REccomendations
• Analytical and clinical validation of new biomarkers for early diagnosis: the network, the resources, the methodology, the QC, the
analysis of data
• Experimental evaluation of the effectiveness of quality programs to improve pain management both in hospital and at home
• Innate immunity and gastrointestinal cancer as paradigm: from new molecules to the bed side
• Centrosomes and centrosome-associated regulatory proteins in menome maintenance and in the DNA damage response
Ongoing Projects supported by different organizations
200
• New therapeutic strategies based on modulation of immune response in prostate cancer patients
• Melanoma and integrated chip technologies:identification of novel prognosticators and (immuno)therapeutic protocols
• Regulatory T cell immunotherapy after haploidentical stem cell transplantation
• Oncology project of molecular medicine: female tumors
• Use of integrated PET/CT as a first line re-staging technique in oncological patients
• Comprehensive host-and-tumor characterization for individualizing breast cancer treatment strategies
• Identification and isolation of normal and tumoral lung stem cells as a tool for the definition of new therapeutic strategies in lung
cancer
• Integrated unit for the concerted translational early development of new drugs and/or therapeutic approaches in solid tumors
• Personalized treatment of sarcoma
• Hepato-Oncology: a multidisciplinary approach for an emerging specialty
• Development of radiolabelled radiopharmaceuticals for tumor charcterization, molecular imaging and therapy
• Improvement of acute and chronic pain management at the "Fondazione IRCCS Istituto Nazionale dei Tumori"; research on the
organization and implementation: - institution of an "acute, postoperative and procedure related pain team" - implementation of
invasive procedures such as neural blockade or implantation of specialized devices for drug delivery in patients with severe pain difficult to control with systemic drug administration - implementation of chronic pain symptom control: multidisciplinary hospital team
• Research on health determinants and risk reduction interventions
• National epidemiological surveillance system for the prevention of occupational cancer cases
• A system of integrated skills to improve security in chemotherapy
• Rational combinations of molecularly targeted agents in lymphoproliferative disorders
• A regional network of oncologic biobanks for scientific research and care of cancer
• Women with BRCA1 and BRCA2 gene mutations: clinical and psychological care
• Information as first medicine: the National Assistance and Information service in Oncology
• Tumors in Italy: the portal of oncologic epidemiology for professionals and people
• Survival and care for tumors in Italy and Europe
• Rare Cancers in Italy: surveillance and evaluation of the access to diagnosis and treatment
• Tailored Beta-catenin mutational approach in extraabdominal sporadic desmoid tumor patients
• Role of delta16HER2 splice variant in tumor progression and in response to biodrugs targeting HER2 receptor
• IGF-I isoforms and Breast Cancer
• Interaction framework between patient advocacy groups and cancer centers on sarcomas, as a model for rare cancers
• Peritoneal Mesothelioma: Optimize Outcomes by the Integration of new Prognostic Factors and Potential Therapeutic Targets in a
Individualized Treatment based on Molecular Characterization and Chemosensitivity Profile on Primary Cultures
• Cerebrospinal fluid proteome from Central Nervous System pediatric tumours: patient related pattern
• Potentiating clinical and immunological effects of chemotherapy by neutralizing acidic pH at tumor site: a phase II randomized study in
melanoma patients
• Preoperative TPF chemotherapy in locally advanced resectable oral cavity squamous cell cancer in order to improve pathological
complete response rate: a phase II study
• Safety, traceability and reliability of collection, processing and transplantation of haematopoietic stem cells (HSCs) and therapeutic
cells (TCs): integrated procedures and tools to support operations, clinical care and banking
• Neoadjuvant targeted agents followed by surgery in squamous cell carcinoma of head and neck: detection of promising agents
through identification of molecular and imaging parameters to predict treatment activity and/or resistance
• Tailored Accreditation model for comprehensive cancer centers: validation through the applicability of the experimental OECI-based
model to the Network of Cancer IRCCS of Alleanza contro il cancro
• Role of nutrients involved in one-carbon metabolism in the development of different molecular subtypes of breast cancer in the
ORDET
MINISTERO DELL’UNIVERSITA' E DELLA RICERCA
• Identification of disease genes by genotyping at high population density
• Identification of innovative antitumoral agents: from genomics to therapy
• New drugs for anticancer target therapy
• Health school: educational training on smoke, diet and environment for students of first and second level secondary schools
201
REGIONE BASILICATA
• Controlled extension of conventional criteria for liver transplantation in hepatocarcinoma (HCC): a prospective randomised study
using down-staging response and the metroticket model as predictors of survival (extension trial)
REGIONE LOMBARDIA
• Lombardy Network in Oncology
• Biobanks project for colorectal carcinoma
• Extracorporeal photochemotherapy for GVHD prophylaxis in patients submitted to allogeneic stem cell transplantation with
reduced-intensity conditioning
• Patient transfusion safety: from safe and integrated transfusions in hospital to total blood traceability and management of clinical risk
with Radio Frequency Identification (RFID) technology
• Development of an experimental model within Lombardy Network in Oncology for identification and follow-up of women with and
at risk for hereditary breast cancer
• An experimental model of a pediatric hemato-oncological network between Varese hospital and referring centers for the treatment
of pediatric oncological pathology
• Circulating microRNAs and cancer. Diagnostic anticipation and disease monitoring: retrospective and prospective study in solid
tumors at high incidence and mortality
• A study with diffusion tensor of radio-induced cerebral damage related to cognitive deficits in the pediatric population
• NEPENTE - Lombardy network of excellence for the development of drugs of natural origin aimed to modulate the tissue microenvironment for the prevention and therapy of tumors and neurodegenerative diseases
TELETHON
• Inherited defected in DNA damage signaling causing neuronal degeneration: understanding the mechanisms
Editor
Marco A. Pierotti
Coordinator
Aurora Costa
Editorial management and Graphic Design
Rosaria Parentela
Collaborators
Tiziana Camerini, Daniela Majerna
Copy editing and Translation
Patrick Moore
Photographer
Massimo Brega
Tel. +39 02 2390 2300
Fax +39 02 2390 3141
[email protected]
http://www.istitutotumori.mi.it
Printed in June 2012
Copyright © 2012 Fondazione IRCCS Istituto Nazionale dei Tumori.
No part of this communication may be cited, reproduced, stored in a retrieval system, or transmitted
by electronic or other means without prior written permission of the Scientific Director and the
appropriate investigator.
SCIENTIFIC REPORT
2011
THE ISTITUTO NAZIONALE DEI TUMORI
ADOPTS A HOLISTIC APPROACH TO
CANCER, IN PARTICULAR BY PLACING
THE ILL PERSON AT THE HEART
OF ITS PHILOSOPHY OF CARE
AND RESEARCH
FONDAZIONE IRCCS
ISTITUTO NAZIONALE
DEI TUMORI
PREVENTIVE
NUTRITION
ETIOLOGICAL EPIDEMIOLOGY
PREDICTIVE
MOLECULAR PROFILE
GENETIC SUSCEPTIBILITY
THERAPY RESPONSE
PARTICIPATORY
PATIENT ADVOCACY GROUPS
QUALITY OF LIFE
PERSONALIZED
TARGETED THERAPIES
EARLY DETECTION
TARGET DISCOVERY
BIOMARKERS DISCOVERY
CLINICAL TRIALS
PALLIATIVE CARE
Istituto Nazionale dei Tumori
FONDAZIONE IRCCS
ISTITUTO NAZIONALE
DEI TUMORI
www.istitutotumori.mi.it
Comprehensive Cancer Center

scientific report 2011 - Istituto Nazionale dei Tumori

Transcription

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