Clinical Activity

Transcription

Clinical Activity

SCIENTIFIC
REPORT
2010 - 2011
ISTITUTO ONCOLOGICO VENETO
I.R.C.C.S.
CONTENTS
FOREWORD
THE INSTITUTE
Chief Officer Address
The IOV Governance
CLINICAL ACTIVITY ORGANIZATION
Chief Medical Officer Report
Clinical Activity Data
Multidisciplinary Groups
THE DEPARTMENTS Department of Clinical Oncology
Clinical Oncology 1
Clinical Oncology 2
Evaluation and Introduction of New Drugs in Cancer Therapy Department of Surgery
Surgical Oncology Breast Surgery
Melanoma and Soft Tissue Tumors
Diagnostic and Operative Endoscopy Anesthesiology
Department of Imaging, Radiology and Pathology
Radiology
Breast Imaging Pathology
Department of Radiotherapy and Nuclear Medicine
Radiotherapy and Nuclear Medicine
Medical Physics
Department of Experimental, Laboratory and
Translational Oncology
Immunology and Molecular Oncology
Hereditary Endrocrine Cancer Unit
5
9
13
16
19
21
24
28
31
33
34
46
54
57
58
64
68
76
82
89
90
96
104
107
108
120
Department of Services
Pharmacy
Cardiology
Psycho-Oncology
Tumor Registry
161
THE RESEARCH Scientific Director Address
185
172
178
187
188
Scientific Directorate Organization
191
SWOT Analysis
195
Research: Input and Output
197
Clinical Trials and Biostatistics Unit
202
Strategic Scientific Options
Pharmacogenomics
Cancer Stem Cells
209
RESEARCH ACTIVITY REPORT Line 1 - Tumor Epidemiology and Prevention
217
Workflow Project List Line 2 - Mechanisms of Cancerogenesis
Introduction
Workflow Project List Line 3 - Instrumental and Molecular Approaches
for Diagnosis, Staging and Follow-Up
Introduction
Workflow Project List Line 4 - Innovative Therapeutic Approaches:
Chemotherapy, Radiotherapy and Surgery Introduction
Workflow Project List CONTENTS
3
168
General Considerations
Introduction
127
128
154
162
212
214
218
218
219
220
220
221
222
222
223
226
226
227
Line 5 - Tumor Immunology and Innovative
Therapeutic Approaches Introduction
Workflow Project List Line 6 - Quality of Life in Cancer Patients
and Geriatric Oncology
Introduction
Workflow Project List CLINICAL RESEARCH
Ethics Committee
Clinical Trials
230
230
231
VENETO ONCOLOGY NETWORK
245
EDUCATION
249
Internal Education & Training
Post-graduate Schools
Meetings and Seminars
250
255
257
232
232
233
AWARDS 261
235
PUBLICATIONS
265
236
237
Index
305
CONTENTS
4
Foreword
FOREWORD
5
This volume is the third edition of the Scientific
Report of the IRCCS-Istituto Oncologico Veneto
(IOV), and its format is very similar to that of the
2008-2009 Report; since research programs which
characterize the scientific profile of the Institute mostly
have a wide breath, we felt that a biennial report of the
results achieved and the developments foreseen could be
appropriate. Again, we chose to publish this Report in
English to stress the international dimension in which
the Italian IRCCS must confront, and to underline the
meaning of the report itself, as we intend it. Indeed, data
reported in this kind of publications are also available
in the yearly reports forwarded to the Italian Health
Ministry; in any case, the array of research projects
focused on specific aspects of oncologic research (the socalled Ricerca Corrente Programs) is summarized in a
dedicated Section. We instead decided to privilege the
presentation to colleagues involved in our field in Italy
and abroad a more faithful and comprehensive profile
of the Institution we are working in. For this purpose,
we gave more room to the analytical description of the
Departments and of the clinical and research activities
of the individual Units, who were asked to present
in a more extended way a selection of their leading
programs. The presence at the end of the book of an
Analytical Index witnesses our hope to render this
book a useful tool for researchers in Italy and abroad
to establish new fruitful interactions on specific topics
of interest.
We did not feel it appropriate to distinguish our
research activities into basic, translational and
clinical investigation. Firstly, we are firmly convinced
that only two types of research exist, good research
and bad research. Secondly, progress is only achieved
by the steady crosstalk of scientists belonging to very
distant areas, and the interconnection of different
FOREWORD
6
disciplines is terrific; it is impossible to foresee the
future fallouts of an apparently “basic” research on the
clinical management of patients in terms of diagnosis
or therapy. In the light of the modern concepts in
Oncology and more in general in Medicine, our work
must go “from bed to bench and back from bench to the
bed”, in search of innovative markers of disease and
therapeutic targets. In this perspective, all the work at
the Institute is carried out in a multidisciplinary way;
this means that for every oncologic disease a group of
concerned and dedicated workers (medical oncologists,
radiologists, radiotherapists, surgeons, psychologists
etcetera) strictly interact in the daily effort to provide
patients with the best state-of-the-art standards of care.
On the other hand, we are perfectly aware that
clinicians and researchers also are only a part of the
story. What we are daily carrying out in our labs,
guards, and operating theaters would be vane, if our
activities were not complemented by the steady help
of many people more or less directly involved in the
management of the oncological disease. These include
a wealth of persons, from the patients themselves to
their relatives and caregivers, the nurses, the many
volunteers belonging to the different Associations, and
many others. This plethora of humble, often unknown,
generous people do not have a place in this book, but
without them our research would be a sterile, solipsistic
exercise. To this silent multitude our grateful thinking;
the struggle against cancer is a multifaceted task, and
if we want to transform cancer into a curable disease,
the efforts of everybody will be essential.
Alberto Amadori, Scientific Director
FOREWORD
7
The Institute
THE INSTITUTE
9
The Institute
The IRCCS Istituto Oncologico Veneto (Veneto Oncology
Institute - IOV) was established in December 2005, after obtaining
recognition of its scientific character from the Italian Health
Ministry; following a site visit in 2008, this qualification was
confirmed by the Ministry. The Institute has a juridical personality,
and it is subordinate to both Veneto Regional Authorities and the
Ministry of Health. The IOV is the only Cancer Center in the
Veneto region; it participates in the Italian network of Cancer
Institutes (Alliance Against Cancer), which includes the Italian
Cancer Centers under the patronage of the Istituto Superiore di
Sanità in Rome. Since January 2009, the IOV is a member of the
Organization of European Cancer Centers (OECI), that includes
over 70 Comprehensive Cancer Centers in Europe.
The IOV stems from a long tradition of excellence
in Oncology, which was first recognized in 1989 by the
establishment of the Regional Oncology Center (COR) in Padova.
The activity of COR was mainly devoted to fostering interactions
among epidemiologists, clinicians and basic researchers in the
field of Oncology, and to create a multidisciplinary approach
to face the new frontiers of information on cancer genetics and
biology. This strict collaboration among professionals involved
in different areas of Oncology anticipated the modern concept
of “translational medicine”, now considered as a strategic field
within evidence-based medicine.
Moreover, the IOV is a true Comprehensive Cancer Center,
since it integrates in its mission clinical activity, research and
education: the IOV offers, in fact, preventive, curative and palliative
services to the population, and it combines this fundamental
mission with a constant research activity on several different
aspects of cancer, as well as maintaining a special commitment
to educational issues, in strict collaboration with the Faculty of
Medicine of the Padova University. The IOV is located in Padova in
close proximity to the University Hospital, within an area known
as “Ospedale Busonera”, a hospital that was established in 1932
and was formerly dedicated to the care of tuberculosis patients.
For this reason, the Ospedale Busonera is embedded in a park
of about 40,000 square meters, populated by a collection of rare
and magnificent trees, whose balsamic properties were thought
to aid the recovery of tuberculosis patients; according to a recent
agreement with the mayor of Padova, this park will soon be
fully restored, and its beautiful environs shared by our patients
and the general public. Because of its peculiar architectural
characteristics, the major body of the hospital (recently flanked
by a modern laboratory building) is under the patronage of the
Artistic Superintendence of the Veneto Region; despite the great
attention to our needs and the generous collaboration provided
by this Authority, any refurbishment of the structures is complex
and difficult.
THE INSTITUTE
10
Aerial view of the Busonera area
THE INSTITUTE
11
Map of Busonera Hospital area in the 30’s
THE INSTITUTE
12
Chief Officer
Address
THE INSTITUTE - Chief Officer Address
13
Chief Officer Address
achievements and the goal under implementation are described
in detail.
I would like to underline two important targets: the first is
the extraordinary solidarity and generosity of our citizens already
from the first year, the second is that the economic balance of the
Institute has always been positive before tax, and today we have a
significant income proving that also a public institution, even in its
start-up, can be not a burden for the taxpayer, but an investment
both at a scientific and a working level, as demonstrated by the
patents taken out and now under development.
We were few dozen of people at the beginning, today we are
more than five hundred persons dedicated to research and medical
care in the interests of the welfare of
our patients.
Thanks to each of you.
When we started the project of the IOV, just five years ago,
even with the most steady optimism we could not have thought
that we would set up what has been created.
The Veneto Region had believed in this project and the Italian
Ministry of Health too, but we had an aura of skepticism and
doubts around, that did not leave us completely calm.
Today we can say we have worked hard and we have all worked
well.
Results are more than satisfying both in terms of clinical care
and of research and innovation.
IOV is recognized as a reality at a regional, national and
international level.
In this report, which sheds light
on the improvements of the last two
years and on the work in progress, the
Pier Carlo Muzzio
14
The Iov Governance
The IOV is governed through the joint and coordinated effort of a Directive Board,
which includes several persons each endowed with specific commitments and interacting
within the Strategic Directorate.
General Directorate: legal representative of the Institution, responsible for legal and
administrative affairs, through an Administrative Directorate.
Scientific Directorate: responsible for scientific research and all activities connected
to the scientific life of the Institute.
The organization, monitoring and evaluation of clinical activities is the responsability
of the Medical Directorate.
According to the Italian law and regulations, the Institute functioning is superintended
by a specific Committee (Comitato di Indirizzo e Verifica, CIV), whose duty is to supervise
the strategic decisions of the General Directorate, to verify all the administrative aspects of
the Institute, and to suggest lines of development to the Scientific Directorate, in order to
guarantee a harmonic and fruitful development of the life and mission of the Institute.
The CIV includes members endowed with scientific and administrative expertise, and
it is presently composed by the following persons:
Prof. Ermanno Ancona (President), Prof. Carlo Foresta, Dr. Eligio Grigoletto, Dr. Claudio
Paccanaro and Dr. Adriano Paccagnella.
The following diagram schematically illustrates the basic organization of the
Institute.
16
GENERAL DIRECTORATE
SCIENTIFIC DIRECTORATE
ECONOMICAL
AFFAIRS
EDUCATION
LIBRARY
RESEARCH
RESEARCH
LABORATORIES ADMINISTRATION
CLINICAL
TRIALS &
BIOSTATISTICS
UNIT
LEGAL
AFFAIRS
IMAGING,
RADIOLOGY
& PATHOLOGY
BREAST
IMAGING
MEDICAL
DIRECTORATE
RADIOTHERAPY
& NUCLEAR
MEDICINE
PATHOLOGY
RADIOLOGY
MEDICAL
PHYSICS
CLINICAL
ONCOLOGY
CLINICAL
ONCOLOGY 1
SURGERY
CLINICAL
ONCOLOGY 2
SERVICES
CARDIOLOGY
EVALUATION & INTRODUCTION
OF NEW DRUGS IN CANCER THERAPY
RADIOTHERAPY
& NUCLEAR
MEDICINE
SURGICAL
ONCOLOGY
PSYCHOONCOLOGY
PHARMACY
BREAST
SURGERY
DIAGNOSTIC
MELANOMA
& SOFT TISSUE
TUMORS
ANESTHESIOLOGY
& OPERATIVE
ENDOSCOPY
17
EXPERIMENTAL
LABORATORY
& TRASLATIONAL
ONCOLOGY
TUMOR
REGISTRY
IMMUNOLOGY
& MOLECULAR
ONCOLOGY
HEREDITARY
ENDOCRINE
CANCER
UNIT
AS FAR AS SCIENTIFIC ACTIVITIES ARE CONCERNED
ADMINISTRATIVE MARKETING &
DIRECTORATE COMMUNICATION
Nicoletta Zanotto
Gloria Miarti
Morena Piovan
Donatella Pivetta
Marica Pizzello
GENERAL DIRECTORATE
Pier Carlo Muzzio (Director)
Francesca Pagnin
Bruno Bandoli (Marketing, Communication and Fund Raising)
Flavia Dalla Rosa
Daniele Ciresola (Preventive Medicine)
Cristina Maritan
Daniela Chiusole (Certification and Quality Assurance)
Marco Tria
Michela Pinton
Roberta Pozzani
Maurizio Peci
Andrea Azzalini
Isabella Colpo
Salvatore D’Amico
Giuseppe Borella
Ampelio Preo
Marcello Valente
Lisa Rigato
Silvia Volpi
Marina Malipensa
Sara Rossetti
Federica Vascon
Daniela Grosso
SCIENTIFIC DIRECTORATE
Alberto Amadori (Director)
Daniela Battistuzzi
Manuela Mtanis
Mauro Apostolico
Alessandro Andretto
ADMINISTRATIVE DIRECTORATE
Pietro Girardi (Director)
Marina Giusto (Deputy Director)
Laura Scappin
Giulia Di Chiara
Simonetta Ive
Cristina Ghirardello
Roberta Signorini
Paola Sorgato
Gian Luca De Salvo
Denise Marie Kilmartin
Paola Del Bianco
MEDICAL DIRECTORATE
Maria Giacobbo (Director)
Maria Pia Bellavere
Antonella Frasson
Emilio Pacchiega
Isabella Calabrese
Catia Farinea
Maria Padovan (Nurses and Research Nurses, Coordinator)
Massimo Cacco
Franco Sterpi
Margherita Casotto
Manuela De Marchi
Isabella Degli Agostini
Martina Mattiazzi (Client Relation Office - URP)
Paolo Turri (Medical Services)
Alberto Bortolami
Mauro Pegoraro
Gianni Forzan
Lucia Lion
Demis Sinigaglia
Simone Polacco
Fortunata Marchese (Education)
Stefania Facchin
Filippo Paccanaro
Michele Ferrin
Federica Lea
Luciana Nalin
Roberta Candian
Marta Amato
Michelle Elisabeth Quinn
Margherita Merone Perone
Emiliano Zabatta
18
Clinical Activity
Organization
CLINICAL ACTIVITY ORGANIZATION
19
Chief Medical Officer
Report
CLINICAL ACTIVITY ORGANIZATION - Chief Medical Officer Report
21
Chief Medical Officer Report
Graduated in Medicine in 1976, Maria Giacobbo was from
the beginning involved in public health management. Since 1986
she acted as Medical Director in several Hospitals and headed
different Health Agencies of the Veneto Region; from 1993 to
2000 she was also engaged as teacher at the Post-Graduate School
of Hygiene and Preventive Medicine of the University of Verona.
Since 2008 she acts as Medical Director of the IOV.
The Medical Directorate is responsible for the management
of all the clinical activities, and for the global governance and
integration of the services provided by the individual Units of
the Institute. In this setting, the Medical Directorate plays a key
role in mediating among the requirements of the Clinics (efficacy
of interventions and maintenance
of high standards of care), of
the Research activities (need of
innovation and experimentation), and
of the Administrative area (efficient
resource employment). This function
guarantees to both IOV workers and
the public (patients and Institutions)
elevated and consistent levels of care,
also dedicating special attention to
crucial aspects of modern Oncology
and Medicine:
safeness and risk prevention;
treatment appropriateness;
equal opportunity of access to care;
care humanization and strict
observation of deontological rules.
In this frame, the Medical
Directorate is strongly motivated
to develop and optimize, in steady collaboration with the other
Directorates, new models of organization and governance which
could improve the quality of the services in terms of efficacy,
efficiency, safety, and appropriateness.
The Medical Directorate includes several Offices, which
superintend specific aspects of the clinical governance of the
Institute:
Quality and accreditation
Chief: Daniela Chiusole
This Office is dedicated to the following activities:
to guarantee, monitor and verify the maintenance and
implementation of the quality of
services, by providing appropriate
indexes of control;
to promote among the personnel of
the Institute the culture and value
of the quality, through dedicated
tools such as educational courses on
quality assurance and control;
to plan and monitor all the activities
needed to obtain and maintain
the institutional accreditation,
according to national and regional
rules and requirements;
to organize, monitor and maintain
the ISO 9001 certification, now
extended to all the clinical and
administrative activities of the
Institute;
22
claims and/or suggestions by the public to implement the quality
of the medical assistance, in strict collaboration with the Quality
and Accreditation office. To this end, a 24h phone line is active
to facilitate the interactions with patients and their caregivers;
more than 2,000 contacts are established yearly. Furthermore,
in collaboration with volunteers operating within the Institute,
a continuous analysis of client satisfaction is performed by
appropriate forms exploring the opinion of the patients on
waiting times, perceived quality of services, including information
on health status, and availability of medical and non-medical
personnel. The relevant information is periodically collected and
analyzed within the Medical Directorate.
t o interact with other IRCCS to promote shared standards of
the quality assurance system among Institutions with similar
features and mission, and to favor the constant amelioration of
governance tools also in view of international models of quality
governance.
Working risk prevention and radioprotection
Chief: Daniele Ciresola
This Office superintends to monitor the health of all the
workers of the Institute, with particular attention to the evaluation,
prevention and follow-up of the professional risks of individual
categories and typologies of employment. This endeavor is carried
out according to the regulations provided by both national and
regional risk prevention agencies.
The Medical Directorate also superintends to other Units, in
collaboration with other structures of the Institute; in particular,
the Education Office and the Clinical Trial Office will be
mentioned within the appropriate section.
Client satisfaction and claims
Chief: Martina Mattiazzi
This Office monitors the perception of the quality offered
by the clients or patients, and his mission is to exploit all the
23
Clinical Activity Data
Hospitalisation
Surgical index
9000
100
94%
8000
80
7000
85%
67%
6000
5000
6.100
2.304
3000
2.343
40
2.334
2000
2.651
2.314
2.387
2.516
Inpatients
2008
2009
2010
6%
2006
Day Hospital
2007
2008
Surgical
2009
Medical
Inpatient admission by geographical areas
Padua
Veneto except Padua
32%
57%
Northen Italy except Veneto
Central Italy
Southern Italy and Islands
Outside Italy
1%
40%
15%
0
2007
34%
33%
20
1.888
0
2006
60%
5.157
4000
1000
66%
60
4%
3%
3%
24
2010
Average length of stay
DRG average relative weight
4,5
Medical
8
4,0
Inpatients
7
3,5
Surgical
6
3,0
5
2,5
4
2,0
1,5
1,0
0,5
0,0
2006
2007
2008
2009
3
Medical
2
Inpatients
1
Surgical
0
2010
2006
2007
2008
2009
2010
Endoscopic procedures
Pathological examinations
2500
3500
3000
2000
2500
1500
2000
1500
1000
1000
Cytological
500
0
500
Istological
2006
2007
2008
2009
0
2006
2010
2007
25
2008
2009
2010
Chemotherapy courses
Radiodiagnostic and Nuclear Medicine examinations
20000
45000
18000
40000
16000
35000
14000
30000
12000
25000
10000
20000
8000
6000
15000
4000
10000
2000
5000
0
2006
2007
2008
Inpatients
2009
0
2006
2010
Outpatients
2008
Nuclear medicine
Laboratory tests
2009
2010
Radiodiagnostic
Outpatient visits
160000
80000
140000
70000
120000
60000
100000
50000
80000
40000
60000
30000
40000
20000
20000
10000
0
2006
2007
2007
2008
2009
0
2006
2010
2007
26
2008
2009
2010
Radiation treatments
Cardiologic examinations
1200
12000
1000
10000
800
8000
600
6000
400
4000
200
2000
0
2006
2007
Inpatients
2008
2009
0
2006
2010
2007
Day Hospital
27
2008
2009
2010
Multidisciplinary Groups
The clinical and research activity of the Institute is carried out
according to a model of multidisciplinarity. While this modality
of approach to cancer patients fully fits the most accredited trends
of modern Oncology, it also reflects the spirit of our Institute,
where the presence of spikes of true excellence in some areas does
not obscure the collegial work that permits the expression of this
excellence. In other words, we are all convinced that the constant
advancement of the clinical and research levels of our Institute,
and the eventual steady improvement of the standards of care and
the quality of life of our patients, only rely on the work of all of us.
As in the functioning of a watch, the merit of indicating the real
time is not attributable to one or the other piece composing the
mechanism, but it is the result of the coordinated movement and
function of all the parts of the watch. This spirit is reflected on the
fact that most activities are carried out through organ-oriented
multidisciplinary groups, which include all the experts needed to
face a single pathology, from prevention to therapy to rehabilitation
and palliation in terminal patients. This is possible because the
IOV is embedded in a fertile milieu of different expertise, spread
among the University of Padova and the other health structures
operating in this area. Thus, some multidisciplinary groups also
include researchers not formally belonging to IOV, and conversely
many specialists belonging to IOV are asked to participate in
clinical and research multidisciplinary groups based on other
sanitary structures. This cross-fertilization makes it possible the
constant rise to excellence of the Medicine and Oncology in
Padova.
The oncologic multidisciplinary groups operating since many
years are listed in the Table with the indication of the contributing
structures.
28
The experts of these groups meet at least at weekly intervals
in fixed days, or if necessary in extemporary sessions. In these
meetings, the clinical situation of every patient is collegially
examined, and the most appropriate diagnostic/therapeutic plan
is chosen. The patients are then also collegially re-evaluated during
Field of interest
the treatment, and eventual decisions on the therapeutic layout
stem from the discussion of the relevant experts. These meetings,
beyond their importance for the management of the clinical
situation of the patients, are also fundamental opportunities to
generate new and foster existing scientific collaborations.
Units
Brain tumors
Clinical Oncology 1, Radiotherapy and Nuclear Medicine, Immunology and Molecular Oncology - IOV
Pathology, Neurosurgery, Neuroradiology - University Hospital of Padua
Breast tumors
Breast surgery, Clinical Oncology 1 & 2, Radiotherapy and Nuclear Medicine, Breast Imaging, Radiology, Pathology,
Immunology and Molecular Oncology, Hereditary Endrocrine Cancer Unit - IOV
Clinical Surgery II - University Hospital of Padua
Esophageal tumors
Clinical Oncology 2, Radiotherapy and Nuclear Medicine, Immunology and Molecular Oncology, Radiology,
Surgical Oncology - IOV
Clinical Surgery I - University Hospital of Padua
Lymphomas
Clinical Oncology 2, Immunology and Molecular Oncology, Radiotherapy and Nuclear Medicine - IOV
Hematology Unit, Pediatric Hematology-Oncology Unit of Department of Pediatrics - University Hospital of Padua
Gynecologic cancers
Clinical Oncology 1, Radiotherapy and Nuclear Medicine, Radiology - IOV
Pathology, Clinical Surgery II, Gynecology - University Hospital of Padua
Lung tumors
Clinical Oncology 2, Radiotherapy and Nuclear Medicine, Radiology, Immunology and Molecular Oncology - IOV
Thoracic Surgery - University Hospital of Padua
Head/neck tumors
Clinical Oncology 2, Radiotherapy and Nuclear Medicine, Pathology - IOV
Otolaryngology Unit - University Hospital of Padua
Thyroid tumors
Clinical Oncology 1 & 2, Radiotherapy and Nuclear Medicine, Hereditary Endocrine Cancer Unit - IOV
Surgical Pathology Unit, Endocrinology Unit - University Hospital of Padua
Gastro-Intestinal tumors
Clinical Oncology 1, Radiotherapy and Nuclear Medicine, Pathology, Radiology, Immunology and Molecular
Oncology, Family Cancer Clinics - IOV
Surgery Branch - S. Antonio Hospital of Padua
Melanoma
Clinical Oncology 2, Melanoma and Soft Tissue Tumors Unit, Immunology and Molecular Oncology, Pathology,
Radiotherapy and Nuclear Medicine - IOV
Clinical Surgery II, Dermatology - University Hospital of Padua
Soft Tissue Sarcomas
Melanoma and Soft Tissue Tumors Unit, Clinical Oncology 1, Radiotherapy and Nuclear Medicine, Radiology - IOV
Orthopedics, Radiology - University Hospital of Padua
For Ewing sarcoma and rhabdomyosarcoma: periodical consultation with Pediatric Hematology-Oncology Unit University Hospital of Padua
Hepatic carcinoma
and liver disease
Clinical Oncology 1, Radiology - IOV
Hepatobiliary surgery, Pathology - University Hospital of Padua
29
Peritoneal Carcinomatosis
Melanoma and Soft Tissue Tumors Unit, Clinical Oncology1, Radiotherapy and Nuclear Medicine, Radiology - IOV
Tumors of the Urinary
System and Male genital
organs
Medical Oncology I, Radiotherapy and Nuclear Medicine, Radiology - IOV
Urology, Pathology, Cryopreservation of Male Gametes - Department of Medical and Surgical Sciences - University
Pancreatic tumors
Clinical Oncology 1, Radiology - IOV
Clinical Surgery I & II - University Hospital of Padua
Pediatric Soft tissue
sarcomas and Pediatric
brain tumors
Radiotherapy and Nuclear Medicine, Clinical Oncology 1, Anesthesiology - IOV
Pediatric Hematology-Oncology Unit - University Hospital of Padua
Hospital of Padua
Family Cancer Clinics
tests, distributing these samples to the concerned laboratories,
and collecting results for further contacts with the patients. Even
though the interest in heredo-familial cancers is widespread
among Italian IRCCS, the IOV Family Cancer Clinics is the sole
structure collecting in a single operating unit the management of
these conditions, thus contributing to increase the critical mass
in the field. In addition, the Family Cancer Clinics works in
strict contact and collaboration with a research group dedicated
to the study of heredo-familial colorectal cancer. This surgical
group, wich operates at the University of Padova-Padova General
Hospital under the direction of Professor Donato Nitti, over
the last 10 years has focused his interest on these neoplasms; its
activity entails counseling, genetic testing, and most importantly a
certified tissue bank which has collected over the years more than
20,000 biological samples from about 2,000 patients. It is a firm
auspice and hope of the Scientific Direction of the IOV that these
structures could soon converge into a single inter-institutional
Unit, where the critical mass, the mechanistic knowledge, and the
quality of assistance could undergo a terrific growth.
The interest in heredo-familial tumors originated in the late
’90s, much before the birth of IOV, thanks to the illuminated
idea of a group of researchers of the Department of Oncology and
Surgical Sciences of the University of Padua (Emma D’Andrea,
Marco Montagna, Chiara Menin), who subsequently joined the
IOV. At the beginning, the interest was centered on breast and
ovary tumors, where inheritable alterations of the BRCA1-2
genes had been first documented. Later on, the attention was
extended to heredo-familial melanoma, and a further drive was
given when an academic endocrinologist (Giuseppe Opocher)
with a strong interest and expertise in inheritable neuroendocrine
tumors joined the IOV. At that time (2009) an operative Unit
was founded, denominated “Family Cancer Clinics”. This Unit,
coordinated by Professor Opocher, collects the entire expertise on
the field of heredo-familial tumors expressed within the Institute
(and partly outside, as we shall see later). The Family Cancer
Clinics structure has the responsibility for managing the afflux
of patients to the structures where specific genetic testing and
counseling is performed, organizing blood sampling for genetic
30
The Departments
The Departments
31
THE
DEPARTMENTS
CLINICAL
ONCOLOGY
SURGERY
RADIOTHERAPY
& NUCLEAR
MEDICINE
IMAGING,
RADIOLOGY
& PATHOLOGY
The Departments
32
EXPERIMENTAL,
LABORATORY
& TRANSLATIONAL
ONCOLOGY
SERVICES
Department
of
Clinical Oncology
The Departments - Department of Clinical Oncology
33
Clinical Oncology 1
Chief
Vittorina Zagonel, MD
Vittorina Zagonel worked at the Clinical Oncology Division of the CRO Aviano Cancer Center
(IRCCS) from 1983 to 1999. From 2000 to 2009, she served as Head of the Clinical Oncology
Unit at the Fatebenefratelli Hospital, Rome, where she also acted as Director of the Department
of Oncology for eight years. Since October 2009 she has been serving as Head of the Clinical
Oncology 1 at Istituto Oncologico Veneto (Padua). She was a member of the National Oncologic
Committee 2008-2009 and a member of the Ministry of Health board for palliative care in 2010.
She coordinates the AIOM task force on Continuous Care in Oncology since 2008. She is author
and coauthor of more than 150 articles in indexed journals.
Main Pubblications
Detecting functional impairment in older patients Falci C, Brunello A, Monfardini S.
with cancer: is vulnerable elders survey-13 the right
prescreening tool? An open question.
J Clin Oncol. 2010; 28:665-6
Pegylated liposomal doxorubicin and gemcitabine in Lombardi G, Zustovich F, Farinati F, Cillo U, Cancer. 2011; 117:125-33
patients with advanced hepatocellular carcinoma: results Vitale A, Zanus G, Donach M, Farina M, Zovato
of a phase 2 study.
S, Pastorelli D.
Primary tumor response to preoperative chemoradiation
with or without oxaliplatin in locally advanced rectal
cancer: pathologic results of the STAR-01 randomized
phase III trial.
Aschele C, Cionini L, Lonardi S, Pinto C, Cordio J Clin Oncol. 2011; 29:2773-80
S, Rosati G, Artale S, Tagliagambe A, Ambrosini
G, Rosetti P, Bonetti A, Negru ME, Tronconi MC,
Luppi G, Silvano G, Corsi DC, Bochicchio AM,
Chiaulon G, Gallo M, Boni L.
Advanced gastric cancer (GC) and cancer of the gastro- Cappetta A, Lonardi S, Pastorelli D, Bergamo F, Crit Rev Oncol Hematol. 2011; in
oesophageal junction (GEJ): focus on targeted therapies. Lombardi G, Zagonel V.
press.
Neoplastic meningitis from solid tumors: new diagnostic Lombardi G, Zustovich F, Farina P, Della Puppa Oncologist. 2011; 16:1175-88
and therapeutic approaches.
A, Manara R, Cecchin D, Brunello A, Cappetta A,
Zagonel V.
34
Clinical and Research
Staff
Vittorina Zagonel
Umberto Basso
Renato Ceravolo
Sara Lonardi
Ornella Nicoletto
Fable Zustovich
Antonella Brunello
Elena Calore
Alessandro Cappetta
Maurizia Dalla Palma
Miriam Farina
Pasquale Fiduccia
Giuseppe Lombardi
Valeria Zafferri
Administrative Staff
Anna Schiavon
Nursing Staff Monica Patrizia Dori
Eleonora Fontana
(Shared between Clinical
Oncology 1 & 2)
Luisa Friso
Debora Gabellotto
Barbara Giacomin (Coordinator) Valeria Gallimberti
Samuela Aggio
Antonietta Gallocchio
Monica Benetti
Nicola Galtarossa
Debora Bertin
Monica Gechele
Flavio Berto
Valentina Giurisato
Carmela Bisceglia
Maria Chiara Gobbo
Mariaelisa Bonaldo
Evelina Lamberti
Elisabetta Bonfanti
Chiara Lando
Silvia Bottazzo
Patrizia Lazzaro
Chiara Canova
Cristina Magro
Paola Canton
Elena Mancini
Susanna Cedrone
Gabriella Maritan
Cinzia Ciesa
Jossie Veronica Mella
Maria Gliceria Collu
Michela Michielotto
Elisa Degortes
Miriam Milanese
Silvia Dell’Oste
Alessandra Modenese
Sandra De Paoli
Cristina Naliato
Orejeta Diamanti
Ornella Nuccio
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Tatiana Peruffo
Rossella Prando
Caterina Pravato
Antonella Prospero
Cristina Raise
Attilio Rambaldi
Elena Rosa
Laura Rossi
Serena Ruzza
Fabiola Sandonà
Maria Cristina Saracini
Paola Schiavon
Veronica Schiavon
Imelda Secondin
Annalisa Spagolla
Emanuela Tombolato
Daniela Tonello
Mbuyi Tshiala
Elena Vittadello
Anna Zambon
Stefania Zanella
Monica Zanocco
Mission
The mission of the Unit of Clinical Oncology 1 is carrying
out diagnosis and treatment of solid tumors in adult and
senior patients, through multidisciplinary approaches involving
surgeons, radiation oncologists, radiologists, pathologists,
molecular biologists, geriatricians and different specialists. The
principal aim is taking care of patients diagnosed with cancer,
with special attention to all the needs of the person in order to
have the best results for both cancer treatment and quality of life.
In this perspective, the effort of the Unit is to guarantee integration
of the clinical interventions, together with implementation of
clinical and translational research to allow patients to be treated
with innovative antitumor therapies, as well as with supportive
and palliative care. An important task of the Division of Clinical
Oncology 1 is the theoretical and practical formation of Clinical
Oncology fellows, in the fields of antitumor treatment, supportive
and palliative care.
Areas of Excellence
Treatment of patients with gastrointestinal cancer (stomach,
colon, rectum, anus, liver, pancreas and biliary tract);
Treatment of patients with central nervous system tumors;
Treatment of patients with gynecologic malignancies (ovary,
uterus, vagina, vulva);
Treatment of patients with breast cancer, in particular elderly
patients and patients with heredo-familial cancers;
Treatment of patients with genito-urinary tumors (kidney,
bladder, prostate, testicle, penis);
Treatment of patients with soft tissue sarcomas;
Diagnosis, assessment and therapeutic strategies for elderly
patients with cancer;
Phase I-II trials;
Supportive and palliative care, with particular emphasis on
continuity of care and socio-sanitary services;
Treatment of patients with rare tumors (in particular GIST,
neuroendocrine tumors).
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Clinical Activity
Clinical Activity 2010
No.
Admissions
889
Inpatients
486
Outpatients
403
Medical examinations
11.733
First medical examinations
1.868
Follow-up
4.432
Medical examinations
5.433
Hospital services
11.001
Chemotherapy
10.770
Other treatments
231
Distribution of patients by cancer site
300
271
250
200
174
150
123
96
100
103
95
67
71
62
50
29
69
64
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Major Collaborations
Multidisciplinary Teams of Disease
The Clinical Oncology 1 participates in multidisciplinary
teams for studying cancers of the rectum, sarcomas, liver
metastases, urologic tumors, brain tumors, breast cancer, liver
tumors and peritoneal carcinomatosis.
Within the IOV, steady interactions involve: Clinical
Oncology 2, Molecular Immunology and Oncology, Surgery,
Endocrinology, Radiotherapy and Nuclear Medicine, PsychoOncology, Cardiology, Radiology, Endoscopy, Pathology.
National Working Groups:
GISCAD (Gruppo Italiano per lo Studio dei Carcinomi
dell’Apparato Digerente)
Mango (Mario Negri Gynecologic Oncology Group)
ISG (Italian Sarcoma Group)
GUONE (Gruppo Uro-oncologico del Nord Est)
International Collaborations
SENDO - Southern Europe New Drug Organization (Dott.
Silvia Marsoni)
New York University, Clinical Cancer Center, New York (Prof.
F. Muggia)
UCSF Medical Center, San Francisco (Prof. S. Chang)
Memorial Sloan-Kettering Cancer Center, New York (Dr. A.
Omuro)
University of Losanne (Prof. R. Stupp)
Division of Medical Genetics, Department of Medicine,
Abramson Cancer Center, University of Pennsylvania (Prof.
Katherine L. Nathanson)
EORTC brain group
EORTC elderly group
EORTC sarcoma group
National Collaborations
Azienda Ospedaliera-Università, Padova
Ulss 16, Padova
CNR Aging Center, Padova
Istituto Mario Negri (Milano)
Istituto Nazionale Tumori (Milano)
Istituto Humanitas (Milano)
Istituto S. Raffaele (Milano)
CRO (Aviano)
Oncologia Medica (Pisa)
Oncologia Medica (Ancona)
Oncologia Medica Niguarda (Milano)
IRST Meldola (Forlì)
INRCA-Roma
Neuro-oncologia, Università Torino
Istituto Besta (Milano)
Oncologia Medica (Verona)
Oncologia Medica (Rovigo)
Oncologia Medica (Vicenza)
38
Major Ongoing Research Projects
New therapeutic strategies in the treatment of
gastro-intestinal (gi) tumors
the worldwide standard adjuvant therapy for high-risk stage II
and III colorectal cancer, but the optimal duration of therapy and
the management of toxicities remain to be resolved. Hopefully,
it would be useful to find predictive/prognostic markers that
could allow future adjuvant strategies to be optimized and
individualized. Genomic polymorphisms in drug target genes,
genes encoding DNA-repair enzymes and detoxification pathways
may influence the activity of 5-Fluorouracil/capecitabine and
Oxaliplatin, and their identification may improve the tailoring of
chemotherapy and the choice of the optimal treatment strategy.
In the present multicenter study, a panel of 17 polymorphisms
within eleven genes in patients with radically resected high-risk
stage II and III colon cancer undergoing adjuvant FOLFOX-4/
XELOX chemotherapy and bevacizumab within a prospective
phase III randomized clinical trial will be evaluated.
Prospective evaluation of -1498 C/T VEGF polymorphism
in the prediction of benefit from first-line FOLFIRI plus
bevacizumab in metastatic colorectal cancer patients.
Many studies have demonstrated that specific VEGF single
nucleotide polymorphisms (SNPs) may affect gene transcription
with a consequent variable production of VEGF and a probable
indirect effect on pathogenesis and evolution of several disorders
in which angiogenesis may be critical. Patients bearing -1498
T/T genotype had significantly shorter progression-free survival
(PFS) and worse, but not statistically significant, overall
survival (OS) compared to patients carrying at least one C
allele. On this basis we planned to prospectively evaluate the
potential predictive role of -1498 C/T VEGF polymorphism in
CRC patients treated with first-line FOLFIRI plus Bevacirumab.
Primary objective is to evaluate the correlation between -1498
C/T VEGF allelic variants and first-line PFS, while the secondary
objectives is to evaluate the correlation with response rate, overall
survival and toxicities attributable to Bevacizumab.
Principal Investigators: Sara Lonardi, Davide Pastorelli, Vittorina
Zagonel
The management of GI tract cancers (both colorectal and
non-colorectal) has widely changed over the last years, switching
from a “tumor” perspective to a “patient’s tailored” approach.
Identification of prognostic and predictive markers, optimization
of multidisciplinary strategies, and new targeted drug development
are some of the major points of interest for clinical and experimental
research. Several trials are currently ongoing at our Institution in
collaboration with multidisciplinary groups of Padua and others
Oncology Units and national groups.
A. Prognostic and predictive factors
The identification of patients characterized by a worse
prognosis or by a higher probability of response to certain
treatments is crucial to select the “better population” for the
“better therapeutic strategy”, and it is one of the main areas of
research at our Institution.
Molecular factors predictive of response to pre-operative
chemo-radiation in locally advanced rectal cancer.
Pre-operative chemo-radiotherapy (pCRT) approach for
locally advanced rectal cancer is worldwide accepted as a standard
treatment. The prediction of response to CRT has the potential
to spare unnecessary toxic treatments for non-responders and,
in selected cases, to allow a conservative surgery (local excision).
Multiple patient- and tumor-related factors have been evaluated
as potential predictors of response, but few studies take the tumor
biology into account. Patients with rectal cancer, candidate to
receive the same schedule of pCRT will be prospectively evaluated
to assess the correlation of carcinoembryonic antigen (CEA),
cell-free circulating DNA (cfDNA), levels of telomerase reverse
transcriptase (h-TERT) and circulating tumor cells (CTC) with
pathological response after pCRT and disease recurrence.
Pharmacogenetic profiling and clinical outcome of patients
with high-risk stage II and III colon cancer treated with adjuvant
FOLFOX-4/XELOX chemotherapy and bevacizumab.
Oxaliplatin plus a fluoropyrimidine (FOLFOX/XELOX) is
B. Optimization of the timing of adiuvant chemotherapy
Gastric and pancreatic cancers are a major cause of mortality
worldwide. Prognosis is poor unless the cancer is diagnosed at
a very early stage. Therapeutic options for patients with stage
I-III gastric and pancreatic cancer include surgery plus adjuvant
chemotherapy with or without radiotherapy, but the optimal
39
sequence of treatments and the role of radiotherapy in both
diseases are still unclear.
ITACA-S 2: comparison of the efficacy of pre-operative
versus post-operative chemotherapy (CHT) in patients with
resectable gastric cancer (GC).
The role of adjuvant therapy in GC has been extensively
studied during the past three decades in an attempt to improve
the prognosis of patients who have undergone curative surgery.
Metanalyses of some of these trials found that post-operative
CHT led to marginal but statistically significant reductions in
mortality compared to surgery alone. Neo-adjuvant CHT has
recently received increasing attention in an attempt to improve
the rate of complete tumor resection, to combat systemic
metastases, and to prolong survival in patients with GC.
Data from randomized, controlled, prospective trials comparing
the two strategies are as yet not available. This Italian, multicentre,
open-label, randomized, superiority, phase III trial enrolls patients
with histologically confirmed, localized, resectable GC to compare
the efficacy in terms of OS of a pre-operative vs. a post-operative
CHT treatment.
Randomized phase II-III study on pre-operative or
post-operative chemotherapy in resectable pancreatic
adenocarcinoma.
Pancreatic tumor is the fourth leading cause of death in cancer
patients. Only 10-20% of patients is amenable to surgery with
a curative intent, and 5-yr survival is about 1-4%. Some phase
III trials demonstrated a benefit of post-operative adjuvant
chemotherapy vs. surgery alone in radically resected patients,
but no data from randomized clinical trials on the role of neoadjuvant therapy are available. Some phase II studies suggest
that a pre-operative treatment could increase the rate of patients
operated with tumor-free margins and negative lymphnodes
without affecting surgery morbidity and mortality.
To evaluate the impact of a pre-operative CHT vs. a postoperative CHT, a multicentre national phase III trial has been
recently launched. The primary objective is to compare the diseasefree survival in patients affected by resectable pancreatic cancer
treated with pre-operative polychemotherapy (PEXG), postoperative PEXG or post-operative monotherapy (gemcitabine).
the vascular endothelial growth factor receptor-2 (VEGFR-2)
signaling pathway via a number of approaches, including antiVEGF antibodies, anti-VEGFR-2 antibodies, and small molecule
tyrosine kinase inhibitors (TKI), has been shown to inhibit new
blood vessel formation and tumor growth in a variety of animal
models. Ramucirumab is a recombinant human monoclonal
antibody that specifically binds to the extracellular domain of
VEGFR-2 with high affinity. Phase I studies and initial Phase II
studies investigating Ramucirumab have provided information
regarding safety and tolerability at clinically relevant doses, with
preliminary evidence of clinical efficacy in a variety of human
cancers. The drug is now undergoing Phase III studies in secondline treatment of multiple diseases.
A randomized, double-blind, multicenter phase III study
of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI)
plus Ramucirumab or placebo in patients with metastatic
colorectal carcinoma progressive during or following first-line
combination therapy with bevacizumab, oxaliplatin, and a
fluoropyrimidine
This is a multicenter, randomized, double-blind, placebocontrolled phase III trial in which patients with metastatic
colorectal cancer progressing to first-line combination therapy
with bevacizumab, oxaliplatin, and a fluoropyrimidine will be
randomized to receive either FOLFIRI plus placebo or FOLFIRI
plus Ramucirumab. Approximately 1050 patients will be
randomized to observe 756 events. The primary objective of this
study is to compare overall survival; secondary objectives are to
compare progression-free survival, objective response rate, patientreported outcome measures, safety profile, assessment of the
association between biomarkers and clinical outcome, assessment
of anti-Ramucirumab antibodies and assessment of serum levels
of Ramucirumab.
A randomized, multicenter, double-blind, placebo-controlled
phase III study of weekly paclitaxel with or without
Ramucirumab in patients with metastatic GC, refractory
to or progressive after first-line therapy with platinum and
fluoropyrimidine.
To date, no randomized controlled trials have established a
standard second-line treatment regimen for GC after failure of a
cisplatin/fluoropyrimidine-containing regimen. At present, there
is no evidence that any given single agent or combination therapy
is clearly superior to other agents/regimens in terms of efficacy.
This is a multicenter, randomized study evaluating the efficacy
C. New targeted drug development
Inhibition of angiogenesis is considered as a promising
approach to the treatment of cancer. Disabling the function of
40
standard first-line systemic treatment in this disease, based on
favorable results of two phase III trials. No data from randomized
trials on the role of a second-line treatment are available as yet.
This is a Phase III multicenter, randomized study evaluating the
safety and efficacy of Ramucirumab plus BSC as a double-blind,
placebo-controlled (placebo plus BSC) comparison. The primary
objective is to compare the overall survival in patients with HCC
who had disease progression during or following sorafenib therapy,
or were intolerant to this agent.
of Ramucirumab using a double-blind, placebo-controlled
design. The primary objective is to demonstrate efficacy in terms
of OS in patients treated with paclitaxel plus Ramucirumab
compared to patients treated with paclitaxel plus placebo as
second-line treatment of metastatic gastric or gastro-esophageal
adenocarcinoma after failure of any platin and fluoropyrimidine
combination.
Ramucirumab and best supportive care (BSC) versus
placebo and BSC as second-line treatment in patients with
hepatocellular carcinoma following first-line therapy with
sorafenib.
Hepatocellular carcinoma (HCC) confers a limited prognosis.
Many patients present at a stage in which potentially curative
surgery or orthotopic liver transplant is not feasible and, even
when feasible, tumor recurrence is frequent. For patients with
advanced disease, systemic chemotherapy is of marginal benefit
and associated with significant toxicity. Sorafenib, a multitargeted
TKI with activity against VEGFR-2, is now considered the
Targeting angiogenesis in advanced renal cell
carcinoma
Principal Investigator: Umberto Basso
The approval of six targeted therapies for advanced Renal Cell
Carcinoma (RCC) has completely changed the management of
this disease over the last 5 years, opening several fields of clinical
41
(up-front or after a few cycles) are frequently needed, but median
PFS of about 13 months compares favourably with published data,
with only three cases of cardiotoxicity. Results were presented at
the ECCO Conference in October 2009. In cooperation with
IRST-Meldola we are currently conducting a larger analysis in
elderly patients receiving sunitinib as a first-line treatment for
advanced cancer.
and experimental research. Several workers at IOV are now
deeply involved in the treatment of this disease, aiming at buiding
a multidisciplinary approach which has proven crucial for the
progress of research in other more common cancers.
A. Circulating tumor cells (CTC) in patients treated with
first-line sunitinib
CTC have a strong prognostic significange in breast,
colorectal and prostate cancer, but their value in patients with
advanced kidney cancer is sill poorly documented. A pilot study
evaluating CTC counts in advanced RCC patients treated with
first-line sunitinib has been carried out in cooperation with the
Immunology and Molecular Oncology Unit of IOV, and other
Oncological Units. More than 50 patients have been accrued so
far, and about two thirds of them had one or more CTC in the
blood. Total counts of CTC did not appear to correlate with the
number of metastatic sites, and response or progression during
sunitinib. However, when a count of apoptotic CTC was carried
out, we found that an increase in these biologically inactive cells
correlated with prolonged disease control. Based on these findings,
we plan to extend the accrual to this study in order to prove the
prognostic role of apoptotic CTC in advanced RCC.
D. Pharmacokinetics
of oral drugs and correlation with
response and toxicity
Both sunitinib and everolimus (an inhibitor of m-TOR
complex) are administered at fixed oral doses with no modifications
according to age or body surface. Yet, recent data show that
plasma drug levels may be different among patients due to dose
reductions and heterogeneity in pharmacokinetics (mainly due
to polymorphisms of Cytochrome P450 family proteins and/or
concomitant medications). Different blood concentrations may
translate into different toxicity rates as well as reduced tumor
control. In cooperation with the Pharmacology Unit of CROAviano and IRST-Meldola we plan to conduct a study evaluating
the blood levels of sunitinib and everolimus administered to
young and elderly RCC patients. Our aims are to assess agerelated differences, to clarify situations of unexpected toxicity and
to elaborate predictive models in which daily dose modifications
of sunitinib and everolimus might be driven by pharmacogenomic
polymorphisms (Cytochrome 3A4 or other proteins), actual
blood concentrations of native drug and its active metabolites as
well as co-administration of other drugs interfering with hepatic
drug metabolism.
B. Sunitinib in Von Hippel-Lindau Syndrome
Loss of function of the von Hippel-Lindau (VHL) gene located
on chromosome 3 is the cause of this rare syndrome, but is also
a key pathogenetic step in the development of sporadic clear cell
RCC, with ensuing over-expression of VEGF-R, Platelet-Derived
Growth Factor Receptor (PDGFR) and their ligands by the tumor
and surrounding endothelial cells. In cooperation with the Unit
for Hereditary Cancer of the IOV we started collecting data on
VHL syndrome patients with advanced or recurrent RCC seen at
our Institution. They were all treated with the TKI sunitinib as a
first line regimen. Preliminary results have been presented at the
ASCO Genitourinary Congress on February 2011.
E. Cardiotoxicity of oral TKI
Since hypertension, decrease in Left Ventricular Ejection
Fraction (LVEF), clinically symptomatic congestive heart failure,
myocardial hyschemia and rhythm alterations have been described
in patients treated with sunitinib and sorafenib, all patients
with RCC treated at IOV undergo cardiologic monitoring in
cooperation with the Cardiology Unit. Over the years 2006-2010,
around 70 patients were followed with clinical examination,
electrocardiogram and echocardiography performed at 4 to 6
months intervals. Several cardiac events were registered, mainly
grade 1 or 2 according to CTCAE and reversible after appropriate
treatments, allowing the majority of patients to resume treatment.
A retrospective evaluation of type, treatment and outcome of these
C. Sunitinib in elderly patients
Since the activity and tolerability of sunitinib in unselected
elderly patients ≥ 70 years are still poorly documented, we
performed a retrospective analysis on feasibility and outcome
of first or second-line sunitinib in 67 elderly patients with renal
carcinoma followed in six oncological centers (IOV, Verona,
Vicenza, Rovigo, Udine, Lucca). We found that dose reductions
42
events has been planned in order to establish the actual relevance
and risk factors of cardiovascular events in unselected patients
treated with sunitinib and sorafenib.
high grade glioma response to antiangiogenic treatments.
Preliminary Results. We have interesting results in terms of
activity and effectiveness reported from phase II and phase III
clinical trials using new antiangiogenic drugs such as sorafenib,
bevacizumab and cilengitide. Regarding predictive factors, in a
recent work presented at the European Association of NeuroOncology Congress 2011, we have shown that patients with a good
ECOG-PS (0-1) have a better chance of prolonged survival when
treated with antiangiogenic drugs, regardless of the type of agent.
Furthermore, in another work submitted to the American Society
of Clinical Oncology Congress 2011, we have shown that patients
with a good ECOG-PS and disease control on MRI according to
Macdonald Criteria after two months of antiangiogenic treatment
have a better chance of prolonged survival.
Conclusions. Antiangiogenic drugs are emerging in the
treatment of high-grade gliomas and recent evidence indicates
that the molecular profile of gliomas may strongly influence the
sensitivity of these tumors to both conventional treatments and
targeted therapies. Thus, it is important to know new predictive
factors for designing more personalized therapies and rapidly
assess the real response to treatment by new radiologic methods
and new possibly non-invasive biomarkers in urine and serum.
Gliomas of the central nervous system: analyzing
idh1, idh2 and mgmt genes, predictive factors,
new drugs and response to treatment in the
antiangiogenic era
Principal Investigators: Giuseppe Lombardi, Vittorina Zagonel,
Fable Zustovich
Gliomas are the most common form of primary brain tumors in
adults. The majority of these are malignant, comprising glioblastomas
and anaplastic astrocytomas, as well as other less common variants
such as oligodendrogliomas and oligoastrocytomas. Low-grade
gliomas also have the potential to became highly malignant neoplasms.
Temozolomide, a DNA alkylating agent, is now the standard therapy
against glioblastomas and anaplastic astrocytomas. In the recent
period, new antiangiogenic drugs are emerging, such as bevacizumab,
sorafenib and cilengitide; however, their effectiveness remains
uncertain, and this is mainly due to the absence of randomized trials.
Recent studies have shown the presence of IDH1 and IDH2 gene
mutations in low-grade gliomas and secondary glioblastomas;
this mutation leads to an increase of 2-HG levels in neoplastic
cells and maybe in serum and urine. Elevated 2-HG levels could
eventually lead to an increase in HIF-1 expression and VEGF levels.
Furthermore, with the recent introduction of antiangiogenic drugs,
which affect the permeability of tumor vasculature, there are significant
limitations for evaluating the response by MRI, especially for the
presence of pseudo-responses. Cerebral MIBI SPECT could help to
define patients who really respond to therapy and patients who have a
sole drop of the gadolinium uptake at MRI.
Thus, for all these reasons, we have focused our attention on:
Activity and efficacy of new antiangiogenic drugs
Predictive and prognostic factors in patients treated with
antiangiogenic drugs, with special attention to IDH1, IDH2 and
MGMT mutations
2-HG levels in serum and urine as a biomarker, in particular
during follow-up
Potential role of proton magnetic resonance spectroscopy in the
evaluation of IDH mutation in neoplastic cells
Potential role of cerebral MIBI SPECT in the evaluation of
Cancer in elderly patients: comprehensive
geriatric assessment and tailoring treatment
options
Principal Investigators: Umberto Basso, Antonella Brunello,
Vittorina Zagonel
We are increasingly facing in the routine clinics cancer patients
aged 70 years or more. Nevertheless, data show that elderly cancer
patients (ECP) are less likely to be treated according to accepted
treatment guidelines; the eventual undertreatment can have a
detrimental effect on both relapse-free OS and quality of life.
Understanding the physiologic and functional changes associated
with aging can assist in developing useful strategies of treatment in
elderly cancer patients. In our Unit we are currently studying the
different aspects of ECP, especially in breast cancer, which is the
most common neoplasm in the female population. In particular,
we have focused our attention on:
the impact of Comprehensive Geriatric Assessment on survival
of ECP (“CGA” study);
43
the influence of the function of the immune system and
thymic reserve on aging and tumor development, and the role
of telomerase and telomere length in ECP vs. geriatric nononcologic patients (“TELOTREC” study, in collaboration with
Clinical Oncology 2, the Immunology and Molecular Oncology
Unit and the Geriatric Unit, University of Padua);
prevalence and assessment of pain in ECP (spontaneous study)
and of depressive symptoms in ECP (“DAMA” study, in
collaboration with INRCA, Rome);
the polymorphisms of cytochrome CYP2D6 and activity and
safety of Tamoxifen (“TAMOXIFENVENETO” study, in
collaboration with other Clinical Oncology Units in Veneto);
the polymorphism of aromatase gene and the activity of
aromatase inhibitors in ECP with locally advanced/metastatic
breast cancer;
the impact of adjuvant treatment on cognitive functions in
ECP with breast cancer (“ITACAm” study, in collaboration
with INRCA, Rome.
Preliminary results. So far, as to the above mentioned
ongoing studies, we have been recruiting patients and enrolment
is still ongoing. For the CGA study, data have been collected and
analyzed and an abstract submitted to ASCO 2011.
The aim of the study was to compare a large cohort of ECP
for all-cause survival according to their condition of fitness,
vulnerability or frailty. All consecutive cancer pts ≥70 years
admitted to our Geriatric Oncology Program underwent CGA and
were prospectively followed. Kaplan-Meier survival method was
used and univariate/multivariate (Cox) analyses were applied to
different prognostic factors. In 880 patients enrolled from 9/2003
to 10/2010, we observed that CGA correlates with mortality,
independently from diagnosis of cancer stage and treatment.
Conclusions and Future Perspectives
Moreover, multidisciplinary collaborations will be implemented
to define an optimal diagnostic-therapeutic strategy for the main
types of tumors (gastrointestinal, urologic, gynecologic, neurologic
and breast cancer in the elderly), as it is already the case for other
neoplasms.
A further area of development is the activation of research
programs in the field of support therapy and symptom control
(pain, nutrition, comorbidities, etc.), with the intent of optimizing
the quality of life and guaranteeing continuity of care for all cancer
patients.
Geriatric Oncology is a field of increasing interest, as
demonstrated by the Italian National Oncologic Plan for the
years 2010-2012, and efforts are being put in developing models
and strategies to optimize and tailor treatments. In the coming
years we intend to continue our ongoing clinical and research
activities, with the aim of optimizing care and facilitating clinical
applications of the results obtained from translational studies.
Several collaborations are underway to implement phase I-II
studies with access to and availability of new antitumor drugs, as
well as studies to recognize the factors that could predict response,
and eventually be used in clinical practice.
45
Clinical Oncology 2
Chief
Vanna Chiarion-Sileni, MD
She earned her degree in Medicine from the University of Padova in 1980, subsequently specializing
in Oncology (1983) and in Hematology (1988). Junior staff physician of Clinical Oncology at San
Bortolo Hospital in Vicenza from 1987 to 1989, and then at the Padova Hospital from 1989 to 2007.
Managing staff physician since 2007 at the Veneto Institute of Oncology; since 2008 head of the
Melanoma and Skin Cancer Unit. Her experience abroad includes: observer at the Memorial Sloan
Kettering Cancer Center (New York 1996); Yale University, Department of Medicine and Surgery
(1997); Institute Gustave Roussy, Villejuif, Paris (1999). She received ESMO certification in Clinical
Oncology in 1989. Since 1980, she is a member of AIOM and the Veneto Regional Secretary; since
1987 member of ASCO; since 1989 member of ESMO, founder and elected member to the Italian
Melanoma Intergroup from 1997. She was a professor for the post-graduate school in Oncology at
the University of Padova. She published more than 150 papers in peer-reviewed journals.
Main Pubblications
Bleomycin-based electrochemotherapy: clinical outcome from a Campana LG, Mocellin S, Basso M, Puccetti Ann Surg Oncol. 2009; 16: 191-9
single institution’s experience with 52 patients.
O, De Salvo GL, Chiarion-Sileni V, Vecchiato
A, Corti L, Rossi CR, Nitti D.
IL4Ralpha+myeloid-derived suppressor cell expansion in cancer Mandruzzato S, Solito S, Falisi E, Francescato J Immunol. 2009; 182: 6562-8
patients.
S, Chiarion-Sileni V, Mocellin S, Zanon A,
Rossi CR, Nitti D, Bronte V, Zanovello P.
Multicentre, open, noncomparative phase II trial to evaluate Ridolfi L, Fiorentini G, Guida M, Dichiara Melanoma Res. 2009; 19: 100-5
the efficacy and tolerability of fotemustine, cisplatin, alpha M, Bichisao E, Ridolfi R. Italian Melanoma
interferon and interleukin-2 in advanced melanoma patients.
Intergroup (IMI).
Complete and lasting healing of bone melanoma metastasis after Pigozzo J, De Rossi C, Rossi CR, Nitti D, Melanoma Res. 2009; 19: 193-4
hypertermic limb perfusion.
Chiarion-Sileni V.
Role of the EGF +61A>G polymorphism in melanoma Casula M, Alaibac M, Pizzichetta MA, Bono BMC Dermatol. 2009; 22: 9-7
pathogenesis: an experience on a large series of Italian cases and R, Ascierto PA, Stanganelli I, Canzanella S,
controls.
Palomba G, Zattra E, Palmieri G. Italian
Melanoma Intergroup (IMI).
46
Clinical and Research Staff
Vanna Chiarion-Sileni
Savina Aversa
Cristina Falci
Adolfo Favaretto
Cristina Ghiotto
Haralabos Koussis
Davide Pastorelli
Nursing Staff
(See Oncology 1)
Laura Bonanno
Giovanni Faggioni
Dario Marino
Davide Maritan
Giulia Pasello
Jacopo Pigozzo
Sara Polimini
Giovanna Rossi
Silvia Stragliotto
Giulia Zago
Loredana Casagrande
Silvia Salmaso
47
Mission
The mission of this Unit is to provide patient access to new
drugs and protocols through participation in major national and
international studies. The whole staff is engaged in implementing
the culture of quality and research as an added value that allows
the activation of Phase I studies. Also, a major commitment is
to provide continuity and quality of care through a rigorous
multidisciplinary approach and networking with both regional
and extra-regional centers, in order to avoid the need for patients
to migrate to gain access to study protocols.
Areas of Excellence
The Unit is especially dedicated to the following areas:
study of new drugs and translational research in melanoma,
lung neoplasms, and hepatocarcinoma;
high-dose therapy and peripheral stem cell support in refractory
lymphoma, myeloma and lymphomas of the elderly;
development of protocols for patients with solid tumors or
lymphoproliferative disease after organ transplantation or
acquired immunodeficiency;
assessment of the role of PET/CT in staging of breast cancer
at high risk, in metastatic ocular melanoma, in the staging and
restaging of esophageal cancer;
study and treatment of breast tumors in patients younger than
35 years;
definition of new criteria for evaluation of efficacy and
immunomodulatory therapies;
definition of new schemes in the combined treatment of head
and neck and esophageal cancer;
evaluation of risk factors in the development of brain metastases
and their treatment;
study of systemic and locoregional treatment combination in
the treatment of metastatic melanoma.
Clinical Activity
In 2010, 1358 new patients were seen: the tumors most
represented were, in the following order: breast cancer, lung cancer
and melanoma, constituting 72% of the total. Two hundred-fifty
eight patients entered study protocols. Most services were provided
in the outpatient setting with 11,626 accesses for treatment and
9,821 for follow-up. The inpatient admissions were 389.
48
Distribution of patients by cancer site
600
540
500
400
299
300
212
89
84
52
44
37
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200
Azienda Ospedaliera “Istituti Ospitalieri”- Chirurgia Generale
(Cremona)
Gruppo interdisciplinare per lo studio e trattamento dell’epatocarcinoma
Gruppo interdisciplinare per lo studio e trattamento dei GIST
(“G.I. - GIST”)
Gruppo interdisciplinare per lo studio e trattamento dei tumori
neuroendocrini (“G.I. - NET”)
META (Melanoma Task Force)
IMI (Italian Melanoma Intergroup)
Inside the IOV
For all the malignancies (lung, head-and-neck, esophagusstomach, liver, lymphoma, melanoma, breast, endocrine,
hepatocellular carcinoma), multidisciplinary weekly meetings
are active. Moreover, scientific investigations which involve
the dedicated oncologist, the dedicated radiation oncologist,
the appropriate surgeon, the radiologist, a nuclear physician, a
gastroenterologist endoscopist are also ongoing. Multidisciplinary
clinics and meetings are open to all specialists and trainees.
Azienda ULSS “Veneziana” (Oncologia Medica)
Dipartimento di Scienze Otorino-Odonto-Oftalmologiche-Cervico
Facciali (Università degli Studi di Parma)
IRCCS - HSR Ospedale San Raffaele (Milano)
IRCCS - INT Istituto Nazionale dei Tumori (Milano)
IRCCS - CRO Centro Riferimento Oncologico (Aviano)
IRCCS - IEO Istituto Europeo di Oncologia (Milano)
Azienda Ospedaliero Universitaria “Ospedali Riuniti”- Clinica
di Endocrinologia (Ancona)
Azienda Ospedaliera S. Croce e Carle - Oncologia Medica (Cuneo)
University Hospital, Zurich, Switzerland (Prof. R. Stahel)
Istituto Oncologico Catalano, Barcelona, Spain (Prof. R. Rosell)
Theaghenion Anticancer Hospital - Salonicco (Greece)
EORTC Melanoma Group
EORTC EBMT (European Bone Marrow Transplantation
Group)
ECOG (East Cooperative Oncology Group) Melanoma Group
GMGT (Global Melanoma Task Force)
49
Identification of new molecular targets for
We will evaluate the effect of these treatments associated
with the inhibition of anti-apoptotic proteins of the
IAP (inhibitors of apoptosis proteins) family and BCL2.
At this stage, senescence and apoptosis will be evaluated using
specific markers.
In the second phase of the study, we will evaluate the
potential therapeutic effect of biological agents identified
in in vitro studies in a preclinical murine model. In the
third year, the project will focus on the analysis of tumor
samples from patients before and after chemotherapy.
The expression of molecular markers of apoptosis and
senescence will be correlated to the clinical and radiological
response of patients to identify markers that can
distinguish patients sensitive and refractory to treatment.
Based on the results of this study, we will evaluate the possibility
of developing a Phase I clinical trial in first-line treatment
of pleural mesothelioma based on the association of selected
biological agents with standard chemotherapy regimens.
biological agents for chemotherapy of malignant
pleural mesothelioma
Principal Investigator: Giulia Pasello
The objective of this study is to identify new biological
agents to enhance the cytotoxic activity of chemotherapeutic
regimens currently used to treat mesothelioma, forcing
cancer cells to undergo apoptosis and to avoid cell cycle
arrest in a metabolically active status (cellular senescence).
In the first phase of the study, we plan to expose 3 mesothelioma
cell lines to different treatments that can positively or negatively
modulate the levels of ROS (reactive oxygen species) to induce
apoptosis mediated by TRAIL (tumor necrosis factor-related
apoptosis-inducing ligand). The analysis of the cell lines of
malignant pleural mesothelioma ZL34, ZL55 and H28 is
ongoing. The cell lines were kindly provided by the laboratories
of Molecular Oncology, University Hospital of Zurich.
50
Analysis of the prognostic and predictive impact of
EGFR and KRAS mutations, and of EGFR FISH in
this biological heterogeneity. CTC are present in many metastatic
solid tumors. Their measurement in breast cancer has a prognostic
and predictive value. EPC are cells derived from bone marrow and
may play an important proangiogenetic role in the early growth
of metastases. In 30 NSCLC patients we plan to count CTC
and EPC at the beginning and at the end of concurrent chemoradiotherapy. In the case of sequential therapy, the count is also
planned at the end of each treatment. The CTC will be evaluated
with the CellSearch (Veridex, LLC, Warren, NJ) system.
To this end, 15 ml of peripheral blood are incubated with
magnetic nanoparticles conjugated with monoclonal antibody
to the cell surface marker EpCAM, specific for epithelial cells.
Through a magnetic field, EpCAM positive cells are selected
and labeled with antibodies specific for white blood cells (antiCD45) and epithelial cells (anti-cytokeratin 8, 18, 19) and a
specific marker for cell nuclei (DAPI). A CTC, by definition,
must express EpCAM, have a nucleus (DAPI positivity), and
express markers for epithelial cells but not leukocytes. EPC are
defined as endothelial cells in the peripheral blood expressing
C-kit, VEGFR2, VE-cadherin but not expressing CD11b. Up to
now, 6 patients with locally advanced NSCLC were enrolled and
completed the counting of CTC and EPC.
advanced lung adenocarcinoma
Principal Investigator: Adolfo Favaretto
The non-small cell lung cancer (NSCLC) has demonstrated
considerable heterogeneity of biological and clinical behavior.
Reversible inhibitors of EGFR have proven effective in a group of
patients with specific clinical and molecular features. Mutations in
the tyrosine domain of EGFR were found to be the best predictor
in terms of objective response and PFS, while FISH for EGFR
seems to identify a larger group of patients who might benefit
from treatment. KRAS mutations are associated with failure to
respond to such therapy. The three molecular markers will be
analyzed retrospectively in patients with stage IIIB and IV NSCLC
undergoing surgery for diagnostic or therapeutic purposes; the
patients will be selected based on the presence of at least one of
the clinical features which appear to be predictive of response to
EGFR inhibitors (non-smoker status, female). The purpose of this
study is to determine whether mutations in the tyrosine domain
of EGFR or gene amplifications evaluated by FISH analysis can
confirm their predictive value in a selected population of patients
with clinical features indicative of response to inhibitors of EGFR
tyrosine kinases, and to assess their prognostic value in a specific
clinical context. Samples were collected from 67 patients with
lung adenocarcinoma. Mutational analysis of EGFR (exons 1821), KRAS (exon 2) and FISH analysis for EGFR are ongoing.
The overall survival and disease-free survival will be analyzed in
relation to the molecular findings to investigate their prognostic
significance. The influence of treatment with inhibitors of EGFR
on overall survival and disease-free survival in different patient
groups will then be analyzed.
Tumor markers for adenocarcinoma of the
esophagus and cardias. A retrospective study
Principal Investigator: Vanna Chiarion-Sileni
Tumor markers may correlate with the presence or progression
of cancer. In cancers of the colon and pancreas, the predictive
and prognostic value of CEA and Ca199 are defined, whereas
for cancers of the esophagus and cardias only a few studies
have evaluated the significance of their increase in the natural
history of disease. The purpose of this study is to evaluate, both
retrospectively and prospectively in patients treated from 1998
with cardias gastric cancer, the significance and predictive value
of CEA and Ca199 and their possible prognostic and predictive
role.
Data collection began in March 2010 and will continue until
a suitable number of patients to obtain statistical significance will
be reached. In case of evidence of a predictive and/or prognostic
role, a prospective validation study will be proposed by the Italian
Research Group on Biomarkers.
Evaluation of circulating tumor cells (CTC)
and endothelial progenitor cells (EPC) as a
prognostic factor in locally advanced lung
cancer
(NSCLC)
Principal Investigator: Adolfo Favaretto
Patients with locally advanced NSCLC have a median survival
of about 1 year, and at 3 years about 20% are still alive. Aim of this
study is to assess whether two cell markers could partially explain
51
New therapeutic strategies in the treatment of
Furthermore, we assessed and are currently evaluating the
clinical activity and tolerance profile of several new molecules in
the treatment of melanoma such as the antiCD137 (BMS006)
monoclonal antibody, the intralesional allovectina-7 (VICAL),
Vemurafenib and GSK 2118436 BRAF inhibitors.
In testing the effect of Braf inhibitors we are particularly
focused on defining the mechanism of resistance, the effect on
brain metastases and the best combinations, schedules and timing
in the treatment strategy and planning in order to improve the
effect on survival.
These studies will have important implications on the selection
of the most appropriate drugs and combinations in the different
context of the disease. In this regard, a strict collaboration with
dermatologists is underway in order to better understand and
manage the skin toxicities of these drugs.
For mucosal and c-kit positive melanoma we are participating
in the study of the evaluation of Nilotinib, and testing the
effectiveness of Ipilimumab in the European access programme.
Our Unit is a national reference center for choroid melanoma.
For this very rare disease, we have developed a combined, systemic
and local intrahepatic treatment method (TACE) with significant
results, and we are currently testing the best integration of
Ipilimumab in the treatment of the metastatic phase.
We are also collaborating with colleagues at the Melanoma and
Soft Tissue Tumor Unit regarding the combined use of systemic
and electro-chemotherapy in order to define both prognostic and
predictive factors related to the best local and systemic control
and to an immunological response. In addition, a prospective
assessment of the impact on the Quality of Life is underway.
Clearly, training and educational activities are an important
part of the Unit’s mission and specific programs on melanoma
are provided also in collaboration with the Italian Melanoma
Intergroup.
Finally, the Unit was involved in the layout of regional
guidelines for the diagnosis and treatment of melanoma and this
task was a preparatory step in the implementation of the regional
melanoma network now in progress. Currently we are involved
with CNR in the set-up of the national melanoma guidelines.
melanoma
Principal Investigator: Vanna Chiarion-Sileni
Within the clinical and translational research programs, many
resources are devoted to melanoma. In addition to the design
and coordination of non-profit, national clinical trials, the Unit
has actively participated in and contributed to both academic
(EORTC) and sponsored international studies, designed to test
new molecules and identify new gene profiles and/or prognostic
and predictive factors.
Among the non-profit studies, the TRECEM trial (a phase
III randomized, open-label study) prospectively evaluated the
development of brain metastases in relation to the systemic use
of Dacarbazine or Temozolomide, demonstrating that cerebral
progression depends more on the effectiveness of the drug than its
ability to cross the blood-brain barrier, and that the prognosis of
patients who develop brain lesions is no worse than those who do
not, thus supporting the issue that these patients are unjustifiably
excluded from studies of new drugs. The Mel.A. trial (a phase III
randomized, open-label study) has evaluated the effectiveness of
intravenous intensified interferon alpha-2b compared to standard
high-doses in patients after surgical excision of metastastatic
lymph nodes, demonstrating that a shorter but more intensive
treatment regimen is more feasible and not more toxic than a
conventional one. In EORTC and sponsored trials, we have
actively participated in the study of the anti-CTLA-4 antibodies
(Ipilimumab) (BMS 008, BMS 024, BMS 025, BMS 029, BMS
184 EAP studies). By treating more than 120 patients, we were
able to identify new immune-related response patterns and
implement the guidelines for the monitoring of immune-related
adverse reactions for a more effective and safer drug use in the
clinical practice. We are also studying possible surrogate markers
of response that could be employed in the clinical evaluation of
the patients during the phase of the immunological activaction
when radiological imaging is not able to distinguish between true
or false progression making the clinical decision difficult.
Moreover, we contributed to the clinical evaluation of
the MAGE 3 A recombinant protein by participating in the
EORTC 16032-18031 study which allowed the identification
of a predictive gene profile of efficacy, and we are now testing
prospectively this profile in the metastatic (Predict study) and
adjuvant setting (Derma study).
52
Evaluation and Introduction
of New Drugs in Cancer Therapy
Chief
Antonio Jirillo, MD
Antonio Jirillo was born on 24th September 1952. He graduated in Medicine at the University
of Bari in 1977 cum Laude. He specialised in Oncology and Radiotherapy cum Laude. Then he
attended the National Cancer Institute of Milan as a visiting fellow from 1977 to 1980. He worked
as a Medical Doctor at the Division of Radiotherapy and Oncology at the Hospital of Legnago
(Verona, Italy) from 1981 to 1987. He was Deputy Director at the same Division from 1988 to
1996. Then he was the Director at the Division of Oncology of Legnago Hospital (Verona, Italy)
from 1996 to 2000. From 2001 to June 2007 he was Deputy Director of Clinical Oncology of
Azienda Ospedaliera di Padova and later Istituto Oncologico Veneto (IOV) (from 2005). During the
period 2007-2010 he was Director of the 2nd Division of Clinical Oncology IOV. Since November
2010 he is Director of Unit of Evalutation and Introduction of New Cancer Therapies at IOV. He is
author/coauthor of over 150 publications.
Main Pubblications
Mechanisms of acquired resistance to epidermal growth Bonanno L, Jirillo A, Favaretto A.
factor receptor tyrosine kinase inhibitors and new
therapeutic perspectives in non small cell lung cancer.
Curr Drug Targets. 2011; 12:922-33
Platinum-based doublet chemotherapy in pre-treated Pasello G, Nicotra S, Marulli G, Rea F, Lung Cancer. 2011; 73:351-5
malignant pleural mesothelioma (MPM) patients: a mono- Bonanno L, Carli P, Magro C, Jirillo A,
institutional experience.
Favaretto A.
Sorafenib in hepatocellular carcinoma - a post marketing Trojniak MP, Palozzo AC, Mazurek M, Immunopharmacol Immunotoxicol. 2011;
evaluation.
Jirillo A.
in press.
Evaluations of new drugs after they reach the market.
Jirillo A, Trojniak MP.
54
Health Aff (Millwood). 2011; 30:2028
Antonio Jirillo
Magdalena Mazurek
Silvia Imbevaro
55
This Unit was founded in November 2010 and it is a part of the
Department of Clinical Oncology.
Objectives:
critical evaluation of new cancer drugs when used in routine
clinical practice;
study of pharmacoeconomics;
application of health technology assessment in Clinical
Oncology;
development of Phase I studies.
Phase I study with agents dithiocarbamate gold (III) in cancer
patients;
Analysis of real clinical practice;
Green Oncology: cultivating sustainability in Medical
Oncology;
Analysis of the first relapse in patients with operable breast
cancer. A monoinstitutional experience.
56
Department of Surgery
The Departments - Department of Surgery
57
Surgical Oncology
Chief
Carlo Castoro, MD
Carlo Castoro obtained his degree in Medicine in 1983, his specialization in General Surgery in 1988
and in Thoracic Surgery in 1993 at the University of Padua. He is an Assistant Professor of Surgery
at the Postgraduate school of General Surgery at the University of Padua School of Medicine. His
research interests and activities include thoracic and abdominal surgery, esophageal diseases, with
special attention to multimodal treatments, Day Surgery and reorganization of surgical services,
and Medical Education (new technologies and distance learning). He has published 45 indexed
full papers; a book on Lichtenstein Hernia Repair, 1998; the Policy Brief “Day Surgery: Making it
Happen” published in 2007 by the European Observatory on Health Systems and Policies, WHO
Office for Europe; he is author of many videos and multimedia resources on surgical techniques. He
is a member of the Executive Committee of the International Association for Ambulatory Surgery
(IAAS), head of the sub-committee on Education and Training, and President elect of the IAAS for
2011-2013.
Main Pubblications
Nodal Metastasis From Locally Advanced Esophageal Cancer: Castoro C, Scarpa M, Cagol M, Ruol A, Cavallin Ann Surg Oncol. 2011; 18:3743How Neoadjuvant Therapy Modifies Their Frequency and F, Alfieri R, Zanchettin G, Rugge M, Ancona E.
54
Distribution.
Mucosal immune environment in colonic carcinogenesis: Scarpa M, Bortolami M, Cecchetto A, Faggian D, Eur J Cancer. 2011; 47:611-9
CD80 up-regulation in colonic dysplasia in ulcerative colitis. Kotsafti A, Ruffolo C, Navaglia F, Pozza A, D’Incà
R, Plebani M, Sturniolo GC, Angriman I.
A systematic review of diagnostic procedures to detect midgut Scarpa M, Prando D, Pozza A, Esposti ED, Castoro J Surg Oncol. 2010; 102:877-88
neuroendocrine tumors.
C, Angriman I.
Interval between neoadjuvant chemoradiotherapy and surgery Ruol A, Rizzetto C, Castoro C, Cagol M, Alfieri R, Ann Surg. 2010; 252:788-96
for squamous cell carcinoma of the thoracic esophagus: does Zanchettin G, Cavallin F, Michieletto S, Da Dalt
delayed surgery have an impact on outcome?
G, Sileni VC, Corti L, Mantoan S, Zaninotto G,
Ancona E.
Prophylactic thoracic duct mass ligation prevents chylothorax Cagol M, Ruol A, Castoro C, Alfieri R, Michieletto World J Surg. 2009; 33:1684-6
after transthoracic esophagectomy for cancer.
S, Ancona E.
58
Nursing staff
Carlo Castoro
Rita Alfieri
Matteo Cagol
Marco Scarpa
Luigi Dall’Olmo
Alessandra Fasolo
Fabio Bassan
Chiara Beghin
Christina Drace
Enrica Malpeli
Eleonora Pinto
59
Mission
The Surgical Oncology Unit’s mission is to provide high
standards of treatment, research and education on GastroIntestinal malignancies. It strives to deliver high quality care and
appropriate follow-up for each patient. This is achieved through a
multidisciplinary approach involving oncologists, radiotherapists,
surgeons, pathologists and basic science researchers.
Clinical research involves the implementation of new
protocols and new surgical techniques aimed at improving the
surgical treatment of cancer. Research activities focus on clinical
management, quality of life and cancerogenesis of digestive tract
diseases.
Clinical Activity
The unit performs surgery on abdominal and digestive tract
tumors, especially esophagus, esophago-gastric junction, stomach
and colon. Besides the inpatient ward, the Oncology Day
Surgery Unit meets the clinical needs related to the placement of
vascular access systems for chemotherapy, in collaboration with
anesthesiologists, and interventional radiology procedures.
Clinical activity 2010
Inpatient Admissions
207
Day Surgery Admissions
320
Admissions for tumors of the esophagus and cardias
Admissions
In 2010 General surgery for cancer was performed on 339
patients and procedures including:
147
(61% from outside the Veneto Region)
New Patients
Major upper and lower Gastro-Intestinal surgery
Laparoscopy, lymphnode radical dissection and biopsies
Vascular access systems placement and other procedures
112
Admission by pathology
The area of clinical excellence is the treatment of Upper G-I
malignancies and the Surgical Oncology Unit is a high volume
national referral center for esophageal cancer in collaboration with
the Department of Surgery of the Padova University Hospital
(Director Prof. E. Ancona).
Admissions to the Surgical Oncology Unit are reported in
the table, while the figure shows the relative caseload for major
surgeries performed.
Esophagus
Stomach
Colon - rectum
Other
60
Major Research Collaborations
Dept. of Diagnostic Sciences and Special Therapy, Università di
Padova (Pathology Unit)
Inside the IOV
Diagnostic and Operative Endoscopy Unit
Clinical Oncology 1
Clinical Oncology 2
University of Sheffield – Sheffield (UK)
Katholieke Universiteit te Leuven – Louvain, Belgium
Dept. of Surgical and Gastroenterological Sciences, Università
di Padova
An integral part of the activity of the Unit of Surgical
Oncology is research. The Unit collaborates with research groups
from other departments of the IOV and University of Padua.
Research activity focuses on clinical management, quality of life
and cancerogenesis of digestive tract diseases. During the 20102011 period the research on clinical management of esophageal
and esophago-gastric junction cancer has mainly been focused
on quality of life after esophageal resection for cancer, and
nodal metastasis distribution and prognostic role before and
after neoadjuvant therapy for esophageal cancer. These studies
were conducted in collaboration with the Dept. of Surgical and
Gastroenterological Sciences, University of Padova (Prof. Ancona)
and with the Endoscopy Unit, Veneto Institute of Oncology (Dr.
Battaglia).
define how neoadjuvant CT-RT changes nodal metastasis patterns
in locally advanced esophageal cancer. A total of 402 consecutive
patients with cancer of the esophagus or esophagogastric junction
(181 adenocarcinoma [AC] and 221 squamous cell carcinoma
[SCC]) (evaluated at clinical stage T1N1, T2N1, T3N0, or
T3N1 and pathological stage M0) presenting in our Department
between 1992 and 2007 and who underwent complete resection
(R0) were included in this retrospective study on a prospectively
collected database. All dissected lymphnodes were retrieved and
microscopically analyzed. Nodal metastasis patterns in patients
who underwent chemotherapy (CT) or chemoradiotherapy (CTRT) neoadjuvant therapy were compared with those in patients
who underwent surgery alone. Almost 30% of the AC patients
and approximately 40% of the SCC patients showed effective
tumor downstaging after neoadjuvant therapy. There were fewer
paracardial node metastases (P = .002) in the AC patients who
underwent CT-RT neoadjuvant therapy. There were, likewise,
significantly fewer paraesophageal, paracardial, and subcarinal
node metastases in the SCC patients in whom the perigastric
nodes became the second most frequent site of metastasis. In
conclusion, not only was frequency of lymphnode metastases
decreased after neoadjuvant therapy, but nodal localization and
pattern were also significantly modified.
Nodal metastasis from locally advanced
esophageal cancer: how neoadjuvant therapy
modifies their frequency and distribution
Principal Investigator: Carlo Castoro
Neoadjuvant chemoradiotherapy (CT-RT) before esophagectomy
seems to affect the number of nodal metastases and to alter the
distribution of those that remain. The aim of this study is to
61
A systematic review on health-related quality
of life after esophagectomy for esophageal
cancer
early generic HRQL of 651 patients with QLC-30 questionnaire
and four studies analysed disease-specific HRQL of 521 patients
with OES-18 questionnaire at different step of the early followup (3, 6, 9, 12 and 24 months, respectively). A trend to the
improvement of the generic HRQL can be observed in the first
24 months of follow-up after esophageal resection. This trend is
confirmed by the progressive decrease of the symptoms burden in
the first 12 months of the follow-up. Five studies analysed long
term generic HRQL of 236 patients with SF-36 questionnaire.
In these patients (median follow-up range: 24-63 months) the
pooled physical function, role physical, social function, vitality,
general health perception scores resulted lower than US and
Canadian norms. On the contrary, the pooled bodily pain, mental
health and emotional functional scores resulted comparable to US
and Canadian norms. Although based on low-level evidence from
uncontrolled studies, this systematic review showed a trend to the
improvement of the generic and disease-specific HRQL in the first
12 months of follow-up after esophageal resection. Nevertheless,
in long term survivors the pooled physical function, role physical,
social function, vitality, general health perception scores resulted
lower than norms.
Principal Investigator: Marco Scarpa
Recent studies concluded that esophageal resections are
associated with significant deterioration of the health related
quality of life (HRQL), which persists during the followup period. When esophageal resection is proposed, patients
want to know, beside their prognosis, what their quality of life
will be like. The aims of this study are to assess the long-term
HRQL of these patients compared to the established norms and
to evaluate HRQL evolution at the different step of follow-up
after esophageal resection. A systematic review was performed by
searching medical databases (Medline, EMBASE and Cochrane
Library) for potentially relevant publications between January
1975 and June 2009. Studies were included if dealing with HRQL
after esophageal resection for esophageal cancer. Two researchers
independently performed study selection, quality assessment, data
extraction and analysis. Eleven observational, case series, studies
were included with a total of 887 patients. Six studies analysed
Other Programs and Future Perspectives
Our research program in the future will be mainly focused on:
perceived quality of care and quality of life in patients after
radical and palliative treatment for gastrointestinal cancers;
gut microbiota and innate immune environment in non
inflammatory gastro-intestinal carcinogenesis;
molecular mechanisms at the basis of the association between
obesity and esophageal carcinogenesis;
immunosurveillance in the gastrointestinal carcinogenesis.
62
Breast Surgery
Chief
Fernando Bozza, MD
Born in 1951, he graduated in Medicine in 1977 at the University of Padova. He then obtained
a specialization in General Surgery and subsequently in Thoracic and Cardiovascular Surgery at
the same University. Surgeon at the Padova General Hospital until 2009, when he moved to the
IOV where acts as Head of the Breast Surgery Unit. He attended several national and international
training courses at very qualified Institutions, such as Institute Gustave Roussy, Paris; Istituto Europeo
di Oncologia, Milan; Istituto Nazionale Tumori, Milan; Memorial Sloan Kettering, New York;
IRCARD, Strasbourg; Istituto Regina Elena, Rome. Member of the major surgical and oncologic
Societies, he published several papers on general and breast surgery in national and international
journals.
Main Pubblications
Phase II study of neoadjuvant gemcitabine, pegylated Artioli G, Mocellin S, Borgato L, Cappetta J Plast Reconstr Aesthet Surg. 2011;
liposomal doxorubicin, and docetaxel in locally advanced A, Bozza F, Zavagno G, Zovato S, Marchet 64:1161-6
breast cancer.
A, Pastorelli D.
Correlation between magnetic resonance imaging and Nicoletto MO, Nitti D, Pescarini L, Corbetti Tumori. 2008; 94:481-8
histopathological tumor response after neoadjuvant F, Mencarelli R, Cappetta A, Galligioni A,
chemotherapy in breast cancer.
Pogliani C, Marchet A, Bozza F, Ghiotto
C, Griggio L, Zavagno G, Donach ME, Di
Maggio C.
A Randomized clinical trial on sentinel lymph node biopsy Zavagno G, De Salvo GL, Scalco G, Bozza F, Ann Surg. 2008; 247:207-13
versus axillary lymph node dissection in breast cancer: Barutta L, Del Bianco P, Renier M, Racano
results of the Sentinella/GIVOM trial.
C, Carraro P, Nitti D, GIVOM Trialists.
Analysis of technical and clinical variables affecting sentinel Rubello D, Zavagno G, Bozza F, Lise M, De Nucl Med Commun. 2004; 25:1119-24
node localization in patients with breast cancer after a single Salvo GL, Saladini G, Mariani G, Casara D.
intradermal injection of 99mTc nanocolloidal albumin.
Could the serial determination of Ca15.3 serum improve Evangelista L, Baretta Z, Vinante L, Cervino Ann Nucl Med. 2011; 25:469-77
the diagnostic accuracy of PET/CT? Results from small AR, Gregianin M, Ghiotto C, Bozza F,
population with previous breast cancer.
Saladini G.
64
Fernando Bozza
Raffaello Grigoletto
Nursing Staff
Fabio Bassan
Chiara Beghin
Lisa Rigato
Silvia Michieletto
Tania Saibene
Stefano Valente
65
Mission
The mission of the Breast Surgery Unit is to offer to patients
with breast cancer a rapid and efficient diagnostic and therapeutic
pathway, according to the most modern guidelines of management
of mammary tumors. The Unit tackles the neoplastic disease in a
multidisciplinary manner, and follows the patient from diagnosis to
the choice of the therapeutic program and reconstructive surgery/
rehabilitation in strict collaboration with medical oncologists,
radiotherapists, psycho-oncologists. One major interest is focused
on new integrated therapeutic approaches, such as intra-operative
radiation therapy.
Clinical Activity
300
Number of surgical interventions
Clinical activity (year 2010) includes (see figure):
187 mastectomies (21 bilateral with reconstruction, 143
monolateral with reconstruction, 23 monolateral without
reconstruction);
290 conservative surgery interventions (233 with sentinel node
technique, 82 with controlateral breast remodelling);
246 mammary biopsies;
13 prothesis application;
151 day-hospital mammary surgery.
250
200
150
100
50
0
Mastectomy
Biopsies
Conservative surgery
Day-hospital surgery
Inside the IOV
Clinical Oncology 1
Clinical Oncology 2
Breast Imaging Unit
Familial Cancer Clinics
Radiotherapy
Nuclear Medicine
IRCCS CRO, Aviano
Breast Unit, Ospedale Morgagni (Forlì)
Division of Surgery and Interventional Science, University
College, London
66
Intra-operative Radiotherapy - The TARGIT
Protocol
Sentinel node biopsy in patients with
recurrent breast cancer - The LISER Q Protocol
Principal investigator: Fernando Bozza
Principal investigator: Raffaello Grigoletto
The combination of radiotherapy following surgery is now
a gold standard in the management of breast cancer. While
radiotherapy usually follows surgery and adjuvant chemotherapy,
the recent introduction of intra-operative radiotherapy may
present several advantages for the management of at least a part of
breast malignancies. On the one hand, in fact, the simultaneous
application of radiotherapy allows women to avoid the 5-7
weeks of fractionated radiotherapy application; on the other, the
local administration of radiation may allow a better focusing on
affected tissues, while sparing surrounding non-target tissues and
consenting a limitation of the cutaneous damage with eventual
improvement of the esthetic results. The TARGIT protocol
is an international multicenter study comparing the standard
radiotherapy approach to intra-operative radiotherapy. The study
entails the enrollment of patients >45 yr-old bearing non lobular
infiltrating adenocarcinoma of the breast of <3 cm diameter. The
patients are randomized in two groups, one operated and during
surgery treated with IntraBeam radiation (5 Gy), and the other
undergoing surgery and subsequent fractionated radiotherapy.
The two cohorts will be monitored over 5 years to evaluate the
clinical outcome in terms of local or distant repetition, the side
effects of the IORT treatment, and the esthetic results of the two
interventions.
The sentinel node technique has greatly impacted on breast
cancer surgery. Thanks to the careful monitoring of the female
population at risk of breast cancer and to the steady progress
in surgical techniques, which allow much more conservative
interventions on both the mammary gland and the axillary
lymphnodes, a great fraction of patients has negative sentinel
nodes, and does not undergo radical surgery. Thus, the number of
patients with local tumor recurrence who did not undergo radical
axillary lymphadenectomy and hence could again take advantage
of the sentinel node technique is increasing. However, in this
patient population the sentinel node technique has not been as
yet validated. Aim of this study is to assess the reliability of the
sentinel node biopsy in this category of patients. To this end, the
patients with a local recurrence following the first surgery with a
negative sentinel node will again undergo research and removal of
the sentinel node; whatever the result, however, the patients will
undergo total axillary lymphadenectomy according to the current
guidelines. The evaluation of the sentinel node and of all the other
lymphnodes removed will allow to establish whether the sentinel
node has a predictive value also in these patients; if this were the
case, the technique could be applied also to patients with local
breast cancer recurrence, thus avoiding the need for the extensive
removal of axillary lymphnodes and its eventual side effects.
The experimentation with IORT will be continued, and new
collaborations will be activated in order to better define the value
of this technique and its limitations in the different categories
of breast cancer patients.
Even though the work of the Breast Surgery Unit is carried
out in a multidisciplinary way and involves the steady,
strict interaction with many persons of different but
complementary expertise, it is a firm priority of the Unit
to obtain the EUSOMA certification as “Breast Unit”.
It is likely that this operation could be carried out in synergy
with other colleagues working in different structures of the
health system in Padua (such as the University-Hospital) and
also involved in the management of breast malignancies; in this
perspective, a single Breast Unit will take care of all the patients
of our geographic area, thus greatly increasing the critical mass
in this field.
Thanks to the participation in the LISER Q Protocol, and
exploiting the national and international guidelines, we
intend to develop and implement regional guidelines for the
management of axillary nodes in breast cancer.
67
Melanoma and Soft Tissue Tumors
Chief
Carlo Riccardo Rossi, MD
Born in Rosolina (RO), Italy, on March 3rd, 1950. He graduated in Medicine at the University of
Padova in 1975, then specialized in General Surgery and Oncology. Full Professor of Surgery at
the Department of Oncology and Surgical Sciences of the University of Padova, he has headed the
Sarcoma and Melanoma Unit at IOV (Veneto Region Oncology Research Institute) since 2004.
Member of several Italian and International surgical and oncological scientific societies. President of
the Italian Melanoma Intergroup. He has published 131 scientific papers in international journals.
Member of the Editorial Board of Melanoma Research and reviewer for many scientific journals.
His research activity has been mainly focused on melanoma, sarcoma and loco-regional treatment
of tumors. He has beeen financially supported by the University of Padova, the Veneto Region, the
National Research Council and the European Commission.
Main Pubblications
Prognostic factors and oncologic outcome in 146 patients with Cavaliere F, De Simone M, Virzì S, Deraco M, Rossi CR, Eur J Surg Oncol.
colorectal peritoneal carcinomatosis treated with cytoreductive Garofalo A, Di Filippo F, Giannarelli D, Vaira M, Valle M, 2011; 37:148-54
surgery combined with hyperthermic intraperitoneal Pilati P, Perri P, La Pinta M, Monsellato I, Guadagni F.
chemotherapy: Italian multicenter study S.I.T.I.L.O.
Long-term results of melphalan-based isolated limb perfusion Rossi CR, Pasquali S, Mocellin S, Vecchiato A, Campana Ann Surg Oncol.
with or without low-dose TNF for in-transit melanoma LG, Pilati P, Zanon A, Nitti D.
2010; 17:3000-7
metastases.
Targeted Therapy Database (TTD): a model to match patient’s Mocellin S, Shrager J, Scolyer R, Pasquali S, Verdi D, PLoS One.
molecular profile with current knowledge on cancer biology. Marincola FM, Briarava M, Gobbel R, Rossi C, Nitti D.
5:e11965
2010;
A European project on incidence, treatment, and outcome of Mastrangelo G, Fadda E, Cegolon L, Montesco MC, Ray- BMC Public Health.
sarcoma.
Coquard I, Buja A, Fedeli U, Frasson A, Spolaore P, Rossi 2010; 10:188
CR.
Interferon alpha adjuvant therapy in patients with high-risk Mocellin S, Pasquali S, Rossi CR, Nitti D.
melanoma: a systematic review and meta-analysis.
68
J Natl Cancer Inst.
2010; 102:493-501
Carlo Riccardo Rossi
Antonio Sommariva
Antonella Vecchiato
Luca Campana
Sandro Pasquali
Marco Rastrelli
Francesco Russano
Dermatology
Mauro Alaibac
Maria Paola Amici
Cristina Bonacin
Matteo Bordignon
Paolo Del Fiore
Elisabetta Oro
Barbara Pigozzi
Elena Tonin
Plastic Surgery
Leonardo Sartore
Data Managers
Cristina Bonacin
Paolo Del Fiore
Nursing Staff
Administrative
Staff
Cinzia Bellesso
Elisa Bonaldi
Debora Borella
Sabrina Carraro
Concetta Collu
Patrizia Gesuato
Chiara Lando
Michela Pinton
Marta Rotella
Valeria Siscaro
Elisa Tognana
69
Mission
The Melanoma and Soft Tissue Tumors Unit main purpose is
to be a leader in treatment, research and education on Melanoma,
Sarcoma and Peritoneal Carcinomatosis. The Unit integrates
different expertise in Surgery, Dermatology, Oncology, Pathology,
Radiology and Molecular Biology in multidisciplinary groups
specifically committed to patient care and clinical translational
research.
Clinical Activity
The out-patient clinical activity includes: first and followup visits for Melanoma, Sarcoma and Carcinomatosis patients;
cutaneous biopsies for atypical nevi; and wide excisions for less
advanced cutaneous malignancies. The Unit is also strongly
involved in diagnosis of suspicious pigmented lesions and
dermatologic follow-up of patients at risk.
The caseload is constantly increasing and a report of our
2009-2010 ambulatory activities is shown in table 1.
Table 1
2009
list and creating a dedicated database to provide an important
amount of data for epidemiological studies.
Before surgery, the clinical situation of almost all patients
is discussed in weekly multidisciplinary meetings, in which the
optimal diagnostic work-up and the most appropriate integrated
treatments are planned. The in-patient surgical activity is
performed weekly in three operating theaters, two for ordinary
hospitalization and one for day or week surgery (figure 1).
Figure 1.
2010
Surgery
First visit
684
521
Follow-up visit
1992
2315
Biopsies/Wide excision
2569
3496
First visit
2816
2679
Follow-up visit
3350
4997
566
601
Ordinary surgery
Day surgery
183
176
Dermatology
Cutaneous Mapping
Surgery is mainly directed to melanoma and sarcoma patients
and during 2010 more than 400 melanoma and sarcoma patients
have been treated (table 2).
Recently, a project for a Network in the Padova district for
management of cutaneous pigmented lesions and melanoma
(RETEMELA Project) has been promoted by our Unit.
The main objective of this project is to improve early
diagnosis (educating family physicians and favoring
access to a dermatologist) and to define a more rational
diagnostic and therapeutic course for these patients.
RETEMELA should be effective in shortening the waiting
Table 2
Melanoma
Sarcoma
70
2009
2010
329
342
47
68
Clinical Areas of Excellence
The Group has developed a specific competence on
management of metastatic tumors confined in a unique organ
and therefore amenable to the so-called “loco-regional therapy”.
Under this definition we include different approaches: techniques
developed to increase drug concentration in a specific area of the
body (regional chemotherapy) or techniques that determine the
immediate destruction of tumor nodules using physical or chemical
approaches. Sometimes the loco-regional approach is proposed for
improving radicality and functional outcome of surgery.
The procedures set-up by the group in this field are: Isolated
Limb Perfusion (ILP), Cytoreductive Surgery (CRS) associated
with Hyperthermic Intra-Peritoneal Chemotherapy (HIPEC) and
Electrochemotherapy (ECT).
Isolated limb perfusion (ILP) consists of the injection under
hyperthermic conditions of drugs (Melphalan and Tumor
Necrosis Factor-alpha) into a limb-extracorporeal circuit. The
therapeutic efficacy of ILP for the treatment of locally recurrent
melanoma and in-transit metastases is well established as well
for non resectable limb sarcoma. ILP has undoubtedly led to
improvement in local results compared to those achieved with
systemic drug administration, preventing the drawbacks of
systemic toxicity.
Cyto-reductive Surgery (CS) combined with Hyperthermic
Intra-Peritoneal Chemotherapy (HIPEC) has been developed as
a loco-regional treatment for peritoneal carcinomatosis confined
within the abdominal cavity. This multimodal approach is
directed to surgically eliminate all the peritoneal visible nodules,
followed by direct instillation of heated chemotherapy (Cisplatin,
Doxorubicin and Mytomicin C at various combinations and
doses) into the abdominal cavity, with the objective to eradicate
the remaining microscopic tumoral foci and free cancer cells.
Nowadays we have adopted this technique as a standard of care
for pseudomixoma peritonei (PMP) and malignant peritoneal
mesothelioma. In colon and ovary abdominal carcinomatosis,
the role of CS+HIPEC is still under study and it is proposed only
in selected cases. In gastric carcinomatosis and sarcomatosis the
procedure must be considered still experimental and we do not
recommend it outside clinical trials.
Electrochemotherapy (ECT) is an effective method of drug delivery
into cancer cells based on the mechanism of electroporation,
consisting of the synergistic association of locally applied brief
electrical voltages (reversible electroporation) and low permeant
chemotherapeutic agents (bleomycin and cisplatin). At present,
the technique is proposed as a palliative treatment for patients
with melanoma and non-melanoma small cutaneous metastases.
Education and Dissemination
After a discussion forum among the most relevant specialists in
the Veneto Region, the Unit coded and published the guidelines
for Melanoma and Sarcoma patient treatment, which are freely
accessible on the Unit’s Web Site. The Guidelines have also been
divulgated in two different scientific sessions. With the same
“educational” view, on the Website it is also possible, through a
dedicated on-line form, to refer patients for clinical evaluation,
multidisciplinary discussion and/or radiological/pathological
second opinions. In the last few months, technical equipment has
been put in place that will allow Oncology and Surgery Units of
the Veneto region to attend our meetings and present and discuss
complex cases in teleconference sessions.
Inside the IOV
Dermatopathology
Family Cancer Clinics
Clinical Oncology 1
Clinical Oncology 2
Radiology
71
CONTICANET (CONnnective TIssue CAncer NETwork)
Melanoma Institute of Australia, Sydney, Australia
Rotterdam Cancer Center, The Netherlands
Stanford University, California
EORTC Sarcoma Group
EORTC Melanoma Group
Sentinel Lymphnode working group
University of Leeds, United Kingdom
Italian Sarcoma Group
Italian Melanoma Intergroup
SITILO-Società Italiana di Terapie Integrate Locoregionali
The research and clinical programs are focused on different
research areas (figure 2):
1. Describing disease distribution by characteristics relating to
time, place, and person (descriptive epidemiology);
2. Investigating and rating treatment options according to their
benefits and side effects (patients selection);
3. Testing further therapeutical procedures (innovative treatments);
4. Defining the methods for monitoring the quality of therapies
(quality control).
The ongoing research activity is based on the following four
main projects.
The Molecular Melanoma Map Project
(MMMP)
Background and aim. MMMP is an open access, interactive
web-based multidatabase dedicated to research on melanoma
biology and therapy. MMMP has been built by six databases on
molecular aspects of melanoma (Biomaps, Biocards, Melanoma
Molecular Profile, Drug Development Database and Clinical
Trial Database). The major aim of MMMP is to gather the huge
amount of information scattered in thousand of papers about
melanoma biology. Therefore, the investigators could formulate
new mechanistic/therapeutic hypotheses and thus further
stimulate basic, translational and clinical research. Considering
the interests of our group in the research of new predictive and
prognostic biomarkers for melanoma patients treated with surgical
and medical therapies, we are implementing two new databases in
the MMMP: the Individual Patients Database (IPD) and Targeted
Therapy Database (TTD).
The Individual Patients Database (IPD) is a collection of
patient data about common clinico-pathologic features, such as
those belonging to the 7th edition of the AJCC TNM staging
system and information regarding the availability of biological
specimens, such as frozen tissues, serum samples, paraffin blocks.
The Italian Melanoma Intergroup (IMI) has been involved in the
IPD and several Italian melanoma centers have joined the project.
Special interest has been raised by the recently implemented
Targeted Therapy Database (TTD), a manually annotated
Figure 2.
QUALITY
CONTROL
PATIENT
SELECTION
MELANOMA
SARCOMAS
CARCINOMATOSIS
DESCRIPTIVE
EPIDEMIOLOGY
INNOVATIVE
TREATMENTS
72
database where the relevant data on anti-melanoma therapies is
gathered in a formal representation that can be computationally
analysed. With the collaboration of Stanford University, dedicated
algorithms have been set up and published for identification of the
prevalent therapeutic hypotheses based on the available evidence
from clinical and pre-clinical studies present in the literature.
Achievements. Since its inception up to 2010, the MMMP
has gathered over 3,000 records, over 282,000 contacts and over
1,200 registered users. It is also the #1 hit on Google when searching
“melanoma database”, and it is increasingly quoted in articles.
Future directions. The database needs constant updating
(scientific information) and implementation of patients’ clinical
and logistic data. This represents a remarkable opportunity to
create a national/international network of Centers, collaborating
in particular on quality control studies and search of molecular
markers for patient selection. Moreover, the prediction performance
of Targeted Therapy Database (TTD), in the light of its theoretical
nature, must be validated before it could be implemented in a
routine clinical setting.
“oncomiRs”). Some investigators have proposed to target these
miRNA in view of a therapeutic perspective. Very little is known
about the involvement of these short RNA sequences in the
pathogenesis and aggressiveness of soft tissue sarcomas. The aim
of the project is to obtain STS oncomiR expression patterns
and thereafter to identify the deregulated oncomiRs as potential
targets of new therapeutic strategies for the treatment of this class
of tumors.
Results. In these years we have obtained expression signatures
of over 850 different miRNAs from several fibroblastic/
myofibroblastic sarcomas and cell lines. From about 100
differentially expressed miRNAs we focused our attention on the
most deregulated oncomiRs that are involved in various phases
of cancer progression (figure 3). We have also validated all the
microarray data through the use of a more sensitive method than
microarrays: the qRT-PCR with TaqMan® method.
Future directions. At present we are studying the behavior of
cell lines derived from STS in terms of proliferation, migration,
apoptosis and invasiveness after overexpression or downregulation
of oncomiRs identified in our previous studies. The therapeutic
value of modulating oncomiR expression levels in STS biology
will be also assessed in vivo in xenograft models of human soft
tissue sarcomas. In particular, STS cell lines will be engineered to
ONCOMIRS as new therapeutic targets for
soft tissue sarcomas
Background and aim. Soft tissue sarcomas
(STS) are a group of solid tumors for which
radical surgery remains the only therapeutic
option with curative potential: conventional
treatments (chemotherapy and radiotherapy)
can only slightly change the dismal prognosis
of patients affected by this type of cancer.
Therefore, more effective therapeutic strategies
are urgently needed and a new understanding of
the cancerogenesis process could be of great help.
A recently identified class of non-coding small
RNAs, microRNAs (miRNAs), may provide
new insights into cancer research. MicroRNAs
are short single-stranded RNA molecules that
control the expression of several genes involved
in many cellular processes. They play important
roles in almost all kinds of cancer, where they
modulate key processes during tumorigenesis
such as metastasis, apoptosis, proliferation, or
angiogenesis (in which case they are defined
RNA ISOLATION
total RNA
small RNA
small
RNA
GENE
EXPRESSION
PROFILING (mRNA)
miRNA
EXPRESSION
PROFILING
ANALYSIS OF
EXPRESSION DATA
ANALYSIS OF
EXPRESSION DATA
IN SILICO ANALYSIS OF
PUTATIVE miRNA-mRNA TARGET
INTERACTION
miRanda
FUNCTIONAL CORRELATION between miRNA
and mRNA expression profiling of predicted targets
Figure 3.
Identification of target genes
involved in the specific miRNA
biological functions analyzing the
functional correlation between miRNA
and mRNA expression profiles.
73
IDENTIFICATION OF POTENTIAL
TARGET GENES
PITA
laboratories, techniques (RT-PCR versus FISH for traslocations)
and tissue status (paraffin versus frozen). The third study area
was focused on Medical practice. The ‘global’ conformity of
management depends on eight categories; if one of them is not
compliant, the ‘global’ patient management is considered not
compliant. The ‘global’ conformity of this population is in most
cases ‘not compliant’ (56%). Nevertheless, conformity is excellent
for the following aspects: chemotherapy, radiotherapy and followup in more than 90% of patients; it is still good (80%) for initial
examination, histology and secondary surgery revision. Surgery
reaches conformity in only 46% of cases.
Future directions. The following new projects are going to start:
correlating geographical distribution of sarcomas and
deprivation index in the three European countries;
genotyping of NER and HR genes polymorphisms and
evaluation of their potential use as predictive markers to the
alkylating agent trabectedin in sarcoma subtypes from a
representative population in the three European areas;
cost-effectiveness profile evaluation for treatment of sarcomas
in two European Regions (Veneto and Rhone-Alpes).
express bioluminescent or fluorescent proteins, and the assessment
of tumor cell growth and response to therapy will be carried out
by an optical imaging approach. This project could also open the
avenue to the development of new miRNA-based diagnostic/
prognostic signatures and target therapies against this class of
tumor, which is highly refractory to conventional anticancer
agents.
CONTICANET - CONnnective TIssue CAncer
NETwork - the epidemiology project
Background and aim. STS and GIST (Gastrointestinal
Stromal Tumors) are rare tumors and their low incidence and
the complex therapeutic approach to these tumors can justify, at
least in part, the lack of an adequate initial treatment which can
significantly worsen the clinical outcome. Moreover, data reporting
from tumor registries is burdened by different and concurrent
biases (i.e. wrong histological diagnosis, missing of visceral sarcoma
registration) which bring to underestimate the actual incidence of
these tumors. On the basis of these considerations, the European
Commission has funded a Network of Excellence (CONnnective
TIssue CAncer NETwork) with the following aims:
to delineate the descriptive epidemiology and molecular
epidemiology of STS & GIST in Europe;
to evaluate quality control of diagnosis and the impact of
molecular analysis on the final diagnosis;
to evaluate conformity of medical practice to Standard Options
Recommendations and its impact on patients prognosis.
The project is structured according to three main tasks:
descriptive epidemiology, molecular epidemiology and medical
practice.
Results. The project is ongoing in three European Regions:
Rhone Alps, Aquitaine and Veneto, and some preliminary results
have been reported. For the first task, the incidence of STS, after
taking into account the distribution by age and sex, was not
significantly different in the three European Regions. No major
difference in incidence by histotype among the 3 Regions was
observed except for Kaposi’s sarcoma, whose rate was higher in
Veneto. Considering the second task (Molecular epidemiology),
the histologic and molecular distribution of sarcomas and the
impact of histologic review and molecular analysis on the final
diagnosis have been defined. The reproducibility of molecular
analysis has been tested, calculating difference between
Electrochemotherapy (ECT) as a new cancer
treatment
Background and aim. Electrochemotherapy (ECT) is
based on the mechanism of electroporation, an effective way
for drug delivery into cancer cells, on the basis of the synergistic
association of locally applied brief electrical voltages (reversible
electroporation) and low permeant chemotherapeutic agents
(bleomycin and cisplatin). The aims of the project are: 1) to verify
the palliative and possibly curative value of ECT at the present
status of delivering; 2) to improve the methods of administration;
3) to investigate the biological impact of ECT.
Results and conclusions. In a previous paper we verified the
validity of ECT in palliative treatment of small nodules in 52
patients (34 with melanoma). In this setting, we demonstrated
that ECT is highly active both in melanoma and non-melanoma
tumors and that ECT proved to be safe and useful in preserving
patients’ quality of life. Recently, we identified 85 patients with
cutaneous metastases from melanoma who received repetitive
bleomycin-based ECT. After the first ECT, an objective response
was observed in 92% of patients, with a complete response up to
78% after a second ECT. On multivariate analysis, the significant
74
positive predictive factors for response were the decreasing size
and number of nodules; the number of electrode applications and
ECT cycles were the only predictors for local control. On the other
side, thickness of primary melanoma and anatomical location of
cutaneous metastases were predictive factors for survival.
Future directions. Once established that the procedure
is effective, some limitations of ECT have emerged from its
clinical application: 1) the lack of comparative studies with other
therapies; 2) ECT can not be used for treating deep/large tumors
because of the length of the currently available electrodes. Future
investigations are focused in the clinical setting on testing ECT
itself as a cure and on extending its indications, alone or in the
context of new therapeutic associations. A planned phase II study
will randomise patients with a limited number of limb metastases
from melanoma between loco-regional chemotherapy and ECT.
Moreover, the availability of new technical instrumentations
(longer electrodes and hardware) could expand the indications
for ECT allowing the treatment of bigger and deeper tumors.
Up to now, ECT has been limited to the skin and subcutaneous
tissue because of the current technology wich does not allow the
treatment of deeply seeded or large tumors. A phase I/II study on
ECT with longer needle electrodes for the treatment of deep and/
or large soft tissue tumors (3-6 cm) is ongoing, mainly to assess
the feasibility and safety of this new ECT modality. Beside testing
ECT clinical activity/efficacy, a growing number of biological data
on tumor response are going to be collected, which will permit
to better understand the intrinsic mechanisms of action and the
many factors that may influence it.
Future research is mainly focused on developing new clinical
projects, which could permit better patient selection and a more
appropriate treatment.
The following projects are underway or starting:
RULL (Radioguided Ultrasound Lymphnode Localization in
melanoma patients). The technique consists in detecting and
removing non palpable lymphnodes suspicious for melanoma,
after injection of radio-labelled albumin macro-aggregates
under ultrasonography. The feasibility of the technique has been
already confirmed and its diagnostic accuracy will be tested.
ROLL (Radioguided Occult Lesion Localization). By using the
same method of the RULL, the feasibility on suspected non
palpable sarcoma lesions will be tested.
Oncovision. Radioguided lymphnode localisation using an
intra-operative portable gamma camera in conjunct with
sentinel biopsy for melanoma.
p53 status in Isolated Limb Perfusion (ILP). The aim of
this study is to evaluate the role of p53 protein status and its
correlation with histopathologic response after loco-regional
delivering of TNF-alpha and melphalan in soft tissue sarcoma
patients.
PET volume leg/arm evaluation before ILP. The study will
evaluate the efficacy of PET in defining leg/arm volume for drug
dosing in patients candidates to ILP.
Videoscopic groin dissection for melanoma. Feasibility study
on a minimally invasive approach to lymphode groin dissection
in melanoma patients.
PET-CT and contrast-enhanced CT in carcinomatosis.
Observational study on the diagnostic value of FDG-PET
combined with a contrast-enhanced CT scan in selection of
patients for cytoreductive surgery and HIPEC.
Laparoscopy before CRS+HIPEC. The study is going to
evaluate the potential diagnostic benefit of laparoscopic
examination before cytoreductive surgery and HIPEC.
MSLT II trial. Phase III multicenter randomised trial of
sentinel node biopsy and complete lymphnode dissection versus
sentinel node biopsy alone, in cutaneous melanoma patients
with molecular or histopathologic evidence of metastases in the
sentinel node.
Stage IV. Randomised Multicenter Prospective Trial comparing
metastasectomy versus best medical treatment in patients with
resectable metastatic melanoma.
Quality of life in melanoma. Multicenter Prospective Trial
evaluating quality of life in early and advanced melanoma
patients.
Parameters for quality assurance in melanoma surgery.
Retrospective study on the number of lymphnodes as a quality
parameter after radical lymphnode dissection.
75
Diagnostic and Operative Endoscopy
Chief
Giorgio Battaglia, MD
Giorgio Battaglia graduated in Medicine in 1974 at the University of Padova, and obtained the
specialization in General Surgery and in Vascular Surgery in 1978 and 1981, respectively.
Assistant Professor at the Padova University since 1980, he has been heading the Digestive Endoscopy
Unit of the 1st Surgical Chair of the Faculty of Medicine of Padova from 1992 to 2007, when he
moved to the IOV as Head of the Diagnostic and Operative Endoscopy Unit. He is member of several
scientific Societies and Committees: Member of the Editorial Board of Acta Endoscopica; secretary
of the Italian Society of Digestive Endoscopy from 2004 to 2007; Member of the Veneto Center
for esophageal diseases and of the EBRA Registry for Barrett’s esophagus; Member of European
RFA-Academia; Coordinator of the Italian Registry for radiofrequency in the therapy of Barrett’s
esophagus. Throughout his career, his interest has been mainly focused on all the aspects related
to digestive endoscopy, with special attention to the problems associated with gastro-intestinal
bleeding. More recently, his attention is centered on pre-neoplastic and early neoplastic lesions of
the gastro-intestinal tract, in particular of the upper portion, where innovative research approaches
are allowed by the availability of unique technical devices such as confocal laser endoscopy and
autofluorescence.
Main Pubblications
High-frequency miniprobes and 3-dimensional EUS for Bocus P, Realdon S, Eloubeidi MA, Diamantis Gastrointest
preoperative evaluation of the etiology of congenital esophageal G, Betalli P, Gamba P, Zanon GF, Battaglia G. 74:204-7
stenosis in children (with video).
Endosc.
2011;
Quality of life in patients with esophageal stenting for the Diamantis G, Scarpa M, Bocus P, Realdon S, World J Gastroenterol. 2011;
palliation of malignant dysphagia.
Castoro C, Ancona E, Battaglia G.
17:144-50
Programmed cell death 4 (PDCD4) expression during multistep Fassan M, Pizzi M, Battaglia G, Giacomelli L, Clin Pathol. 2010; 63:692-6
Barrett’s carcinogenesis.
Parente P, Bocus P, Ancona E, Rugge M. J.
Aurora kinase A in Barrett’s carcinogenesis.
Rugge M, Fassan M, Zaninotto G, Pizzi M, Hum Pathol. 2010; 41:1380-6
Giacomelli L, Battaglia G, Rizzetto C, Parente
P, Ancona E.
Caustic ingestion and esophageal cancer: intra- and peri-tumoral Ruol A, Rampado S, Parenti A, Portale G, Eur J Cardiothorac Surg. 2010;
fibrosis is associated with a better prognosis.
Giacomelli L, Battaglia G, Cagol M, Ancona E. 38:659-64
76
Nursing Staff
Giorgio Battaglia
Paolo Bocus
Stefano Realdon
Elisa Dassie
Giorgio Diamantis
Martina Cesarotto
Francesca Giacomini
Manuela Ruffato (Coordinator)
Stella Bortolotto
Loredana Celadin
Cristina Gallo
Andreina Schiavon
Chiara Zampieri
Emanuela Zoncapè
77
Mission
The mission of the Unit is to provide patients the most advanced
standard of care in gastrointestinal neoplasms, by implementing
the quality of the offered services through careful monitoring
of both medical results and patient satisfaction. Beside the
state-of-the-art endoscopic and surgical procedures, in fact, one
major commitment is to offer to patients a friendly, humanized
surrounding, including a special attention to the communication
aspects with patients, families, and caregivers. This is obtained
through a constant collaboration in a multidisciplinary team which
includes several specialists, and in particular anesthesiologists and
psycho-oncologists. Special attention is also dedicated to the
educational aspects, in order to translate to peripheral Centers the
critical mass acquired at the Unit.
Clinical Activity
documented suspect of neoplastic transformation of the mucosa
exists; this instrument allows very selective biopsies, and may also
be useful in early monitoring of the effects of new anti-tumoral
treatments, such as anti-angiogenic drugs.
The Diagnostic and Operative Endoscopy Unit is located in a
totally renovated area of the Institute, and it occupies 2 operating
rooms plus one room with three beds for patient rest and awakening
after the intervention. All these beds are under strict video and
instrumental monitoring. Most procedures are performed in
sedation, thanks to the collaboration of anesthesiologists. About
2,700 endoscopic examinations are performed yearly; about 35%
of these are operative endoscopies (it has to be stressed that the
mean percentage in Italy is 6%). About 500 ecoendoscopies are
performed yearly, 15% of whom are operative ecoendoscopies.
Ecoendoscopy. As far as ecoendoscopy is concerned, the
Unit is fully equipped with standard ecoendoscopic probes as
well as 3-D miniprobes; these latter allow accurate calculation of
the tumor volume to better monitor the response to therapies.
In addition, our Unit is the only Italian Center equipped with a
“blind” probe which permits the study of stenotizing esophageal
tumors. Finally, we can also utilize an operative probe, which
permits to obtain biopsies from deeply located tissues (such as
pancreas, lymphnodes etcetera), often avoiding the need for
invasive surgical interventions.
Videoendoscopy. The Unit is equipped with the most upto-date instrumentation in the field. In particular, the personnel
utilizes last generation Olympus Videoendoscopies equipped
with Narrow Band Imaging (NBI) technology. Besides the highdefinition view normally allowed by the instrument, the selection
of the NBI function exploits the green and blue light bands, thus
permitting to highlight the mucosal vascularization and eventually
evidence cancerous and pre-cancerous lesions, usually more
vascularized: in addition, by activating a 150X lens, it is possible
to reveal minimal lesions otherwise invisible at the standard vision.
In addition, the Unit is the sole in Italy (and the second in Europe)
equipped with a Fluorescence Videoendoscope; this technology
exploits the autofluorescence generated by normal tissues and
reveals as “black holes” areas of malignant transformation. Finally,
the Unit recently acquired a new revolutionary technology,
that thanks to a 1,000X magnification allows visualizing single
mucosal cells in a sort of “in vivo histologic examination”. This
technology is present in only 3 italian endoscopy Centers, and its
use is limited to selected patients where a strong but otherwise non
Operative endoscopy. The operative endoscopy activity
is mostly focused on the therapy of Barrett’s esophagus, a precancerous lesion that affects over 500,000 patients in Italy.
The mainstay of the surgical therapy of this condition is the
removal of the metaplasic mucosa, which is obtained through
radiofrequency or by a special hydro-dissector that very
accurately detaches from the deeper layers the affected mucosa.
All these invasive procedures are performed under deep sedation
in collaboration with anesthesiologists; the level of sedation is
monitored by a system (BIS) that records the cerebral waves of
the patient, and automatically regulates the administration of the
sedative according to a precise algorythm. Also, the recovery phase
is strictly monitored by a computerized system.
78
2010 Clinical Activity
EGDS
Esophageal-gastro-duodenoscopy
1318
COLON
Colonoscopy
295
EUS
Endoscopic ultrasononography
434
EUS FNA
Endoscopic ultrasononography Fine
Needle Aspiration
31
RFA
Radiofrequency ablation of Barrett’s
esophagus
22
EMR-ESD
Endoscopic Mucosectomy/Endoscopic
submucosal dissection
31
STENT
Esophageal-gastric-colonic stent
40
Diverticula
Endoscopic esophageal diverticula section
19
Dilation
Gastrointestinal dilation
93
Confocal
endomicroscopy
Confocal endomicroscopy
25
AFI
Auto-fluorescence endoscopy
40
Areas of Excellence
This Center stems from the very long experience and sound
critical mass generated at the 1st Surgical Clinic of the University
of Padova (Director: Ermanno Ancona), and acts as the reference
Center of this Clinic for all endoscopic approaches. The major
fields of interest are: Early diagnosis and staging of neoplasms
of the gastrointestinal tract; In vivo histologic diagnosis through
confocal laser endomicroscopy; Early diagnosis of minimal
disease by tissue autofluorescence; Endoscopic and ecoendoscopic
therapy of early and advanced neoplastic lesions of the upper
gastrointestinal tract.
The Unit is involved in several management programs,
including:
coordination of the National Barrett’s esophagus Registry;
coordination of the “Barrett’s Unit”, which collects in Padova
in a multidisciplinary team personnel endowed with different
expertise and specialization; the attractive potential of this Unit
for patients from the rest of Italy is great;
School of Ecoendoscopy on behalf of the Italian Ecoendoscopy
Society (IEC);
second level Masters in Diagnostic and Operative Endoscopy in
Oncology;
School of Esophageal Radiofrequency Ablation on behalf of
International RFA – Academy.
Clinica Chirurgica I Università Policlinico (Padova)
Radioterapia (Padova)
Clinica Chirurgica Pediatrica (Padova)
Banca Biologica, Università di Padova
Gastroepatologia, Ospedale Molinette (Torino)
Istituto Clinico Humanitas (Milano)
Istituto Europeo di Oncologia – IEO (Milano)
CRO (Aviano)
Facoltà di design e arti – IUAV (Venezia)
Division of Gastroenterology and Hepatology, American
University of Beirut, Lebanon
Department of Gastroenterology & Hepatology, Mayo Clinic,
Jacksonville, Florida
Metabolism Institute, Mount Sinai University, New York
Laboratoire IMRCP (Interactions Moléculaires Réactivité
Chimique et Photochimique, CNRS UMR 5623) Toulouse, France
ITAV (Institut des Technologies Avancées pour le Vivant) UMS
CNRS 3039 Université Paul Sabatier and Centre Hospitalier
Universitaire (CHU) of Toulouse, France
Faculty of Chemical and Process Engineering, Warsaw University
of Technology, Poland
79
From confocal endoscopy to targeted endoscopy:
the role of insulin resistance in esophageal carcinogenesis. From
the clinical point of view, Barrett’s patients will be studied for
a series of antropometric (body mass calculation, abdominal
circumference) and serological parameters (serum levels of
glucose, insulin, leptin, adiponectin, IRS-1, IGFBP-3, Homa-IR
index). These insulin resistance indexes will be correlated to the
extent of Barrett’s lesions, the levels of the eventual dysplasia, and
the presence of frank adenocarcinoma.
preclinical and clinical studies in esophageal
cancer
Principal Investigators: Giorgio Battaglia, Stefano Realdon
This study aims at exploiting fluorochrome-labeled
monoclonal antibodies and peptides to be used for the early
diagnosis and eventually therapy of patients undergoing neoplastic
transformation on a Barrett’s esophagus background. The study
entails a pre-clinical approach, where a mouse/rat model of
Barrett’s esophagus, already validated at our Institute, will be
employed to explore the ability of transformed mucosal tissues
to bind fluorescent monoclonal antibodies and peptides. In the
clinical part of the project, these same fluoresceinated reagents
will be administered to patients in a Phase I study, to assess their
ability to detect early displastic/neoplastic lesions, compared to the
results obtained by biopsy and canonical histologic examination.
Restaging of esophageal tumors through
Ecoendoscopy (EUS)
Principal Investigators: Giorgio Battaglia, Paolo Bocus
The survival rate of esophageal cancer patients is strictly
related to the clinico-pathologic staging at presentation. Recently,
a neo-adjuvant chemotherapy has been proposed to reduce tumor
mass, thus allowing more conservative interventions, with the
aim of both preventing early recurrence and consenting a better
quality of life to patients. In this setting, an accurate initial staging
and a careful post-chemotherapy restaging are essential. Best
results are obtained by ultrasound endoscopic ecography, which
is able to provide precise information on the depth of tumor
invasion of the surrounding tissues, on tumor dimensions, and
on the possible lymphnode involvement. Restaging after radiochemotherapy also exploits TC-PET imaging, but reliability of
this approach is uncertain. Aim of this project is to assess EUS
accuracy in restaging of neo-adjuvant-treated esophageal masses,
in comparison to the gold standard provided by macroscopic and
microscopic examination following surgery.
Role of obesity and insulin resistance in the
Barrett’s-Displasia-Adenocarcinoma sequence
Principal Investigators: Giorgio Battaglia, Stefano Realdon
The major risk factors recognized for Barrett’s esophagus and
eventual malignant transformation are gastro-esophageal reflux and
obesity. Even though these factors are at least in part independent, the
possible interconnection of these elements is as yet unexplored. The
mechanisms underlying the favoring effect of obesity on Barrett’s
and adenocarcinoma development could be partly “mechanical”,
but a role of obesity-associated metabolic alterations (such as high
insulin and leptin levels) cannot be ruled out. In the pre-clinical
part of this project we will study the effect of insulin resistance
on the esophageal reflux carcinogenesis induced in rodents.
To this end, we will take advantage of the mouse model of
esophageal reflux set up at our Institute; in fact, following
esophago-jejunal anastomosis, these animals undergo metaplastic
transformation of the esophagus and carcinoma development.
In collaboration with Mount Sinai Hospital, New York, we will
compare the outcome of the anastomosis in a transgenic model of
insulin resistance (MKR+/+ mice), in order to better understand
Radiofrequency treatment of dysplastic Barrett’s
esophagus
Principal Investigators: Giorgio Battaglia, Giorgio Diamantis
Intestinal metaplasia of the esophageal mucosa is the hallmark
of Barrett’s esophagus. The eventual genomic instability leads over
time to dysplasia, possibly followed by the appearance of localized
foci of neoplastic transformation, which progressively evolve from
80
in situ neoplasia to diffuse, invasive adenocarcinoma. Aim of
this study is to verify the feasibility of the eradication of the preneoplastic lesions through radiofrequency in patients with Barrett’s
esophagus and low/high grade dysplasia. The major endpoints of
this project are the evaluation of mucosal epithelium regeneration,
and the evaluation of the recurrence of new dysplastic foci under
the newly generated epithelium. The follow-up of these patients
aims at establishing whether endoscopic surveillance could be
reduced in these patients, thus minimizing both the patient
distress and the eventual costs.
We have recently won two important GRANTS (AIRC
investigation grant and Euronanomed 3th Call) focused on the
study of possible new applications of confocal endoscopy both
in animal models and humans. It is intention of the Unit to
implement an Internet network to foster discussion and sharing of
projects among Clinical Oncology Units within the Veneto area.
In addition, we plan to further expand our educational network
for the diffusion of innovative techniques among colleagues
strongly concerned with endoscopic approaches. As far as research
is concerned, a special accent will be placed on developing all
the possibilities offered by the most recent techniques, such as
confocal endomicroscopy, in the firm convincement that these
approaches will allow great advances in understanding the
molecular mechanisms of esophageal carcinogenesis, in improving
diagnosis, and in offering innovative therapeutic strategies.
81
Anesthesiology
Chief
Muzio Meroni, MD
Born in Induno Olona (Varese) on 22nd May 1951. He graduated in medicine in 1979 and specialized
in Anesthesiology in 1982 at the University of Padua. Head of Intensive Care Unit of the University
Hospital of Padua since 2001 and Head of the Anesthesia Unit of Istituto Oncologico Veneto
since 2011.
In 2005 he obtained the National Certification of Coordinators for Organ donation and
transplantation activity.
He has been a member of the Ethical Committee for clinical practice at the University hospital of
Padua since December 2006. He is a Professor at the post-graduate school of Anesthesia, Nephrology,
Dermatology and Venereology.
Author of more than 20 papers published in International Journals and 27 abstracts presented at
International meetings.
Main Pubblications
Comparison of two methods for cardiac output Saraceni E, Rossi S, Persona P, Dan M, Rizzi S, Br J Anaesth. 2011;106:690-4
measurement in critically ill patients.
Meroni M, Ori C.
Protein C concentrate to restore physiological values Baratto F, Michielan F, Meroni M, Dal Palù A, Intensive Care Med. 2008;34:1707-12
in adult septic patients.
Boscolo A, Ori C.
Use of protein C concentrate in adult patients with Baratto F, Michielan F, Gagliardi G, Di Gregorio G, Minerva Anestesiol. 2004;70:351-6
severe sepsis and septic shock.
Pasqualetto A, Meroni M, Giron GP.
Hepatocyte transplantation as a treatment for Muraca M, Gerunda G, Neri D, Vilei MT, Granato Lancet. 2002;359:317-8
glycogen storage disease type 1a.
A, Feltracco P, Meroni M, Giron G, Burlina AB.
Prognostic systems in intensive care: TRISS, SAPS Barbieri S, Michieletto E, Feltracco P, Meroni M, Minerva Anestesiol. 2001;67:519-38
II, APACHE III.
Salvaterra F, Scalone A, Gasparetto M, Pengo G,
Cacciani N, Lodi G, Giron GP.
82
Muzio Meroni
Sandra Cappellato
Connie Celentano
Angelo Ciccarese
Elisa Granziera
Valentina Manfredi
Donatella Soranzo
Matteo Vescuso
83
Mission
The mission of the Unit of Anesthesiology is to provide the
anesthesiologic help needed in most phases of the diagnostic/
therapeutic/rehabilitative plan of patients with cancer, according
to the international guidelines in this field. This fundamental role
includes, only to make most obvious examples, deep sedation for
major invasive diagnostic techniques (such as endoscopy), full
anesthesia in surgical interventions, acute post-surgical pain relief.
Appropriateness, efficiency, steady attention to the patient anxiety
and needs, and friendly approach to the patients and colleagues are
the key words that inspire the work of this dedicated personnel.
Clinical Activity
The clinical work burden of the Unit is very high, since
the physicians must guarantee a non-interrupted, continuous
availability for all the invasive procedure performed at the Institute.
The paucity of the personnel in front of the commitments required
to the Unit clearly impacts on the possibility of combining clinical
activity with research; nevertheless, all the anesthesiologists
are also engaged in research collaborations with the colleagues
(mostly surgeons and radiotherapists, but also psycho-oncologists)
to contribute to generating new models of intervention in both
technical approaches and patient-physician interrelations.
The major commitments of the Unit include:
Anesthesiologic assistance to the Units of Surgical Oncology,
Breast Surgery, Melanoma and Sarcoma Surgery, Diagnostic
and Operative Endoscopy, Radiotherapy, Nuclear Medicine;
Anesthesiologic assistance to all the IOV Units which require
anesthesiologic help for the management of acute and/or
chronic pain, or for emergency interventions in very critical
patients;
Intravascular device implant for chronic chemotherapies.
The volume of activity is depicted in the accompanying Tables.
Anesthesia for surgical interventions
“Busonera” Theatres
“Giustinianeo” Theatres
2010
1.1 – 31.12
Deep Sedation for Digestive
Endoscopy
431
918
286
1993
717
2011
1.1 – 30.4
Operative
317
114
EUS
438
179
343
132
1098
425
Diagnostic
Deep Sedation for Radiotherapy
2010
1.1 – 31.12
2011
1.1 – 30.4
Pediatric Patients
Radiotherapy
Nuclear Medicine
Ce.Mu.RNI
Central Vascular Access Positioning
Port-a-Cath
2011
1.1 – 30.4
1075
2010
1.1 – 31.12
353
233
24
16
395
110
2010
1.1 – 31.12
301
124
PiCC
86
36
CVC
22
14
409
174
Anesthesiologic Consults
2010
1.1 – 31.12
3537
85
2011
1.1 – 30.4
2011
1.1 – 30.4
1281
Major Ongoing Research Project
A randomised study on the practice of
informed consent to anesthesia: could a skilled
communication be the key? Comparison between
patient relationship. A structured pre-operative anesthesiology
interview based on an effective communication and on a
specific training to deal with the psychologic aspects of illness
may contribute to improve comprehension of the information
provided to breast cancer surgical patients. A psycho-oncologic
approach seems to be useful if high-level anxiety is detected.
Future perspective. Pre-operative administration of STAI
questionnaire can be routinely used to identify high-level anxiety
patients who could benefit from a psycho-oncologic approach
before surgery.
a structured anesthesiologic interview and an
integrated psycho-oncology approach
Principal Investigators: Barbara Donà, Eleonora Capovilla
Background. It has been suggested that emotional factors may
contribute to alter the acquisition of information. The aim of this
randomized study was to verify the hypothesis that an integrated
psycho-oncology approach would reduce anxiety before the
anesthesiologist visit and improve the comprehension of the
information received.
Methods. The study was designed as a single-center,
randomized, controlled, open-label trial. Patients undergoing
surgery for primary breast cancer were randomly assigned
to the structured anesthesiologic interview group (SAI)
or to the integrated psycho-oncological approach (IPA).
In the IPA arm, before the pre-operative anesthesia evaluation,
patients received the integrated psycho-oncology approach, that
is patients underwent an interview with the psycho-oncologist
and afterwards the anesthesiologist was instructed briefly on
how to best communicate with the patient. To evaluate the
efficacy of integrated psycho-oncology approach to reduce the
anxiety of patients, the State-Trait Anxiety Inventory (STAI)
questionnaire was used. In the SAI arm, patients received the
anesthesiology interview only.
Results. 251 patients were randomized: 130 in the IPA
arm and 121 in the SAI arm. For both groups, mean anxiety
scores were statistically lower after the anesthesiology visit
than at baseline, with a reduction of 6.2 points for the IPA
arm and of 4.5 points for the SAI arm [p<0.0001]. For the
high-anxiety patients, the state anxiety score was significantly
lower in the IPA group (10.2 points) than in the SAI group
(6.8 points) [p<0.0001]. The information provided during the
anesthesiology visit was correctly understood by more than 80%
of patients and was similar in both groups.
Conclusions. Our results shows the importance of doctor-
Totally implantable venous access ports: analysis
of different placement techniques and predictors
of complications based on a prospectively
collected database
Principal Investigator: Elisa Granziera
Background. This study involves a retrospective review of
a prospective database including a consecutive series of Totally
Implantable Venous Access Port (TIVAP) implantations performed
from November 2006 in the Department of Oncological Surgery
of the IOV-IRCCS. Three different techniques for implantation
have been used. From November 2006 until January 2008 devices
were placed using either a cephalic vein cutdown or a blind
percutaneous approach based on anatomic landmarks. The choice
of the insertion technique was at the discretion of the surgeon.
Since January 2008 the percutaneous approach was improved
using ultrasound guidance.
Methods. Patient characteristics, which included diagnosis,
indication for catheter placement, age, height, weight, results
of laboratory test parameters and current medications were
recorded. Device type, site of venous access, surgeon and
anesthesiologist performing the procedures, and placement
complications were documented. Data from hospital and
telephone follow-up were recorded at regular intervals and
collected prospectively in a database. All device-associated
complications were recorded in the database during follow-up.
Complications were classified into two main categories: 1) early
(intra-operative and post-implantation period to first use) and 2)
86
Anesthesiological management for
late (occurring after the first chemotherapy course administered
through the device). Patients satisfaction or complaint about the
device were also recorded.
Results. 796 TIVAP implanted over a 4-year period were
followed prospectively for overall complications. In 102 patients
placement of TIVAP via the cephalic vein cutdown approach was
initially attempted, 87 patients underwent successful insertion
while 15 required conversion to a percutaneous approach, 11 using
the blind technique, 3 using the ultrasound guided technique.
In 1 patient it was impossible to access any central vessel for
anatomical pitfalls and a peripheral inserted central venous access
(PICC) was inserted under ultrasound guidance. Success rate was
85.3%. The percutaneous blind technique was used initially in 48
patients, and was successful in its first choice vessel in 45 patients.
Three patients required conversion to a surgical approach.
Success rate was 93.7%. The ultrasound guided approach was
used as a primary technique in 646 patients and was successful
in its first choice vessel in 644 patients. In 13 patients a second
attempt changing vessel was necessary, while 2 patients required
conversion to a surgical approach because of fibrotic or collapsed
vein. Success rate was 99.7%. Mean operating time was 51
minutes for cephalic vein cutdown approach, 49 minutes for blind
percutaneous technique and 33 minutes for ultrasound guided
technique. The only severe intraoperative complications requiring
immediate treatment were three of the four pneumothoraces and
one of the two arrythmias. All the other complications did not
require any treatment except a longer monitoring before discharge.
Late complications occurred in 49 of 796 pts (6.1%), requiring
removal 42 (5.2%).
Conclusions. The ultrasound guided technique using the low
lateral approach with cannulation of the brachiocephalic vein has
a lower rate of early and late complications and a higher success
rate compared with the other implantation techniques.
Future perspective. Statistical analysis to identify
predictors of early and late complications is still ongoing. The
identification of these factors may influence patient selection or
timing of implantation, or suggest further clinical strategies of
management.
electrochemotherapy treatments delivered
outside operating room: a proposal for
implementation of
Standard Operanting
Procedures
Principal Investigator: Elisa Granziera
Background. Electrochemotherapy (ECT) is a recent
approach for treatment of superficial metastases, based on the
synergistic association of locally applied brief electrical currents
(reversible electroporation) and anticancer agents like bleomycin
and cisplatin. The European Standard Operating Procedures of
Electrochemotherapy (ESOPE) project has allowed to standardize
treatments by developing guidelines to select properly drugs,
delivery routes, type of electrodes and type of anesthesia.
According to the Standard Operating Procedures (SOP)
electrochemotherapy may be delivered under local anesthesia
or analgosedation using reversible agents like propofol and
remifentanil. Patients who complete treatment in our department
have an advanced stage of disease, involving large anatomical
regions. ECT is performed in a radiotherapy department requiring
a non operating room anesthesia. Adequate strategies are required
in order to avoid complications and improve the quality of life
as far as possible. Pursuing a cost saving policy, early discharge
is planned. Outpatients undergoing day-care procedures require
a perioperative analgesic technique that is effective, has minimal
side effects, is intrinsically safe, and can be easily managed away
from the hospital or surgery center. Use of Monitored Anesthesia
Care (MAC) techniques involving the use of local anesthesia
via infiltration and sedative-analgesic drugs can facilitate a
fast-track recovery after surgery and can be discharged home
earlier due to the low incidence of post-operative side effects.
However, careful intra-operative vigilance to avoid respiratory
complications is mandatory to ensure patient safety. The
combination of propofol and ketamine has the potential to provide
better sedation with less toxicity than either drug alone or the
propofol-opioid association. We therefore tested the hypothesis
that the combination of local anesthesia, propofol and low-dose
ketamine produces superior analgesia than propofol and opioids,
minimizing the need for supplemental opioids, and that the
combination is associated with improved spontaneous ventilation
and faster recovery.
87
Methods. The main aim of this retrospective study was to
evaluate the safety and efficacy of low doses of ketamine-based
monitored anesthesia care to perform ECT procedures in an
outpatient setting. The safety outcomes were the incidence
of complications in terms of frequency and severity of
cardiorespiratory events and adverse effects.
Efficacy measures included procedural success (providing
optimal surgical conditions in order to complete the
planned procedure) as well as recovery and discharge times.
Secondary aims of the study were the evaluations of patient’s
satisfaction with the intraoperative and postoperative pain
management.
Results and conclusions. The study is still ongoing and the
data underwent preliminary statistical analysis.
88
Department of Imaging,
Radiology & Pathology
The Departments - Department of Imaging, Radiology and Pathology
89
Radiology
Chief
Fabio Pomerri, MD
Born on 22nd September 1950. Degree in Medicine, University of Padua (1975). Post-Graduate
specializations in: Radiology (1979), Gastroenterology (1983), and Nuclear Medicine (1990), University
of Padua. Fellowship: Institute of Radiology, University of Padua (1975-1986). Assistant Professor of
Radiology at the Department of Medical and Diagnostic Sciences and Special Therapies (Radiology
Section), University of Padua (1987-2005). Associate Professor of Radiology at the Department of
Medical and Diagnostic Sciences and Special Therapies (Radiology Section), University of Padua (since
2005). Head of the IOV Oncological Radiology Unit (since 2010). Member of the Italian Society of
Medical Radiology (SIRM). Member of the European Society of Radiology (ESR). Member of the
Gastrointestinal Radiology Advisory Board of SIRM (1986-1991). Member elected of the Abdominal
and Gastrointestinal Radiology Advisory Board of the SIRM (since 2009). Member of the Editorial
Board of “Pelviperineology” (since 1991). Publications: 230 papers, 56 of them in indexed journals,
and three books. Main fields of radiologic experience and research: abdominal diseases, esophageal,
colonic, rectal and thyroid cancer, pelvic floor diseases, obesity.
Main Pubblications
Prospective assessment of imaging after preoperative Pomerri F, Pucciarelli S, Maretto I, Zandonà M, Del Surgery. 2011; 149:56-64
chemoradiotherapy for rectal cancer.
Bianco P, Amadio L, Rugge M, Nitti D, Muzzio PC.
Synovial sarcoma: CT imaging of a rare primary Polverosi R, Muzzio PC, Panunzio A, Pasquotti G, Radiol Med. 2011; 116:868-75
malignant tumor of the thorax.
Schiavon M, Rea F.
Digital breast tomosynthesis versus digital Gennaro G, Toledano A, Di Maggio C, Baldan E, Bezzon Eur Radiol. 2010;20:1545-53
mammography: a clinical performance study.
E, La Grassa M, Pescarini L, Polico I, Proietti A, Toffoli
A, Muzzio PC.
Positive experience of intraperitoneal chemotherapy
followed by intravenous chemotherapy in heavily
pretreated patients with suboptimal residual
ovarian cancer and primary peritoneal cancer.
Nicoletto MO, Dalla Palma M, Donach ME, Gusella M, Tumori. 2010; 96:918-25
Cappetta A, Shams M, Marchet A, Nardin M, Pintacuda
G, Di Maggio A, Marchesi M, Carli P, Fiduccia P, Artioli
G, Nitti D.
Are Hodgkin and non-Hodgkin patients at a Bilora F, Pietrogrande F, Campagnolo E, Rossato A, Eur J Cancer Care. 2010; 19:417-9
greater risk of atherosclerosis?
Polato G, Pomerri F, Muzzio PC.
90
Technicians
Nursing Staff
Fabio Pomerri
Elisabetta Bezzon
Chiara Dal Bosco
Davide Fiore
Antonio Di Maggio
Gisella Gennaro (Medical Physicist)
Margherita Nardin
Giovanna Pintacuda
Roberta Polverosi
Simone Corradin
Manola Garato
Elisa Baraldo
Massimo Bedei
Simonetta Cavinato
Davide Discardi
Federico Maggetto
Roberta Sorgato
Carla Versini (coordinator)
Enrico Zennaro
Anna Bozzato
Giorgia Ceccato
Manuela Frasson
Mauro Menon
Linda Prunotto
Patrizia Rossetti
Marina Bettin
Antonella Ferrigno
Maurizio Peci
Maria Carmela Zorzato
91
Mission
The mission of the Oncological Radiology Unit is to improve
the length and quality of life of cancer patients through the
conduct of clinical trials of diagnostic imaging and image-guided
therapeutic technologies. The Oncological Radiology Unit intends
to accomplish its mission by addressing a number of objectives, of
which the following are among the most important:
to evaluate innovative methods of diagnostic imaging and imageguided treatment that have the potential to improve survival and
quality of life of cancer patients;
to compare established patterns of imaging diagnosis, staging,
and palliative or curative image-guided treatment to alternative
approaches, in order to improve the effectiveness of care for
patients with cancer and reduce the costs of this care;
to examine diagnostic and therapeutic strategies that combine
different imaging procedures with non-imaging technologies,
in order to improve the efficiency of cancer detection and
treatment;
to assess the value of the use of imaging for detection of cancer in
high-risk patient populations (ie, screening);
to determine the value of imaging in reducing the anxiety of
individuals who have symptoms suggestive of cancer but who are
found to be free of malignancy.
Clinical Activity
Clinical Activity 2010
No.
Diagnostic examinations performed:
24.858
CT
9.366
X-rays
8.273
US
5.707
MRI 1.512
Inside the IOV
All IOV Units
University of Padua
Azienda Ospedaliera di Padova
ULSS 16 di Padova
92
Differentiated thyroid carcinoma (DTC) has a
good prognosis with a 10-year survival rate higher
than 90%, but 5-24% of patients experience
was evaluated using the T parameter of the TNM staging system.
Several pharmacokinetic parameters were also evaluated. Based on
T status, patients were classified as either T0 or T1–4. Sensitivity,
specificity, positive predictive value, negative predictive value, and
accuracy were calculated for each staging modality used. Findings
were compared with the pathological tumor stage.
Preliminary results. On histopathological analysis, 9 patients
had pT0 and 40 had pT1–4 lesions. The statistically significant
parameter was the partition constant (the mean in the T0 group
was 0.3 and in the T1-4 group 0.4) and the area below the curve
up to 30 seconds (T0: 3.2; T1-4: 3.4). The sensitivity, specificity,
positive predictive value, negative predictive value, and accuracy
in predicting T status (T0 vs. T≥1) were 90%, 55.6%, 90%,
55.6%, and 83.7%, respectively, for the partition constant and
82.5%, 88.9%, 97.1%, 53.3%, and 83.7% for the area below the
curve up to 30 seconds, with a cut-off of 2.65.
Conclusions. The area below the curve up to 30 seconds
and the partition constant showed a good accuracy, sensitivity
and positive predictive value; these parameters can be applied in
clinical practice to morphological MRI findings.
persistent or recurrent disease
Principal Investigator: Fabio Pomerri
DTC management guidelines recommend PET for imaging
patients with 131I-negative whole body scans and increasing serum
thyroglobulin levels. The aim of this study is to assess the impact
of PET/CT on the therapeutic management of patients with
recurrent DTC.
Materials and methods. DTC patients who have undergone
surgery and post-operative thyroid remnant ablation with 131I, and
who develop rising basal or recombinant TSH-stimulated serum
thyroglobulin levels will be studied using PET/CT.
Preliminary results. Three clinical issues were identified:
diagnostic indications for 131I-negative scanning and increasing
thyroglobulin levels; the planning of surgery for recurrent disease;
and the effectiveness of systemic therapy.
Conclusion. The emphasis will be placed on how imaging
is changing from a purely diagnostic role in locating disease to
supporting the design of appropriate therapeutic strategies.
To assess the post-chemoradiotherapy performance
of dynamic contrast-enhanced magnetic resonance
imaging in distinguishing residual cancer from
postirradiation peritumoral vasculopathy and
desmoplastic reactions
Principal Investigator: Fabio Pomerri
Materials and methods. Since 2009, 60 patients have been
recruited. The patients considered to date had mid-low rectal
tumors potentially amenable to neoadjuvant therapy. The sample
mean age was 59.3 years (range, 21-78 years). Eleven patients did
not meet the inclusion criteria. The outcome of dynamic magnetic
resonance after radiochemotherapy has been evaluated for 49
patients. The instrumental investigations were performed using
a MRI equipment with a 1.5 T magnet, and local tumor stage
93
Future prospects are mainly based on Interventional oncology.
Areas of application are: intravascular and extravascular.
Extravascular
1)Percutaneous ablation of the lesions using radiofrequency,
laser, cryoablation, or microwave to induce tissue necrosis. The
procedure can be performed under ultrasound guidance (liver,
thyroid and soft tissues in general) or CT guidance (lung, kidney
and bone). The goals can be healing as in the case of primary
and secondary liver lesions, lung, kidney and thyroid cancers.
The thyroid lesions represent an area of clinical research. The
treatment of liver lesions by combining radiofrequency and
chemoembolization with drug eluting beads represents another
area of clinical research. The percutaneous ablation using MRguided HIFU (High Intensity Focused Ultrasound) may be
the main area of clinical research in oncology.
2)Percutaneous biliary drainage. The procedure is performed
under fluoroscopic guidance with the aim to treat obstructive
jaundice before curative or palliative surgery. Pancreatic and
biliary tract cancers, and in rare cases extrinsic compression
of the biliary tract are possible clinical applications of this
technique.
3)Vertebroplasty is a palliative treatment to relieve pain in cases
of spinal metastases and can be done by direct injection of
cement into the spine or vertebral body following percutaneous
ablation.
4)Nephrostomy drainage may be performed under ultrasound
guidance for puncturing the urinary tract or under fluoroscopy
for placement of nephrostomy drainage.
Intravascular
1)Chemoembolization of primary and secondary liver cancers
with drug eluting beads. Areas of clinical research are the
treatment of hepatocellular carcinoma and liver metastases.
The treatment may be employed in hepatocellular carcinoma
patients out liver transplantation in order to re-include them in
the MC (Milan Criteria) for liver transplantation. In the matter
of metastases, the actual clinical utility of randomized studies
using associated chemoembolization and systemic therapy
(chemotherapy or biologic agents) is under investigation.
2)Percutaneous isolated limb perfusion in the case of melanoma
or sarcoma or percutaneous isolated liver perfusion.
3)Embolization of hypervascular bone metastases.
94
Breast Imaging
Chief
Luigi Pescarini, MD
Born in Thiene (VI), on August 11, 1947, he earned his degree in Medicine at the University of
Padova in 1972, subsequently specializing in Diagnostic Radiology (1975) and in Radiology (1977).
Since 1973, his work has focused on breast imaging and is now acting as chief of the Breast Imaging
Unit at the IOV. He is Associate Professor of Radiology at the Department of Oncology and Surgical
Sciences of the University of Padova. His teaching activity includes the undergraduate schools of
Medicine and Surgery, Dentistry and Dental Prosthetics, Radiology for technicians, and 5 postgraduate medical schools. As a member of the Italian Society for Medical Radiology (SIRM), he cofounded the Breast Imaging section of SIRM and has held positions in the directive council for the
sections of Breast Imaging and Radiation Protection studies; he was president of the SIRM Regional
Group for the Veneto Region (2001-2005) and President of the section of Ethics studies and forensic
radiology (2006-2008). His scientific activity includes participation in numerous national and
international congresses and publications predominant in breast imaging. He is part of the Editorial
Board for the Ethics section of the journal “La Radiologia Medica”.
Main Pubblications
Correlation between magnetic resonance
imaging and histopathological tumor response
after neoadjuvant chemotherapy in breast
cancer.
Nicoletto MA, Nitti D, Pescarini L, Corbetti F, Mencarelli Tumori. 2008; 94: 481-488
R, Cappetta A, Galligioni A, Pogliani C, Marchet A, Bozza
F, Ghiotto C, Griggio L, Zavagno G, Donach M. E, Di
Maggio C.
Automated analysis of phantom images for the Gennaro G, Ferro F, Contento G, Fornasin F, Di Maggio C. Phys Med Biol. 2007; 52:1387-1407
evaluation of long-term reproducibility in digital
mammography.
Systematic approach to human error in Pescarini L., Inches I.
radiology.
Radiol Med. 2006; 111:252-267
Digital breast tomosynthesis versus digital Gennaro G, Toledano A, Di Maggio C, Baldan E, Bezzon Eur Radiol. 2010; 20:1545-53
mammography: a clinical performance study.
E, La Grassa M, Pescarini L, Polico I, Proietti A, Toffoli A,
Muzzio PC.
Analysis of malpractice claims in mammography:a Fileni A, Magnavita N, Pescarini L.
complex issue.
Radiol Med. 2009; 114:636-644
96
Technicians
Nursing Staff
Luigi Pescarini
Enrica Baldan
Elisabetta Bezzon
Chiara Dal Bosco
Gisella Gennaro (Medical Physicist
affiliated to the Radiology Unit)
Ilaria Polico
Alessandro Proietti
Lorenzo Roverato (Head and Coordinator)
Lina Ciampani
Tiziana Masiero
Maria Petrioli
Tiziana Pisapia
Micaela Ceretta
Eva Granziero
Eliana Salviato
Antonella Scelta
Stefania Zaramella
97
Mission
The Breast Imaging Unit mission is manifested in the Diagnostic
service for breast disease for the population of Padova, the Veneto
Region and Italy, and in the specialist support given to the medical
and surgical units of the IOV. The Breast Imaging Unit has been
organized to provide tailored diagnostic paths, on the basis of
individual patient needs, using multiple imaging techniques,
and ensuring the integration of all diagnostic information, as well
as humanization of doctor-patient relationship in all phases of
workup, from communication of diagnosis to follow-up planning.
Examinations are carried out under the direction of each radiologist
who always works in team with a breast radiographer. The Breast
Imaging Unit is ISO-certified since 2004 and its quality manual is
continuously updated.
Clinical Activity
The Breast Imaging Unit is equipped with all standard
modalities used in breast imaging:
Three direct digital mammography units, including review
workstations;
Four ultrasound scanners with suitable soft tissue probes;
One dedicated prone table for vacuum-assisted breast biopsy,
X-ray guided;
One optical microscope for analysis of fine needle aspiration
cytology specimens;
One 1.5 magnetic resonance imaging (MRI) scanner, shared
with the Radiology Unit, where the equipment is installed.
for intervention planning of subclinical lesions which require
ultrasound-or x-ray-guided localizations, as well as patient followup after treatment. Patient follow-up scheduled as planned by the
medical oncology units. The “complex cases” are reviewed and
discussed in consensus multidisciplinary meetings, involving
radiologists, surgeons, oncologists, and any other specialist who
is part of the Breast Unit. The Breast Imaging Unit represents
an area of excellence for diagnosis of subclinical lesions, in both
diagnostic and preoperative phases. The Breast Imaging Unit also
represents a possible diagnostic reference during patient follow-up
in detection of recurrences or in evaluation of breast reconstruction
with implants and/or biological tissues.
This permits both diagnostic and interventional actions,
according to clinical needs.
Types and amounts of examinations performed in 2010
Outpatient services
The Breast Imaging Unit mission is diagnosis of breast diseases,
in particular early cancer detection, using imaging techniques
evidence-based. Each breast radiologist, after initial clinical
assessment, is responsible, for the full patient management and
workup, including integration of multiple imaging techniques
and/or interventional procedures image-guided in sub-clinical
lesions. Diagnostic actions include pretreatment cancer staging
by MRI with contrast media.
Clinical and instrumental breast examinations (breast
examination, ultrasounds, and mammography)
MRI of the breast with and without contrast media
Fine needle aspiration cytology
Inpatient services
Priority is given to the needs of the Medical Oncology Units,
with special care to consultations for surgical and/or pharmacological
strategies. The Breast Imaging Unit works in close collaboration
with all the other Units involved in breast cancer care, especially
550
1.165
Tru-cut needle aspiration biopsy (microbiopsy)
297
External Consultation
474
Preoperative localization ultrasound-guided
235
Preoperative localization x-ray-guided
120
Intraoperative mammographic evaluation
98
9.975
77
Research activities are related to the Breast Imaging Unit field
of interest and its mission. Therefore, the Unit is collaborating
within the multidisciplinary Team of the Breast Unit with most
IOV Units, and in particular with Breast Surgery, Medical
Oncology, Molecular Oncology, Radiology.
Research subjects include digital breast tomosynthesis, dose
reduction in mammography, effects of neoadjuvant chemotherapy
on circulating tumor cells in early stage breast cancer, surveillance
of high risk women for familial-hereditary tumors, characterization
of in situ tumors and so-called “border line” lesions.
Moreover, clinical aspects related to breast imaging unit
organization are specific interest of this Unit, within the frame
of the workgroup “Breast Imaging” and “Ethics and Forensis
Radiology” of the Italian Society of Medical Radiology.
Surveillance
of women at high genetic-familial
suitable techniques for detecting lesions starting at 25 years of age
and, possibly, to demonstrate long-term reduction in mortality
through screening strategies.
Materials, methods and results. In 18 Italian centers
participating in HIBCR-1, showed the superior sensitivity of
magnetic resonance imaging (MRI) in detecting malignant
lesions compared to other imaging techniques, as published by
the National Institute of Health (ISS) (research leaders Podo F.
and Sardanelli F).
risk of breast cancer: Italian
National Institute of
Health Network “ISSIN HIBCR-1 - HIBRC2”
Principal Investigator: Luigi Pescarini
Background. Epidemiological knowledge on the incidence
and onset of breast cancer at a young age in families leads to the
control of high-risk groups of women, in order to assess the most
99
This picture pushed us to propose a project addressed to digital
screening only, on the basis of two simple considerations: (1) it is
easy to guess that in a few years the last screen-film systems will be
replaced by digital ones; (2) use of digital images support quality
control automation and data sharing, simplifying the project
management. Such Project, described in the following sections,
was approved by the Veneto Region at the end of 2010, and is
now going to start.
Methods. The Project proposes a unique Quality Assurance
Program for all digital mammography systems involved in
mammography screening of the Veneto Region. The Project is
structured in two phases.
Phase 1: regards Acceptance/Commissioning and Status tests,
normally performed by a physicist (Medical Physics Expert,
MPE) when the equipment is installed and subsequently with
annual or semi-annual frequency. Goal of Phase 1 is to centralize
collection of QC data resulting from physicists’ measurements,
using a common protocol. This protocol, partially extracted from
the “European Guidelines for Quality Assurance in Breast Cancer
Screening and Diagnosis 4th edition”, includes the following
tests:
1. Dosimetry (both measurements include the compression
paddle in the beam):
1.1 Tube output (all anode/filter combinations and
kVp values used in the clinical practice)
1.2 Half Value Layer, HVL (all anode/filter combinations
and kVp values used in the clinical practice);
2. Automatic Exposure Control (AEC):
2.1. Contrast-to-Noise Ratio (CNR) versus object thickness;
2.2. Average Glandular Dose (AGD) versus object
thickness;
2.3. Figure of merit (FOM):
;
3. Detector:
3.1. Response function;
3.2. Noise evaluation;
3.3. “Homogeneity”;
3.4. Imaging plate variability (only for CR systems);
4. Monitor:
4.1. DICOM Grayscale Standard Display Function;
4.2. Uniformity.
Physicists of screening sites should perform tests according
to procedures provided by the project manager, using their own
calibrated instruments. Test results will be gathered from the
Regarding the new HIBRC2 study, the Veneto Institute of
Oncology focused its attention, unlike what was done in the
previous study, to women “supposed to be healthy”, belonging
to risk groups as identified by the national program. Main data
from the Breast Imaging Unit collected during years 2009-2010
are reported: 79 healthy women with an alleged hereditary risk
for breast cancer undergoing annual surveillance with integrated
breast mammography and MRI, with and without contrast were
enrolled in the study. Two breast cancers were identified, both
with histologic findings of DCIS, one visible by mammography
and MRI, the other by MRI only.
Quality Controls in Digital Breast Screening
Principal Investigator: Gisella Gennaro
Background. High image quality is one of basic requirements
within a breast screening program to ensure successful results.
Some screening descriptors as Recall Rate (percentage of women
recalled for further workup, caused by suspicious mammography
images) and Detection Rate (cancers found in the screened
population) are calculated assuming that mammography images
evaluated by radiologist have high image quality. For this reason,
in mammography, and even more in a screening program, quality
controls (QC) of mammography equipment are considered
important, and the definition of the QC protocol is one of the
constraints in any accreditation process. Since 1st Jan, 1996,
quality controls are mandatory by law in Italy (DLg 195/230)
for any radiology equipment; this duty was confirmed by the
Decreto Legislativo n. 187 (May 26, 2000) “Attuazione della
direttiva 97/43/EURATOM in materia di protezione sanitaria
delle persone contro i pericoli delle radiazioni ionizzanti connessi
ad esposizioni mediche”, better identifying responsibilities and
roles of involved professions. In the last decade, transition from
screen-film to digital mammography has required a review (still
ongoing) of old QC protocols, to adapt them to needs of new and
more complex technologies.
In 2010, the Veneto Region asked the Veneto Institute of
Oncology to propose a Project to face the issue of quality controls
for equipment used in mammography screening. After a quick
preliminary survey, it was noticed that 80% of mammography
systems used in screening were already digital (both direct digital,
DR, and computed radiography, CR), while only 20% of systems
still used films, and some of them were going to be replaced.
100
Veneto Institute of Oncology which will summarize them in a
report and send to the Veneto Region.
A web site will be developed to include all information related
to the Project, the protocol, and possible analysis tools, which
could simplify work of all people involved.
Phase 2: it regards reproducibility tests, which should be
performed by radiographers with weekly frequency. Purpose
of Phase 2 is the application of an automatic procedure for
reproducibility tests, using a software package for automatic
analysis of images obtained by exposing an appropriate test-object
(named “phantom” in the following) and an Expert System for
diagnosis of malfunctions derived from the analysis of variations
of image quality parameters compared to a baseline previously
defined. Mammographic phantom used should have absorption
characteristics equivalent to a “mean breast”, and include a proper
number of “details” such as image analysis will allow to measure:
Spatial resolution
Contrast resolution
Contrast
Contrast-to-Noise Ratio (CNR)
Structured noise.
The Expert System should analyze variations of parameters
listed above versus the baseline values and provide to the user realtime information regarding right operating of the system, or the
existence of fluctuations which could be caused by a malfunction,
suggesting possible causes and potential corrective actions.
Results. At present, the project on quality controls has been
presented to both reference radiologists for screening sites, and
to physicists involved in Phase 1. In particular, the QC protocol
has been shared with physicists, finding their agreement, and test
procedures will be available by the end of 2011. Phase 1 start and
the first round of measurement collection should be closed within
June 2012. The update of equipment used in mammography
screening has shown that the number of digital systems is increased
compared to the last year, up to 94% (figure 1).
Conclusions. Application of the project described above
will be an important step for harmonization of quality controls
in digital mammography; this could have a significant impact in
optimization of mammography screening program. Monitoring
of image quality reproducibility using automatic procedures
increases test efficacy and reliability, removing variability which
would be unavoidable if image quality stability would be evaluated
by human observers.
Digital
5
Analog
4
3
2
1
0
digital
analog
Figure 1. Analog and digital equipment in mammography screening of the
Veneto Region.
Future perspectives. Automation of quality controls planned by
the project will allow monitoring of an increasing number of systems.
Proposed method could be extended to other imaging modalities.
Comparison
of
Digital Breast Tomosynthesis
and
standard mammography in symptomatic women
Principal Investigator: Gisella Gennaro
Background. Mammography is an effective modality
for the detection of early stage breast cancer. However it
has significant limitations, due to masking of suspicious
lesions by fibroglandular densities, reducing its diagnostic
performance, particularly in denser breasts. Another limitation
of mammography is that some features interpreted as lesions
are merely summation densities. Digital breast tomosynthesis
(DBT) is expected to overcome those inherent limitations of
mammography by segmenting images of the breast into a number
of planar images that can be individually reviewed by radiologists
without the interference of superimposed fibroglandular tissues.
A clinical study at the Veneto Institute of Oncology was designed
in collaboration with GE Healthcare, aiming to compare clinical
performance of DBT over full-field digital mammography (MX)
in a diagnostic population, and is still ongoing. In the following,
main summary results of Phase 2 are illustrated (Phase 1 study
results already reported in the previous Annual Report).
101
Methods. Patient accrual, following approval by competent
authorities (Ethics Committee and Ministry of Health), started in
April 2007 and finished in July 2008. Study population included
250 women with a breast lesion found by mammography
(two views: cranio-caudal, CC, and medio-lateral-oblique,
MLO) or/and ultrasound, who consented undergoing also
bilateral tomosynthesis (one view: MLO). The study (image
interpretation) was conducted retrospectively in two phases,
involving 6 readers per each: Phase 1, performed during patient
accrual, aiming to compare clinical performance of tomosynthesis
in one-view versus standard mammography in two-views; Phase
2, performed after patient accrual, aiming to verify if the adjunct
of the CC mammographic view could increase DBT performance
compared to the reference standard (MX in two-views). Receiver
Operating Characteristics (ROC) analysis of dataset from Phase
1 demonstrated non-inferiority by 5% of DBT in one-view
versus MX in two-views, at comparable dose level, while perlesion analysis of the same dataset showed that DBT significantly
increased lesion detection compared to MX, especially for benign
lesions. Figure 1 depicts the timeline of the DBT research at the
Veneto Institute of Oncology. Results reported in the following
section, regarding Phase 2, are still unpublished.
Results. Phase 2 dataset included image readings of
469 breasts from 6 independent readers. The overall clinical
performance analysis (ROC analysis) confirmed non-inferiority
of DBT(MLO) versus MX(CC+MLO) already found in Phase 1,
but showed a trend to superiority of DBT it was combined with
the mammographic CC-view (DBT+MXCC), as depicted in Figure
2. The plot represents the space of difference between the mean
areas under the ROC curves of DBT vs. MX and of (DBT+MXCC)
vs. MX, respectively. Zero line represents the “equality” condition,
and -0.05 line the “tolerance” accepted as possible difference
between areas, set at 5%. The “tolerance” is named “noninferiority margin”. Confidence intervals (95%) together with
the absolute differences between areas are represented, such as
variability due to variance across multiple cases and readers is
taken into account. If the difference and the related confidence
interval are above the non-inferiority margin, non-inferiority of
the investigational technique versus the reference standard can be
concluded, otherwise, if the difference and the confidence interval
are both above zero, superiority can be concluded.
Thereby, adjunct of MXCC to tomosynthesis moved
tomosynthesis alone towards superiority compared to
mammography, even if it is not achieved. Moreover, in terms of
Regulatory Approvals
Objective: compare clinical performance
Phase 1: DBT(MLO) vs. MX(CC+MLO)
Phase 2: DBT(MLO) + MXCC vs. MX (CC+MLO)
Patient Accrual
START
END
2006
2007
2008
2009
2011
Readings: Phase 2
Readings: Phase 1
Per-breast analysis
(ROC)
2010
Per-lesion analysis
(JAFROC)
Per-breast analysis
(ROC)
Per-breats analysis
publication
Figure 1. Timeline of the DBT research at the Veneto Institute of Oncology.
102
0.10
0.08
mean AUC difference
0.06
0.04
SUPERIORITY
0.02
0.00
-0.02
NON-INFERIORITY
-0.04
-0.06
-0.08
5% NI-margin
INFERIORITY
-0.10
DBT - MX
(DBT + MXCC ) - MX
Figure 2. ROC results from Phase 2: clinical performance of DBT(MLO) was confirmed to be non-inferior to MX(CC+MLO), while the combination of DBT(MLO)
with one mammographic view (CC) showed an increase in clinical performance.
sensitivity, it was found that DBT and MX detected comparable
number of cancers, while the new protocol DBT+MXCC led to
increase cancer detection: on average, DBT+MXCC detected
2.3 extra-cancers compared to the reference standard. Finally,
specificity was higher than MX with both DBT alone (significantly)
and DBT+MXCC (not significantly).
Conclusions. Results from Phase 2 showed the potential
benefit of the new reading protocol, DBT+MXCC, combining
tomosynthesis with one mammographic view. Furthermore,
comparison of results obtained in the two phases of the clinical
study suggested that further improvement in clinical performance
of DBT alone could be expected, while the effect of radiologists’
learning curve will get more evident.
Future perspectives. Some manufacturers have already
launched and others are going to launch tomosynthesis products
onto the market. However, the clinical use of this new technology
is still debated and it is easy to imagine it will be the subject of
several papers in the next years.
103
Pathology
Mission and Clinical Activity
The mission of the Patholgy Unit is the diagnosis of tumors.
To this end, the Unit exploits histologic, histochemical, and
immuno-histochemical techniques, as well as molecular biology
approaches. In most instances, this activity is performed within
the frame of a strict collaboration with Clinical Oncology and
Surgical teams; for this reason the Pathology Unit participates in
the activities of most Multidisciplinary Groups. Clinical activities
range from secondary prevention screening activities to histologic
and cytologic diagnosis of pre-neoplastic and neoplastic diseases,
including sentinel node examination, intra-operatory diagnosis,
and pathologic staging of tumor. The Unit is also involved in
organ transplant in tumor-bearing patients, as well as in the
activities of Tumor Registry and Barrett’s Esophagus Registry.
Most activities, coordinated by Dr. A. Galligioni, are performed
under the supervision of and in collaboration with the Pathology
Unit of the Azienda Università-Ospedale of Padova, headed by
Professor Massimo Rugge. The IOV Institute is now re-organizing
this area, in the frame of an autonomous Unit.
Research Collaborations and Projects
The Unit maintains a strict collaboration with all the Clinical
Units of the Institute and of the Azienda Università-Ospedale,
with special attention to the Pathology Unit headed by Prof. M.
Rugge, from which the Units depends for the administrative
aspects. Translational research is a major commitment, with special
attention to morphologic and molecular characterization of preneoplastic syndromes. Within the Veneto Oncology network,
the Unit is involved in setting up guidelines and protocols for
appropriate diagnostic and therapeutic approaches to several
neoplastic diseases.
104
foto
Department of Radiotherapy
& Nuclear Medicine
The Departments - Department of Radiotherapy and Nuclear Medicine
107
Chief
Guido Sotti, MD
University of Padova: MD (1973); University of Padova, specialisation in Radiology (1977), and
Clinical Hematology (1980). Full time assistant at the U.O. of Radiotherapy and Nuc. Medicine,
Padova Hospital (1974-1986); vice-Head Physician at the U.O. of Radiotherapy and Nuc.
Medicine, Padova Hospital (1986-1997). Head Physician at the U.O. of Radiotherapy and Nuc.
Medicine, Padova Hospital (1998 - 2006). Head Physician at the U.O. of Radiotherapy and Nuc.
Medicine, IOV Padua (2006 - to date) 1983-2011 University of Padova, teaching of the School of
Specialisation in Oncology. 1989-2011 University of Padova, teaching of the School of Specialisation
in Radiology. 1997-1999 University of Padova, teaching of the School of Specialisation in Nuclear
Medicine. Member of the Associazione Italiana di Oncologia Radioterapica (AIRO); Member of
the International Society of Paediatric Oncology (SIOP); Member of the European Group for Bone
Marrow Transplantation (EBMT). More than 100 publications and 10 books chapters cover many
aspects of pediatric radiation oncology and adult cancer, including brain tumors, Hodgkin’s disease,
malignant lymphomas, soft tissue sarcomas and the late effects of cancer treatment.
Main Pubblications
Patterns of care and survival in a retrospective
analysis of 1059 patients with glioblastoma
multiforme treated between 2002 and 2007: a
multicenter study by the Central Nervous System.
Scoccianti S, Magrini SM, Ricardi U, Detti B, Buglione M, Sotti G, Krengli M, Maluta Neurosurgery 2010; 67:
S, Parisi S, Bertoni F, Mantovani C, Tombolini V, De Renzis C, Lioce M, Fatigante L, 446-58
Fusco V, Muto P, Berti F, Rubino G, Cipressi S, Fariselli L, Lupattelli M, Santoni R,
Pirtoli L, Biti G. Study Group of Airo (italian Association of Radiation Oncology).
Infant ependymoma in a 10-year AIEOP
(Associazione Italiana Ematologia Oncologia
Pediatrica) experience with ometted or deferred
radiotherapy.
Massimino M, Gandola L, Barra S, Giangaspero F, Casali C, Potepan P, Di Rocco C, Int J Radiat Oncol Biol
Nozza P, Collini P, Viscardi E, Bertin D, Biassoni V, Cama A, Milanaccio C, Modena Phys 2010; 18:1-8
P, Balter R, Tamburrini G, Peretta P, Mascarin M, Scarzello G, Fidani P, Milano GM,
Sardi I, Genitori L, Garrè ML.
Sequential intensified chemotherapy with stem
cell rescue for children and adolescents with
desmoplastic small round-cell tumor.
Bisogno G, Ferrari A, Rosolen A, Alaggio R, Scarzello G, Garaventa A, Arcamone
G, Carli M.
Bone Marrow Transplant.
2010; 45:907-11
Clinical outcome of low risk differentiated Vianello F, Mazzarotto R, Mian C, Lora O, Saladini G, Servodio O, Basso M, Clin Oncol (R Coll
Radiol). 2011; in press.
thyroid cancer patients after radioiodine Pennelli G, Pelizzo MR, Sotti G.
remnant ablation and recombinant human
thyroid stimulating hormone preparation.
Infant ependymoma in a 10-year AIEOP
(Associazione Italiana Ematologia Oncologia
Pediatrica) experience with omitted or
deferred radiotherapy.
Massimino M, Gandola L, Barra S, Giangaspero F, Casali C, Potepan P, Di Rocco Int J Radiat Oncol Biol
C, Nozza P, Collini P, Viscardi E, Bertin D, Biassoni V, Cama A, Milanaccio C, Phys. 2011; 80:807-14
Modena P, Balter R, Tamburrini G, Peretta P, Mascarin M, Scarzello G, Fidani
P, Milano GM, Sardi I, Genitori L, Garrè ML.
108
Technical Staff
Guido Sotti
Franco Berti
Caterina Boso
Maria Samaritana Buzzaccarini
Anna Rita Cervino
Luigi Corti
Laura Evangelista
Maria Luisa Friso
Michele Gregianin
Ornella Lora
Lucio Loreggian
Giorgio Saladini
Giovanni Scarzello
Federica Vianello
Michela Basso
Alessio Casetta
Sara Galuppo
Elena Groff (Psychologist)
Federica Pellegrino (Speech therapist)
Tiziana Proto
Claudio Pagnin (Coordinator)
Davide Bettin
Francesca Bissacco
Tommaso Brunoro
Maria Colombis
Michele Da Riva
Doriana Di Tommaso
Stefano Ferrioli
Debora Gambetta
Giorgio Lusiani
Alessandro Novo
Michela Raimondi
Antonella Sanità
Michael Sartori
Giancarlo Zonzin (Coordinator)
Marino Bortolami
Giorgio Masiero
Laura Memo
109
Riccardo Sanco
Silvia Zampieri
Manuela Anna Zappalà
Elena Zaramella
Nuclear Medicine
Morena Busatto
Alessandra Biscotto
Eva Carpin
Michele Trevisan
Nursing Staff
Socio-sanitary operators
and Socio-sanitary auxiliaries (OSS – OT – OS)
Fabrizio Boscolo
Manola Colcera
Miranda Longetti
Pietro Marin
Renza Meneghin
Patrizia Quadrio
Ivana Salvò
Fabio Tamiazzo
Renato Toffano
Admission Department
Cristina Tridello (Coordinator)
Marina Bezzati
Roberto Bilato
Deborah Borella
Giulia Carletti
Fabiola Carrossa
Franco Fiorotto
Fabio Lincetto
Roberta Luisetto
Alessandro Paggiaro
Monica Perotti
Astrid Rossi
Francesca Ruffo
Graziella Sandon
Elisa Zago
Federico Zancato
Carmela Zeoli
Daniele Bertin
Marisole Celegato
Sonia Celladin
Simonetta Di Genni
Graziella Formaggio
Michele Pignataro
Luigi Polanzan
Ambulatories
Barbara Giacomin (Coordinator)
Graziella Alfonsi
Sandra Bonato
Vania Boscolo
Licia Canovese
Daniela Filira
Iolanda Fronzetti
Carla Masiero
Franca Smaniotto
Liliana Spangaro
110
Clinical Activity
The acquisition of a helical tomotherapy system and a
new accelerator is foreseen in the near future. Besides external
radiotherapy, other treatments as high-dose rate brachytherapy
for lung, esophageal, gynecologic cancer and choroidal melanoma
are performed.
A peri-intraoperative brachytherapy service is available for soft
tissue sarcomas in adult and pediatric patients A photodynamic
therapy (PDT) unit is also available, providing a photosensitizer
chemical compound fixing on neoplasia, excited by light of
a specific wavelength. Patients treated with this therapy are
usually affected by Head&Neck, gynecological, esophageal and
bronchial tumors no longer treatable with standard care. Other
different lasers are used for endoscopic bronchial, esophageal and
dermatologic surgery.
The Section of Nuclear Medicine, endowed with two 2-head
gamma cameras, 1 hybrid PET-CT tomography and 1 gammacounter, offers traditional nuclear medicine tests to oncology
patients such as bone scans, 131I whole-body scans, sentinel node
scintigraphy, somatostatin analogue scans etcetera, as well as
functional examinations such as lung and myocardium perfusion
scans, kidney, parathyroid and thyroid studies. FDG-PET scans
are routinely performed in diagnosis, staging and clinical followup of patients. In 2010 over 15,000 nuclear medicine studies were
performed, including about 1,000 sentinel node studies and more
that 2,500 were PET-CT scans.
Distribution by pathology (%)
Beds in admission department
Ordinary
18
Day Hospital
4
Protected
8
Breast tumors
Head/neck tumors
1,4
Patients in admission department
10,8
20,7
19,3
Lung tumors
6,7
Esophagus
Ordinary
306
DH
261
Metastases
Protected
481
Prostate cancer
TOTAL
1.048
Gynecological
tumors
Brain tumors
Health services Ambulatories
Examinations/visits
4,9
10.721
5,1
5,4
5,4
2,9 5,0
8,6
GI tumors
(with ano-rectum)
First examinations/visits ambulatories and
multidisciplinary examinations
3500
Patients
2600
Thyroid tumors
Treatments
(performed 72.427 health services in the cure department)
3583
Germ cells tumors
3,8
Lymphomas
Other
Total activities in the cure department 72.427
111
Radiotherapy Equipment
Lasers:
1 Level M300 1 Dornier MBB Nd Yag
1 Diomed D60 Diodo
1 Diomed PDT Diodo
1 Deka laser CO2
1 Candela Dye-laser
Radiotherapy systems:
1 Accelerator PRIMUS Siemens – energy 6 MeV - El 5-14;
1 Accelerator MX2 Siemens – energy 6 MeV;
1 Accelerator ONCOR Siemens – energy 6-15 MeV - El 5-21;
1 Accelerator MX2 Siemens – energy 6 MeV;
1 Microseletron System HDR Nucletron (for therapy High Dose
Rate);
1 Simulator TAC PQ6000 – Picker;
1 Radiology simulator Mevasin-Siemens;
1 portable Radiology System (for simulations) Sirmobil-Siemens.
- bio-stimulant;
- endoscopy;
- surgery;
- photodynamic therapy;
- skin;
- skin.
Nuclear medicine equipment
1 γ Camera Siemens mod. Ecam;
1 γ Camera Picker mod. Axis;
1 TC-PET.
Treatment planning system:
1 Oncentra Masterplan;
1 Oncologist Siemens;
1 Plato Nucletron.
Mission
The mission of Radiotherapy and Nuclear Medicine Unit is
the diagnosis and care of patients affected by malignant neoplasia.
The Radiotherapy Unit provides multiple ways to deliver radiation
therapy offered by modern oncology radiotherapy: conformal
radiation therapy, intraoperative radiation therapy, radiosurgery,
fractionated stereotactic radiotherapy and total body irradiation
for conditioning allogeneic bone marrow transplantation.
112
Areas of Excellence
Thyroid cancer
thyroidectomy. It is a potential diagnostic and prognostic marker
for papillary thyroid carcinoma (PTC) and is used 1) to increase
diagnostic accuracy in fine-needle aspiration biopsies for PTC
and for minimal disease metastatic to cervical lymphnodes, 2) in
determining the aggressiveness of PTC because BRAF mutations
could be associated to unfavorable patient outcome.
The Unit is part of a multidisciplinary team involving experts
from the Units of Surgery, Radiotherapy, Nuclear Medicine,
Endocrinology, Clinical Oncology, Pathology, and Physics.
Systemic isotope therapy is available in the form of:
A) 131I for remnant ablation or treatment of persistent or
relapsed disease in patients with differentiated thyroid cancer.
About 480 patients, both pediatric and adult, are treated each
year. After treatment, all patients enter follow-up; more than
2,500 patients are evaluated yearly in the follow-up program and
the data from this large database permit evidence-based decisions
for future patient management;
Pediatric tumors
Special attention is paid to pediatric patients, designing a
section with a comfortable environment with toys and audiovisual
systems and with the constant presence of an anesthesiologist for
deep sedation treatment. The pediatric patients are about 150
per year; sarcomas, brain tumors and hematologic malignancies
predominate.
Protocols within the International Society of Pediatric
Oncology: EpSSG RMS & nRMS (Padova Center coordinator
for radiotherapy); High-risk neuroblastoma; Hodgkin Euronet
(Padova Center coordinator for radiotherapy); Wilms’ tumor;
Low-grade glioma (Padova Center coordinator for radiotherapy);
High-grade glioma (Padova Center coordinator for radiotherapy);
Germ cell brain tumors; Craniopharyngioma; Ependymoma;
Atipical theratoid rhabdoid tumors.
B) Meta-I-benzyl-guanidine for metastatic medullary
carcinoma or other neural crest tumors such as metastatic
pheochromocytoma and paraganglioma, both in pediatric and
adult patients.
The major advance in thyroid cancer management over the last
decades has been the ability to identify patients with or without
disease after primary treatment by thyroglobulin measurement
after recombinant human TSH stimulation (Tg test). Tg test
also allows a more precise selection of patients who require
further treatment or may enter follow-up. Another important
advance in thyroid cancer management is the use of 18 FDGPET for the prognostic evaluation of patients with differentiated
thyroid cancer. All patients with advanced or metastatic disease
undergo 18 FDG-PET, thus allowing to select patients who may
benefit from 131I treatment from those who need surgery or
external beam radiotherapy. For anaplastic cancer, association of
surgery (whenever possible), chemotherapy and external beam
radiotherapy is performed with the aim of improving the poor
control of loco-regional disease.
Molecular tumor profiling is one of the most promising
strategies for achieving an improvement of risk stratification
and prognostic evaluation of differentiated thyroid carcinoma.
Mutation analysis of the gene encoding B-type Raf kinase
(BRAF) is performed in parallel to classic cytology before total
113
Iodine episcleral plaque brachytherapy of
choroidal melanoma
From June 1994 to December 2010, in collaboration with the
Clinica Oculistica of the University of Padova, we have treated
710 patients with choroidal melanoma and ciliary body with
125
Iodine brachytherapy. Local control was obtained in more than
90% of patients; useful visual acuity (>1/10) was maintained
in 65% of treated eyes. The major complication was radiation
chorioretinopathy (60% of treated eyes), in particular radiation
maculopathy and optic neuropathy.
125
The treatment of choroidal melanoma can be performed using
several different therapeutic options, including surgery (partial
resection or enucleation) and different modalities of radiotherapy.
The application of episcleral plaques charged with 125Iodine is
an effective approach in the conservative treatment of choroidal
melanoma. The Collaborative Ocular Melanoma Study (COMS),
with over 20-year experience, has shown that the length of survival
following radiation or enucleation is not different. Choroidal
melanoma is a relatively radioresistant disease that grows in an
organ very sensitive to radiation. Other tissues, such as optic
nerve and chiasma, can be damaged by relatively low doses of
radiation. A dose higher than 50 Gy can cause a permanent vision
loss, and the therapeutic dose for treatment of the disease ranges
between 50 and 100 Gy. For this reason, it is necessary to irradiate
with a highly collimated technique that could preserve the more
radiosensitive structures of the eye, with a significant decrease in
dose outside the target. There are different isotopes that are used
like Rutenium, but the 125I energy can better cover the target up
to the depth of 10 mm. The ophthalmic plaque is positioned by
the ophtalmologist to direct contact of the sclera for a period
determined by the Physicist. The dose administered is 85 Gy to
the apex of the lesion, with a dose administration rate ranging
between 50 and 105 cGy/h.
The INFN Legnaro laboratories Boron
Neutron Capture Therapy (BNCT) project
The Legnaro BNCT project is a collaborative enterprise that
involves the INFN Legnaro Laboratories, the Radiotherapy Dept.
of the IOV, the Department of Physics of Padova University and
the Department of Biology of Padova University. BNCT is a
binary radiation therapy. First, a boronated substance is injected
into patients, then the patient is irradiated with thermal or
epithermal neutrons. The boron transport molecule is harmless
and designed to be preferably captured by tumor cells. Because of
the high 10B thermal neutron capture cross section (3837 barn),
the nuclear reaction 10B(n, )7Li is likely to occur. The nuclear
reaction fragments thus produced (4He of 1.47 MeV and 7Li of
0.84 MeV) are densely ionizing charged particles, whose reach
in soft tissues (~8 μm for the α particle, 5 μm for the lithium
ion) is as short as cell diameter (~10 μm). Therefore, only cells
Fig. 1a-b: a) left side. Complete RFQ structure installed at LNL. b) right side. First RFQ electromagnetic segment ready for the high power test in France.
114
The first BSA design points out that the Legnaro source will be the
most intense and clean neutron source available in Italy. It will be
ideal for shallow tumor BNCT treatment.
Center for the study of Acute and Late
Effects of Irradiation in Head-and-Neck Area
We recently activated a center for the study, prevention and
treatment of oropharyngeal toxicity. It is at the forefront in the
provision of diagnostic and therapeutic services for patients
suffering of dysphagia as an effect of either head-and-neck cancer
or radiochemotherapy. Patients with suspected swallowing
disorders should be carefully evaluated and appropriate treatment
initiated in order to prevent complications such as dehydration,
malnutrition, choking and pneumonia. The approach to dysphagia
is interdisciplinary and performed by professionals skilled in the
management of the disease. The interventions of the center are:
Instrumental examination: fiberoptic examination of
swallow (FEES).
Speech and language therapy: evaluation and management of
oropharyngeal diysphagia by means of clinical bedside assessment
and swallowing therapy, such as diet modification, compensatory
techniques and strategies designed to facilitate or stimulate the
swallow.
Psychological support: continuous evaluation of patients’
quality of life, by offering help in disease control, renewed purpose
in life, changes acceptance and late side effects adaptation.
Nursing support: health education, weight control,
management and monitoring of toxicity, such as oral mucositis,
xerostomia, pain and dermatitis.
Fig. 2. The thick Beryllium target, with the inlet and outlet water pipes
for cooling, has been designed at LNL and constructed at the Efremov
Institute of St. Peterburg (Russia).
containing 10B are damaged, while the healthy surrounding cells
are spared.
The INFN Legnaro National Laboratory (LNL) has been
constructing the high power proton accelerator that will be used
to generate the intense neutron source for BNCT. The proton
source (TRIPS) has been developed at the INFN South National
Laboratory of Catania and optimized at LNL in 2007. Protons
are transported into the accelerator through a beam line, which
is ready to be assembled with magnets, pumping system, non
interceptive profile and current diagnostics, interceptive profiler
and current monitor. The proton accelerator, a radio frequency
quadrupole (RFQ), has been completed in October 2009. The
complete structure was installed at LNL in November 2009
(Fig.1a) and was successfully tested at low power at the beginning
of 2010. The next step is the RFQ high power test. Such test will
be performed at Saclay (France) in 2011. Fig.1b shows the first
RFQ electromagnetic section ready for the high power test.
The 30 mA – 5 MeV proton beam will impinge the thick
beryllium target (Fig.2), which will generate, because of a well
known nuclear reaction, the intense neutron flux for BNCT
clinical studies.
Neutrons emerging from the Beryllium target have 1.35 MeV
mean energy. They have to be slowed down to thermal energy to
be used for BNCT on shallow tumors. Neutrons are slowed down
with a multilayer, multi-material heavy structure (BSA), which
has to be properly designed. The physical parameters for such a
design have been measured with the Legnaro accelerator facility.
115
Boron neutron capture therapy (bnct) in
cutaneous recurrences of breast cancer: the
utility of pet/ct
if aged 45 years or older and suitable for wide local excision for
invasive ductal carcinoma, unifocal on conventional examination
and imaging. Preoperative diagnosis of lobular carcinoma is an
exclusion criterion. Patients’ assessments are scheduled at entry, 3
months, and 6 months later; thereafter, they are scheduled every 6
months up to 5 years, and then yearly for up to 10 years.
The primary outcome of the trial is pathologically confirmed
local recurrence in the conserved breast. The secondary outcome
measure is local toxicity or morbidity.
Principal Investigator: Laura Evangelista
The rational of our study is based on the execution of BNCT
in cutaneous recurrences of breast cancer, mainly taking into
account the knowledge about the selective adsorption of 10B in
tumor sites using molecular imaging. The 10B is accumulated in
cancer cells by a specific carrier: Boron Phenylalanine (BPA).
Positron emission tomography/computed tomography (PET/
CT) with 18F-BPA is able to determine the in vivo concentration
of BPA at the site of relapse, generating a clear map of 10B-BPA
distribution. The biodistribution of BPA is selective for the
cells with high turnover; therefore 18F-BPA PET/CT is able to
characterize all sites of disease recurrence beyond those already
known determining a change of the therapeutic management.
The execution of 18F-PBA PET/CT, as a valid alternative for
the evaluation of 10B-BPA concentration, could let us decide if the
indication to the routine examination is correct and if the approach
with BNCT can be considered as a valid choice.
This is a prospective study recruiting patients with cutaneous
recurrence of breast cancer. The selected patients will undergo 18FBPA PET/CT and subsequently surgery. Comparison between
imaging and histologic examination will be made.
Intraoperative radiotherapy as a tumor bed
boost (TARGIT−B)
Principal investigator: Guido Sotti
Patients with high risk of local recurrence are defined by either
being 45 years or younger, or between 46 and 50 years but with any
of the following risk factors: grade 3, ER negative, lymphovascular
invasion, nodal involvement, positive margins. These patients will
undergo a boost of intraoperative radiotherapy of the tumor bed
followed by standard external beam irradiation. The control group
will receive standard external beam radiotherapy only.
Imaging Studies by Pet-Ct
Principal investigators: Anna Rita Cervino, Laura Evangelista,
Michele Gregianin, Giorgio Saladin
Intrabeam project for intraoperative
radiotherapy versus whole breast irradiation
in breast cancer (TARGIT-A Trial)
PET-CT scans in Lymphoma
Both Hodgkin’s lymphoma and non-Hodgkin’s lymphomas
are potentially curable malignancies. A large part of patients
with these diseases achieve complete clinical response, however
disease relapse rate can be as high as 30-35%. Despite different
efforts to define the impact of clinical and pathological factors on
disease behavior, it is evident that risk stratifying systems are as
yet inadequate to individualize or personalize therapy. The use of
18
F-FDG and PET-CT integrated platforms has recently changed
the definition of therapy response, but it has also imposed a
significant change in disease management. Different national and
international multicentric studies are in progress in this particular
Principal Investigator: Guido Sotti
Ninety percent of local breast cancer recurrences occur within
the index quadrant despite the presence of multicentric cancers
elsewhere in the breast. For selected patients with early breast
cancer, a single dose of radiotherapy delivered at the time of surgery
by use of intraoperative radiotherapy should be considered as an
alternative to external beam radiotherapy delivered over several
weeks. Women with early breast cancer are eligible for enrolment
116
field and the Nuclear Medicine Service of IOV is participating
in two different studies, in particular in evaluating the rapidity
of response to therapy (PET interim evaluation) that represents
the main prognostic factor for these patients. The preliminary
results demonstrate that an early poor response evaluated by
means of FDG-PET may suggest a shift towards more intense
chemotherapy regimens, and indicate that FDG-PET can be
considered a very important diagnostic and prognostic tool in
lymphoma management. FDG-PET is used with the same purpose
also during clinical follow-up of patients with lymphoma at the
end of therapy, because of its ability to detect an early relapse of
the disease.
today not significantly different from that recorded in the ’70s.
The lack of increased mortality despite increasing incidence was
interpreted as evidence of an early diagnosis and adequate therapy
based on surgery and 131I treatment. At IOV we follow a large series
of differentiated thyroid carcinoma (DTC) patients undergoing
different regimens of treatment based on the stage of disease. FDGPET scanning is assuming a more central role in the follow-up of
patients with DTC. It is well established that DTC lesions most
visible by FDG-PET scans are those that are less able to capture
iodine; in DTC management FDG-PET is used in our Department
for many purposes: a) diagnosis of disease recurrence in patients with
increased thyroglobulin and negative 131I whole body scan; b) as a
guidance for selective reintervention in patients with a local disease
relapse; c) for patients with metastatic disease out of 131I therapy
to estimate the progression of disease and to enter the patient in a
chemotherapy protocol; d) in selected cases, in combination with
recombinant human TSH, with the aim of increasing diagnostic
sensitivity of scanning in patients with increased thyroglobulin
levels and negative 131I whole body scan.
PET-CT scans in Colorectal Carcinoma (CRC)
CRC is the most frequent cancer in western countries and
it is now considered as a social disease because of its impact on
the health system. FDG-PET seems to be the most sensitive
imaging approach for early detection of local recurrence and
distant metastases. Recently our Nuclear Medicine Service in
collaboration with Surgery and Oncology Departments undertook
a prospective study aimed at comparing the diagnostic value of
FDG-PET versus Multislice CT and MRI in distant metastasis
detection, in particular for liver metastases. A second study is
ongoing on FDG-PET scanning impact on CRC local recurrence
detection after surgery and radiotherapy.
PET-CT in Pediatric Oncology
There is an increasing interest of PET-CT application in
pediatric oncology, derived by an increasing number of papers
indicating that lymphomas and other solid tumors in children
accumulate FDG in the same manner as in adult patients. The
European Nuclear Medicine Society recently published the
Guidelines for FDG PET-CT imaging in pediatric oncology.
In particular, in patients with soft-tissue sarcoma (STS), the
early assessment of treatment response is important. We are
determining in a group of patients with STS the usefulness of
FDG-PET in evaluating treatment response after chemotherapy
and chemoelectric therapy. FDG-PET is performed before therapy
and after the first cycle of therapy to distinguish responder from
non-responder STS patients.
PET-CT in Radiation Therapy Planning
A recent report of IAEA agency stated that PET-CT is a
significant advance in cancer imaging with great potential for
optimizing radiation therapy planning, thus improving the patient
outcome. Numerous studies support the routine use of FDGPET for radiotherapy volume determination in lung cancer, headand-neck cancer, lymphomas and esophageal cancer. We began in
patients affected by lymphoma a program of acquisition of PETCT images in radiotherapy treatment position by means of the
same carbon bed used during radiation treatment. Moreover, we
are testing and validating a new technique to decide the volume
to treat based on the contemporary acquisition of contrast CT
images and PET images, and matching anatomical images of CT
with functional PET images.
FCH PET-CT in Prostate Cancer
Since 2010 we perform 18F-choline PET-CT (FCH PETCT) for evaluation of patients with prostate cancer after radical
treatment. As reported in the literature, this survey is particularly
indicated in patients with increased serum prostate-specific
antigen (PSA) and negative conventional imaging. FCH PET-CT
could become a crucial tool in radiotherapy target volumes and
early therapy evaluation.
PET-CT in Thyroid Cancer Management
Thyroid cancer incidence is rising, even though mortality is
117
Programs and Future Perspectives
Set up of Intraoperative Radiotherapy (IORT) with
INTRABEAM through participation in a clinical trial for the
Prevention of recurrences in breast cancer. The study, called
Targit A (Intraoperative Targeted Radiotherapy), is randomized and
controlled, comparing conventional post-operative radiotherapy with
intra-operative radiotherapy in patients over 45 years undergoing
conservative surgery. There are more than 25 participating centers
in the world and two in Italy. The study has already been approved
by the Ethics Committee of the IOV. Another important study
that will help to improve the knowledge and use of Intraoperative
Radiation Therapy protocol will be the Targit B, in preparation,
dedicated to breast cancer patients at high risk of relapse.
The Boron Neutron Capture Therapy (BNCT) is a new
technique of radiation therapy that uses the “Boron neutron
capture” by a substance injected into the patient carrying the 10B
isotope that binds selectively to cancer cells and is subsequently
irradiated with an accelerator of protons. This allows a high
selectivity of the target to be achieved with less damage to
surrounding tissues. The project is advanced and two clinical
trials, in collaboration with the Universities of Pavia, Catania
and the laboratories of the Institute of Nuclear Physics (INFN),
Legnaro are programmed.
The acquisition of a tomotherapy is mandatory, due to the
continuous search for improvement of therapy for patients with
cancer who are referred to our Unit. The renewal of certain
equipment as a new Rapid Arc accelerator, a simulator and a SpecTac CT dedicated to nuclear medicine is also foreseen.
IOV (Breast Imaging, Clinical Oncology 1, Clinical Oncology
2, Breast Surgery)
University of Padova (Clin. Chir. II; Chir. Toracica; An.
Patologica)
Dip. of Pediatria (Oncoematologia, Chirurgia)
CRO Aviano
AIRO (Associazione Italiana Radioterapia Oncologica)
INFN (Istituto Nazionale di Fisica Nucleare) Legnaro
INFN (Istituto Nazionale di Fisica Nucleare) Pavia
NYU Clinical Cancer Center – New York University School of
Medicine
University College, London
International Society of Paediatric Oncology
118
Medical Physics
Chief
Marta Paiusco, Physicist
Born in Mantova on June 6, 1962, she graduated in Physics at the University of Parma. Since 1996
she has worked at the Department of Medical Physics of the “Arcispedale S.Maria Nuova” Hospital
in Reggio Emilia. The principal field of interest is radiation dosimetry including: quality assurance,
in vivo dosimetry and planning optimization, mainly dedicated to IMRT.
Member of the ESTRO, AIFM and ISS groups, she is co-author of guidelines on IMRT dosimetry.
She is co-investigator in a project on the use of functional images in Tomotherapy. Author of several
articles she has been invited in many national and international congresses.
Current research interests include image-guided radiotherapy, adaptive interventions for IMRT,
radiation dose-response assessment and health technology assessment.
Main Pubblications
Commissioning Siemens Virtual Wedges in the Oncentra Ferretti A, Simonato F, Zandonà R, Reccanello Med. Phys. 2010; 37:6310MasterPlan treatment planning system using Gafchromic EBT S, Fabbris R.
6316
film.
PET/CT and radiotherapy: data transfer, radiotherapy workflow Fioroni F, Iotti C, Paiusco M, Versari A, Grassi Q J Nucl Med Mol Imaging.
and quality assurance.
E, Salvo D, Iori M.
2010; 54:476-89
Physical radiotherapy treatment planning based on functional Thorwarth D, Geets X, Paiusco M.
PET/CT data.
Radiother Oncol. 2010; 96:31724
Dosimetric verification of IMAT delivery with a conventional Iori M, Cagni E, Paiusco M, Munro P, Med Phys. 2010; 37:377-90
EPID system and a commercial portal dose image prediction tool. Nahum AE.
A two-variable linear model of parotid shrinkage during IMRT for Broggi S, Fiorino C, Dell’Oca I, Dinapoli N, Radiother Oncol. 2010; 94:206head and neck cancer.
Paiusco M, Muraglia A, Maggiulli E, Ricchetti 12
F, Valentini V, Sanguineti G, Cattaneo GM,
Di Muzio N, Calandrino R.
120
Technical Staff
Marta Paiusco
Davide Canonico
Sonia Reccanello
Lucia Riccardi
Franca Simonato
Roberto Zandonà
Michele Bignotto
Simonetta Bacco
Carlo Merlo
Nicola Pivato
Marco Rossato
Grazia Rossetto
Mariella Zuanon
121
Mission
To assure safe, accurate and high-quality patient care in
collaboration with Clinical Services in Diagnostic, Radiation
Oncology, and Nuclear Medicine.
Clinical Activity
The Medical Physics Unit provides services for three Institution
in Padua: Istituto Oncologico Veneto, Azienda Ospedaliera –
Università di Padova, and ULSS16.
supports clinical services in optimizing patient radiation exposure
in diagnostic and interventional procedures, estimating fetal dose.
It collaborates with clinical Units for Quality Assurance. In the
field of Radiation Protection it covers all aspects dealing with
radiation safety of the workers and the population, according to
national regulations.
The Medical Physics Unit evaluates and commissions
equipment and systems appropriate for clinical practice and in
any area takes an active role in research. The staff is involved in
the teaching and training medical students of Padua University
on Physics in Radiotherapy, Radiology and Nuclear Medicine and
on Radiation Safety. Furthermore, the physicists are engaged in
teaching courses and internships for the Post-Graduate School of
Medical Physics.
In the field of radiation therapy the Unit provides quality
assurance of imaging, treatment delivery equipment and
treatment planning systems to ensure optimal, accurate and
safe dose delivery. It is responsible for radiation dosimetry and
QA of sophisticated radiotherapy treatments like Stereotactic
Radiotherapy (SRT), Stereotactic Radiosurgery (SRS), Intensity
Modulated Radiotherapy (IMRT), Image Guided Radiotherapy
(IGRT), Total Body Irradiation (TBI), HDR Brachytherapy and
COMS 125I eye plaque Brachytherapy.
In the area of Diagnostic and Nuclear Medicine, the Unit
Radiation Therapy and Nuclear Medicine Unit of the IOV
Breast Surgery of the IOV
Nuclear Medicine Department of Azienda Ospedaliera di
Padova
Radiology Department of Azienda Ospedaliera di Padova
Neurological Surgery Department of Azienda Ospedaliera di
Padova
CRO Aviano
NYU Clinical Cancer Center -New York University School of
Medicine
University College, London
122
Commissioning of a commercial TPS based on the
VMC++ MC code for electron beams: validation
and comparison with EGSnrc
The Medical Physics Unit has been recently involved in two
projects concerning the verification of the accuracy of the dose
distribution calculated by a commercial treatment planning
system.
Principal Investigator: Andrea Martignano
Contributors: Alice Ferretti, Franca Simonato
Commissioning Siemens Virtual Wedges in the
Oncentra treatment planning system using
Gafchromic EBT film
Purpose. Some commercial TPS already use MC engines
for dose calculation. The aim of this work was to perform the
commissioning of the VMC++ Monte Carlo (MC) engine
implemented in the Oncentra Masterplan TPS for electron dose
calculation, and to verify its accuracy comparing the results to the
EGSnrc MC code.
Methods. The commissioning procedure for the TPS consists
of measurements of output factors and profiles in x,y and z
direction, in both air and water. The BEAMnrc MC code was
used as a benchmark: BEAMnrc required the geometries of the
LINAC head, which were provided by Siemens; the optimisation
was done considering PDD and profiles in water. Commissioning
results were evaluated by means of 1D Gamma Analysis (2%,
2mm), calculated with a home-made Matlab program.
Masterplan dose distribution maps were compared to the
results of BEAMnrc, in two virtual phantoms: one made of
water with an air insert, and the second with a bone insert. The
comparison was done by means of 2D Gamma Analysis (3%,
3mm), and comparing significant profiles and PDD.
Results and conclusions. The results of the commissioning
of the TPS were good. The optimisation of the BEAMnrc model
of the LINAC required the modification of some components to
match the calculated and measured profiles: the final agreement
was very good. The agreement of the dose distributions calculated
with the TPS and with EGSnrc with the air-insert phantom was
high; with the bone-insert phantom there were differences of
about 10-15% in the bone region. This is due to the fact that
the Masterplan implementation of VMC++ reports the dose as
“dose to water”, instead of “dose to medium” (therefore it is not a
dosimetric error).
Principal investigator: Franca Simonato
Contributors: Roberto Fabbris, Alice Ferretti, Sonia Reccanello,
Roberto Zandonà
Purpose. Virtual Wedges™ were introduced in Siemens
LINAC to improve the treatment workflow. The aim of the work
was the validation of dose calculation by MasterPlan-Oncentra
treatment planning system for virtual wedged beams.
Methods. The Oncor Siemens accelerator installed in the
Radiation Therapy Unit produces 6 and 15 MV photon beams.
At first, the consistency of VW LINAC production was tested and
the EBT film measuring method was verified. Then, the measured
and calculated wedge factors and beam profiles were compared.
For 15°, 30°, 45°, and 60° wedge angles, the wedge factors for
different field sizes were measured by an ionization chamber and
the dose profiles acquired by Gafchromic EBT film.
Results. The comparison between measured and calculated VW
factors shows discrepancies that increase with field size and angle.
The OTP Enhanced algorithm fits better with measurements than
the Classic one, with overall improvement visible for large angles.
The agreement between measured and planned beam profiles is
within the limits reported by the ESTRO Booklet No. 7 in terms
of confidence limits.
Conclusions. The MasterPlan-Oncentra treatment planning
system determines wedge factors and VW profiles within the
requested accuracy in the majority of treatment conditions. For
big field dimensions and wedge angle, wedge factor accordance
was worse, but it could be increased with an improvement of the
LINAC dosimetric board calibration.
123
Dosimetric verification and implementation
of IMRT and IGRT for prostate and head-andneck cancer
Three new treatment modalities are going to be implemented
at the IOV: the Intra Operative RadioTherapy (IORT) for
breast cancer, the Prone Breast radiotherapy and the IMRT for
prostate and Head and Neck cancer. In close collaboration with
the Radiotherapy Unit, the Medical Physics Staff will be involved
in the technique development. The primary focus will be on the
dosimetry aspects and three projects have been designed.
Principal investigator: Simonato Franca
Contributors: Davide Canonico, Andrea Martignano, Marta
Paiusco, Sonia Reccanello, Roberto Zandonà
Purpose. Intensity-modulated radiation therapy (IMRT)
is an advanced delivery technique that, thanks to the intensity
modulation of the beams, allows doses highly conformed to the
tumor. Moreover the possibility to create steep dose gradients
makes it possible to escalate the dose inside the tumor while
minimizing the dose to surrounding normal structures.
On the other hand, because of the gradients, the IMRT can
be safely implemented only with an Image Guided Radiotherapy
system (IGRT). The IGRT has the aim to guarantee that the
planning position is the same during the delivery time.
IMRT- IGRT will be implemented for Head-and-Neck and
prostate tumors according to several steps:
Commissioning and clinical introduction of the IGRT system:
BATCAM
Margin definition for prostate
Definition of a verification protocol for head-and-neck
treatments
Margin definition for Head-and-Neck
Dosimetric verification with EPID
Implementation and dosimetry optimization
of IORT for breast cancer with IntraBeam
System
Principal investigator: Sonia Reccanello
Paiusco, Franca Simonato, Roberto Zandonà
Purpose. Many studies demonstrate that after breastconserving surgery conventional post-operative whole breast
radiotherapy might be unnecessary but could be suitable an
intra-operative single fraction radiotherapy targeting only the
peritumoral tissue. The Istituto Oncologico Veneto has recently
bought the Intraoperative System IntraBeam and will participate
in the breast protocol TargitA[1] by testing whether radiotherapy
to the index quadrant alone can achieve as good a local control as
radiotherapy to the whole breast.
To determine the success of the radiotherapy treatment a key
role is played by the dosimetric accuracy of the treatment. The
project has therefore the aim to develop efficient and effective
methods to verify the delivered dose.
It will be divided in four phases:
1.Equipment acceptance tests, dosimetric characterization and
clinical implementation
2.Dosimetric verification by Monte Carlo simulation
3.Dosimetric characterization of a new specific dosimeter
4.Research and development of a methods to optimize the dose
distribution
In addition, multicenter dosimetry will be programmed.
[1]
Implementation and dosimetry optimization of
prone breast radiotherapy
Principal investigator: Sonia Reccanello
Paiusco, Franca Simonato, Roberto Zandonà
Purpose. The radiotherapy goal is to increase the probability
of locoregional tumor control without severe toxicity to the
surrounding normal tissues. Highly conformed delivery techniques
allow to escalate the dose to the tumor while sparing the organ
at risk. Regarding breast cancer the “Prone Breast” technique,
developed by Dr. Silvia Formenti, New York University School
(Jayant S. Vaidya et al - Lancet Vol 376 - July 10, 2010).
124
of Medicine, seems to be a promising modality. The Medical
Physics Department in collaboration with NYU will assess the
actual feasibility of this new set-up. At first the technique will be
clinically implemented as at the NYU. The reproducibility of the
technique will then be evaluated. A dosimetric comparison, in
term of tumor coverage and complication probability will be done
between prone and supine position.
125
Department of Experimental,
Laboratory & Translational
Oncology
The Departments - Department of Experimental, Laboratory and Translational Oncology
127
Immunology and
Molecular Oncology
Chief
Annarosa Del Mistro, MD
1976-1982: Medical School at the University of Padua. Degree of Doctor in Medicine (Honour)
1982-1985: Postgraduate School in Oncology, University of Padua. 1987-1991: Postgraduate School
in Pathology, University of Verona. 1982-1985: Scholarship from the Ministry of Education for the
Postgraduate School in Oncology. 1985-1987: Research Associate at the Pathology Department,
Montefiore Medical Center, New York, USA. 1987-2006: employment by Azienda Ospedaliera
di Padova. 2006-ongoing: employment by Istituto Oncologico Veneto - Temporary Director since
February 2008. Main research interests: Human Papilloma Viruses (HPV): prevalence, pathogenetic
role and application of HPV tests in cervical screening and patient management (ano-genital and
head-and-neck tumors); mechanisms of lymphomagenesis (studies on cases of human lymphomas
and on the experimental SCID mouse model); HTLV-1/2 and HIV-1/2 infections and associated
neoplastic diseases. Co-author of 70 papers on peer-reviewed journals.
Main Pubblications
Ligand-driven activation of the notch pathway in Indraccolo S, Minuzzo S, Masiero M, Amadori A.
T-ALL and solid tumors: why Not(ch)?
New Technologies for Cervical Cancer screening
(NTCC) Working Group: Efficacy of human
papillomavirus testing for the detection of invasive
cervical cancers and cervical intraepithelial neoplasia:
a randomised controlled trial.
Cell Cycle 2010; 9:80-85
Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Lancet Oncol 2010; 11:249-257
Palma P, Del Mistro A, Ghiringhello B, Girlando S, GillioTos A, De Marco L, Naldoni C, Pierotti P, Rizzolo R,
Schincaglia P, Zorzi M, Zappa M, Segnan N, Cuzick J.
Relationship between telomere shortening, genetic Rampazzo E, Bertorelle R, Serra L, Terrin L, Candiotto C, Brit J Cancer 2010; 102: 1300instability, and site of tumor origin in colorectal Pucciarelli S, Del Bianco P, Nitti D, De Rossi A.
1305
cancers.
Tumor-induced tolerance and immune suppression Marigo I, Bosio E, Solito S, Mesa C, Fernandez A, Dolcetti Immunity 2010; 32:790-802
depend on the C/EBPbeta transcription factor.
L, Ugel S, Sonda N, Bicciato S, Falisi E, Calabrese F, Basso
G, Zanovello P, Cozzi E, Mandruzzato S, Bronte V.
A MicroRNA targeting dicer for metastasis control.
Martello G, Rosato A, Ferrari F, Manfrin A, Cordenonsi Cell 2010; 141:1195-1207
M, Dupont S, Enzo E, Guzzardo V, Rondina M, Spruce T,
Parenti A R, Daidone M G, Bicciato S, Piccolo S.
128
Annarosa Del Mistro
Laura Bonaldi
Roberta Bertorelle
Vincenzo Bronte
Maria Luisa Calabrò
Vincenzo Ciminale
Donna D’Agostino
Emma D’Andrea
Anita De Rossi
Giovanni Esposito
Antonella Facchinetti
Stefano Indraccolo
Susanna Mandruzzato
Chiara Menin
Marco Montagna
Sonia Minuzzo
Antonio Rosato
Daniela Saggioro
Rita Zamarchi
Marisa Zanchetta
Paola Zanovello
Simona Agata
Valentina Agnusdei
Lorena Baboci
Elisa Bergamo
Lorena Biasini
Cinzia Candiotto
Francesco Carmona
Silvia Dalla Santa
Adamo Diamantini
Helena Frayle Salamanca
Riccardo Freguja
Sonia Keppel
Laura Lignitto
Annalisa Martines
Barbara Molon
Giorgia Nardo
Elena Negri
Enrica Rampazzo
Enrica Rumiato
Mukherjee Subhamoy
Elisabetta Tebaldi
Silvia Tognazzo
and Technicians
Vito Barbieri
Emanuela Colucci
Barbara Filippi
Monica Gardin
Antonella Ghinatti
Margherita Marangoni
Raffaella Marcato
Monica Quaggio
Elisabetta Rossi
Cristina Sartorato
Pietro Savelli
Paola Sorgato
Rossana Trevisan
Salvatore Vettura
Daniela Zullato
129
Mission
The Unit includes personnel directly employed by the IOV
and academic personnel exploiting their institutional duties
(research, assistance and teaching) in collaboration with IOV.
Historically, two components constitute the nucleus of the Unit:
Tumor Immunology and Viral and Molecular Oncology. These
two components have been operating and creating a critical mass
several decades before the IOV formation, and still continue to
carry out their activities within the spirit of the new Institute.
The mission of the Unit is to investigate the alterations which
characterize tumor development, on both the cancer cell site
(intrinsic molecular alterations) and the host tissue in which the
tumor grows (the tumor microenvironment). Along with research
activity, a fundamental component of the mission of the Unit is the
implementation, standardization and performance of molecular
analyses and innovative strategies for up-to-date diagnostics, as
well as effective follow-up and therapeutic regimens of patients
affected by solid and hematologic neoplasms.
Clinical Activity
Within the Unit molecular assays and innovative strategies for
the characterization, the prognosis and the selection for the new
targeted therapies of the main neoplastic diseases are implemented
and performed. In particular:
analyses for cytogenetic and molecular markers of oncohematologic diseases;
analyses of the genes involved in the heredo-familiar forms of
breast cancer and cutaneous melanoma;
analyses for molecular markers of solid tumors;
analyses for constitutive markers (farmacogenetics);
search for circulating tumor cells in patients with metastatic
breast carcinoma and other malignancies;
viro-immunologic analyses of tumors and immunodeficiencies
associated to infection with oncogenic viruses and retroviruses;
virologic analyses of preneoplastic and neoplastic lesions of the
ano-genital area.
Analyses for hematologic malignancies by year
2500
Number of analyses
2000
1500
1000
500
0
2008
2009
2010
Year
The Unit comprises 5 sub-units: Virologic Oncology
(Responsible A. De Rossi); Cervical Cancer Screening
(Responsible A. Del Mistro); Molecolar Biomarkers in Oncology
(Responsible R. Bertorelle); Heredo-familiar Tumors of Breast
and Ovary (Responsible M. Montagna); Tumor Immunotherapy
(Responsible V. Bronte).
molecular analyses
cytogenetic and FISH analyses
130
projection
2011
Analyses for solid tumors by year
Analyses for hereditary cancers by year
250
500
450
200
Number of analyses
350
300
250
200
150
150
100
100
50
50
0
0
2008
2009
2010
projection
2011
Year
2008
2009
2010
Year
projection
2011
Her2
number of new breast/ovarian cancer families (comprehensive test)
KRAS
number of family members tested for specific BRCA 1
and BCRA 2 mutations
EGFR
CTC
number of new melanoma cases
Assays for oncogenic viruses
2000
1800
1600
Number of analyses
Number of analyses
400
1400
HPV
1200
retroviruses
1000
800
EBV
600
HHV8
400
200
0
2008
2009
2010
Year
projection
2011
131
Istituto Scientifico Romagnolo, Forlì
Università di Genova
ICGEB Trieste
Inside the IOV
Clinical Oncology 1
Clinical Oncology 2
Familiar Cancer Clinics
Azienda Ospedaliera di Padova (Clinica Pediatrica, Clinica
Chirurgica 2, Ematologia, Clinica Oculistica)
Registro Tumori del Veneto
Azienda Ospedaliera di Verona
Azienda Ospedaliera di Treviso
CPO Piemonte
ISPO Toscana
CRO-IRCCS Aviano
Università La Sapienza Roma
CNR Milano
Università di Modena
Università di Trieste
HSR Milano
ISS Roma
IARC Lyon, France
Institute of Child Health, London, UK
MRC, London, UK
Imperial College, London, UK
NCI, NIH, Bethesda
Tokyo University, Japan
University of Erlangen, Germany
University of Miami, Miami
University of Mainz, Germany
IDIBELL, Barcelona, Spain
Oncomed Pharm., USA
Columbia University, New York
Weatherall Institute of Molecular Medicine (WIMM), Oxford,
UK
Areas of Excellence
Virologic oncology. It is known that about 20% of the
tumors rely on the pathogenetic involvement of microrganisms,
in particular viral agents. The interest for this aspect of oncology
in humans has been steadily pursued for the last 30 years. Special
attention is dedicated to: 1) the role of HPV in cancer of the
uterine cervix and other sites (anus, esophagus); 2) the role of
HHV-8 (also called KSV) in Kaposi’s sarcoma and Peritoneal
Exudate Lymphomas; 3) the role of Retroviruses such as HTLV-I
in adult leukemias; 4) the role of EBV in lymphomagenesis,
especially in immunodeficient subjects (such as children and
adults infected by HIV who eventually develop AIDS).
Molecular oncology. The alterations arising in cells undergoing
neoplastic transformation are a very hot issue in modern
oncology, thanks to the availability of the most sophisticated
techniques which allow an even deeper understanding of the
molecular pathways governing cell cycle and the possibility of
high-throughput genome and transcriptome analysis. In this
The long research activity of the components of the Unit of
Immunology and Molecular Oncology translates into over 780
publications in the last 20 years, with a total IF value of over 3,660.
The major fields of interest, where the research groups are
highly competitive on the national and international scenarios are
the following:
Study of heredo-familial tumors, with a particular accent
on the genetic predisposition to breast and ovary tumors, and
to melanoma. It is known that about 10% of the tumors are on a
heredo-familial basis, due to inheritable alterations in some key genes
controlling activation pathways or crucial DNA repair mechanisms
within the cell. Two research groups within the Unit focus their
interest on these aspects, and participate in several national and
international networks aimed at characterizing all these alterations
and unravelling the importance of accessory genes in determining
the clinical manifestations of the genetic defects.
132
regard, the activity of some researchers of the Unit also entails
a more applicative sense, since it allows dissecting the molecular
alterations that confer a growing advantage to tumor cells by
precluding apoptosis of the cells, and establishing whether some
of these alterations could be exploited for therapeutic purposes
with the so-called target molecules.
Tumor-microenvironment relationship. It is becoming
increasingly clear that tumor cells engage a strict interplay with the
host cells that compose the bulk of tumor: fibroblasts, infiltrating
inflammatory cells, endothelial cells. This relationship may be a
double-edged sword; if it is undoubted that the host immune
system can control tumor growth and keep neoplastic cells in check
at least to a certain extent, it is also clear that some inflammatory
cells of the host may play a favoring role for tumor expansion, by
down-regulating the above immunological mechanisms of tumor
growth control. The role of these cells, the so-called Myeloidderived Suppressor Cells, is at present a topic of great interest,
because their elimination from the host could represent a smart
strategy to potentiate the anti-tumor mechanisms of the host.
Innovative approaches of immunotherapy. Immunotherapy
of tumors is a constant dream of immunologists since the
Burnett’s era, but the idea that vaccination against tumors
could eradicate neoplasms has never maintained what it
looked to promise. The reasons for this failure are numerous,
and this report is not the right place to summarize them.
In any case, the modern tendency of tumor immunology is to
design innovative vaccination protocols by the use of more efficient
adjuvants, and to combine immunotherapic approaches with the
simultaneous administration of classical chemotherapeutic drugs.
It is no longer time for standard interventions for everybody; a
complex and well-balanced, personalized strategy that combines
different therapeutic tools, including chemotherapy, will probably
contribute to improve the success of these approaches in individual
patients.
Innovative therapeutic strategies. Several researchers at our
Unit are attempting new strategies of tumor therapy, in particular
anti-angiogenetic therapies aimed at deprivation of oxygen and
nutrients in the tumor microenvironment. In this setting, the
researchers are engaged in studying the factors that preclude
a favorable response in a part of patients; this could be due to
features inherent to the tumor cell itself, or rather depend on
other factors linked to a particular microenvironment.
Genetic Predisposition To Breast And Ovarian
Cancers
range from 40 to 80% for breast cancer and from 18 and 40% for
ovarian cancer.
Research and clinical activities. The BRCA1 and BRCA2
genetic tests are provided within the framework of a larger
multidisciplinary clinical and diagnostic activity that includes
pre- and post-test genetic counseling, psychological support to
the patients and their relatives, as well as clinical indications for
prevention and/or strict surveillance of the predisposed subjects.
The Unit offers this Service to the IOV Clinical Oncology Units
as well as to other oncology or medical genetics Units from
the Veneto Region, by coordinating a network of Centers that
extends to Trentino Alto Adige. Collaborating Centers include
first level facilities where one or more clinicians keep in contact
with the Unit by reporting new potential high-risk families,
and second level facilities that perform the pre- and post-test
counseling in-house and send directly patients’ samples to our
Principal Investigators: Marco Montagna, Emma D’Andrea
Background. The hereditary breast and ovarian cancer Unit
was established in 1995 as a multidisciplinary group interested
in the identification, analysis and management of heredo-familial
tumors. The Unit’s scientific projects represent one of the best
examples of translational research as all research lines and clinical
activities stem from the recruitment of families with breast and
ovarian heredo-familial tumors. Most often research results are
readily translated into the clinics with targeted medical interventions
and/or preventive options and surveillance procedures for at risk
healthy and affected subjects. Indeed, carriers of mutations in
genes such as BRCA1 and BRCA2 face an exceedingly high risk of
developing breast and ovarian cancer lifetime. Penetrance figures
133
Unit. The Unit mission includes collaborative efforts with other
regional hospitals to set up clinical genetic counseling facilities
according to national and international guidelines for the genetic
tests in hereditary breast and ovarian cancer patients. During the
last three years, 577 new breast and ovarian cancer families were
recruited and screened. A total of 760 BRCA1 and BRCA2 tests
were performed using highly comprehensive mutation detection
strategies that cover the entire BRCA1 and BRCA2 mutational
spectra, including major genomic rearrangements. Mutationspecific tests were offered to eligible relatives of the positive cases,
allowing for the identification of at risk family members who were
counseled and clinically managed according to the result of the
specific test. To date, the number of BRCA1/2 mutation positive
families identified by the Unit from the start of its activity has
raised to 253 for a total of more than 450 carriers of deleterious
mutations.
Results and conclusions. The understanding of the genetic
determinants of the non-informative families is one of the key
goals of our most recent studies. Evaluation of the clinical relevance
of BRCA1 and BRCA2 sequence variants of unknown pathogenic
significance, currently identified in 10-20% of individuals
undergoing BRCA1/2 genetic testing, represents a valid possibility
of increasing the number of informative tests. To address this
problem we have used a combination of bioinformatic tools,
based either on the predicted splicing effect, or the evolutionary
conservation as well as the chemical/physical properties of
aminoacid changes, and identified 12 unclassified variants with a
high probability of being deleterious. Two of these variants have
already reached classification: the BRCA c.301+6T>C classified
as likely neutral or of low clinical significance and the BRCA1
c.5074G>C p.Asp1692His which was previously mis-classified as
a missense mutation. Using in vitro transcript assays we showed
that this is a splicing mutation leading a cryptic splice site 153
nucleotides in intron 17 of the BRCA1 gene that brings about
a frame-shift in the protein and a premature termination codon.
For the remaining ten variants we are currently collecting data and
family members to be used in a multifactorial likelihood model,
that integrates independent sources of evidence of disease causality
derived from: co-segregation of the disease with the variant, LOH,
and histopathology data on available tumor specimens, as well as
evolutionary conservation and molecular epidemiology analyses.
A second research line focuses on the identification of other
susceptibility genes with moderate-low penetrance. While
these genes are more likely to be critical in the development
of the sporadic breast or ovarian cancer, at the same time they
provide the tools for better defining the risk profile of BRCA1
and BRCA2 carriers. To address these studies with a sufficiently
powered approach, the Unit joined in 2007 the Consortium of
Investigators of Modifiers of BRCA1/2 (CIMBA) that currently
includes about 50 research groups located world-wide and with
a sufficient sample size to allow large scale studies in order to
evaluate reliably the effects of genetic modifiers. By the candidate
gene approach, these studies have so far led to identification
of five loci which modify the risk of breast cancer for BRCA1
mutation carriers (CASP8, TOX3, 2q35, 19p13 and 6q25.1)
and nine loci which modify the risk of breast cancer for BRCA2
mutation carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35,
SLC4A7, 5p12, ZNF365 and 1p11.2). For the ovarian cancer
risk, one SNP rs3814113 at 9p22.2 was associated with a reduced
risk of cancer among BRCA1 and BRCA2 mutation carriers (HR
= 0.78). BRCA1 mutation carriers with the TT genotype were
predicted to have an ovarian cancer risk to age 80 of 48%, and
those with the CC genotype were predicted to have a risk of 33%.
Two two-staged genome-wide association studies (GWAS) were
also carried out within the Consortium as collaborative projects
using the Affymetrix 6.0 SNP platform. The study of BRCA2
mutation carriers identified several SNP previously associated with
sporadic breast cancer risk and two novel loci on chromosome
20 (rs311499) and chromosome 10 (rs16917302); FGFR2
rs2981575 showed the strongest association with breast cancer
risk (per allele HR = 1.28). Five SNP on 19p13 were associated
with breast cancer risk from the GWAS in BRCA1 carriers. The
five SNP were also associated with triple-negative breast cancers in
a separate study of 2,301 triple-negative cases and 3,949 controls.
Although altogether these variants account for a small proportion
of the variability in the genetic risk of breast cancer (3-6%), it has
been demonstrated that these SNP have implications for absolute
risk prediction in mutation carriers.
Familial Malignant Melanoma
Principal Investigator: Chiara Menin
The studies on the genetics of familial melanoma are developing
along two major lines: a) molecular analysis of constitutive genetic
alterations in high/low penetrance genes which are considered
predisposing to familial melanoma in probands/relatives belonging
134
to high-risk families; b) assessment of the bio-pathological role of
CDKN2A unclassified variants (UV) in conferring predisposition
to familial melanoma. The first line is part of a clinical/diagnostic
service that is offered to patients for the diagnosis of hereditary
melanoma and, when appropriate, for the implementation of
specific protocols for primary and secondary prevention, while
the second line represents a research project that should increase
the number of families that could take advantage of the molecular
assessment for their melanoma risk.
“Centro Regionale Specializzato per il Melanoma Cutaneo” of
the IOV. The majority of the analysed families (72%) had only
two cases of melanoma, and multiple primary melanoma (MPM)
patients were present in 27% of them. No germline mutations were
identified in the specific hot spot of CDK4 exon 2. Sequencing
analysis of CDKN2A revealed 3 missense mutations: p.G23D,
p.P48T, and p.G101. Altogether, only 6 families were found to
be CDKN2A mutation positive, thus the mutation detection rate
in melanoma-prone families from Veneto is approximately 8.5%,
which is a much lower mutation rate compared to Italian figures.
In fact, a recent Italian cooperative study on 204 families with
two or more cases of melanoma reports a global 33% CDKN2A
mutation rate, but single studies on families from different Italian
regions report different mutation frequencies, and our data are
more similar to those obtained in the Emilia Romagna region.
A. Genetic analysis
We have performed genetic testing and evaluation of the
influence of the main genes with either high (CDKN2A and
CDK4) or low (MC1R) penetrance for cutaneous melanoma
in about 100 familial melanoma patients, recruited within the
135
The presence of at least one MPM case is a feature of all our
mutated families. If we consider only the families with 2 or more
melanoma cases and presence of at least one MPM, the CDKN2A
mutation rate increases to 31.6%. In agreement with previous
studies, our results support the presence of at least one MPM case
in melanoma-prone families as the strictest criterion for identifying
CDKN2A mutations. Additionally, we have investigated the
influence of MC1R variants to melanoma susceptibility in these
families, and we have found that MC1R variants are extremely
common and they act as independent risk factor for melanoma as
well as number of nevi or presence of atypical nevi.
Besides bona-fide pathogenic mutations, many sequence variants
have been identified, but their effect is not well known. We
detected the p.Gly23Asp missense mutation in one of two tested
melanoma patients of a family with 3 melanoma cases. Even
though the mutated amino acid is located in a conserved domain
that specifically binds to and blocks the function of CDK4/6, its
lack of segregation with disease suggested a series of functional
assays to discriminate between a pathogenic variant and a neutral
polymorphism.
The effect of this mutation has been investigated exploiting
four p16INK4A properties: its ability (i) to bind CDK4, (ii) to
inhibit pRb phosphorylation, (iii) to evenly localize in the cell,
and (iv) to cause cell cycle arrest. The mutant protein properties
were evaluated by transfecting three different cell lines (U2-OS
and NM-39, both p16-null, and SaOS 2, p53 and pRb-null)
B. Evaluation of CDKN2A UV
CDKN2A germline mutations have been associated with
familial predisposition to melanoma and other tumor types.
136
Use of HPV test in the screening for cervical
cancer: multicentric study “New Technologies
for Cervical Cancer screening” (NTCC) and the
feasibility project in the Padova area
with plasmids expressing either p16wt, p1623Asp, or the p1632Pro
pathogenic variant. We found that p1623Asp was less efficient than
p16wt in CDK4 binding, in inhibiting pRb phosphorylation and in
inducing G1 cell cycle arrest; moreover, its pattern of distribution
throughout the cell was suggestive of protein aggregation, thus
assessing a pathogenic role for p1623Asp in familial melanoma.
Future prospects. Genetic counseling and testing will be
extended to more melanoma-prone families from the Veneto
region, through the recently developed regional network for
hereditary cancers (Rete Veneta per i Tumori Eredo-Familiari).
The functional analysis on the UV of the CDKN2A gene will
be extended to the critical residues that are of vital importance for
the specific folding and function of the p16INK4A protein.
Principal Investigator: Annarosa Del Mistro
Background. Cervical cancer screening by cytology (Pap
test) is in use since many years and recognized as effective. In
Italy organized programmes for women 25-64 year-old are
recommended every three years. In recent years new technologies
have become available for cervical cancer screening; the use of
molecular search for HPV sequences is particularly promising
since persistent infection with high risk human papillomavirus
(hrHPV) types is a necessary cause for cervical cancer development.
137
Methods. The NTCC trial is a randomized study with two
arms (conventional: Pap test) and two phases for the experimental
arm (phase 1: hrHPV test plus Pap test; phase 2: hrHPV test only).
All women are followed-up by Pap test every six years. The hrHPV
test used in both NTCC trial and feasibility project is Hybrid
Capture 2 (HC2, Digene/Qiagen) with high-risk probes. In the
feasibility project, triage of hrHPV-positive women is performed
by cytology; women with atypical cells undergo colposcopy,
women with negative cytology repeat hrHPV test one year later.
Results and conclusions. In the NTCC trial some 95,000
women (of whom 10,605 from the Veneto region, i.e. Padova and
Verona) were enrolled during 2002-2005. During 2005-2008 rescreening by cytology at six years was performed in women of both
arms; moreover, hrHPV test was repeated for a random group of
hrHPV test negative patients at enrollement. During 2008-2010
re-screening by cytology at three years was performed in women
of both arms; data analysis is ongoing.
Cervical HPV infection is very common and its prevalence
is higher among younger women; only a small percentage of
women with persistent infection with high-risk types will develop
the tumor, while the majority of infections clear spontaneously.
Several randomized controlled studies investigating the use of
HPV testing as primary screening test are ongoing. In 2001 the
Italian multicentric NTCC trial started in 9 organized screening
programs within 6 Italian Regions. Aim of the study is to evaluate
the performance of HPV test in comparison to cervical cytology
as primary test, by cross-sectional and longitudinal analyses. Since
the results of NTCC and the other randomized studies ongoing in
Europe indicate higher sensitivity but lower specificity of hrHPV
test than cytology, in 2009 feasibility studies have been initiated
in Italy to evaluate organizational impact, women’s compliance
and costs derived from the routine introduction of hrHPV test as
primary screening test, and to define the most effective protocols
for triage and follow-up of hrHPV-positive cases.
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The results published so far indicate that hrHPV test is more
sensitive than Pap test in the identification of women at risk of
developing high-grade lesions and has higher efficacy in preventing
invasive cervical cancer. Sensitivity and specificity of hrHPV test
depend on women’s age; in particular, detection of transient
infections and regressive lesions is most common among women
younger than 35 years. Therefore means to increase specificity
without affecting sensitivity are necessary; the triage strategies
evaluated within the NTCC trial include cytology, higher cutoff of the HC2 test and p16INK4A immunocytochemistry. In
2009 a feasibility project for the use of hrHPV test as a primary
screening test has been started in the Veneto region; it includes all
women of the 5 screening programs within Padova and Rovigo
areas. The hrHPV test for the Padova area is performed at IOV;
the target population for this area is about 80,000 women per
year. Enrollement started April 2009 for the ULSS 17 program;
July 2010 for the ULSS 15 program; June 2011 for the ULSS 16
program. The results for the ULSS 17 and 15 programs indicate
a 10% increase of the compliance as compared to the previous
years, and good compliance to 1-year recall. Pap test was used as
a triage test in both phase 1 of NTCC and feasibility project, and
was performed blind and open to the hrHPV result, respectively;
the results indicate the need to redefine the reading criteria of the
triage Pap test, and to perform specific training for all operators
involved in the screening.
Future perspectives. For the NTCC trial, analyses for
genotyping, viral load and viral variants of HC2-positive samples at
enrollement and follow-up are ongoing. For the feasibility project,
indicators of efficacy and quality control will be monitored and
compared to those obtained with Pap test as primary screening
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toward immortalization and tumorigenesis. Recent findings
suggested that h-TERT, the rate limiting component of telomerase,
may have prognostic value in several tumors and its detection in
blood could constitute a marker for tumor diagnosis.
We have developed PCR-based assays to quantify levels of
h-TERT mRNA and to estimate the length of telomeres. We have
set up methods to extract nucleic acids from blood and from cellfree biological fluids, and to quantify RNA and h-TERT mRNA
from plasma.
Our studies on hematological malignancies demonstrated that
h-TERT mRNA is a useful prognostic marker in B-cell chronic
lymphocytic leukemia (B-CLL). Studies aimed at evaluating the
prognostic role of telomere/telomerase interplay and its relationship
with chromosomal abnormalities are undergoing in a large series
of B-CLL. Studies on colorectal cancers (CRC) demonstrated that
test within the same programs and those obtained in the other
projects ongoing in other Italian regions.
Assessment of new non-invasive strategies for
diagnosis and prognosis of tumors: study of the
telomere/telomerase interplay
Principal Investigator: Anita De Rossi
Brief description. Telomere/telomerase interplay is a key
mechanism in controlling cellular replicative potential. While
erosion of telomeres beyond a critical point may impair their
function in protecting chromosome ends, resulting in genetic
instability, a key event in the initiation of carcinogenesis, the
maintenance of telomere length by telomerase is a critical step
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levels of h-TERT mRNA increased with tumor progression and
that h-TERT mRNA in plasma significantly correlated with those
in tumors. Furthermore, telomeres were significantly shorter
in CRC than in adjacent tissues, thus suggesting that telomere
shortening in CRC is a key initial event in colorectal carcinogenesis,
before telomerase activation. Studies aimed at evaluating h-TERT
mRNA as a predictive marker of tumor response to neoadjuvant
chemoradiotherapy in rectal cancers are ongoing.
cell lines, we reproduce in vitro the cellular interactions existing
in body cavities to study: (i) the contribution of mesothelial cells
to PEL cell turnover and cell-to-cell interactions; (ii) the role of
IFN-induced genes expressed by mesothelial cells and involved in
the in vivo anti-neoplastic activity of this cytokine, by analyzing
the effects of TRAIL expression by human mesothelial cells on
PEL cell apoptosis and by the identification of other IFN-induced
genes expressed by mesothelial cells; (iii) the susceptibility to
HHV8 infection of mesothelial cells and the effects of HHV8
infection on mesothelial cell function.
Role of microenvironment in PEL pathogenesis
Principal Investigator: Maria Luisa Calabrò
Molecular Markers in Esophageal Cancer
Primary effusion lymphoma (PEL) is a HHV8-associated
B-cell non-Hodgkin’s lymphoma growing as lymphomatous
effusion within serous body cavities, which are lined by mesothelia.
While the association between HHV8 and PEL development
is widely accepted, the role of microenvironment remains to
be fully elucidated. To analyze the specific role of the host
microenvironment on tumor growth, we developed a xenograft
SCID model of PEL that mimicks the liquid-phase growth and,
most of all, the aggressive course of human PEL. We compared
the activity of a murine (i.e. host-specific) interferon (IFN)-alphaexpressing lentiviral vector (mIFN-alpha-LV) to that of a human
hIFN-alpha-LV. Treatment of PEL/SCID mice with hIFN-alphaLV significantly prolonged mice survival and reduced ascites
development. Interestingly, in vivo gene therapy experiments
using the mIFN-alpha-LV showed an anti-neoplastic activity
comparable to that observed with the hIFN-alpha-LV. As mIFNalpha did not exert any direct anti-proliferative, pro-apoptotic
and antiviral effect on PEL cells in vitro, it likely acted in vivo on
the intracavitary murine milieu, thus indicating that the specific
targeting of microenvironment may impair PEL development.
mIFN-alpha-treated murine mesothelial cells were found to
express tumor necrosis factor-related apoptosis-inducing ligand
(TRAIL) and to significantly induce apoptosis of co-cultured PEL
cells in a TRAIL-dependent manner. These data suggest that the
interaction between lymphomatous and mesothelial cells may be
central to PEL pathogenesis, and also indicate that the specific
targeting of microenvironment may impair PEL development.
Ongoing studies are aimed at investigating the crosstalk between
lymphomatous cells and mesothelial cells to dissect mechanisms
involved in PEL cell survival and proliferation in body cavities. By
co-culturing human primary mesothelial cells with PEL-derived
Principal Investigator: Daniela Saggiaro
Esophageal cancer represents the eighth most common cancer
in the world. Despite improvement in diagnosis and treatment,
the overall survival remains lower compared to other solid tumors.
Thus, understanding the molecular mechanisms underlying the
onset and progression of esophageal cancer is mandatory to
the development of better treatments. The two predominant
histological subtypes of esophageal tumor are the squamous cell
carcinoma (SCC) and the adenocarcinoma (ADC). The latter is
thought to arise from an acquired precursor condition, known
as Barrett’s esophagus (BE), in which the squamous epithelium
of the lower esophagus is replaced by columnar epithelium. It is
believed that BE is a premalignant condition caused by chronic
gastro-esophageal reflux; other risk factors include smoking and
obesity. SCC arise in the upper or middle esophagus and, although
the etiology is unclear, factors such as smoking, alcohol, diet and
chronic inflammation are considered as favoring elements. While
the incidence of SCC has remained relatively stable over the last
few decades, ADC incidence has steadily increased in the Western
world and, though to lower extent, in Asia.
It is generally accepted that initiation and progression of
human cancer are associated with the accumulation of alterations
in important regulatory genes. Indeed, DNA copy number
abnormalities are a hallmark of nearly all advanced tumors and
amplified genes represent attractive targets for the development of
new diagnostic, prognostic and therapeutic approaches.
In an attempt to define esophagus-specific biomarkers, we
investigated DNA copy number changes of esophageal tumor
samples, stratified into ADC and SCC. Analysis was carried
out using the multiplex ligation-dependent probe amplification
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(MLPA) technique. MLPA, contrary to chromosomal-CGH,
allows detection of single gene alterations and represents an efficient
method for simultaneous screening of copy number imbalance in
multiple genomic regions while maintaining a single gene resolution;
in terms of robustness MLPA has been compared to array-CGH.
Our findings, in agreement with previous data, indicate that
structural genetic changes involving several chromosomes are very
frequent events in esophageal tumors. Nevertheless, by comparing
the ADC and SCC samples we found that some chromosomal
gains or losses were tumor subtype-specific. Looking for putative
genes involved in DNA copy number alterations, we found that in
ADC only a few genes were specifically altered at high frequency,
and the same cytogenetic region often showed amplifications in
one subset of patients and deletions in another, thus indicating
that ADC are characterized by an elevated genetic instability.
In contrast, in SCC the same probes exhibited either gains or
losses at high level. The observed differences in DNA copy number
patterns between ADC and SCC might suggest that genes within
these regions are specific and could play a relevant role in the
pathogenesis of the two esophageal cancer subtypes. On the other
hand, the common alterations might indicate that shared genes
are involved in tumor progression and growth.
By analyzing the correlation between DNA copy number
changes and overall survival (OS), we found that the total number
of alterations in ADC correlated with OS and could be considered
as an independent prognostic parameter. Thus, it seems that in
ADC patients an increased genomic instability correlates with
the aggressiveness of the tumor. On the contrary, no association
between OS and total DNA alterations was found in SCC
patients.
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More recently, given that the real benefit of a neoadjuvant
therapy in esophageal cancer is still controversial, we undertook
studies devoted to understanding the influence of patient genetic
variants on response to neoadjuvant therapy. Indeed, there is a
growing body of evidence suggesting that, beside variables such
age, sex, diet and organ function, the drug therapeutic effects can
be affected by genetic factors. Analyses devoted to the discovery
of genetic variants involved in drug excretion and metabolism,
as well as DNA repair, appear thus a promising tool to identify
patients that will respond better to therapy.
Cisplatin- and 5-fluorouracil (5-FU)-based chemotherapy
in association with radiation still remains the cornerstone of
treatment for esophageal cancer. Among polymorphic genes
implicated in the response to cisplatin and 5-FU treatment,
glutathione S-transferase family (GST), thymidylate synthase
(TS), excision repair cross-complementation group 1 (ERCC1)
and Xeroderma Pigmentosum group D (XPD/ERCC2) genes
seem to play an important role due to their involvement in the
drugs detoxification, inactivation or DNA adducts repair.
The GST isoenzymes are divided into at least seven major classes;
among these, the GST-P1, GST-M1 and GST-T1 polymorphic
variants have been associated with changes in enzymatic activity.
In GST-P1 gene, a change in exon 5 (A313G; rs1695) gives
rise to Ile105Val amino acid substitution. This modification
leads to an alteration in substrate affinity and consequently to a
reduced detoxification activity. Activity of GST-T1 and GST-M1
enzymes is modulated by inherited homozygous or heterozygous
deletions that lead to a complete or partial absence of enzymatic
activity, and their role in cisplatin detoxification is still debated.
DNA adducts including those induced by cisplatin are removed
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of Tax overrides its potential pro-apoptotic effects. In previous
studies, using murine fibroblasts and human HeLa cells, we
have shown that Tax expression induces resistance to apoptosis
triggered by different stimuli. Analysis of potential mechanisms
revealed that the observed resistance was linked to high levels of
transcriptionally active CREB and to the presence of a functional
Ras protein. Ras proteins are small GTPases that function as
molecular switches, alternating between inactive (GDP-bound)
and active (GTP-bound) states. Like many genes involved in
the regulation of multiple cellular signaling pathways (i.e.,
differentiation, proliferation and survival), Ras contributes to
cancer development, when aberrantly expressed.
While investigating the molecular mechanisms of Taxmediated resistance to apoptosis in T-cells, we found that cells
expressing Tax either transiently or constitutively have higher
levels of Ras-GTP (active form) than their control counterparts.
Furthermore, by using FTS (S-farnesylthiosalicylic acid), a Ras
farnesylcystein mimetic that selectively interacts with the activated
form of Ras, we were able to increase the sensitivity of Tax-expressing
cells to cisplatin treatment. These data strengthen previous
findings indicating that Tax-mediated resistance to apoptosis is, at
least in part, associated with Ras activity. Interestingly, increased
apoptosis susceptibility of Tax-expressing cells to treatment with
FTS was accompanied by a consistent reduction in phosphoERK, suggesting a direct involvement of ERK activation in
the apoptosis protection mediated by Tax. Moreover, although
several reports stressed the potential relevance of Akt activation in
survival of HTLV-1 infected or Tax-expressing cells, no reduction
in phospho-Akt was observed after FTS treatment.
The different behavior of ERK and Akt could be the result of
the diverse activation pattern of the two proteins. Indeed, ERK
activation is directly linked to Ras through the Raf-MEK pathway,
whereas Akt is a downstream effector of PI3K, whose activation
can be driven not only by Ras but also by diverse inducers. Thus,
Ras inhibition has likely a more direct and rapid effect in ERK
activation.
Our data provide evidence of Ras signaling activation in Taxexpressing T-cells, and indicate this occurrence as a possible cause
of ATLL cell resistance to death by chemotherapeutic agents.
Although additional studies should evaluate whether the levels
of Ras-GTP correlate with disease prognosis and the extent of
apoptosis resistance, our data designate Ras as a possible target for
ATLL therapy.
mainly by the nucleotide excision repair (NER) pathway, thus,
suboptimal NER activity may render cancer cells more sensitive
to cisplatin treatment. The ERCC1 and XPD gene products play
a leading role in the NER pathway.
It has been reported that variants rs11615 and rs3212986
within ERCC1 and rs1799793 and rs13181 within XPD may
alter their expression and subsequently their DNA repair capacity.
As mentioned before, 5-FU remains an important drug in the
chemotherapeutic treatment of esophageal cancer and high levels
of its target, the thymidylate sinthase, have been correlated with
drug resistance and a poor outcome. Several polymorphisms in
the TS untranslated regions (UTR) which may influence TS
mRNA transcription or protein expression, have been described
recently. The prognostic significance of GST, ERCC1, XPD and
TS polymorphisms have been studied in different solid cancer
types treated with platinum compounds and 5-FU. Many of these
studies have found an involvement of these genes in treatment
response and in elevated risk of relapse.
Although further analyses are required, preliminary results
obtained in our cohort of esophageal cancer patients suggest a
correlation between variants in NER genes and patient survival
after neoadjuvant therapy.
HTLV-1 Tumorigenesis
Principal Investigators: Vincenzo Ciminale, Donna M. D’Agostino
HTLV-1 is the causative agent of adult T-cell leukemia/
lymphoma (ATLL) and HTLV-1 associated myelopathy/tropical
spastic paraparesis (HAM/TSP). Even though the mechanisms
by which the virus engenders disease are not yet completely
understood, numerous data indicate the multifunctional Tax
protein as essential for malignant transformation. Indeed, Tax
causes leukemia in transgenic mice, and immortalizes human
lymphocytes when expressed in either a herpes- or retroviral
vector. This oncogenic potential is accounted for by Tax ability
to modulate the synthesis or the activity of many cellular proteins
that control a variety of fundamental cellular processes.
A key feature of malignant transformation is the induction of
apoptotic resistance, and aberrant cell death is usually associated
with uncontrolled cell growth. Tax contribution to apoptosis
is still controversial since the protein was shown to possess
both anti-apoptotic and pro-apoptotic activity. However, at
present, it is generally accepted that the anti-apoptotic activity
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Advanced applications of Circulating Tumor Cells
been included as a standard clinical routine in the majority of the
European Member States, remaining a research tool for clinical
studies or in selected patients. Peripheral blood represents an
alternative minimally invasive source of spreading tumor cells. In
current practice, cancer tissue is usually taken at diagnosis and
used to assess the presence of treatment targets. This however is
a suboptimal approach, since tumor cells evolve due to genomic
instability. Assessment of the phenotype and (hopefully) genotype
of the tumor cells in peripheral blood will provide insights into
treatments which could be most beneficial for the individual
patient.
Methods. Circulating tumor cells (CTC) refer to cells that
detach from a primary tumor or metastatic site, and circulate
in peripheral blood and may settle down at secondary sites
forming metastasis. In the past decade, technology advances
investigation
Principal Investigators: Rita Zamarchi, Elisabetta Rossi
Background. Metastasis is the major cause of death from
cancer. In the past decade the traditional model of metastasis
has been challenged by direct and indirect evidence, contrasting
the view that tumor cells spreading to secondary sites is a late
event in the tumorigenesis. The implications for diagnosis and
therapy are that it may not be sufficient to characterize the
primary tumor to assess the risk for disease recurrence and to
determine the appropriate therapeutic regimen. Investigation of
tumor cells disseminated into bone marrow should be included in
patient analysis. Nonetheless, bone marrow screening for occult
metastatic tumor cells in patients with epithelial tumors has not
145
enabled detection of these rare cancer cells, shedding some light
on the disease natural history and showing promise to serve as a
"liquid biopsy" used to tailor treatment for individual patients.
At present, the only validated assay for CTC detection that has
been cleared by the U.S. Food and Drug Administration is the
CellSearch system. Prospective multicenter studies in metastatic
breast cancer, prostate, and colon cancer, conducted with this
system demonstrated that the presence of CTC was associated
with poor survival; failure to eliminate the CTC after the first
cycles of therapy strongly suggests futile therapy.
Results. Addressing the role and mechanism of CTC in
metastasis we started by quantifying apoptosis in these cells. Indeed,
cell death is of fundamental importance for the development of
multi-cellular organisms and homeostasis of their tissues; aberrant
cell death can lead to many human diseases, including cancer.
Furthermore, the induction of tumor cell death is a primary
goal of many targeted therapies, directly or indirectly hinting to
molecular components of apoptosis regulatory pathways. As a
proof of concept that tumors respond to drug, we developed an
M30-integrated CTC assay for quantifying apoptotic CTC, by
using an anti-M30 mAb specific for epithelial cell apoptosis. To
express the dynamic changes of live vs. apoptotic CTC during
treatment, the difference (named Delta AUC) between live and
apoptotic CTC concentration-time Area was calculated following
a procedure which is commonly adopted for tumor markers. The
integrated assay proved to disclose an active disease in metastatic
breast cancer under chemotherapy. The new test and the
companion algorithm are applied for the first time in metastatic
renal cancer patients undergoing first-line Sunitinib, for which
no predictive markers are currently available. We found that
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Identification of regulatory network
of myeloid-derived suppressor cells by integrating
gene expression and microRNA expression data
the persistence of more aggressive (EpCam-positive, live) CTC
predicts disease recurrence in these patients, and it is linked with
distant relapses during first-line Sunitinib.
Conclusions and Future perspectives. The renal cancer
experience in CTC investigation is now applied to other
malignancies. By exploiting the CellSearch platform we have
developed integrated CTC assays for both phenotypic and
molecular characterization, that is now included in multicenter
clinical trials:
To investigate the role of insulin/IGF pathway in metastatic
breast cancer, we developed a new integrated assay for
quantifying IGF1R-positive CTC as a proof of mechanism that
drug hits target. The IGF1R-integrated assay is included in the
multicenter Phase II comparative study of metformin plus firstline chemotherapy (CT) versus CT alone in HER2-negative,
insulin-resistant (IR), no diabetic metastatic breast cancer, (PI:
A. Gennari, D. Amadori) [2010 ASCO Annual Meeting J Clin
Oncol 28:7s, 2010 (suppl; abstr TPS134)]. The validation of
the Insulin Sensitivity Score in these cells is ongoing.
For monitoring tumor response to neoadjuvant treatments and
tumor recurrence total and apoptotic CTC count is assessed in
colorectal cancer patients, in collaboration with S. Pucciarelli
(Dept. of Oncology and Surgical Sciences, University of
Padova).
Total and apoptotic CTC enumeration is assessed in prostate
cancer patients during neoadiuvant treatment (Janus trial:
A phase II study of Zoledronic Acid as Neoadjuvant therapy
in invasive prostate cancer), in collaboration with D. Santini
(Policlinico Universitario Campus Biomedico-Roma)
For quantifying the dynamic changes of live vs. apoptotic
Circulating Melanoma Cells (CMC) throughout anti-BRAF
treatment [Pilot study “Predictive value of Circulating Melanoma
Cells (CMC) in anti-BRAF treated Metastatic Melanoma” (PI
P. Zanovello, University od Padova)] the CMC assay is used
in conjunction with anti-DeltaH2AX mAb, specific for histone
H2AX which undergoes phosphorylation in response to double
strand DNA breaks, occurring during apoptosis. The study is
conducted in collaboration with V. Chiarion-Sileni (Oncologia
Medica 2, IOV) and C.R. Rossi (Melanoma e Sarcomi dei
Tessuti Molli, IOV).
Principal Investigators: Susanna Mandruzzato, Paola Zanovello
Background. Our research group is involved in studying
myeloid-derived suppressor cells (MDSC), a cell population
that comprise immature myeloid cells composed of monocytic,
granulocytic and dendritic progenitor cells or myeloid cells at
different stages of differentiation. Several groups have demonstrated
that expansion of MDSC in tumor-bearing mice and in cancer
patients is associated with an impairment of T cell responses.
It is currently believed that the origin of MDSC is due to an
arrest of myeloid development process caused by cytokines and
growth factors released by the tumor microenvironment: the bone
marrow immature myeloid cells fail to develop fully and do not
acquire surface markers of mature monocytes and granulocytes.
After being recruited into the peripheral lymphoid organs and in
the tumor site, MDSC may undergo a process of activation and
trigger mechanisms of suppression of T-cell function through cell
surface receptors and the release of short-lived soluble mediators.
Several works have demonstrated that different growth factors
secreted by tumor cells are able to promote the development,
the proliferation and the expansion of myeloid granulocytic and
monocytic progenitors with inhibitory function. Therefore, by
analyzing cytokines present in the microenvironment of tumors
of different histologies, we found that GM-CSF, G-CSF, and IL-6
allowed a rapid expansion of MDSC from progenitors present
in mouse and human bone marrow (BM), that we termed BMMDSC (Marigo et al., Immunity, 2010).
Aim of this project is the definition of the expression profile of
BM-MDSC, that can rapidly be generated in vitro. Moreover, this
information may guarantee a deeper comprehension of biological
mechanisms if expression data can be integrated with other gene
information; to this aim it is mandatory to use new platforms of
expression profiling, and to study the regulation of gene expression
at different levels.
Main results. We have recently defined growth factors able to
generate MDSC in vitro from human bone marrow precursors.
We demonstrated that combinations of some cytokines, such
as G-CSF, GM-CSF and IL-6 induce the expansion of BM
immature myeloid populations (BM-MDSC), with phenotype
and inhibitory activity comparable to patients’ MDSC. BM-
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MDSC are able to suppress the activation of both alloactivated
and mitogen activated T lymphocytes, while ex-vivo isolated BM
cells and untreated BM cells do not interfere significantly with T
lymphocyte proliferation. BM-MDSC consist of a heterogeneous
cell population comprising myeloid cells at various stages of
differentiation, ranging from more immature cells to mature
granulocytes and monocytes. We investigated which myeloid
subpopulation had the highest suppressive activity and our results
clearly indicate that only one fraction of BM-MDSC, containing
an immature myeloid population, has the suppressive activity.
This immature cell population has morphology and phenotype
resembling to promyelocytes, and it is able not only to block
lymphocyte proliferation, but also to affect IFN-γ production and
to induce T cell apoptosis.
When we investigated the relationship between T cell
activation and BM-MDSC-mediated suppression, we found that
the promyelocytic-like population was able to proliferate and
maintain its immature phenotype when co-cultured with activated
T lymphocytes; conversely, the same myeloid subset showed a
diminished proliferative index and differentiated to more mature
myeloid cells when co-cultured with resting T lymphocytes.
In the blood of breast and colorectal cancer patients we could
clearly identify an immature myeloid population resembling in
vitro generated BM-MDSC. Our data suggest that circulating
MDSC levels, phenotypically similar to those described in
human BM experiments, are clinically relevant and: (i) increase
over time in patients with progressive disease; (ii) correlate with
an established prognostic marker (i.e. circulating tumor cells)
in advanced breast cancer; and (iii) their persistently high or
increasing levels following chemotherapy are associated with poor
survival.
Conclusions and future perspectives. The identification of
this population with inhibitory function, and the efficient and
rapid in vitro generation gives us the opportunity to use this model
of expansion of human MDSC to study its expression profile
and to specifically define its regulatory network of expression.
In fact, the integrative analysis of micro(mi)RNA/mRNA
expression profiles allows to reconstruct a network of functional
interactions occurring in cells by analyzing the panel of potential
regulatory relationships predicted from sequence information.
Our integrative approach assumes that the final effect of a truly
functional interaction between miRNA and its predicted mRNA
targets can be seen as a pair of anticorrelated expression profiles.
According to the increasing experimental evidence supporting
the miRNA mechanism of target degradation rather than
translational repression, the integration of target predictions
with miRNA and gene expression profiles has been proposed
to improve the detection of functional miRNA-mRNA
relationships. Since miRNA tend to down-regulate target mRNA,
the expression profiles of genuinely interacting pairs are expected
to be anti-correlated. Integrative analysis can be performed
adopting a variational Bayesian model, or by using a non heuristic
methodology based on the anti-correlation between miRNA and
mRNA expression profiles.
Regulation of tumor dormancy: dissecting the
molecular pathways downstream of notch for
therapeutic purposes
Principal Investigators: Stefano Indraccolo, Alberto Amadori
Background. Angiogenesis contributes to regulate tumor
dormancy, a condition defined by the presence in the host of
fully transformed yet non-tumorigenic cells. Using a model of
angiogenesis-dependent dormancy of T Acute Lymphoblastic
Leukemia (T-ALL) cells, it was previously found that angiogenic
factors induce expression of the Notch ligand Dll4 in the
vasculature. Dll4 appears to activate Notch3 signalling in T-ALL
cells, an event which protects them from apoptosis and initiates
progressive tumor growth. These findings - reinforced by similar
observations in colorectal cancer xenografts - suggest that
endothelial cells embedded in tissues undergoing angiogenesis may
communicate activation signals to tumor cells, which contribute
to the switching towards an aggressive phenotype. Here we wish
to investigate whether novel Notch-targeted drugs could maintain
tumor dormancy in pre-clinical models of cancer.
Methods. Studies on T-ALL make use of a clinically relevant
model of engraftment of primary human leukemia samples in
NOD/SCID mice recently set-up in the lab. Specifically, the
hypothesis that blockade of the Notch3-Dll4 interaction by antiDll4 or anti-Notch1/3 antibodies could exert therapeutic effects
in T-ALL as well as solid tumors is being tested. Tumor burden is
quantified by measurement of blood parameters and live imaging
of the tumors. Effects of anti-Notch drugs on gene expression will
be analyzed by low density arrays on RNA extracted from FACSsorted T-ALL cells. The global effects of Notch inhibition on the
148
phosphokinome will be investigated by a microarray approach.
Results. A correlation was seen between the Notch/Fbw7
genetic status and expression levels of Notch-related transcripts in
T-ALL xenografts. Preliminary results indicate that anti-Notch1
treatment greatly delayed engraftment of T-ALL cells bearing
an active Notch pathway, including samples derived from poor
responders or relapsed patients. Anti-Notch1-treated mice had a
significant reduction in the percentage of blasts in the blood, the
spleen and the BM. Moreover, we observed an increase in the
levels of T-ALL cell apoptosis and a strong inhibitory effect on
Notch transcriptional profile following anti-Notch1 treatment.
Conclusions. These results indicate that Notch1/Fbw7
mutated T-ALL samples are suitable candidates for Notch targeted
therapy and highlight the potential of measurements of Notch
target genes as surrogate biomarkers of the therapeutic response.
Perspectives. Upon completion, this pre-clinical study will
enable us to plan a phase I clinical trial for Notch-targeted therapy
of relapsed or chemotherapy-resistant T-ALL.
Molecular analysis of Gastrointestinal Stromal
Tumors (GISTs) in clinical practice
Principal Investigator: Roberta Bertorelle
Background. The discovery in 1998 of the pathogenic
alteration of Gastrointestinal Stromal Tumor (GIST) has changed
the natural history of this tumor highly resistant to conventional
chemotherapy, providing a target for a molecular therapeutic
approach.
Mutations of KIT or PDGFRA gene, coding for class III
149
central role in the management of GISTs because different gene
alterations not only correlate with clinical behaviour, but also with
different responsiveness to targeted therapy. Moreover, primary or
secondary resistance are correlated to tumor genotype.
Aim of the study. The foundation of the Interdisciplinary
GIST Study Group (G.I.GIST) operating in Padua, have the
best management of the disease as its primary objective, and the
impact of a standardized molecular characterization of tumors in
a clinical setting.
Methods. Cases undergoing surgical resection at Padua
University-Hospital were collected. The enrolment was initially
retrospective (from 1998 and 2005) and prospective from January
2006. Molecular analysis has been performed on DNA obtained
from fixed tumor tissues by sequencing KIT exons 9, 11, 13 and
17 and PDGFRA exons 12, 14 and 18, following a molecular
tyrosine kinase proteins, account for about 75-80% and 8-10%
of the cases, respectively, and lead to a ligand-independent
activation of the receptor. Most of the mutations involve exon
11 of KIT gene (about 65%) being the spectrum of KIT exon
11 mutations heterogeneous. Mutations in other exons of KIT
gene include those in the regulatory extracellular domain (exon
9) and mutations of kinase I domain (exon 13) and kinase II
domain (exon 17), accounting for about 9%, 1% and 1% of cases,
respectively.
PDGFRA gene mutations involve much more frequently
kinase domain II corresponding to exon 18 (6-8%). Rare (<1%)
are mutations in the PDGFRA juxtamembrane region (exon 12).
About 10-15% of GIST’s cases carry wild-type KIT and
PDGFRA genes, additional unknown mutations sites being
potentially present. Molecular characterization of tumor plays a
150
algorithm that takes into account that mutations are mutually
exclusive. Moreover clinico-pathological parameters like tumor
size, mitotic index and tumor location were recorded for tumor
risk assessment.
Results. 157 GIST cases were collected so far. The frequency
of mutated GIST in our Caucasian patients was 82% (65%
KIT and 17% PDGFRA), while 18% were wild-type. The most
frequent alterations involve KIT exon 11, followed by PDGFRA
exon 18 and KIT exon 9 (65%, 16% and 10% of all mutated
cases, respectively). KIT exon 13, exon 17 and PDGFRA exon 12
were less frequently involved (3.9%, 0.8% and 3.9%).
Although KIT and PDGFRA mutations have a controversial
prognostic role, in our series KIT mutations, and in particular
exon 11 deletion involving codon 557 or 558, associate to high
risk of recurrence, to a worse prognosis compared to patients with
other or no mutations, thus representing a strong independent
negative prognostic factor.
Molecular genetic status in GIST correlates with clinical
behavior of the disease but it also predicts the response to treatment
with tyrosine kinase inhibitors. Primary resistance is conferred
by specific mutations, being exon 9 KIT and D842V PDGFRA
mutations the most frequently involved, while a secondary
resistance could occur during the course of therapy. These patients
should therefore benefit from a higher dose of Imatinib or should
be considered for a second-generation TKI treatment.
Conclusions. Molecular analysis of GISTs plays an important
role in the management of the disease. Mutational status could
be considered as a prognostic and predictive factor both for
metastatic and localized resected GISTs. Taking into account the
genetic status of the tumor, the physician could select patients
who benefit from Imatinib establishing the best dosage of the
drug or choose a second-line therapy, also making a prediction
of prognosis.
transplantation-associated viral diseases, donor lymphocyte
infusions of ex vivo-expanded allogeneic T cells to treat relapsed
hematological malignancies following allogeneic hematopoietic
stem cell transplant, and melanoma by infusing patients with
melanoma antigen-specific T cells. Nevertheless, a major obstacle
to the clinical diffusion of ACT is represented by technical factors
limiting the availability of adequate numbers of tumor-specific
T cells to transfer. Viral vector-mediated genetic engineering
of T lymphocytes may represent a valid tool to overcome such
limitations, leading to the rapid generation of large amounts
of tumor-specific T cells endowed with the desired specificity.
This goal can be achieved by transferring a) the TCR derived
from an antigen-specific T cell clone or b) a chimeric antigen
receptor (CAR), an artificial T cell receptor that combines the
extracellular single-chain variable fragment (scFv) of an antibody
with intracellular signalling domains, such as CD3.
Besides to chemical and biotechnological aspects, a powerful
input towards analysis of in vivo behavior of new pharmaceuticals
has come from development of detectors specifically dedicated
to small animals. These innovative instruments, that permit to
represent, characterize and quantify biological processes at cellular
and subcellular levels within living organisms, constitute a real
improvement for promotion and follow-up of new therapeutic
approaches with a consequent acceleration in their transfer to
clinical practice. In this regard, IOV has been equipped with an
outstanding platform for in vivo imaging, comprising a MicroCT
scanner, an apparatus for bioluminescence and a fluorescence
optical imager; these instruments are currently used to analyse
and monitor several experimental protocols.
Methods. TCR cloning from tumor-specific cytotoxic T
lymphocytes; development of CAR constructs; generation of
retroviral and lentiviral vectors; transduction and expansion of
antigen-specific mouse and human T cells; cytofluorimetric and
functional assays (cytotoxic activity and cytokine release detection);
in vivo monitoring of adoptively trasferred lymphocytes, and
analysis of tumor growth and response to therapy by optical
imaging.
Main results. In collaboration with Verona University, we
developed CAR directed to Prostate Specific Membrane Antigen
(PSMA) and Prostate Stem Cell Antigen (PSCA). In particular, we
could demonstrate that the anti-PSMA CAR construct inserted
into an eukaryotic expression plasmid leads to the production of
a membrane molecule on 293T cells, upon transient transfection,
Adoptive immunotherapy of tumors and preclinical
molecular imaging
Principal Investigator: Antonio Rosato
Background. Adoptive T cell therapy (ACT) is a form of
transfusion therapy involving the infusion of large numbers of
T cells to treat malignancies or infectious diseases. Successful
applications include the administration of virus-specific T
lymphocytes to protect immunosuppressed patients from
151
which is identifiable by anti-c-myc tag cytometry analysis and
has the correct molecular weight, as assessed by Western blotting.
Moreover, a LV vector has been also developed that is capable
of co-expressing both a CAR and a reporter gene (luciferase or
fluorescence proteins) and is endowed with a high transduction
efficiency in human T cells. These latter, upon repeated stimulations
with PSMA+ tumor cells, undergo a rapid expansion and generate
an effector population that exhibit strong and highly specific
cytotoxic activity, and exert therapeutic activity in vivo upon
adoptive transfer into mice bearing PSMA+ prostate tumors. On
the imaging side, it was not only possible to follow the biological
fate of transferred T cells, but several biodistribution studies
have been also carried out involving monoclonal antibodies and
the derived single chain fragments (scFv), and novel polymeric
antitumor drugs (bioconjugates between cytotoxic drugs and
hyaluronic acid).
Conclusions and future perspectives. The development of a
rapid and efficient protocol for the production of high amounts
of antigen-specific effector T cells against prostate carcinoma,
represents a fundamental prerequisite to translate this therapeutic
approach to the clinical settings. Therefore, it will be interesting
to verify the potentialities of the treatment with PSCA-redirected
T lymphocytes and of the simultaneous combined redirectioning
against both antigens to minimize the emergence of antigenic
escape mutants. Finally, optical imaging studies of cell, antibody
and drug biodistribution represent the basis for further in-depth
examination and validation with the SPECT/PET/CT apparatus
to be readily installed at our Institute.
(11q-) are highly predictive of decreased survival, whereas patients
with del13q (13q-) as a single abnormality have an excellent
prognosis with survival curves that are even better than those
with normal karyotype. Trisomy 12 conveys high risk of disease
progression, but in contrast to patients with deletions of 17p
and 11q, patients with 12 trisomy respond to fludarabine-based
therapy, and their survival is better. Due to the low proliferative
activity of CLL lymphocytes and their weak responsiveness to
classical B-cell mitogens, conventional cytogenetics does not
yield satisfactory results. Recently, chromosome banding analysis
has improved, thanks to the application of immunostimulatory
oligonucleotides (CpG) in combination with IL-2 during culture.
With this method the success rate reached almost 100% and
chromosome abnormalities have been described in more than 80%
of patients. Moreover, chromosome translocations, particularly
those involving the IgH locus at 14q32, seem to identify a distinct
subset of CLL with poor prognosis.
Aim of the study:
1)to evaluate the usefulness of conventional cytogenetics with
CpG oligonucleotide for detecting chromosomal abnormalities
in comparison to those described by interphase FISH
2)to explore the possible prognostic role of cytogenetic
aberrations, especially among the low-risk FISH group.
Methods. Peripheral blood or bone marrow aspirates
from patients with CLL at diagnosis are collected to perform
conventional cytogenetics and FISH analysis. CpG oligonucleotide
is added in association to the IL-2 to the medium for cytogenetic
culture. Interphase FISH analysis is performed using commercially
available probes for the loci of prognostic interest: 11q22.3
(ATM), 13q14.3 (D13S319), 17p13.1 (TP53), and centromeric
probe for chromosome 12. Preliminary data are available for 23
patients.
Results. In our case series, the success rate of cytogenetic
analysis using CpG oligonucleotides was 96%, with 61% of
samples showing clonal chromosomal aberrations. Among
abnormal cases, 50% of samples showed a complex karyotype (≥
3 chromosomal aberrations), and clonal evolution was described
in 36%. Normal karyotype was established in 32% of cases.
FISH analysis on interphase nuclei detected low-risk chromosomal
abnormalities in 45% (13q- as a sole abnormality) and 23% (no
cytogenetic aberrations) of the cases, and high-risk cytogenetic
abnormalities in 9% (11q-), 4,5% (trisomy 12), and 14% (17p-) of
Conventional cytogenetics and interphase FISH
analysis for a better prognostic assessment of
Chronic Lymphocytic Leukemia
Principal Investigator: Laura Bonaldi
Background. The need for accurate prognostic markers
in Chronic Lymphocytic Leukemia (CLL) is urgent. Major
breakthroughs were achieved by identification of specific
cytogenetic aberrations associated with clinical outcome by
interphase Fluorescence in situ hybridization (FISH) analysis.
FISH is able to identify genomic aberrations in approximately
80% of CLL cases and the most frequent alterations are deletions
in 11q, 13q, 17p, and trisomy 12. Deletions of 17p (17p-) or 11q
152
samples. Except for 13q deletions, that usually are cryptic changes,
all the remaining abnormalities described by FISH were present
at the banding analysis. Moreover, conventional cytogenetics
was able to describe additional chromosome abnormalities in
13 samples, and to better characterize 3 cases resulted normal as
judged by FISH.
Preliminary Conclusions. Mitogen stimulation with CpG
oligonucleotides is particularly useful in uncovering additional
chromosomal abnormalities compared to FISH. In particular,
the identification of subgroups with complex aberrant karyotypes
suggests that conventional cytogenetics might provide additional
prognostic information. Moreover, cytogenetics may help to
further understand the biology of CLL and its related lymphomas
or to differentiate between atypical cases of CLL and other
pathologic entities. We plan to provide a more exhaustive analysis
after the collection of one hundred samples.
153
Hereditary Endocrine Cancer Unit
Chief
Giuseppe Opocher, MD
Born in Treviso, November 5th 1950. Graduated in Medicine; Specialist in Endocrinology and
in Nuclear Medicine. Associate Professor of Endocrinology, Department of Medical and Surgical
Sciences, University of Padua. Since 2009, Head of the Hereditary Endocrine Cancer Unit and
Director of the Familial Cancer Clinic, Veneto Institute of Oncology.
Research Experience: Adrenal gland and hypertension, Atrial Natriuretic Peptide, Angiotensin II
receptors, NF1, VHL, SDHB and SDHC, SDHD, SDHAF2 and TMEN127 genes mutations
in familial and sporadic pheochromocytoma and paraganglioma. Multiple endocrine neoplasias.
Hereditary renal cancer. Author of 115 publications in peer-reviewed Journals (including top journals
as JAMA and Nature Genetics), Chapters in National and International books.
Main Pubblications
Exome sequencing identifies MAX mutations
as a cause of hereditary pheochromocytoma.
Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, Landa I, Leandro-García LJ, Nat Genet. 2011; 19:663-7
Letón R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gómez-Graña A,
de Cubas AA, Inglada-Pérez L, Maliszewska A, Taschin E, Bobisse S, Pica G,
Loli P, Hernández-Lavado R, Díaz JA, Gómez-Morales M, González-Neira A,
Roncador G, Rodríguez-Antona C, Benítez J, Mannelli M, Opocher G, Robledo
M, Cascón A.
Spectrum and prevalence of FP/TMEM127
gene mutations in pheochromocytomas and
paragangliomas.
Yao L, Schiavi F, Cascon A, Qin Y, Inglada-Pérez L, King EE, Toledo RA, JAMA. 2010; 304:2611-9
Ercolino T, Rapizzi E, Ricketts CJ, Mori L, Giacchè M, Mendola A, Taschin E,
Boaretto F, Loli P, Iacobone M, Rossi GP, Biondi B, Lima-Junior JV, Kater CE,
Bex M, Vikkula M, Grossman AB, Gruber SB, Barontini M, Persu A, Castellano
M, Toledo SP, Maher ER, Mannelli M, Opocher G, Robledo M, Dahia PL.
Peptide receptor radionuclide therapy in
a case of multiple spinal canal and cranial
paragangliomas.
Cecchin D, Schiavi F, Fanti S, Favero M, Manara R, Fassina A, Briani C, Allegri
V, Sansovini M, Bui F, Paganelli G, Opocher G.
Research
resource:
Transcriptional
profiling reveals different pseudohypoxic
signatures in SDHB and VHL-related
pheochromocytomas.
López-Jiménez E, Gómez-López G, Leandro-García LJ, Muñoz I, Schiavi F, Mol Endocrinol. 2010; 24:2382-91
Montero-Conde C, de Cubas AA, Ramires R, Landa I, Leskelä S, Maliszewska
A, Inglada-Pérez L, de la Vega L, Rodríguez-Antona C, Letón R, Bernal C, de
Campos JM, Diez-Tascón C, Fraga MF, Boullosa C, Pisano DG, Opocher G,
Robledo M, Cascón A A.
Germline mutations in TMEM127 confer
susceptibility to pheochromocytoma.
Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, Lechleiter JD, Nat Genet. 2010; 42:229-33
Sass M, Aronin N, Schiavi F, Boaretto F, Opocher G, Toledo RA, Toledo SP,
Stiles C, Aguiar RC, Dahia PL.
J Clin Oncol. 2011; 29:e171-4
154
Nursing Staff
Giuseppe Opocher
Stefania Zovato
Francesca Schiavi (Head of the Laboratory)
Francesca Boaretto
Sara Bobisse
Valentina Camozzi
Marina Lorusso
Beatrice Macino
Isabella Mammi
Paola Sartorato
Eugenia Sharova
Elisa Taschin
Roberta Pozzani
Christina Drace
Marina Lorusso
155
Mission
The mission of the Hereditary Endocrine Cancer Unit is
to provide genetic counselling, genetic analysis and clinical
surveillance to individuals with inherited endocrine tumors.
The main interest is focused on neural crest-derived tumors, in
particular pheochromocytoma and paraganglioma, von Hippel
Lindau disease, MEN 1 and MEN 2 syndromes.
Significant activity was also performed in patients with
inherited Cushing syndrome, Carney Complex, familial
hyperparathyroidism and inherited renal cancer. Also, this unit
performs clinical surveillance of individuals with genetic risk
for breast and ovary tumor as well as endocrinological clinical
activity.
San Paulo Endocrine Genetics Unit, University of Sao Paulo
School of Medicine, Brasil (Sergio Toledo);
The Beaston Institute for Cancer Research, Glasgow, UK (Eyal
Gottlieb).
University of Freiburg, Germany (Hartmut Neumann);
CNIO, Madrid, Spain (Mercedes Robledo);
UT Health Science Center, San Antonio, Texas, (Patricia
Dahia);
Clinical Activity
In 2010, the Endocrine Hereditary Cancer Unit performed the followings activities:
No.
Counselling for inherited endocrine tumors
175
Surveillance for inherited endocrine tumors
178
Surveillance for individuals with genetic risk of breast cancer
283
Clinical follow-up of individuals with oncological endocrine disease
692
Analysis of fragments in inherited endocrine tumors
1.428
Paraganglioma syndrome
paraganglia, after originating from the neural crest, differentiate
into sympathetic and parasympathetic paraganglia. The
main difference between the two types of paraganglia is the
endocrine function, since sympathetic paraganglia secrete
catecholamines while the parasympathetic paraganglia do not.
The main sympathetic paraganglia is the adrenal medulla and
Principal Investigators: Giuseppe Opocher, Francesca Schiavi
Paragangliomas are tumors of the paraganglia, a
neuroendocrine organ which originates from the neural crest.
The term paraganglioma includes two different tumors since
156
chain of the inner mitochondrial membrane to the Krebs
cycle enzymes in the mitochondrial matrix. SDH catalyses the
oxidative dehydrogenation of succinate coupled to the reduction
of ubiquinone and the formation of fumarate. SDHB, SDHC
and SDHD genes encode three of the four subunits of the
mitochondrial complex II (Fig. 1) and loss-of-function mutations
of one of the three genes cause decrease of prolyl-hydroxylase and
eventual hyperactivity of hypoxia inducible factor (HIF) 1 alpha,
which delivers a potent angiogenic and anti-apoptotic signal.
Loss-of-function mutations of SDHB, SDHC and SDHD genes
have been found in the majority of familial paraganglioma as the
cause of the paragangliomas syndrome type 4 (PGL 4), type 3
(PGL 3) and type 1 (PGL 1), respectively. An additional locus has
been identified (PGL 2), but the gene is still to be characterized.
Approximately 20-30% of HNP that occur without a family
history or syndromic stigmata may also have mutations in the
SDHD or SDHB genes and, more rarely, in the SDHC gene.
PGL1 can manifest as non-chromaffin head-and-neck tumors
only, adrenal and/or extra-adrenal pheochromocytomas only, or
a combination of the two types of tumors. In PGL1 a maternal
genomic imprinting is associated with the dominant transmission,
and the disease is only transmitted by the paternal branch. SDHD
Figure 1.
the tumor of the adrenal paraganglia is the pheochromocytoma.
Retroperitoneal and thoracic paragangliomas are localized at the
level of the organ of Zuckerkandl, prevertebral and paravertebral
thoracoabdominal and pelvic paraganglia or ganglia in ovary,
EGNA
ROVERE
ANTERIVO
CAPRIANA
Bolzano
testis, vagina, urethra, prostate, bladder or liver. Adrenal andDenno
MAGRÈ SULLA
DELLA
Capriana
STRADA DEL VINO
LUNA
Campodenno
TON
extra-adrenal pheochromocytomas secrete catecholamines, which
CAMPODENNO
Rovere della Luna
SALORNO
are also responsible for the chromaffin reaction of these tumor
CAVALESE
GRAUNO
Sporminore
Salorno
GRUMES
cells. Pheochromocytomas are usually benign tumors, and the
rate
Salurn
MEZZOCORONA
SPORMINORE
VALFLORIANA
Grumes
of malignant cases is about 10%. Parasympathetic paragangliomas
Spormaggiore
Mezzocorona
SOVER
VALDA
are mainly localized in the head and neck (HNP), i.e. at the level Mezzolombardo
FAEDO
SPORMAGGIORE
MEZZOLOMBARDO
FAVER
CASTELLO-MOLINA
of the carotid body and in the jugular tympanic region; most
San Michele
DI FIEMME
SEGONZANO
all’Adige
FAI
DELLA
CEMBRA
CAVEDAGO
LONA-LASES
are benign with less than 10% malignant cases. Multiple lesions
PAGANELLA
Cavedago
Fai della
T R E N T I N O A L T O A D I G E
occur in 20% of patients (50% in hereditary syndromes). The Paganella
NAVE SAN
GIOVO
Cembra
ROCCO
Bedollo
incidence of all paragangliomas, HNP and PHEOS is estimated
Andalo
LISIGNAGO
ZAMBANA
Trento
BEDOLLO
ANDALO
Zambana
to be less than 1/300,000 per year. They can occur as sporadic
TELVE
Albiano
LAVIS
cases but up to 30% of the cases of paraganglioma may have a
BASELGA DI PINÈ
Lavis
ALBIANO
PALÙ DEL
FERSINA
positive family history; in this case, paraganglioma may be part
SANT’ORSOLA
Baselga
TERME
di Pinè
FORNACE
of the paraganglioma syndrome, a hereditary tumor syndrome
TERLAGO
in which parasympathetic- and sympathetic-derived tumors% carrier
are
TELVE
FIEROZZO
TORCEGNO
DI SOPRA
CIVEZZANO
11
associated. Less frequently, paraganglioma may be part of the von
RONCHI
Civezzano
VALSUGANA
Hippel-Lindau syndrome, type 1 neurofibromatosis and, rarely,
PERGINE
6
FRASSILONGO
VALSUGANA
type 2 multiple endocrine neoplasia.
Trento
Telve
Pergine Valsugana
0
RONCEGNO
Borgo
The loss of function of succinate dehydrogenase (SDH) gives
TRENTO
Valsugana
VIGNOLA-FALESINA
origin to the tumors in paraganglioma syndromes. SDH is the
eukaryotic complex II which directly connects the respiratory
Figure 2. PGL 1 syndrome risk map in Trentino.
SP10
SP73 SP124
SP67
SP21
A22
SS90
SS43
SS612
SS12
SP71
SS421
SP58
SP90III
SP64
SP131I
SP131
SP83
SP76
SP224
SP225
SPI35
SP8
SP18
SS12
SS45BIS
SS12
SP47
SP66
SP17
SP85DIR SP85
157
SP65
the paraganglioma; 3) set up of an in vitro models of the PGL1
tumor where to test the biomarkers and the therapeutic effects of
hypothetical new drugs. The major goal of this project is to use
a combination of metabolomic and systems biology analyses to
find biomarkers and synthetic lethal genes in SDH-mutant cells.
Metabolomics has recently emerged as an invaluable analytical
tool to investigate metabolic alterations in cancer cells; thanks
to this approach, the metabolic profiles of prostate cancer,
glioblastoma, and other tumors have been recently revealed.
Metabolomics is not only crucial to uncover the determinants of
the metabolic transformation of cancer cells but it can also be
important to discover potential tumor biomarkers. In addition,
metabolomic data can be used to improve in silico models of
cellular metabolism, to better predict metabolic fluxes and also
to discover potential synthetic lethal genes. Heterozygous germline mutations in SDHB, SDHC, and SDHD subunits have
been found to predispose to a rare hereditary cancer syndrome,
hereditary paragangliomas and pheochromocytomas (hPGL). This
cancer syndrome is characterized by the development of tumors
of the chromaffin tissue arising in the adrenal medulla, defined
pheochromocytoma (PHEO), or derived from the parasympathetic
tissue of the head and neck defined paraganglioma (PGL). In
addition, SDHB mutation carriers have increased susceptibility
to renal cell cancers (RCC). Generally, the germ-line mutations
are followed by a somatic “second hit” of the normal allele in
the tumor cells, causing a complete loss of SDH activity in these
tissues. It is still unclear how SDH-deficient cells can survive and
proliferate in the absence of a functional TCA cycle. In fact, the
TCA cycle is in not only required to provide the mitochondrion
with redox equivalents for oxidative phosphorylation but it also
integrates several metabolic pathways that generate intermediate
metabolites for cellular growth and proliferation.
Therefore, it is reasonable to think that in the absence of an
intact TCA cycle, SDH-deficient cells would require a metabolic
adaptation, i.e. a rearrangement of the metabolic network of the
cell, in order to proliferate and accomplish the metabolic request
of a fast proliferating tumor tissue. Hence, SDH-deficient cells
would become dependent on specific metabolic pathways to
survive and proliferate but this will also represent their Achilles
heel. In fact, the targeting of these alternative metabolic pathways
should specifically affect the proliferation of mutant cells and will
not have an effect on the normal cells. These metabolic pathways
would be synthetic lethal (SL) with SDH. As we said, the major
mutations confer 50% penetrance by 31 years and 86% by 50
years. Despite the high risk of multiple paragangliomas, a strong
variability in phenotype has been observed among SDHD
mutation carriers and even among families segregating the same
mutation; this can range from early-onset with multiple localization
and malignancy, to late-onset with a single localization. We have
identified and characterized the SDHD founder mutation,
c.341 A>G p.Y114C. This founder effect occurs in a population
established by a small number of people, living in a well-defined
geographic area in Northern Italy (Fig. 2), comprising three
alpine valleys (Val dei Mocheni, Altopiano di Pinè and Val di
Cembra) and Alta Valsugana, being in the past a sort of a cultural
and geographic enclave (SDHD Trentino population). Actually,
for the SDHD c.341A>G founder mutation a large number
of carriers are available; in three years we collected 75 families
for a total of 233 mutation carriers. The penetrance and the
expression of the disease in this founder population has been well
characterized. Penetrance was about 80% and disease phenotype
was variable with high prevalence of bilateral carotid glomus
tumors, low prevalence of pheochromocytomas. The relative age
of this founder mutation has been investigated by examining the
distance over which haplotypes are conserved: it was estimated at
1400 a.D. The age of the mutation together with the low rate of
emigration/immigration have determined a high prevalence of the
mutation in the population of this particular area of Trentino, so
far estimated to be about 2%. In summary, we have detected and
fully characterized the largest SDHD founder effect. Combining
molecular medicine, history and molecular biology, now we know
when, why and how PGL1 developed and spread in the Trentino.
An example of how a rare disease may became endemic.
Endemic type 1 paraganglioma syndrome:
the search for new biomarkers and the
identification of a possible drug treatment
Trentino country harvests the largests (and probably the
oldest) founder effect for PGL1 syndrome. Despite the success in
the identification, description and characterisation of the endemic
PGL1 syndrome in Trentino we think there are still several
important questions to answer: 1) identification of a biomarker
of the disease; 2) identification of a possible drug treatment of
158
goal of this project is to use a combination of metabolomic and
systems biology analyses to find biomarkers and SL genes in
SDH-mutant cells (see Table 1). First, we will perform a large scale
unbiased metabolomic analysis of various body fluids and tumor
tissues from SDH-mutant patients. This analysis will then lead to
the characterization of the metabolic profiling of SDH mutant
cells. Importantly, this analysis would reveal potential biomarkers
to be used both for screening of the at-risk population and also to
follow the success of chemotherapy. The parallel transcriptomic
analysis will also be employed to establish the effects of different
SDH mutations on metabolism. To further investigate the effect of
SDH mutations on cellular metabolism, we will generate primary
cell lines from tumor tissues and perform steady-state and flux
endo- and exo-metabolomic analyses. With this metabolomic
database, we will build a specific in silico model of SDH-mutant
cells which will eventually allow us to predict SL metabolic
pathways. The validation of these SL reactions will be initially
performed on primary cell cultures.
has been established: the overall prevalence of mutations is near
to 40% of consecutive cases and more than 20% in apparently
sporadic cases. Again, a very high number of different predisposing
genes has been isolated, ten at the beginning of 2010, but the
number is increasing. Consequently, pheochromocytoma and
paraganglioma can well be considered an extremely interesting
model to study cancer genetics and to understand how multiple
genes can affect cancer development.
The eleventh gene, that we contribute to discover (Qin Y
et al, Nature Genet 2010), is the new tumor suppressor gene
TMEM127. Mutations of this gene predispose to the development
of pheochromocytoma: we have data supporting that TMEM127
plays an important role in the regulation of the mTOR pathway.
Genetic events leading to a deregulated mTOR signaling provide
tumors with a selective growth advantage. Indeed, numerous
oncogenes and tumor suppressors converge on the regulation
of mTORC1, including those that most frequently underlie the
development and progression of malignant tumors. Moreover,
elevated mTORC1 signaling has been detected in a large
percentage of the most common human cancers. These data could
suggest a role for TMEM127 in other tumors with disruption of
the mTOR pathway. In addition, they open the possibility that
additional cancer-related genes remain to be identified.
This project is aimed to the possibility to define the
TMEM127 phenotype, to evaluate the pathogenetic role of
sequence variant along the new gene, and to deeply investigate the
role of TMEM127 in disregulation of mTOR pathway including
the effect on new rapamycin inhibitors. The genetic analysis was
extended to 200 new cases of pheochromocytoma referred to our
clinic with apparently sporadic pheochromocytoma and wild type
for RET, VHL, SDHB, SDHC, SDHD gene analysis. Based on
preliminary data we have the possibility to clinically characterize
7 families with different TMEM127 mutations. Our preliminary
clinical data suggest an emerging pattern in association with
TMEM127 mutations: while bilaterality combined with familial
history accounts for almost half of the mutant cases, more than
one-third of the mutation carriers presented with a sporadicappearing, benign pheochromocytoma after the age of 40.
Although malignancy can also occur in association with these
mutations, this was a very infrequent presentation.
To address the problem of defining whether USV are
pathogenetic or not, first we will perform experiments using
in silico approaches in order to evaluate if they act as cis-acting
Table 1. Tasks of the project
Task 1
Enrolment of the cohort of SDH mutant patients and
collection of body fluids
Task 2
Metabolomic studies on human body fluids
Task 3
In silico model of SDH-mutant cells
Task 4
Establishment of human paraganglioma primary cell lines
Task 5
Steady-state endo- and exo-metabolomic and flux analyses
TMEM 127, the eleventh gene
Characterization of the entire spectrum of disease-associated
alleles is an overarching goal of contemporary and future medicine
and can inform on patient diagnosis, treatment and surveillance.
This may be particularly important in cancer genetics.
We have many arguments to support the concept that genetics
of pheochromocytoma and paraganglioma are really peculiar and
that this scientific knowledge is rapidly expanding. In any other
case of endocrine tumor a so strong relationship with genetics
159
membrane and the cytoplasm, both in a punctuate pattern and
as perinuclear clusters. Moreover, exogenous TMEM127 protein
associates dynamically with endosomes. Transcription signature
of TMEM127-mutant tumors revealed high statistical association
with kinase receptor signals which had been previously linked to
NF1 and RET mutants, inspiring further functional investigation.
In particular, TMEM127 knockdown does not induce HIF1alpha
and its targets in HEK293 or HeLa cells, nor increases RAS
activity, nor enhances AKT phosphorylation. On the contrary,
analogous tests demonstrated that TMEM127 knockdown leads
to increased phosphorylation of 4EBP1 in various cell lines,
establishing a relationship between TMEM127 and mTOR
signalling. Based on these results, it is conceivable that the most
important criterion for TMEM127 physiological and pathogenic
role might be the evaluation of its effect on mTOR signalling.
A reliable and clear functional assessment of the variants should
explore TMEM127 properties, namely its ability to modulate
mTORC1 pathway.
To complement genetic studies, we will study whether
TMEM127 mutations affect cellular sensitivity to pharmacological
mTOR inhibition in vitro and in a preclinical setting. Transcription
signature studies of TMEM127-mutant tumors revealed high
statistical association with kinase receptor signals. In particular,
the aberrant expression of TMEM127 results in an altered
mTORC1, but not mTORC2 signalling, while co-localization
studies denostrated that TMEM127 protein occupies the same
intracellular domain as active mTOR. Overall, results suggest
that TMEM127 contributes to controlling mTORC1 signals and
support a role for TMEM127 as a tumor suppressor.
regulatory functional variants, disrupting or creating regulatory
elements in DNA or RNA sequence.
After evaluation of sequence conservation it is interesting to
examine the different RNA stability when the variations are present
in the 5’ or 3’UTR by using the RNAfold web server (http://rna.
tbi.univie.ac.at/cgi-bin/RNAfold.cgi) that provides elements to
perform RNA secondary structure analyses. Functional regulatory
elements in TMEM127 will be identified by means of UTRScan
(http://bighost.area.ba.cnr.it/BIG/UTRHome/).
In addition, to better understand intronic mutations leading
to splicing defects, further investigations will be performed using
helpful tools like Human Splicing Finder website (http://www.
umd.be/HSF/), the SpliceView (http://wwwspliceview.html),
NNSPLICE0.9 (http://www.fruitfly.org/seq_tools/splice.html)
and others.
Secondly, by using in vitro analysis, in order to test whether
the UTR variations could actually affect the expression levels of
the TMEM127 gene we will prepare different plasmid constructs
in which the luciferase reporter gene is under the control of either
wild-type or mutant regions. We will use these plasmids to perform
transient transfections of the HEK293 cell line. Instead we will
investigate the effect of the intronic variations using minigene
system in order to identify intronic elements that enhance or
repress splicing.
The study of the functionality of the wild type TMEM127
protein as well as the effects of its newly described variants
has just begun. The physiological and pathogenic roles of
TMEM127 deserve further investigation. Wild type TMEM127
protein encoded by exogenous vectors localizes to the plasma
160
Department of Services
The Departments - Department of Services
161
Pharmacy
Chief
Angelo Claudio Palozzo, Pharm D
Graduated in Pharmacy in 1978 at the University of Padova, he specialized in Hospital Pharmacy
in Milano 3 years later. From 1981 to 1991 he works as a Pharmacist in several Hospitals of the
Veneto and Abruzzi regions. From 1991 he acts as Pharmacy Director in Veneto, and since 2007 he
directs the IOV Pharmacy. Following some stages abroad (Providence, USA, 1985 and Barcelona,
Spain, 1988), his interest has focused on pharmacokinetics, artificial nutrition, pharmacoeconomy,
epidemiology, and health governance. He is the national referent for Oncology within the Pharmacist
Italian Society SIFO, and he is member of several scientific societies (SINPE, ISOPP, ESOP).
He teaches pharmacology in several post-graduate schools, and is very active in promoting educational
issues. He is author of numerous scientific publications in the field of clinical pharmacology.
Main Pubblications
Photoreactivity of 5-fluorouracil under UVB light: photolysis Miolo G, Marzano C, Gandin V, Palozzo Chem Res Toxicol. 2011; 24:1319-26
and cytotoxicity studies.
AC, Dalzoppo D, Salvador A, Caffieri S.
Short-term bisphosphonate therapy could ameliorate Greggio NA, Pillon M, Varotto E, Zanin A, Case Report Med. 2010; 2010:206132
osteonecrosis: a complication in childhood hematologic Talenti E, Palozzo AC, Calore E, Messina C.
malignancies.
Italian Society for Parenteral and Enteral Nutrition Executive
Committee. Prevalence of home artificial nutrition in Italy
in 2005: a survey by the Italian Society for Parenteral and
Enteral Nutrition (SINPE).
Pironi L, Candusso M, Biondo A, Bosco Clin Nutr. 2007; 26:123-32
A, Castaldi P, Contaldo F, Finocchiaro E,
Giannoni A, Mazzuoli S, Orlandoni P,
Palozzo AC, Panella C, Pastò S, Ruggeri E,
Sandri G, Stella E, Toigo G.
162
Nursing and Technical Staff
Angelo Claudio Palozzo
Sonia Faoro
Francesco Paganelli
Maurizio Cavalli
Lucia Esposito
Enrico Gori
Marta Paulina Trojniak
Fabiola Bellotti
Silvia Bruno
Giovanna Cazzadori
Alessandra Misserianni
Anita Moresco
Francesca Pipitone
Luisa Schivo
Marinella Zanin
163
Mission
The Pharmacy Unit of the IOV has the mission of performing
and verifying all the activities involved in the preparation,
distribution and administration of pharmacologic products.
Clinical Activity
The clinical activities of the Unit include:
the implementation of the quality system and the computerized
management of all the prescriptions for individual patients;
the manipulation of cytotoxic drugs, biotechnologic drugs, and
antalgic recipes until the delivery of the ready-to-use product;
the storing and conservation of all the pharmaceutical products
in the appropriate quantities for satisfying the needs of the
different Units and in the appropriate temperature and humidity
conditions;
the management of the informative fluxes to central
pharmaceutical authorities and agencies;
the maintenance of the registries (Onco-AIFA for new oncologic
drugs; NSIS; SIRFAC) and the computerized management of
these databases;
the vigilance on pharmaceuticals and medical devices;
the appropriate periodical information to the personnel about
AIFA regulations on single drugs.
Christies NHS Trust, Pharmacy Unit, Manchester, UK
Dept. of Public Health Science, School of Medicine, Kings
College, London, UK.
Inside the IOV
The Pharmacy Unit interacts with several structures, and in
particular with the Clinical Oncology Units and the Unit for the
Introduction of New Drugs.
A retrospective observational study to
evaluate effectiveness vs. efficacy and to
determine the characteristics of patients with
lung cancer responsive to Erlotinib treatment
possible to obtain data on the efficacy of Erlotinib administered
to NSCLC patients as a second line treatment following a
therapeutic failure with conventional chemotherapy. The
observation period goes from January 1, 2007 to January 31,
2011, and comprehends 130 cases to be compared with data
present in the registration study (RCT). The retrospective analysis
will allow to identify critical points in the clinical practice, where
conditions are less standardized than in RCT. The major clinical
outcomes will be evaluated as Progression-Free Survival (PFS)
Principal Investigator: Angelo Claudio Palozzo
This project intends to retrospectively analyze data obtained
through the onco-AIFA register in lung cancer patients treated
with the target drug Erlotinib. From this registry, in fact, it is
164
according to the onco-AIFA Registry, Overall Survival (OS) and
Time to Progression (TTP), obtained from medical records. A
detailed analysis of potential factors able to predict response (such
as clinical features and genetic status) will also be performed, in
order to better ascertain the prescriptive appropriateness of this
drug.
schedules. This study has two major objectives:
1)to identify cost-effective anti-emetic treatments for every
chemotherapic regimen associated with nausea and vomiting;
2) to prepare appropriate anti-emetic kits to be distributed not
only inside the Hospital, but also for at home use. This last
approach could contribute to standardize the most appropriate
anti-emetic intervention for every anti-tumoral medication, to
obtain a better therapeutic compliance and hence quality of
life of patients, and finally to potentially reduce the costs of the
therapy of such adverse events.
A retrospective study to evaluate
effectiveness and prescriptive appropriateness
of Pemetrexed in patients with lung cancer
Retrospective analysis of the administration
of Fulvestrant in patients with ER+ metastatic
breast cancer: evaluation of appropriateness
and effectiveness of the treatment
Principal Investigator: Francesco Paganelli
The introduction of new anti-tumoral drugs often entails a
conspicuous economic burden to the community. Thus, the use
of these drugs is strictly regulated by a dedicated agency (AIFA),
which emanates periodic guidelines on their use and continuously
monitors the appropriateness of prescription. The extraction of
data from the onco-AIFA Registry and the record-linkage with
other administrative databases allows obtaining epidemiologic
data (OS, PFS, TTP, toxicities) at different complexity levels (local,
regional, national), thus contributing to delineate the effectiveness
profile of single drugs. These data can be compared with those
present in registration studies and for pharmacoeconomic analyses
(LY, Budget Impact), and may help the decision-making of the
health Authorities. Aim of this project is to compare therapeutic
regimens containing pemetrexed vs. gemcytabine in the treatment
of NSCLC. The project could also be a methodological example
which could be extended to other settings and drugs. In fact,
should the results be substantially different compared to those
obtained in registrative studies, the data could be communicated
to AIFA, with possible changes in the authorization to prescription
of these drugs.
Principal Investigator: Marta Paulina Trojniak
The layout of this study is similar to that conducted on
Erlotinib. The observation period goes from January 1, 2007
to January 31, 2011, and comprehends 100 cases of patients
bearing metastatic hormone-sensitive breast cancer treated with
Fulvestrant. Thanks to the data obtained from the onco-AIFA
Registry and the medical records, this project will allow to
calculate the effectiveness of the drugs in terms of TTP and OS.
The data obtained will permit to identify the subset of patients in
whom the therapy proved efficacious, and to define their clinical
and biologic characteristics; at the same time, the results will allow
to identify patients with clinical features which do not suggest the
use of this treatment.
Anti-emetic treatment in cancer patients
Principal Investigator: Sonia Faoro
It is known that a common side effect of most chemotherapic
treatments is nausea and vomiting. The present project stems
from the observation that in daily clinical practice, especially for
non-hospitalized patients, anti-emetic treatment often differs
from the guidelines of Scientific Societies, and it greatly varies
among patients, with poor control of the efficacy of the different
165
Thanks to standardization, quality controls, and the availability
of data from different sources and registries (AIFA, SIRFAC, SSI,
SCI), the Unit has activated several lines of research in pharmacoepidemiology and pharmaco-economics. In this setting, Dr.
Palozzo is the principal investigator of a regional 2011-2012
project on Health Technology Assessment, which involves most
structures all over the region, and clearly delineates a leading role
of this IOV Unit in the field of oncologic pharmaceutics within
the Veneto region. A future challenge for the Pharmacy, which
is going to move to a new and larger site within the Institute, is
the distribution of cytotoxic drugs over the entire Padova health
system; this implies an increment in work burden calculated in
about 25,000 additional preparations per year.
166
Cardiology
Chief
Alberto Banzato, MD
Degree in Medicine and specialization in Cardiology at the University of Padua with full marks
and honors. From 1994 to 2005 he participated in the opening and development of the Cardiology
Department and Coronary Care Unit of Este General Hospital. Besides the clinical activity, he
performs instrumental diagnostics and implants cardiac pacemakers and defibrillators. In 2006,
he was responsible for the Electrophysiology Unit of Chioggia General Hospital. Since 2007 he
has provided clinical and instrumental cardiology at the Veneto Oncology Institute with highly
specialized tasks as “preoperative stratification of cardiovascular risk.” He was appointed chief of the
Cardiology Unit in April 2010. He is the author of more than 40 scientific publications.
Main Pubblications
Low molecular weight heparin (parnaparin) for cardioembolic Angeloni G, Alberti S, Romagnoli E, Banzato Intern Emerg Med. 2011; 6:117-23
events prevention in patients with atrial fibrillation undergoing A, Formichi M, Cucchini U, Pengo V.
elective electrical cardioversion: a prospective cohort study.
Large infero-posterior wall pseudoaneurysm of the left Targa L, Gaglione E, Scattolin G, Formichi Ital Heart J. 2002; 3:758-61
ventricle: an unusual presentation.
M, Banzato A, Lucà MG, Corbara F.
Effectiveness of fixed minidose warfarin in the prevention of Pengo V, Zasso A, Barbero F, Banzato A, Am J Cardiol. 1998; 82:433-7
thromboembolism and vascular death in nonrheumatic atrial Nante G, Parissenti L, John N, Noventa F,
fibrillation.
Dalla Volta S.
A comparison of a moderate with moderate-high intensity Pengo V, Barbero F, Banzato A, Garelli E, Thromb Haemost. 1997; 77:839-44
oral anticoagulant treatment in patients with mechanical heart Noventa F, Biasiolo A, Zasso A, Dalla Volta S.
valve prostheses.
Revision and optimization of processes: a fundamental Corbara F, Scattolin G, Gabellini A, Caneve G Ital Cardiol. 1995; 25:859-75
timing for adequate use of the resources and technological F, Desideri A, Banzato A, Formichi M.
innovation. An example of intervention in the cardiology field
and considerations on “total quality” in medicine.
168
Nursing Staff
Alberto Banzato
Alessandra Bianchi
Caterina Fabris
Maria Cristina Pancaro
169
Mission
This Unit is mainly devoted to the cardiovascular surveillance
of patients undergoing surgical and/or chemo-radiotherapy
treatment, in order to determine individual cardio-vascular risk
and to monitor the potential cardiotoxicity risks linked to these
therapies. The activity is also addressed to the cardiovascular
monitoring in patients treated with conventional chemotherapy or
more recent biological drugs for the potential risk of cardiotoxicity.
The Unit also provides standard cardiologic support to other units
at the Institute. The nursing staff has, by nature and training,
human capacity and social skills appropriate to approach cancer
patients.
Clinical Activity
The clinical and instrumental pathways are performed mostly
on the same day in order to rapidly determine the cardiovascular
status thus limiting further patient access to the Institute. To
reduce the time between the diagnosis of cancer and its treatment,
access to cardiologic assessment is divided into different priority
levels that exclude the waiting lists for urgent situations (surgery,
chemotherapy start), and provide separate lists for less urgent and
follow-up patients. In the four years of activity, the Cardiology
Unit has refined a work team that provides oncology and
cardiology assessment, the definition of individual cardio-toxicity
risk, the choice of treatment and subsequent oncologic and
cardiologic follow-up. Early detection of cardiovascular damage
through a careful clinical and instrumental monitoring helps
to establish an early therapy in order to avoid worsening of the
damage. The reporting activity is handled through the computer
network in order to be able to ensure a real-time consultation.
During 2010, the Cardiology Unit carried out approximately
10,000 procedures: cardiology consultation, electrocardiogram,
transthoracic and transesophageal echocardiography at rest or with
pharmacological stress, dynamic electrocardiogram, cycloergometer
exercise test, carotid ultrasound, myocardioscintigraphy stress test
(in collaboration with Nuclear Medicine).
2010 Cardiology Unit Activity
4000
3934
3500
Numbers
3000
2801
2491
2500
2000
1500
1000
500
196
145
In collaboration with other Units of the Institute, the Cardiology
Unit participates in 19 clinical trials. It is currently involved in a
project with the Italian Society of Echocardiography.
170
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Major Research in Progress
Troponin dosage as an early marker of
cardiotoxicity during chemotherapy.
irradiation, aim of this study is to identify early markers of
cardiac damage. Troponin is a suitable candidate, but its use has
not been as yet validated. The study enrolls patients undergoing
standard chemotherapy and radiation therapy, patients treated
with Trastuzumab monoclonal antibody, and patients undergoing
IORT.
Principal Investigator: Alberto Banzato
In view of the potential cardiotoxic effect of many chemotherapy
regimens and radiotherapy, especially for left mammary gland
171
Psycho-Oncology
Chief
Eleonora Capovilla, Psychologist
Eleonora Capovilla, psychologist – psychotherapist, has developed and applies a psychological
approach that is specific for the oncological field, called API (Integrated Psycho-oncological
Approach). Formerly appointed to teach Psycho-oncology in the postgraduate course in Pain Therapy
and Palliative Cares at the University of Verona, she is adjunct professor of the University of Padua.
Besides teaching in various public training courses, she is author of a number of scientific works
in the field of psycho-oncology. In 1997 she founded the Veneto Regional Section of the Italian
Society for Psycho-oncology (SIPO) which she co-ordinated until 2002 and in that role she started
the Project “Humanisation of Cares in Oncology”. From 2000 to 2007 she was Regional Board
Member of the Italian Society of Palliative Care. From 2003 to 2007 she was vice-president of the
SIPO. Since 2007 she is a member of the Regional Committee for Palliative Care and Cure of Pain
in the Regional Observatory for Palliative Care and for Cure of Pain (Veneto Region). At present she
coordinates the National SIPO Committee for Medical Humanities.
Main Pubblications
Positive experience of intraperitoneal
chemotherapy followed by intravenous
chemotherapy in heavily pretreated patients
with suboptimal residual ovarian cancer and
primary peritoneal cancer.
Nicoletto MO, Dalla Palma M, Donach M.E, Tumori. 2010; 96: 918-925
Gusella M, Cappetta A, Shams M, Marchet
A, Nardin M, Pintacuda G, Di Maggio A,
Marchesi M, Carli P, Fiduccia P, Artioli G,
Nitti D.
La riabilitazione in psiconcologia: lo sviluppo Capovilla E, Serpentini S, Guglieri I, Cason E.
dell’approccio psicosociale dall’adattamento
alla spiritualità.
Noos: aggiornamenti in psichiatria, Il Pensiero
Scientifico Editore: Roma, in press.
Lo psicologo nell’accompagnamento
malato in fase terminale: l’esserci.
I. Testoni, D. Di Lucia Sposito, F. Martini (a cura
di) Atti del Convegno “Il morire tra ragione e fede.
Universi che orientano le pratiche d’aiuto”. Padova 2021 Marzo 2009. Monografia Endlife.it n°1. Capitolo
Terzo. 2010
al Capovilla E.
Quality of life after radical cystectomy and Månsson A, Caruso A, Capovilla E, Colleen S, BJU Int. 2000; 85:26-31
orthotopic bladder substitution: a comparison Bassi P, Pagano F, Månsson W.
between Italian and Swedish men.
172
Eleonora Capovilla
Malihe Shams
Lucia Bazzo
Eleonora Cason
Simona D’Ippolito
Irene Guglieri
Maria Rosa Mazzolini
Eleonora Pinto
173
Romina Spina
Marco Zoncapè
Mission
The Psycho-oncology Service offers to patients and families
a welcoming setting to minimize the negative impact of cancer
diagnosis and therapy. The main concern is to support the
psychological needs of patients and family members in each
phase of the illness, during both Day Hospital and ordinary
hospitalisation, and during outpatient treatment, with individual
as well as group treatments.
Clinical Activity
The service is addressed to patients in charge of the Operative
Units of the Veneto Oncological Institute, from first entry into
IOV up to the closure of follow-up, as well as to patients’ families.
It is also open to patients from different Hospitals.
The Psycho-oncological team supports patients according to
the integrated model typical of the psycho-oncological discipline,
which aims at the care of patients and families in collaboration
with the other professional figures involved (medical oncologists,
palliative care doctors, physicians, nursing and technical staff,
social workers etc.) and in collaboration with volunteers who are
active within the Operative Units of the Oncological Institute.
mindfulness-based programs for stress reduction;
relaxation groups.
Assistance to family members. Psycho-oncological initial
interviews, counselling and psychotherapy interventions.
In addition the Unit guarantees:
The presence of the psychologist in the ward team and the
psycho-oncological interventions to accompany patients and
families in advanced-terminal stages of illness.
National point of reference for the promotion of “Medical
Humanities” interventions, such as for example MBSR protocol
(Mindfulness Based Stress Reduction), the only experience in
progress at present for oncological patients in Italy.
Continuing education and supervision of AVO and ANGOLO
volunteers active in Clinical Oncology.
Main psycho-oncological assistance available for patients:
psycho-oncological entry structured interviews;
counselling;
psycho-educational interventions;
individual and group therapies;
Inside the IOV
Anesthesia
Clinical Oncology 1
Clinical Oncology 2
Oncological Surgery
Radiotherapy
Breast Unit
Melanoma and soft tissue sarcomas
Unit for hereditary cancers
Nursing Service
Orthopedic Clinic, Azienda
Ospedaliera di Padova
Unit of Physical Medicine and
Rehabilitation
Ospedale Sant’Antonio, ULSS 16,
Padova
Social Psychology - University of Padua
174
Fabio Giommi, Radboud University,
Nijmegen, (The Netherlands)
Fawzy I. Fawzy, UCLA School of
Medicine, Los Angeles, (California)
Camilla Zimmermann, FRCPC Head
Palliative Care program, University
Health Network
Interventions for stress reduction and
promotion of well-being based on the
methodology of Mindfulness (MBSR)
available to oncological patients in follow-up
the percentage of subjects without distress has been observed, a
reduction of subjects with severe distress and an improvement
of “state” aspects such as attention and awareness. As regards
other variables, though not statistically significant, important
improvements from the clinical point of view have been observed:
an increase in the number of subjects with “Emotional level
in the norm” and a decrease of the percentage of subjects with
“adaptation disorder” or “major depression disorder”. The Quality
of life appears tendentially increased.
Re-administration of the instruments at 6 and 12 months
confirms the results found in post-intervention as far as the
principal outcome variables are concerned.
The third intervention has just come to an end (JanuaryMarch 2011).
In conclusion, the analysis of data, in line with the results of
the literature, in the first evaluation post-intervention shows in
the sample of participants to the Mindfulness course statistically
significant improvements in the principal outcome variables, thus
showing the efficacy of the intervention.
Future prospects. Randomised study to evaluate the efficacy
of an MBSR protocol modified for oncological patients under
treatment.
Principal Investigator: Eleonora Capovilla
Background. MBSR is a program which has represented
in the last twenty years a frontier in the area of medical and
psychotherapeutic research called “integrative medicine” or
“mind-body medicine”, which considers mind and body as a unit
requiring to be understood beyond rigid divisions.
The MBSR program is a scientific program developed in the
field of behavioral medicine by Prof. Jon Kabat Zinn and his
collaborators at University of Massachusetts.
Aims: promoting in patients mindfulness-based strategies
for fatigue and stress management.
1)Promoting and implementing an approach of preventionrehabilitation which allows an improvement of the quality
of life of cancer patients. The intervention is not limited to
the acute therapeutic phase, it reduces hospitalisation and the
pharmacologic load of assistance.
2)Implementing a global approach to the patient according to
the principle of “simultaneous care”.
Methodology. Starting in January 2009, three interventions
have been carried out, involving a total of 47 participants.
Quantitative analysis. PRE-POST intervention administration of psychometric instruments : EORTC QLQ-30, Psychological
Well being Index, Kentucky Inventory of Mindfulness Skills
(KIMS), Mindful Attention Awareness Scale (MAAS), Hospital
Anxiety and Depression Scale (HADS).
Descriptive analysis. Main outcome variables, level of
distress and specific abilities of Mindfulness: re-administration
6-12 months.
Qualitative analysis. Administration of a personal data form,
assessment of motivation and expectations; content analysis;
audio-recordings of sessions; administration of evaluation form
12 months after the end of the course.
Main results. The main results regard the first and second
intervention and can be summarised as follows: an increase in
The practice of informed consent to
anesthesia: a randomised study between
conventional and integrated approaches
Principal Investigator: Eleonora Capovilla
Background. The project’s aim is to evaluate both the
emotional state of patients in pre-surgery phase, considered as a
particularly critical moment, when mood variations may condition
also the ability of correctly receiving information and instructions
from the curing staff, and – through such evaluation – to facilitate
the communicative-relational process during the diagnosticinformative interview with the anesthesiologist. The present
project, in collaboration with the Anesthesia Unit, originates
from the perceived difficulties in clinical practice of managing the
anxiety of patients during the anesthesiological pre-surgery visit
and from the observation, on the day of surgery, that the patients
have failed to understand some information.
175
An ad hoc intervention has therefore been devised, whose
effectiveness will be tested. For the study, an experimental group
of patients has been formed, to whom the anesthesiological presurgery visit has been preceded by a briefing with the psychooncologist and by a subsequent contact between the latter
and the anesthesiologist, aimed at adopting the most efficient
communicative strategies to be used with a patient. This group has
been compared with a control group: traditional anesthesiological
pre-surgery visit (with no intervention of the psycho-oncologist).
Methodology. Randomised prospective monocentric study
including a total of 240 patients (women with mammary
carcinoma awaiting for surgery). The patients participating in the
study are assigned to the two groups in a randomised way.
In group P the integrated psycho-oncological approach
is adopted: Group A (control group) simply undergoes the
traditional anesthesiological visit.
The following steps will be followed:
1)Informative briefing and anesthesiological evaluation: the
anesthesiologist after the clinical evaluation informs the patient,
following a fixed protocol subject to periodic reassessment, in
order to obtain the patient’s informed consent to anesthesia.
2)Structured psycho-oncological interview: the psychooncologist gathers useful information for the subsequent
anesthesiologist-patient communication and offers a setting for
the aknowledgement and redefinition of the patient emotional
experience.
3)State Trait Anxiety Inventory (STAI) for the evaluation of
the state of anxiety. This is administered in the two groups
before randomisation and after the signature of the informed
consent.
4)Questionnaire for the patient to assess the subjective
perception of the information received and the degree of its
comprehension.
5)Questionnaire for the anesthesiologist to assess the degree of
difficulty perceived in managing the talk with the patient.
Results. Data have not shown a significant decrease of anxiety
in the experimental group. A significant difference between the two
groups regarding anxiety is shown, instead, in the sub-population
of patients with high anxiety (STAI>51). Both groups showed full
comprehension and a high degree of perceived satisfaction for the
information received.
In conclusion, the results show that the basic factor for an
adequate management of a pre-surgery anesthesiological interview
is the relational quality. On the other hand, both the selection of
the anesthesiologist for the study – highly motivated and sensitive
to the emotional-relational issues – and the “learning factor”
(training to relation and communication provided by the psychooncologist during the informative sessions between the latter and
the surgeon in the two years of the study) could have reduced the
difference in approaching the patient between the experimental
and control group.
Pilot project: emotions in music, “The sounds
to tell it” Proposal for a social Music
Therapy
Principal Investigator: Maria Giacobbo
This study aims to verify the influence of social Music Therapy
on the oncological patient emotional and anxiety state and on
his death representation. It also aims to evaluate the potential of
music experience in conveying emotions and how music could be
the starting point to revise the experience of illness and to give it a
new meaning. The study takes place in Pollini’s academy of music,
with the participation of the Oncological Institute of Veneto and
the University of Padua, with the perspective of including and
reinforcing a supportive social network.
Subjects. 100 patients aged between 25 and 70, with first or
second stage cancer diagnosis, on medication at the Oncological
Institute of Veneto.
Measures. After signing informed consent, research
partecipants will fill in the following questionnaires, before and
after the study:
BDI-II (Beck Depression Inventory-II);
POMS (Profile of Mood States);
TDRS (Test Death Representation Scale).
After each of the five meetings, partecipants will fill in a
questionnaire to evaluate the emotional state related to listening
to the music.
176
Programs and Perspectives for the Future
The Unit intends to pursue and develop the field of researchintervention related to the Medical Humanities; to develop
research projects regarding the advanced stage of illness, with
particular regard to the areas of quality of life and doctor-patient
communication, starting from the validation and creation of
psychometric instruments of measure that may allow a rigorous
approach (the Italian validation of the QUAL-EC test for the
assessment of the Quality of Life in cancer patients in advancedterminal phase is already under way).
177
Tumor Registry
Chief
Paola Zambon, MD
Born on 05.09.950, Researcher, Department of Oncology, University of Padua. Education: July 1976:
Degree in Medicine, University of Padua (cum laude); 1979: OMS Epidemiology Course in Brussels;
July 1979: Post graduate Specialization in Occupational Medicine, University of Padua (cum laude);
December 1982: Post graduate Specialization in Allergology, University of Padua (cum laude); November
1984: ISS Course for planning study on occupational epidemiology, Rome. Professional Activity: 1976 1987: MD at the Institute of Occupational Medicine, University of Padua; 1979: Fellowship on primary
aluminium production risk at the University of Padua; 1980-1986: Fellowship at the High Specialization
Regional Centre on Environmental Cancerogenesis; 1988: Award for a study on cancer risk for silica
exposure; 1988 - Researcher at the Faculty of Medicine - University of Padua. 2000-: coordinator of the
Veneto Tumor Registry; From 2003-: she is in charge of the Regional Centre Veneto Tumor Registry.
Main Pubblications
Cancer prevalence in Italy. Patients living Guzzinati S, Dal Maso L, De Angelis R (Coordinators); Airtum Epidemiologia e prevenzione
with cancer, long-term survivors and cured Working Group.
2010; suppl2; 34: 1-188
patients.
Cancer incidence in people with AIDS in Polesel J, Franceschi S, Suligoi B, Crocetti E, Falcini F, Guzzinati S, International journal of cancer
Italy.
Vercelli M, Zanetti R, Tagliabue G, Russo A, Luminari S, Stracci F, 2010; 127:1437-1445
De Lisi V, Ferretti S, Mangone L, Budroni M, Limina Rm, Piffer S,
Serraino D, Bellù F, Giacomin A, Donato A, Madeddu A, Vitarelli S,
Fusco M, Tessandori R, Tumino R, Piselli P, Dal Maso L, Zambon P.
Occupational exposure to pesticides and Schmeisser N, Kaerlev L, Bourdon-Raverdy N, Ganry O, Llopis-González Cancer causes & control,
bile tract carcinoma in men: results from a A, Guénel P, Hardell L, Merletti F, Zambon P, Morales-Suárez-Varela M, 2010; 21:1493-1502
European multicenter case-control study.
Olsen J, Olsson H, Vyberg M, Ahrens W.
Sarcoma risk and dioxin emissions from Zambon P, Ricci P, Bovo E, Casula A, Gattolin M, Fiore A R, Chiosi Environmental health: a global
incinerators and industrial plants: a F, Guzzinati S.
access science source 2007;
population-based case-control study (Italy).
6:1-10
Efficacy of HPV 16/18 vaccines on sexually Giorgi Rossi P, Zorzi M.
active young women and the impact on
organized cervical cancer screening.
Acta Obstet Gynecol Scand.
2010; 89:846-7
178
Paola Zambon
Maddalena Baracco
Emanuela Bovo
Antonella Dal Cin
Anna Rita Fiore
Stefano Guzzinati
Daniele Monetti
Alberto Rosano
Carmen F. Stocco
Sandro Tognazzo
Manuel Zorzi
Susanna Baracco
Carla Cogo
Chiara Fedato
Melania Pendenza
Alessandra Greco
179
Mission
The main aims of the Veneto Tumor Registry are to define the
incidence of neoplastic diseases; to conduct epidemiological studies
and to evaluate the resources employed in the treatment of cancer;
to coordinate the epidemiological aspects of the implementation,
monitoring and evaluation of cancer screening, at a regional level.
The Registry is part of the Italian Association of Cancer
Registries network (AIRTUM), the European Network of Cancer
Registries (ENCR) and the International Association of Cancer
Registries (IACR).
Research Activities
The Registry participates in the development and management
of the Italian Network of Tumor Registries (AIRTum) database
and in the preparation and publication at a national level of
the incidence, survival and prevalence data. The Registry also
participates in the same project at a European level involving
the European Union and candidate states, in the automated
information system of childhood cancer (ACCIS) and the
European project to identify useful indicators for the organization
of health care systems (CaMon ).
Within the coordination of cancer screening, the Registry
performs the following tasks: link between the National Screening
Centres and Italian Regional Reference centres, coordination
and epidemiological support for screening programs, design and
maintenance of information systems, monitoring of process and
quality indicators, organization of specific training programs,
implementation and evaluation of the impact of screening,
coordination of reporting.
Furthermore, the Registry participates in the multicentre
Italian IMPACT study, to assess the impact of mammographic
screening and in the Italian multicenter NTCC study on the use
of the HPV test in cervical cancer screening.
Defining the incidence of neoplastic diseases in a population
of 2,300,000 residents, the Registry develops indicators of risk
(incidence), results (survival) and burden of care (prevalence)
to provide health authorities with the necessary tools to control
neoplastic diseases and plan health policy interventions.
Analyses of the temporal and geographic variation in the
incidence of cancer, at small area level (municipalities and Local
Health Units), are periodically carried out.
A study on the appropriateness of diagnostic and therapeutic
procedures has been started. Evaluation of colorectal cancer is
currently underway and we aim to expand this experience to breast
cancer. Some analytical epidemiology studies have been activated.
With regards to environmental risks, a study on the risk of
leukemia and neuroblastoma in children in relation to exposure to
electromagnetic fields and a case-control study on non-Hodgkin’s
lymphomas and sarcomas in relation to environmental exposure
to dioxins produced by incinerators are in progress.
An update of the studies on occupational cancer and AIDS/
cancer relationship are being carried out. A collaborative study
aims to use population-based electronic health records to study
the morbidity and mortality of cancer and non-cancer patients.
Study on the Impact of Breast cancer
screening
mortality rates, of incidence rates of advanced lesions and of
mastectomy rates in women who usually accept the mammographic
screening invitation compared to those who usually do not.
The study involves women aged 50-69 yrs invited to the first
round of mammographic screening in selected areas, categorized
As part of the multicenter study “Impact of mammographic
screening”, the Veneto Tumor Registry participates in a cohort
study whose objective is to estimate the reduction of breast cancer
180
Study on the Impact of Cervical cancer
screening
as “frequent”, “irregular” or “never” attenders in relation to
adherence to subsequent screening invitations.
Information on the possible diagnosis of breast cancer and life
status is retrieved by means of linkage between different archives.
The Registry is also involved in a sub-study involving the
breast cancer screening program of the LHU of Rovigo, involving
a cohort of 23,506 women aged 50-69 yrs, invited to the first
round of screening in 1999-2001, in which a total of 509 were
diagnosed with breast cancer. Data collection is in progress.
The Registry is involved in the multicenter study entitled
‘‘Impact of cervical screening”. This study aims to assess the
impact of organized cervical screening programs on cervical cancer
incidence and mortality in areas covered by cancer registries.
More specifically, the study aims to describe the temporal trends of
incidence and mortality rates of cervical cancer in the Italian areas
covered by a Tumor Registry, by age, geographic area, histology
and stage at diagnosis, to compare the incidence rates of cervical
cancer before and after screening in the Italian areas covered by
a Tumor Registry and to estimate the fraction of cervical cancers
attributable to potential problems of the screening process.
The study regards the cases of cervical cancer diagnosed
in areas covered by a Tumor Registry, in women of all ages,
before and after the activation of a cervical screening program.
For each case, specific data on the screening history, the lesion and
the life status of the person are collected.
The Registry participates in the study with 342 cervical cancer
cases diagnosed between 1997 and 2005 in eight LHUs (Belluno,
Feltre, Bassano, Asolo, Dolo Mirano, Rovigo and Verona).
Data collection ended in December 2010. The central study
coordinator is currently processing the data.
Study on the Impact of Colorectal cancer
screening
The Registry coordinates the multicenter study entitled
“Impact of screening”. This study aims to assess the impact of
organized screening programs on colorectal cancer incidence and
mortality in areas covered by cancer registries. More specifically,
the study aims to describe temporal trends in incidence and
mortality rates of colorectal cancer in the Italian areas covered
by cancer registries during pre and post-screening periods, by
age, geographic area, histology, stage at diagnosis and disease site,
to compare the incidence rates during pre-and post-screening
periods according to the different diagnostic modalities in relation
to screening by record-linkage procedures, to evaluate the survival
of populations in screening and non screening areas in relation to
distributions of stage at diagnosis and to quantify other effects of
screening programs such as the impact on invasive surgery rates as
well as neo-adjuvant and adjuvant treatments.
The study involves all cases of colorectal cancer diagnosed in
areas covered by a Tumor Registry in subjects aged between 4079yrs, before and after colorectal screening programs. For each
case, specific data are collected regarding the screening history, the
type of lesion and life status of the person.
The Registry participates in the study with 2,086 colorectal
cancer cases diagnosed between 2000 and 2005 in three LHUs
(Feltre, Dolo Mirano and Rovigo). Data is currently being
collected.
N°
2000-05
Ulss 13 – Dolo Mirano
2000-05
935
2000-05
758
56
Ulss 2 – Feltre
1997-2005
44
Ulss 3 – Bassano
1997-2005
38
Ulss 8 – Asolo
1997-2005
68
Ulss 13 – Dolo Mirano
1997-2005
31
Ulss 18 – Rovigo
1997-2005
69
Ulss 20 – Verona
1997-2005
36
The Veneto and Tuscany Cancer Registries are currently
involved in a project on the estimated health care costs of cancer
patients, initiated by the National Institute of Health, the
University of Rome “Tor Vergata” and the Institute for Research on
393
Ulss 18 – Rovigo
1997-2005
Evaluation of the costs of cancer care in Italy:
an approach on colorectal cancer patients in
the Veneto and Tuscany Regions
N°
Ulss 2 – Feltre
Ulss 1 – Belluno
181
Population and Social Policies. This is one of the first experiences
on the “cost” evaluation of cancer patients in the Veneto and
Tuscany Regions, using a record-linkage between the incidence
data of “cancer registries” and the economic information obtained
from the hospital discharge records by means of Drug Related
Group (DRG).
The preliminary results obtained by examining a limited
cohort of incident cases were:
a “U”-shaped trend of costs in the 3 stages of the disease (early
stage - 12 months from diagnosis, intermediate and terminal 12 months from death);
an increase in the cost for the more advanced stages of cancer;
a decrease in the cost with increasing age.
cancer in these regions is approximately 300 cases in the Bolzano
Province, 300 in Trento Province, and 200 in Belluno Province.
Patients are identified through the records in the cancer registry.
Study design/Analytical procedures
The self-administered questionnaire that will be used in this
study has been developed by the scientific coordinator of the
study (FDV) and has been tested on a series of patients from the
department.
Participants indicate on the questionnaire, whether they are
willing to provide a blood sample. Within three months after
returning the questionnaire, patients are given a date for blood
sampling. Blood sampling takes place in the hospital department,
where the patient is usually followed-up.
Sample elaboration is done in the molecular biology laboratory
in Merano. DNA is extracted and stored; RNA is obtained from
DNA. Direct sequencing will be used for mutation detection.
Cases extracted from the Veneto Tumor Registry data base are:
353 breast cancer and 89 ovary cancer.
The final goal of this first study is to estimate the costs of cancer
survivors, by combining the cost estimates with the estimates of
prevalent cases. The possibility of using other administrative data,
such as outpatient services and pharmaceutical expenditure files,
could help to better determine the cost of cancer patients during
different diagnostic and therapeutic phases, also taking into
account the recent dynamics of moving some treatments from a
day-hospital to an outpatient regimen, such as chemotherapy.
Statistical analysis
Analysis will be done using standard descriptive and analytical
statistical methods. Mutations will be described and compared
to the database of the Breast Cancer Information Core (BIC)
(Szabo, Hum Mutat 2000). The association between presence of
a mutation and clinical-pathological factors will be assessed using
the chi-squared test for categorical variables and the t-test test for
continuous variables. To estimate the risk of carrying a mutation
in relation to the degree of familiarity and other risk factors
regression methods will be applied. Recurrent founder mutations
will be validated by haplotyping.
Genetic-epidemiological study of BRCA1
and BRCA2 founder mutations in sporadic
and familial breast-ovarian cancer in the
population of South Tyrol and the Alpine
region.
The aims of this study are to define:
frequency of familial breast and ovarian cancer in the Alpine
region;
frequency of founder mutations in breast and ovarian cancer,
both in familial and in sporadic cases;
mutation spectrum in the Alpine region and the associated
specific risks of cancer;
variability of the clinical phenotype given specific mutations.
The target is the patient population diagnosed with breast or
ovarian cancer in the Alpine region of Northern Italy, in particular
patients in the Provinces of Bolzano (commonly known as South
Tyrol), Trentino, and Belluno. The annual incidence of breast
182
The RESEARCH
THE RESEARCH
185
Scientific Director Address
The RESEARCH - SCIENTIFIC DIRECTOR Address
187
General Considerations
The Scientific Directorate’s mission is to
supervise basic, translational and clinical research
at the IOV, as well as to implement strategies
for pursuing cutting-edge areas in oncology.
At the same time, a major endeavour is the
constant scouting to offer all IOV researchers
new opportunities to find the financial resources
needed to face the challenges of modern
biomedical research.
In view of its nature as a true Comprehensive
Cancer Centre, the IOV does not operate as
an isolated entity in the medical and scientific
milieu of the surrounding area, but more rather
established strong links with all the subjects
involved in biomedical sciences, allowing for a
complete vision and integrated implementation
of all clinical, management and research tasks
undertaken. Indeed, many components of
our staff are also Members of the Faculty of
Medicine of Padua University, and as such are
engaged in an articulated mission, which entails
patient cure, research, and teaching.
A leading, firm concept of the Scientific
Directorate is that no excellence in clinical care
can be reached in the absence of an outstanding
level of research. Instead of detracting from the
mission of improving prevention, diagnosis,
treatment, and quality of life of cancer patients,
the rapid application of knowledge emerging from
research greatly helps in elevating the general
levels of assistance. A virtuous circuit must be
established between the ward and the laboratory;
innovative results (such as the information
acquired from pre-clinical models) must rapidly
188
be transferred from the bench to bedside, but also viceversa, in
that samples from patients must come back to the laboratory to be
examined and “teach” physicians and biologists newer and more
refined information. In this frame, we do not feel it appropriate to
distinguish research activities into basic, translational and clinical
investigation.
Although the Institute has undergone great cultural and
scientific expansion since its establishment in 2006 and it is now
fully mature as a true Comprehensive Cancer Center, the strategy
underlying its foundation was complex, and it has required great
prudence to succeed; much more attention will be needed to
implement and foster this operation in the next few years. Indeed,
the IOV was not created as a new entity in a cultural desert, but
originated in a very fertile environment of public structures where
oncology was already a piece of excellence within local medical
culture. Thus, re-organizing the entire oncologic research and
clinical assistance network was not a trivial task, but required
great acquaintance with the pre-existing expertise and wise
strategies, from both the political and scientific points of view.
Due to its small dimension, the IOV does not aim (nor in fact
could) at absorbing all the activities related to cancer research and
care; instead, it is our purpose to select strategic areas where a critical
mass has already been achieved or where high-quality expertise is
scattered throughout different laboratories and/or clinical units,
and to concentrate and implement this body of competence in
order to get higher competitiveness levels.
Near to the end of my commitment as Scientific Director,
however, some general considerations on the role of the IOV
within the national IRCCS network are due. My Institution is
part of the national health system and is not a private institution
based on private funding, such as a sizable part of the IRCCS.
It has always been unclear to me how different institutions with
different status (public and private) could benefit from a common
status (for instance the access to the Ricerca Corrente funding) but
partly comply with different rules, nor did I understand how these
different Institutions complying with partly different rules could
by the end be melted in a single pot and evaluated all together
according to identical parameters. I will briefly illustrate a few
examples of this inconsistency.
are different among private and public IRCCS. In public IRCCS,
the Scientific Director has an exclusive employment with the
Ministry of Health, and no other activities are permitted (for
absurd, a pedestrian interpretation of the law would also preclude
scientific research!). Thus, to scientifically direct my Institute, I
had to abandon my academic position, the teaching, the direction
of a Department and of a Specialization School, the possibility of
participating in the national academic life, and many other things.
The same does not occur to colleagues scientifically directing
private IRCCS, who maintain all these positions and prerogatives.
This is not a trivial issue of syndical nature: the renounce to
every commitment by the Scientific Director could preclude the
engagement in public IRCCS of more young, active and motivated
researchers, who would have trouble in abandoning their career
track, and live room as Scientific Directors in public IRCCS to
people at the end of their career, less creative and active.
I. Public and private IRCCS benefit from, and in this regard
they must comply with, rules shared among all the IRCCS; thus,
it is unclear to me why the rules for hiring a Scientific Director
III. A last observation to the IRCCS system, which is not
dictated, as the former also are not, by a critical situation of my
Institute, which instead has a very good positioning among the
II. Public Institutions must comply with public Health System
rules, which are much stricter compared to private institutions.
This is true for hiring people, or for purchasing material from
companies, even when the grant comes to the researcher from a
private charity, and this may cause complications, delays and often
the loss of convenient pricing of some material. As personnel who
refer to both a University department and a public IRCCS, we
several times experienced difficulties in spending money when
the grant had to transit through the IRCCS administration. This
is not attributable to a deficiency of our Administration (which
instead always does its best, and more, to facilitate our problems)
but to a viscous array of rules inherent to certain public entities.
It is therefore easy to understand that the starting conditions for
private and public IRCCS are not the same; yet, by the end of
the year, all the IRCCS are classified in order of productivity (and
eventual financing by the Ministry), irrespective of their public or
private status. To me, this looks like a 100 yard contest in which
males and females, adults and juniors participate all together, and
the athletes are finally classified irrespective of their age or sex. Is
this fully fair, when these classifications are publicized, and you can
see them everywhere, in the specialized and non-specialized press,
without any caveat, comment or explanation?
189
IRCCS, in terms of both overall production and productivity. Can
we compare the production of huge Institutes, having a long history
and a great number of staff researchers, with the production of
newly founded, small Institutes? Yet, as far as I know, the “Ricerca
Corrente” funding is mostly based on total IF generated by the
Institute, and the weight of other parameters (and in particular
productivity, intended as the total research output divided by the
number of staff members) is more limited. It is my firm hope that
the recently established Research Direction of the Health Ministry
could find more appropriate algorythms to evaluate private and
public IRCCS; indeed, a series of very positive signals in terms
of efficiency and transparency have already been sent by this
Direction. Nevertheless, it would also be necessary to revise the
legal frame regulating the IRCCS on the whole; the 288 law is not
that recent, and it may be inadequate to face the changing world
of the Italian sanitary research and of the Institutions that should
lead this research.
These things are very often said among Scientific Directors,
but much more rarely publically discussed and even less written;
it is probably time to tackle this matter in a transparent and
appropriate manner, in the higher interest of the Institutions and
the Health System which we have the honour and the burden to
represent and serve.
190
Scientific Directorate Organization
SIPS: a software tool for
research administration
The Scientific Directorate is responsible for:
Research Administration
Responsible: Alessandro Andretto
Responsible: Daniela Battistuzzi
The Italian Ministry of Health
(MoH) allocates resources through a
performance-based funding system to
IRCCS. The total normalized impact
factor of publications is the indicator
of the scientific productivity of every
IRCCS. Fifty percent of the total
of MoH funds is allocated with regard to this indicator, while
the capacity to attract resources for research and convert it into
clinical practice accounts for another 15% of MoH funds. Thus,
65% of the MoH funds are determined by scientific publications.
The IOV Scientific Directorate recently put in place a new
proprietary software for the management of the institutional
scientific publication database. The new System was created on
the basis of the afore-mentioned MoH criteria and is aimed at
collecting quantitative (article, number of authors and researchers)
and qualitative (bibliometric values and affiliation accuracy)
data.
The main purpose of this software to handle scientific
productivity of IOV, called SIPS, (Information System of Scientific
Publications), is to manage the publications and monitor the
productivity of the IOV.
The SIPS software is composed of three main modules:
1. Publications management
2. Research staff management
3. Funds management.
The “Publications management” is the core of the whole
system: it allows the handling of bibliographic data of scientific
This Office is devoted to
administrating research grants earned by
IOV workers, as well as resources coming
from the Health Ministry (Ricerca
Corrente); the distribution of these latter
resources is planned yearly partly on a
merit basis, according to widely accepted
scientific parameters, and partly on the
basis of the needs of implementation and sustainment of the different
areas. The management of the projects presented by the Researchers,
as well as the monitoring of results, is facilitated by the availability at
IOV of a managing software (SIFF-IOV, generated by CRBM, Pavia,
Italy), as this system is fully compatible with the managing platform
of the Italian Health Ministry (the so-called “Research Workflow”).
At present, the burden of administrative duties, including the annual
scientific and administrative reports to the Ministry of Health
(“Ricerca Corrente”), and the maintenance of relationships with a
wealth of players (Health Ministry, Alleanza Contro il Cancro, the
Veneto Region, the other IRCCS, the national and international
Agencies etcetera) only relies on the work of one administrative unit,
Mrs. Daniela Battistuzzi, whose dedication is gratefully acknowledged
here, with the precious help of Dr. Gian Luca De Salvo of the Clinical
Epidemiogy and Biostatistics Unit, and of the Administrative Office
(Dr. M. Giusto). The Scientific Directorate has recently potentiated
his possibilities by recruiting on research grants a series of collaborators
dedicated to maintain and foster interactions with European
Community in view of FP7 Program, and to implement the librarian
section and the Bibliosan platform.
191
publications of IOV researchers while simplifying and automating
the calculation of many important indexes, such as normalized
impact factor, affiliation accuracy, author byline positions,
citations, etc. The module of “Research staff management” is used
to handle all data of researchers divided by operative units. “Funds
management” allows the monitoring of funds.
Through SIPS it is possible to cross-validate all data from
different modules to create in-depth data analysis, by queries and
significant indexes in order to evaluate publications, researchers
and units together. SIPS is implemented through web-based
technology and is only accessible within the Intranet network of
the Scientific Directorate through members’ different accounts
and distinct privileges, as required. The software also allows the
import of bibliographic data from the citation manager RefWorks
program (accessible to IOV through the BiblioSan consortium
subscription) and it enables the export of data in many formats
such as XML, CSV and Excel.
The system simplifies the operations of data management
as inserting, updating and searching records by automatic
procedures and it also allows the creation of complex data queries
in a few seconds. One of the main features of SIPS is the timely
and labour-efficient creation of reports, formatted as requested
by the user. In doing so, the original “administrative database” is
currently developing into a fully implemented “Decision Support
System” software, which will help to take decisions on the internal
scientific priorities and funds management on the basis of the KPI
(Key Performance Indicator).
Animal facility
The activity performed in the Labs is complemented by the
availability of a SPF animal facility (about 300 square meters),
which hosts about 3,000 mice of wild-type/transgenic strains,
and includes a BL3 room with isolated cages for containment of
high-risk experimental procedures. Experimentation is carried
out under strict control of the internal Ethical Committee
and according to International Guidelines in the field; embryo
transfer techniques are also available in the facility. A complete
imaging platform, including computerized tomography,
fluorescence and chemiluminescence, allows accurate followup of tumor progression in experimental tumor models, thus
minimizing the number of animals needed for experimentation
and the eventual invasive manipulations. Thanks to a “Conto
Capitale 2010” financing by the Health Ministry, the acquisition
of a PET-TAC platform for small animals is now underway. This
instrument will allow a fantastic advancement in the possibility
of testing in a preclinical setting new drugs and biological agents,
in view of their transfer into the clinical practice through phase I
experimentation.
Tissue banking
In view of the growing importance of collecting tumor tissues
according to standardized, reliable operating procedures, the
IOV is implementing tumor tissue banking in collaboration with
surgeons and pathologists. Presently, two bio-banks are established:
a large collection of esophageal tissues, which forms the core of the
Barrett’s Esophagus Italian Registry, including samples from more
that 1,000 patients; a collection of more than 500 samples from
patients with colo-rectal tumors. Work is in progress to extend
biobanking to other pathologies, by also involving in this project
surgeons, pathologists and clinicians all over the Veneto region,
and participating in national and international networks. This
will be made easier by the recent initiative of the Regional Health
Authorities, who recently launched an initiative to count, catalogue,
coordinate and regulate (by establishing minimal requirements
and standard operating procedures to obtain accreditation) all
the structures acting as biological sample repositories all over our
Region. This aspect apart, it is an insofar unsuccessful dream of
the Scientific Directorate to sample constitutive DNA from every
cancer patient attending the Institute, in order to make available
to the IOV researchers and to the oncologic network of the Veneto
region a non-dispensable bank for pharmacogenetic studies.
Laboratories
An important part (about 1,500 square meters) of the
Institute is occupied by research laboratories, fully equipped with
state-of the-art instrumentation, including cytometry, confocal
microscopy, Affimetrix and Agilent platforms, several real-time
PCR platforms, sequencers, DHPLC etcetera. The acquisition of
a last generation cytofluorimeter endowed with cell sorting is now
underway, thanks to the funds deriving from the so-called “5 per
mille” donations.
The major labs, where research activities are strictly
interconnected to the clinical management of patients in a
translational research perspective, include the following Labs:
Heredo-Familial Tumors; Molecular Immunology and Gene
Therapy; Cellular and Molecular Immunology; Viral Oncology;
Molecular Oncology and Cytogenetics; BL3 facility.
192
Library
through a single platform, perfectly connected with a link resolver
(called “Find Full Text by BiblioSan”) available on customized
interfaces of most of the important and used scientific databases
such as PubMed, ISI WoS, and new web-based tools such as
Google Scholar. Strongly addressed to its audience, IOV Library
serves institute staff, departments, internal and external operating
units, recipients of IOV grants, postgraduates and PhD students
training at IOV. Since the beginning of the digital library program
in 2010, IOV library services has increased by about 100 per cent
and registered users have increased by 65 per cent.
In the same year online BiblioSan - IOV catalogue’s page views
were 64,879, an increase of 15% compared to the previous years,
with an estimated growth of 25% in the current year.
In 2011 the Library, with the IOV training office, has started
staff training courses on BiblioSan resources. The courses aim to
provide staff with the skills to use online bibliographic resources
and to enhance research, clinical and health assistance activities.
Responsible: Mauro Apostolico
Library is seeking new ways
to share IOV collection with its
biomedical and academic audience in
Padua. Being a member of Bibliosan,
IOV Library is called to contribute to
the health library network of Italian
research centres.
In recent years, the growth of
technology and the widespread use of the net has stimulated
rapid and huge strides to this regard. The Library is working
with BiblioSan network partners to improve its digital resources
program, paying a specific attention to user-oriented services and
Institutional repositories in order to build a web-based digital
library, constantly open to users, that can be consulted from
everywhere and at anytime.
The IOV Library is enhancing the Library services through the
opportunities offered by new technologies: the development of a
custom Key Performance Indicator (KPI) database or digitisation
and web 2.0 applets, like NILDE 4.0 (“Network for Inter-Library
Document Exchange”). Since September 2010, IOV Library
Website is a gateway to bibliographic and bibliometric sources,
with fee-based and Open Access full text journals, links to health
search engines, authoritative health websites and searchable
catalogues and databases.
IOV library website also include online access to librarian
services such as document delivery and reference assistance.
The regular addition of online periodicals to the BiblioSan
catalogue, has enriched IOV collection in the field of oncology
(125 periodicals) and allied sciences (700 periodicals).
By the group agreements with BiblioSan, our Library has a
collection of 3700 Medical and Health Sciences Journals and
2000 Science Journals, a wide range of knowledge resources aimed
at meeting the needs of oncologists, research scientists, nurses,
healthcare professionals and postgraduates students from different
disciplines. In the year 2011 NILDE, together with ACNP (the
Italian “National Collective Catalogue of Periodicals”), connected
IOV Library with the collections of 2,491 Libraries in Italy
counting 922,922 journals. NILDE allows to borrow and lend
a large number of articles and documents from Italian libraries,
BiblioSan: Antonio Rosato
Dr. Antonio Rosato is the IOV
delegate to interact with the BiblioSan
librarian network and its Director
(Prof. Moreno Curti) on behalf of the
IOV Scientific Directorate.
193
IOV Library 2008-2011 Nilde Exchange
IOV Library 2007-2011 Lending Time
300
7
6
250
5
Time
150
100
4
3
2.8
2.6
2
50
1
0.7
0.3
0
2007
2008
2009
2010
2011
2007
2008
Year
2009
2010
2011
Year
Order not filled
Lending time
(days)
250
Borrowing
223
Lending
200
150
Users
IOV Library users
350
96
100
311
300
50
35
250
Users
Articles
200
0
6.5
0
200
2009
Year
150
Nilde users
96
100
BiblioSan CLAS users
35
50
0
2010
RefWorks users
IOV DD users
2009
2010
2011
Year
194
Total users
2011
(30/06)
Swot Analysis
In the awareness of the difficult tasks that we are facing, and
most of all our limits, we feel it appropriate to conclude this
address by a SWOT analysis that may synthesize the Scientific
Directorate spirit.
Weakness
We are aware of several weakness points, whose removal
would greatly potentiate our possibilities.
A stronger support to the Scientific Directorate in terms of
personnel resources would greatly help in improving the
Institute’s presence within the national and international
scenario; nowadays, steady scouting of financial resources,
intelligent lobbying activities within the European Community,
and careful maintenance of international relationship are
mandatory activities for a Scientific Institute.
Related to the former point, the lack of a structure responsible
for scientific communication is a strong pitfall of the Institute;
the importance of transmitting to the general public a correct
information, with the right and professional modalities, is of
paramount importance to acquire credit and sensitize people
to understand and eventually support our work.
Space constraints are also an important limit to IOV expansion;
its location in an artistically protected and surveyed area renders
any refurbishment intervention very long and difficult.
The huge amount of money earned by IOV researchers to
carry out their research is counterbalanced by the scarcity of
personnel; the resources coming from the “Ricerca Corrente”
are often employed not as a “plus” to implement research, but
as a substitute to face routine clinical activities which would be
difficult to perform due to the poor human resources.
The University of Padova hosts a Specialization School in
Clinical Oncology, which presently needs to be profoundly
reorganized and implemented. Padova has never had in its
Medical Faculty a Full Professor of Clinical Oncology; it is now
time to tackle this problem as a vital priority of the School and
of the IOV itself, where the post-graduate students carry out
their formation in Oncology.
Even though all the queries to the Research Direction of the
Health Ministry are met whenever necessary, a more close and
strict follow-up of the problems of the Scientific Directorate
Strength
Four major points are to be considered.
First, the IOV is greatly grown from its birth, in both
dimensions and quality. The compilation of this Report offered
to me the opportunity of summarizing my 4-year experience at
the Scientific Direction of the Istitute, and to comprehensively
address all the aspects of our life at IOV. All the aspects that
I considered show a more than satisfactory improvement: the
general organization of both research and clinical activity, the
functioning of the Scientific Directorate, the number, and in
particular the quality of the publications, the amount of grants
earned by our Researchers, the growing success in funding by
intenational agencies, in particular European Community.
This progress is beyond any expectation, and it may represent
the guarantee for a further, huge improvement.
Second, the small dimension of the IOV, which only
comprehends about 100 Researchers, greatly facilitates
management, scientific coordination, and collaboration
among groups. Due to the profound embedding in a preexisting excellent expertise in Oncology, we do not pursue a
“generalistic” mission, aimed at tackling all oncological diseases;
instead, we chose to select a few investigative fields and to
implement these sectors by putting together all the experts into
Multidisciplinary Units.
Third, the great ability of our investigators to raise grants from
both public and private agencies permits a high level of quality
in both research and clinical applications.
Finally, the IOV is a true Comprehensive Cancer Center,
where basic and translational research, clinical activities, and
educational programs are fully integrated.
195
would be auspicated, in the interest of a better and more
harmonic governance of the IOV.
IOV would need special attention, care and feeding to foster
its physiologic development. So, the first and more menacing
danger is a lack of adequate support from the Regione Veneto,
especially in terms of the possibility of attracting and hiring
top-level investigators from Italy and abroad.
A second worrying problem is that the ability to design ambitious
research strategies could not be supported by the General
Directorate through adequate platforms, both technologic
(informatics, bio-informatics etcetera) and administrative
(research administration, EC lobbying, international relations
etcetera). We are perfectly aware that an “IRCCS mentality”
has to be progressively acquired and built; however, the lack
of these infrastructures would certainly hinder any effort to
expand the IOV horizons from the relatively narrow visual
angle of its birth.
As far as spaces are concerned, the mid-to-long term possibility
of moving into the future new Hospital of Padova may
represent a menace, in virtue of the temptation of a long-term
blocking of any enlargement/amelioration of the existing IOV
structures, in view of a future permanent location.
The work in Oncology as well as in most medical branches
greatly benefits of the possibility of network working. This
need is particularly urgent for our Institutions, since Oncology
in Veneto is distributed among more than 25 different
Oncology Units scattered over the territory. If this on one
hand represents an opportunity for a better, capillary survey of
oncological diseases, on the other it may represent a difficulty
for creating a network.
Yet, to face the competition
from larger Institutions,
Weakness
from BigPharmas and
Novelty
from foreign countries, the
Space constraints/Uncertainties
Veneto Region must organize
on future location
Lack of adequate support
its oncological work as a
to Scientific Direction (scouting,
network, sharing guidelines,
EC lobbying etc...)
case series, expertise, in the
light of the key words “One
for all, all for one”. Only by
this spirit it will be possible
Threats
to maintain the pace of
Lack of far-reaching,
innovation, progress, and
ambitious strategies
improvement of research
Lack of infrastructural support
and care, the two non Constraints in researcher
separable missions of an
hiring
IRCCS.
Opportunities
Several opportunities are at hand. The Institute has strict
cultural and “physical” connections with the entire academic and
non-academic medical milieu of Padova. Indeed, about one third
of IOV researchers also hold a position at the Padova University;
in addition, a full integration between the Azienda Ospedaliera
and the Medical Faculty of Padova has been operating for more
than 30 years. Also, the presence of a Doctorate School in
Oncology and Surgical Oncology, presently directed by a Full
Professor of the University of Padova working at IOV, guarantees
the formation of new researchers, and for sure it represents a
sort of cultural incubator and reservoir for the future. It is clear
that the IOV may fully benefit from the contiguity with all
these structures, in a common effort to mutually implement the
individual expertise and vocation. Moreover, the greater critical
mass generated by the convergence of different, complementary
expertise will allow the entire Padua Medical School to become
more competitive within the national and international research
networks in Oncology.
Threats
Nowadays, also in view of the constraints due to the
international economic crisis, the horizon may be more cloudy
than in the past.
One of the most relevant
problems in doing research
in Italy is the difficulty of
Strength
recruiting into permanent
Novelty (no “original sin”)
or semi-permanent positions
Small dimensions
High ability to raise
young post-PhDs who for
resources
many years have proven
Comprehensive Cancer
their research skills; in
Center
other words, in both the
academic and non-academic
settings the chance to
offer career perspectives
Opportunities
to most motivated young
Fertile scientific environment,
investigators is very poor.
with high opportunities for
This
problem
is
of
local collaborations
paramount importance in
Embedding in national/
international research
the case of our Institute.
As an infant, in fact, the
196
Research: Input and Output
International Relations &
European Grants Office
The research activities of the IOV are supported by grants
obtained from several national and international agencies, both
public and private, as well as a few pharmaceutical industries and
private charities. In addition, the IOV can count on a substantial
support by the generous donations of patients, familiars, citizens,
etcetera.
The fund raising at IOV mainly relies on two structures, the
one institutional, the other created by the Scientific Directorate to
foster scouting of grants at the European level.
Fund Raising
Office
and
Responsible: Manuela Mtanis
The International Relations and
European Grants (IREG) Office
is charged by the IOV Scientific
Directorate to develop a strategy
aimed at increasing the international
presence of the Veneto Oncology
Institute and obtaining new funds
through highly competitive funding instruments set by the
European Commission and other international agencies. These
two major tasks are being carried out by expanding the scientific
and institutional network base and by obtaining references in
international project proposal participation.
The progress in the implementation of the IREG Office
activities, which started in June 2009, is in line with the slow
but continuous EU funds awareness raising. This is accomplished
after the staff attending courses on European project drafting and
having been regularly notified of the funding opportunities in
order to improve their drafting and networking skills. The IOV
participation in International funding programs has increased
not only in the total number of project proposals but also in the
quantity of researchers involved.
The IOV expresses its needs and priorities while working
towards the common good of the European Community: the
lobbying activities and the strategic relations with international
and national funding institutions that work in this field are carried
out by the IREG Office with the scientific advice of the researcher
involved in seeking for funding. This activity is monitored and
coordinated by the Scientific Director.
These ambitious aims are not pursued by the IOV alone.
The IOV works within a variety of National, European and
International Oncology Umbrella Organizations:
Marketing
Head: Bruno Bandoli
This institutional office, born
since the foundation of the Institute
in 2006, is responsible for the raising
of grants from private citizens, local
associations, private institutions
within the basin of influence of the
Institute. To this end, the Office must
design communication and marketing strategies, which could
render the Institute more visible to the general population. At
the same time, a steady activity is dedicated to promoting and
organizing special events where the income could be totally or
mostly transferred to the IOV.
Data on the events and the fund raising of the Office over the
last 3 years are reported in the table (values in e):
Source
2009
2010
2011
5‰
930,000
970,000
960,000
Donations
270,000
300,000
550,000*
* Data January-July
197
ACC (Alleanza Contro il Cancro);
OECI (Organisation of European Cancer Institutes);
UICC (Union International Contre le Cancer).
The IOV, through the scientific monitoring of Dr. Annarosa
Del Mistro, was appointed for the EPAAC (European Partnership
for Action Against Cancer – the EU platform on oncology
policies) to conduct the activities of Work Package 6, objective
3 on regional screening programs, concerning the Pan-European
Regional implementation of guidelines on Cervical Cancer
Screenings. In October 2012 the IREG staff will organize and
host an International meeting on this specific issue, wich will
be attended by local and Brussels based health and research
stakeholders, European Commission officers and screening
specialists, oncologists and policy markers form all over Europe.
Dr. Indraccolo’s project proposal titled “Metabolic changes
associated with ovarian cancer as possible new diagnostic tools to be
transferred into clinical practice” was selected to be implemented
by IATRIS (the Italian section of EATRIS).
IOV participated in the The EuroNanoMed ERA-NET
initiative. This initiative comprises 24 partners from 18 countries/
regions. EuroNanoMed aims at fostering competitiveness of
European nanomedicine players through the support of transnational collaborative and multidisciplinary Research and
Technology Development (RTD) projects with participants from
academia, clinical/public health communities and industry.
Dr. Enzo Bronte project “Lymphotargh” was ranked as
third in Europe for its scientific rigor. This study proposed to
develop specifically targeted anticancer treatments, by associating
anticancer drug to specific nanostructures composed of lipids and
polymers, which have a specific affinity for the lymphnodes to
prevent the process of metastatic spreading through lymphatic
vessels. The project has as the final goal of achieving the preclinical
evaluation stage with one of these novel nanocarrier systems.
In October 2011 the Project FONDiag (Fluorescent Organic
Nanocrystals for the Early Diagnosis of Esophageal and Colon
Cancer) was ranked as first in Europe in the third call for proposal
of the Euronanomed Programme. The three year European joint
project wil be carried on by the IOV team leader Dr. Giorgio
Battaglia from High Technogy Oncology Endoscopy Unit.
In July 2011 IOV has been awarded with another FP7 grant
in the field: “New Oral Nanomedicines: Transporting Therapeutic
Macromolecules across the Intestinal Barrier”, a NMP Large scale
project with a total cost of 9 million Euro. The consortium is
composed by an international network of 17 partners from
8 countries and among them 2 multinational industries and 3
SMEs. There is an immense potential impact of Nanomedicine
on public wellbeing and on economic growth for Europe. The
field is of considerable importance for Europe and is a politically
To apply for funding from the European Commission Fund
for Research and Development (the 7th Framework Programme),
knowledge of the administrative and technical documentation is
required. Information about this documentation is shared by the
IREG Office with the following institutions:
APRE (Agency for the European Promotion of Research);
IRECOOP VENETO (Technical support service for the
management of EU funds. 16th Padova Company Health
Authority);
UNIVERSITY OF PADOVA, Service of International
Research.
European public relations have been a major consideration
for the IREG Office. The IOV has been benefiting from the
active presence of the Veneto Regional Representative office in
Brussels. The IOV took part in information days for a variety of
oncology-related funding opportunities in Brussels and in other
FP7 countries such as those organised by:
European Commission (Info days and Networking on 7PQHealth Programme);
Committee of the Regions (Regions and cities delivering
growth);
European Parliament (bilateral meetings with MEPs in charge
of Research and Health policy);
ECRIN (European Clinical Infrastructure Network: PanEuropean, distributed infrastructure providing coordinated
services to multinational clinical research in Europe);
EATRIS (European Advanced Translational Research Infrastructure
in Medicine: bridging basic research and medical innovation);
EORTC (European Organization for Research and Treatment
of Cancer);
IMI JU (Innovative Medicine Initiative Joint Undertaking-Info
days and Networking);
EUREGHA (European Regional and Local Health Authorities);
ERRIN (European Regions Research and Innovation
Network);
EPAAC (European Partnership for Action Against Cancer);
ISRAEL BIOMED 2011 (Israeli SMEs looking for public
partners in Biomedical Research).
198
strategic focus for the Government of Veneto Region too. Through
the constant commitment of the office, we can now count on
735Ke European funds dedicated to this field and with new
renowned international partnerships.
and in coordination with the Foundation Tison), to give
necessary advice in a pathologic cancer diagnosis.
In the 2008-2010 period, about 12 million euro were
collected from funding agencies and charities, most of which on
a competitive basis. This success in securing adequate grants to
support research activities witnesses the high level of the research
projects developed at the Institute.
Bilateral cooperations:
Christie Hospital, Manchester (UK)
On March the 26th and 27th of 2010 a IOV delegation
composed by the Scientific Director Prof. Alberto Amadori, Prof.
Giuseppe Opocher, Dr. Carlo Castoro, Prof. Vincenzo Bronte, Dr.
Angelo Palozzo and Ms. Manuela Mtanis has visited the Christies
following the former visit made by the management of the English
Comprehensive Cancer Centre to the IOV in 2008. The two-day
visit layed the basis for mutual understanding agreements in the
areas of basic and translational research, health and education.
Bugando Medical Centre, Mwanza (Tanzania)
In March 2010 the Scientific Director Prof. Alberto Amadori
and Prof. Luigi Chieco Bianchi have visited the Bugando
Medical Center (BMC) in order to identify priorities for the
implementation of the collaborative program between IOV and
the BMC, Mwanza. In particular, the collaboration between the
IOV and the BMC could be achieved in the short / medium term
according to the following guidelines:
1)To start a pilot project for diagnostic and epidemiological
monitoring of viral infections associated with cancer (HPV
and uterine cervical cancer, HTLV-1 and adult T-cell leukemia;
HHV-8 and Kaposi’s sarcoma and peritoneal effusion
lymphonomas; EBV and Burkitt’s lymphoma).
2)To provide accommodation for short periods of professional
training to medical and paramedical staff, and reception of
BMC staff for short stays in order to develop diagnostic tests.
In particular, the IOV could accommodate at its facilities, for
a period of 3-6 months, a general surgeon of the BMC, in
order to gain initial experience, technical and theoretical, in
oncological surgery.
3)To investigate the prevalence of genetic alterations linked to
cancer (BRCA1/2, Rb), transferring blood samples conveniently
mounted on suitable supports, and therefore able to deal with
transportation, to deepen the study of tumor pathology of
hereditary basis.
4)To activate a web-service to doctors within the BMC (possibly
in cooperation with the Central Pathology Service in Venice
The major projects developed thanks to this support include:
Ministry for University and Research
Control of cell proliferation and death by HTLVI-encoded proteins;
EBV-associated lymphomagenesis: interactions
between viral and cellular proteins;
Functional interactions between mitochondria and
proteins coded by human oncogenic viruses;
Functional and pathological aspects of myelomonocytoid suppressor cells in cancer;
Anti-angiogenic strategies in human tumors.
Italian Ministry of Health/ISS
Molecular bases of heredo-familial tumors;
Genetic and functional analysis of regulatory
proteins coded by oncogenic viruses;
Virus-host interactions in a cohort of HIVinfected pediatric patients at risk of lymphoma;
Immune response modulation as a novel
therapeutic strategy in cancer patients;
Idiotypic vaccination in patients with B cell
lymphoproliferative diseases;
Development of new drugs able to modify tumor
microenvironment;
Angiogenesis at the interface between tumor and
microenvironment: therapeutic implications in
hematologic malignancies;
MicroRNA sequences in solid tumors and
hematologic tumors;
Tumor microenvironment: role in neoplastic
progression;
Biocompatible polymers as a carrier of antitumor agents.
199
Italian Association for Research on Cancer
Innovative strategies for early diagnosis and
treatment of esophageal cancer;
Functional dissection of virus-host interactions in
virus-associated lymphomagenesis;
Blocking angiogenesis: a multifaceted approach to
gene therapy in preclinical tumor models;
Molecular and functional characterization of
melanoma-associated myeloid suppressive cells;
Virus-host interactions in EBV-associated
lymphomagenesis;
The role of telomerase in solid and hematologic
malignancies;
MicroRNA in human cancer: a high-throughput
integrated approach based on tissue-specific
microRNA libraries;
Role of arginase in tumor development and in
tumor-associated immune suppression;
Implementation of an oncogenomic platform for
the study of hemopoietic malignancies;
Innovative diagnostic and therapeutic strategies for
gastric and colo-rectal cancer.
European Commission and Foreign Agencies
Subset-specific immunotherapy of B cell
lymphomas;
Nanotechnologies in innovative approaches to
cancer therapy;
Role of chronic infections in the development of
cancer;
HIV infection-associated opportunistic tumors.
Most of the above projects are conducted in collaboration with
leading national and international Institutions; a non-exhaustive
list includes: European Institute of Oncology, Milan (Italy);
Istituto Clinico Humanitas, Milan; Istituto Superiore Sanità,
Rome (Italy); Centro Riferimento Oncologico, Aviano (Italy);
Universities of Padova, Rome, Milan, Verona (Italy); University
of Santiago de Compostela (Spain), Universitè Catholique de
Louvain (Belgium), University of Angers (France), University of
London (United Kingdom), University College Dublin (Ireland),
Uppsala University (Sweden), Warsaw University of Technology
(Poland), Université Paul Sabatier de Toulouse (France), University
of Twente (Netherlands), Ohio State University (USA); Columbia
University, New York (USA); National Cancer Institute-NIH,
Bethesda (USA); Sydney Melanoma Unit (Australia).
200
Impact Factor Trend
6
1000
5
800
4
600
3
400
2
200
1
0
0
2007
2008
Total Impact Factor
2009
2010
2007
2011
Articles
Average IF
201
2008
2009
2010
2011
Clinical Trials and Biostatistics Unit
Chief
Gian Luca De Salvo, MD
Born in Nuoro, Italy on 6th March 1967. Graduated with honours in Medicine and surgery at the
University of Padua in 1993 and specialized with honours in Internal Medicine at the University
of Padua in 1998. Head of the Clinical Trials and Biostatistics Unit (previously named Clinical
Epidemiology Unit) since its establishment in 1997. Research interests and activities include the
methodology of clinical research with particular focus on phase II and III Randomised Clinical
Trials; Quality of Life evaluation; innovative systems for data collection.
Responsible for the organization and conduction of several National and International clinical
trials in the field of oncology, particularly melanoma, breast cancer, colo-rectal cancer and pediatric
tumors. Some of these trials are completely managed via a web-based system. Coordinator of the
Statistical and Data Management panel of the European pediatric Sarcoma Study Group (EpSSG)
and the SIOP-Low Grade Glioma study group. Published over 60 papers in peer-reviewed journals
and presented over 40 abstracts at International scientific meetings (H-index 15).
Main Pubblications
Validity and reliability of the MSKCC Bowel Function Zotti P, Del Bianco P, Serpentini S, Trevisanut P, Barba MC, Valentini Eur J Surg Oncol.
instrument in a sample of Italian rectal cancer patients. V, De Paoli A, Pucciarelli S.
2011 37:589-96
Central nervous system failure in melanoma patients: Chiarion-Sileni V, Guida M, Ridolfi L, Romanini A, Del Bianco P, Br J Cancer. 2011;
results of a randomised, multicentre phase 3 study of Pigozzo J, Brugnara S, Colucci G, Ridolfi R, De Salvo GL; Italian 104:1816-21
temozolomide-and dacarbazine- based regimens.
Melanoma Intergroup (IMI).
Patient-reported
outcomes
after
neoadjuvant Pucciarelli S, Del Bianco P, Efficace F, Serpentini S, Capirci C, De Ann Surg. 2011;
253:71-7
chemoradiotherapy for rectal cancer: a multicenter Paoli A, Amato A, Cuicchi D, Nitti D.
prospective observational study.
Clinical considerations on sentinel node biopsy in Testori A, De Salvo GL, Montesco MC, Trifirò G, Mocellin S, Landi Ann Surg Oncol.
melanoma from an Italian multicentric study on 1,313 G, Macripò G, Carcoforo P, Ricotti G, Giudice G, Picciotto F, 2009; 16:2018-27
Donner D, Di Filippo F, Soteldo J, Casara D, Schiavon M, Vecchiato
patients (SOLISM-IMI).
A, Pasquali S, Baldini F, Mazzarol G, Rossi CR; Italian Melanoma
Intergroup.
A Randomized clinical trial on sentinel lymph node Zavagno G, De Salvo GL, Scalco G, Bozza F, Barutta L, Del Bianco P, Ann Surg. 2008;
biopsy versus axillary lymph node dissection in breast Renier M, Racano C, Carraro P, Nitti D; GIVOM Trialists.
247:207-13
cancer: results of the Sentinella/GIVOM trial.
202
Gian Luca De Salvo
Paola Del Bianco
Denise Kilmartin
Angela De Paoli
Paola Tellaroli
Chiara Zaina
203
Mission
The main aim of the Unit is to develop and coordinate clinical
research program in oncology at national and international levels, in
compliance with existing regulations and ethical requirements.
Moreover, the Unit provides the institute’s researchers with
biostatistical support in data analysis and interpretation of results
deriving from several types of oncological studies.
Finally, the Unit supports the IOV Scientific Direction in
retrieving, monitoring and evaluating the scientific activity of the
Units at the IOV.
Research Activities
1) The Unit provides methodological, statistical and operative
support for all phases (I, II, III, observational) of the development
of research protocols and data management according to Good
Clinical Practice (GCP) principles, in particular:
2) The Unit supplies and manages operative tools for the
monitoring and evaluation of the clinical and scientific activity
of the Units at the Institute and assists in the collection and
processing of the data by means of a dedicated web system (SIFFIOV). The Unit collaborates in the collection and editing of data
for the periodic publication of the Institute’s scientific report.
The Unit deals with the collection, editing and input in the
web data base of Ministry of Health (WorkFlow System) of all
data concerning the clinical and scientific activities of the various
departments at the Institute.
Protocol development and preparation of case report forms;
Statistical design and sample size;
Data Base construction with the use of specific software
programs;
Data management;
Development of methodologies for Data Quality Assurance
according to GCP standards;
Analysis of data and interpretation of results;
Preparation of interim reports and manuscripts;
The Unit has general leadership responsibilities in developing
and coordinating research programs with various departments
and scientific institutions:
Oncologic and Surgical Sciences Department, Padua
University, Padova
Pediatric Department, Padua University, Padova
Medical Oncology, Giovanni Paolo II Cancer Institute, Bari
Division of Melanoma and Soft Tissue Sarcoma, European
Institute of Oncology, Milan
Unit of Psychological-Oncology, National Cancer Institute
CRO, Aviano
Inside the IOV
Medical Oncology 1 and 2
Radiology
Anesthesia
Melanoma and Sarcoma
Psycho-oncology
204
The unit is also the coordinating centre for the activity of various
collaborative clinical trial groups such as the Italian Melanoma
Inter-group (IMI), the Italian Pediatric Haemato-Oncologic
Association (AIEOP), the European Pediatric Sarcoma Study
Group (EpSSG), the Society of Pediatric Oncology-Low Grade
Glioma Consortium (LGG) and the Gruppo Interdisciplinare
Veneto di Oncologia Mammaria (GIVOM).
Emma Children’s Hospital, Academic Medical Center,
Amsterdam, The Netherlands
College of Public Health, University of Nebraska Medical
Center, Omaha, USA
Institut fur Biometrie und Klinische Forschung, Munster,
Germany
At present the Unit is involved in several multicentric clinical
trials related to the diagnosis and treatment of melanoma, breast,
head and neck cancer and pediatric tumors. In particular, two
randomised phase III trials for the treatment of melanoma: one in
the adjuvant setting for the treatment of patients at high risk of
relapse and the other in advanced disease patients to evaluate the
impact of temozolomide in preventing cerebral metastases.
The unit carried out a randomized, multicenter study on the
usefulness of the sentinel node biopsy as an indicator for axillary
lymphadenectomy in patients with breast cancer less than 3cm.
Since the sentinel node biopsy is becoming widely used in the
current clinical practice, we believe it could be important to have
solid evidence on its effectiveness. Therefore, we have recently
started working on a meta-analysis regarding the sentinel node
biopsy method vs axillary standard dissection in breast cancer.
The unit has recently received approval from the Italian
National Institute of Health (ISS) to commence a “first in man”
Phase I study: adjuvant anti-ErbB-2 (RHuT-IDN 6439, plasmid
for DNA vaccine) in patients treated for primary ErbB-2+
stage III and IV carcinomas of the oral cavity, oropharynx and
hypopharynx.
In the pediatric setting, the unit manages several trials
under the auspices of Italian or European co-operative groups:
a comprehensive treatment strategy involving three clinical trials
are offered to all children and adolescents up to an age of 18 years,
with a low grade glioma arising in any part of the central nervous
system; two clinical trials for the management and treatment
of children and young people presenting with non-metastatic
sarcoma. A particular characteristic of the above mentioned studies
is that the management and data collection activities are carried
out via web-based systems. In fact, the unit has a specific interest in
the implementation of telematics for the management and remote
data collection as part of cooperative clinical trials. The Unit also
supports an integrated project focused on pediatric patients with
rare tumors. Specific aims are to collect epidemiological data,
create a clinical and pathological database, develop diagnostic and
therapeutic recommendations, create a cooperation network with
expert specialists, and improve biological studies.
The unit coordinated a randomized trial to evaluate whether
an integrated psycho-oncologic compared to a conventional
approach is more effective in reducing the anxiety of patients with
breast cancer prior to surgery leading to a better understanding
of informed consent to anesthesia and is now in the process of
submitting a scientific paper to an international journal with the
results of this study.
Moreover, the unit is about to start up a study on “the
early detection and prediction of cardiotoxicity in adjuvant
Chemotherapy-Treated breast cancer patients”.
Another area of interest includes the evaluation of Healthrelated quality of life (HRQOL), symptoms and other types of
patient-reported outcomes that have become critical to fully
evaluate overall treatment effectiveness. A number or research
projects, aimed at evaluating how the HRQOL of patients with
melanoma, breast and rectal cancer is affected by the disease,
treatment and symptoms, within randomised clinical trials
and observational studies, using a prospective and longitudinal
approach, are being carried out. Moreover, activities related to
the development of a new instrument to assess the HRQOL
in melanoma patients undergoing electrochemotherapy, and in
the validation of the Italian version of a questionnaire to assess
the recovery and the normal bowel functions in patients after
sphincter preserving surgery are being performed and another to
assess quality of life in patients nearing the end of life.
205
Programs and Perspectives for the Future
Performing no-profit clinical trials is a significant part of the
Institute’s mission. Optimizing the management of these trials
according to high quality standards respecting high ethical values
are main objectives of the Institute. To better accomplish this issue,
the Unit is in the process of applying for a quality certification
according to international standards (ISO 9001).
surgery between February 2003 and June 2006. HRQOL baseline
scores were assessed using the European Organisation for Research
and Treatment of Cancer, Quality of Life Questionnaire-Core30
(EORTC QLQ-C30), and the EORTC QLQ-CR38 colorectal
module.
Impact of treatment in advanced asymptomatic colorectal
cancer and unresectable metastasis patients.
The therapeutic strategy for stage IV colorectal cancer is driven
by the resectability of the metastases. In the setting of asymptomatic
primary tumor and unresectable metastases, although palliative
systemic chemotherapy is clearly indicated, opinion is divided
as to whether these patients should undergo primary tumor
resection. Due to the complexity and cost of performing a
randomized clinical trial, there is interest in using data from a
multicentre observational study to evaluate the overall survival in
patients undergoing asymptomatic primary tumor resection prior
to chemotherapy and in patients receiving chemotherapy, with
or without biological agents, followed by surgery if the primary
becomes symptomatic or the metastases are resectable.
Using observational data to compare outcomes associated
with different treatments may result in biased estimates because of
non-random treatment assignment. To correct for variables that
may confound the association, a propensity score analysis and an
instrumental variable analysis will be applied.
As far as clinical research is concerned, the Unit is currently
involved in planning some trials in different contexts. Some details
of these projects are reported below.
Role of cytoreductive surgery plus hyperthermic
intraperitoneal chemotherapy (HIPEC) in patients with
colorectal cancer at high risk for peritoneal recurrence.
This is a randomized phase II study to investigate the benefit
of second look and hyperthermic intra peritoneal chemotherapy
besides standard adjuvant chemotherapy in patients with colorectal
cancer at high risk for peritoneal recurrence.
Moreover, the Unit is planning a prospective sequential
observational study to verify the additional role of the association
of PET-TC with iodine contrast with respect to the traditional
diagnostic work up in esophageal cancer potentially amenable to
curative resection.
Quality of life as a prognostic factor
Health related quality of life (HRQOL) is recognized to
complement biomedical measures in clinical decision making
by providing relevant additional information for the assessment
of overall burden and effectiveness of treatment. Additionally,
recent research has shown that assessment of HRQOL scales
in conjunction with clinical data might improve survival
prediction.
The aim of this research is to investigate the role of baseline
HRQOL data and changes in HRQOL scores before and after
treatment, combined with baseline clinical variables, as an
independent prognostic factor for post-operative complications,
progression-free and overall survival in patients with mid-low
rectal cancer undergoing pCRT and surgery with curative intent.
The analysis will be conducted on patients who had undergone
206
THE RESEARCH - strategic scientific options
209
In this frame, the major lines of research pursued at the IOV
can be summarized as follows:
this field, and stands as a reference point for all the people that in
Padova and the surrounding region deal with hereditary cancer.
A. Understanding
B. Searching
underlying
the
malignant
complex
molecular
transformation
mechanisms
and
tumor
for novel tools for diagnosis, prognosis and
therapy of tumors
Over the last 30 years, early diagnosis has been a key element
in contributing to improve the quality of life and survival of cancer
patients. This issue is a central research interest at the IOV, and
involves both basic/translational investigators (in search of new
biomarkers through genomic, proteomic and phosphoproteomic
approaches) and clinical researchers (through the identification of
new imaging tools and non-invasive diagnostic procedures).
As far as tumor prognosis is concerned, the most recent
knowledge on tumor biology increasingly underscores how
tumors of a same histotype, which are apparently identical
based on histologic and phenotypic properties, may reflect
totally different neoplastic diseases, destined to a completely
different clinical course and also sensitive to different therapeutic
approaches. Landscape examples of this are the case of lung
tumors, where EGFR and K-ras status condition the response to
Gefitinib, and the case of colon carcinoma, where the presence or
absence of K-ras and B-RAF mutations is able to determine the
efficacy of target therapies. A major goal of modern oncology is
to molecularly characterize tumors, with the aim of designing a
new classification of cancer, which could more closely correlate
with patient prognosis and clinical course. In this setting, through
the application of functional genomic platforms, tumor samples
are studied for their gene expression profile in search of markers
associated with a particular course of the disease or a given clinical
response to therapy. By this means, the dream of a personalized,
tailor-made treatment of cancer patients is becoming closer dayby-day.
Finally, in reference to the search for innovative therapies,
the most modern surgical, chemotherapic and radiotherapic
progression
It is clear that cancer is a genetic disease, in which the stepby-step accumulation of genetic abnormalities leads the cell to
eventually acquire a fully transformed, malignant phenotype.
However, the molecular events which regulate cell proliferation
and death are extremely complex, and high-throughput approaches
at genomic, proteomic and metabolomic levels are needed to
dissect this array of circuitries. At our Institute, special attention
is devoted to the interaction between human genome and
products of several human herpes-viruses and retroviruses, such
as Epstein-Barr Virus (EBV), Human Herpes Virus-8 (HHV-8),
Human Papilloma Virus (HPV) and Human T Lymphotropic
Virus type I (HTLV-I), as well as to the alterations in signalling
cascades that may preclude apoptotic pathways, thus leading to
cell immortalization. Besides the use of gene expression analysis
platforms, this work is also facilitated by the availability in our SPF
animal facility of several animal tumor models, including models
of EBV-associated human lymphomagenesis and transgenic/
knockout models. A special focus is also dedicated to inheritable
alterations of known genes, such as BRCA-1/2, CDKN2A and
others, which are involved in the pathogenesis of heredo-familial
cancers; through the collaboration with international leading
groups, we are steadily searching for new, as yet unidentified genes
responsible for some rare neuroendocrine tumors.
In this setting, particular attention is paid to the search of
modifier genes, which could affect the penetrance of the major
genes, thus accounting for the different incidence of the disease
in individuals sharing identical mutations. An operative unit,
called “Family Cancer Clinics”, collects all the IOV expertise in
210
approaches are tested at the IOV within national or international
multicentric studies. In this setting, special attention is paid to
the so-called “target therapies” (such as Tyrosine Kinase Inhibitors
-TKI- and monoclonal antibodies against molecule expressed at
the cancer cell surface), which target particular signal transduction
pathways that are key to cancer cell survival. One major issue that
IOV researchers intend to address is why, despite similar molecular
features in tumor cells, a part of the patients do not respond to
these agents; also, a major focus of interest is the synergistic
action of the combination of diverse therapeutic agents, targeting
different steps of the complex cascade of alterations leading to
malignant transformation.
cells may recruit into tumors particular inflammatory cells able
to down-regulate immune response to tumor antigens, thus
preventing cancer rejection; attempts are underway to modulate
the activity of these cells by appropriate drugs in experimental
models as well as in man. On the other hand, some of these host
components may represent a suitable therapeutic target; this is the
case of endothelial cells, which may be targeted by appropriate
reagents to induce a dramatic shortage of oxygen and nutrient
support to tumor cells, thus inducing tumor regression.
In this field, studies are currently underway in both experimental
models and selected human tumors, often in combination
with chemotherapic approaches. In addition, innovative active
immunotherapy approaches with tumor antigens or adoptive
immunotherapy strategies with tumor-specific lymphocytes
are also being tested in several preclinical models as well as in a
few phase I/II collaborative studies. In this regard, we are now
launching the first phase I experimentation coordinated by our
Institute, a first-in-man DNA vaccination trial with a Her-2coding plasmid, very recently authorized by the Health Ministry
through the Istituto Superiore di Sanità.
C. Exploring the complex interactions between tumor cells
and host microenvironment as a potential target of new
therapeutic approaches
Even though cancer can be considered as a genetic disease, the
interactions between tumor cells and cells of the host colonizing
or infiltrating the tumor masses (fibroblasts, endothelial cells,
inflammatory cells) may play a significant role in affecting tumor
growth and progression. In some cases, factors released by neoplastic
211
Pharmacogenomics
therapies while the majority is cured with classical non-targeted
chemotherapeutic drugs. This standard anticancer therapy based
on “one size fits all” modality often is ineffective or produces
serious toxicities at doses retained optimal for anticancer effects
(Figure 1). Inter-individual heterogeneity in drug response may
be due to several factors including age, sex, race, organ function,
and interactions among drugs. However, despite the potential
importance of these clinical variables in determining drug effects, a
growing body of evidence indicates that sequence variants (genetic
polymorphisms) in genes encoding drug-metabolizing enzymes,
drug transporter, drug targets or drug-induced DNA damage
repair can have an even greater influence on the efficacy and
toxicity of treatment. In many cases, the genetic polymorphism of
drug metabolizing enzymes is associated with reduced activity of
the encoded variant proteins, usually leading to a modulation of
pharmacologic effects of therapy. Because anticancer drugs have a
narrow therapeutic window, changes in their pharmacokinetics or
pharmacodynamics may directly reduce efficacy or induce severe
toxicity. In view of these premises, one strategy to increase the
effectiveness of chemotherapy is to gain a better understanding
of the influence exerted by the genetic background of patients
in the response to treatment. Thus, development of genetic
tests predicting which variant may influence the efficacy and/or
toxicity of chemotherapy is one critical issue facing oncologists.
The term pharmacogenetics usually refers to studies of genes that
may influence response to drug and chemicals. However, recent
advances in large genome scale sequencing and improvements
in bioinformatics tools in processing large amounts of data led
to the transition of pharmacogenetics (the analysis of one or a
few candidate genes) to pharmacogenomics (study of the entire
spectrum of genes in the human genome).
Many genetic polymorphisms in some relevant drugmetabolizing enzymes are currently well-known, and data on
new polymorphisms in the pathways involved in drug activation,
detoxification and metabolisms are accumulating in the literature:
Oncology has now entered an era in which the knowledge of
genetic variability is helpful for optimal approach to patient care.
Cancer is a complex disorder whose ultimate outcome is the result
of numerous alterations affecting the regulation of genes, and it
is well known that individuals with a same tumor type and stage
do not necessarily carry the same cancer-driving mutations. This
is a very important piece of information, as different molecular
alterations or combinations of alterations may render the malignant
cell sensitive or refractory to a drug targeting specific intracellular
pathways. In this regard, the lesson learnt from non-small cell lung
tumors (NSCLC), as an example of somatic mutations of key
oncogenic pathways, in tumor DNA that are predictive of response
to targeted therapy, is clear. The epidermal growth factor receptor
(EGFR) has been found to be expressed or highly expressed in
a variety of solid tumors, including NSCLC. Molecular studies
revealed abnormal signal transduction in lung cancer cells, and high
levels of EGFR expression have been associated with unfavorable
clinical outcome, making the receptor a promising target for anticancer therapy. Somatic mutations in the kinase domain of EGFR
have been linked to clinical response to Gefitinib, an orally active
small molecule EGFR-associated tyrosine kinase inhibitor (TKI).
These mutations are more common among women, never smokers
and of Asian ethnicity, known clinical predictors of Gefitinib
sensitivity. Recently, high EGFR copy number detected by FISH
has been extensively studied and correlated with other prognostic
factors. Moreover, increased EGFR copy number predicts Gefitinib
sensitivity and has been proposed as an effective molecular predictor
for Gefitinib efficacy in advanced NSCLC.
Another example of the importance of specific genetic
alterations in predicting the response to targeted therapies comes
from colorectal cancer. In fact, patients with colorectal cancer
benefit from the administration of TKI inhibitors only if the RAS
gene is non-mutated; the additional role of the bRAF gene in this
scenario is currently under investigation. Unfortunately, only a
relatively small fraction of patients can benefit of these targeted
212
Thiopurine S-methyltransferase (TPMT). Thiopurine
S-methyltransferase is relevant in the metabolism of
6-mercaptopurine and 6-thioguanine; its activity shows
population variability based on genetic polymorphism. Polymorph
forms usually exhibit a reduced enzymatic activity, and reduced
thiopurine S-methyltransferase activity is associated with severe
toxicity and increased risk of secondary malignancies.
Glutathione S-transferases. Glutathiones play a role in
inactivation of many chemotherapeutics such as platinum agents
and anthracyclines and in detoxification of exogenous products of
reactive oxidation. Genotypes of glutathione S-transferases may
predict not only treatment-related outcomes but will also predict
the induction of severe cardiotoxicity induced by anthracycline,
and severe myelosuppression induced by treatment with temerodal
in glioblastoma and metastatic melanoma.
Dihidropyrimidine dehydrogenase. Dihidropyrimidine
dehydrogenase (DPD) represents the rate-limiting enzyme in
the catabolism of pyrimidine antimetabolic drug 5-fluorouracil
(5-FU); indeed the majority of 5-FU is degraded by DPD.
Decreased activity of DPD accounts for approximately 43% of
grade 3-4 toxicity in 5-FU-treated patients.
Uridine diphosphate glucuronosyltransferase 1A1
(UGT1A1). Uridine diphosphate glucuronosyltransferase 1A1
plays a major role in detoxifying the active metabolite of irinotecan.
Therefore, the analysis of UGT1A1 may be useful to predict
patients at risk of irinotecan toxicity.
Thymidylate syntase (TS). Thymidylate syntase, a
critical enzyme in DNA synthesis, is also the target of 5-FU.
The expression of TS is regulated by several polymorphic tandem
repeats in the TS promoter. Higher number of tandem repeat
copies is related to increased TS activity and by consequence to
a lower sensitivity to 5-FU treatment. By contrast, lower number
of repeats is associated with a higher sensitivity, but also higher
toxicity, to 5-FU treatment.
Tamoxifen and CYP2D6. Tamoxifen is the most prominently
prescribed drug for treating breast cancer; it is a prodrug, and its
activation is mediated by cyrochrome P450 2D6. Polymorphisms
in CYP2D6 are associated with a significantly higher risk of
recurrent breast cancer. Furthermore, polymorphisms in the multi
drug resistant gene-1 (MDR-1) and ATP-binding cassette (ABC)
transporter genes can predict resistance to chemotherapeutic drugs,
and patients with methylenetetrahydrofolate reductase (MTHFR)
gene variants exhibit a higher response to 5-FU-based treatment.
Thus, personalized medicine offers the opportunity to increase
therapeutic efficacy by both targeting the cancer-driving genomic
aberrations and, where the tumor biomarker is not known,
identifying individuals who will benefit most from conventional
“non-targeted” treatment, decreasing at the same time toxicity due
to individually altered drug metabolism. All these tests are available
to clinicians, and may greatly improve the management of most
patients, in terms of both therapy effectiveness and safety. Of
course, these tests may be expensive, but the costs of administering
inappropriate, expensive therapies and of managing eventual
untoward toxicities may largely compensate this effort (Figure 2).
Indeed, pharmacogenomics can have a significant economic impact
by driving therapeutic intervention and prospectively predicting
patient’s drug activation and detoxification status.
NO Benefit
+ Toxicity
Figure 2. Pharmacogenomics studies are
not only beneficial to patients, but also help
sparing money by preventing inappropriate
expensive therapies.
+ Benefit
+ Toxicity
All patients with
the same diagnosis
+ Benefit
NO Toxicity
NO Benefit
NO Toxicity
Figure 1. For an increasing number of situations, it is becoming clear that patients can be
categorized into different classes, according to the benefit/toxicity they have following a
given standard therapy (modified from Walgren RA et al., JCO 23:7342, 2005).
213
Cancer Stem Cells
due to their unlimited replicative potential, normal stem cells
accumulate oncogenic mutations over time, eventually acquiring
specific malignant properties and at the same time retaining
stemness properties. It is however also possible that differentiated
cells could de-differentiate into stem cells upon genetic mutations,
thus re-acquiring stemness properties.
CSC share some features with normal stem cells, including
long life-span, self-renewal and differentiation potential. CSC in
fact are able to persist in vivo for long time perpetuating themselves
thanks to the ability to divide asymmetrically generating a daughter
differentiated cells and a daughter undifferentiated stem cell. Even
in vitro, CSC can be maintained for long time in the absence of
serum or other growth factors; under these culture conditions,
one of the main characteristics of CSC is their ability to give rise
to cellular structures named “spheroids”, which mimic tumor and
micro-metastases organization in vivo and can be expanded in vitro
for several months. In addition, CSC present high tumorigenic
capability and metastatic phenotype; CSC disaggregated from
spheroids are able to engraft and generate tumors at high efficiency
when inoculated into immunodeficient mice, and also seem to be
responsible for chemioresistance and tumor relapse. In fact, a large
fraction of CSC is in a quiescent state, which prevents the response
to conventional chemotherapeutics able to kill proliferating cells.
CSC quiescence could be a reversible condition, and much work
is focused on the possibility of uncovering the signals that drive
CSC into proliferation or, conversely, induce their dormancy.
Over the last 10 years researchers tried to isolate CSC
thanks to the introduction of new technologies that allowed
their characterization in several malignant tissues, including
hematopoietic, breast, renal and colon cancer. Historically,
two different approaches have led to their identification: (I)
examination of the expression of tissue-specific surface markers
(such as CD44, CD133, CD24) that are selectively expressed on
CSC but not on the bulk of tumor cells, and (II) examination
Normal tissues are organized in a hierarchical fashion; rare
somatic cells give origin to a population of differentiated cells
forming the bulk of tissue. In this setting, the skin and the gastrointestinal tract undergo a tremendous turnover of the epithelial
component, which entails the existence of a self-renewing
population able to steadily face the continuous replacement of
the dying epithelial cells. These self-maintaining cells, called stem
cells, are able to divide symmetrically to perpetuate themselves
(self-renewal) and asymmetrically to maintain the progeny
(differentiation). Stem cell true nature can be entirely understood
only within its natural microenvironment, the so-called “niche”,
where the exposure to growth factors and extracellular matrix,
secreted and organized by neighboring differentiated cells, allows
stem cells to maintain their identity.
A landscape example of stemness of solid tissues comes from
the gastro-intestinal tract. The intestinal niche is organized into
crypts and villi, populated by different types of cells that maintain
their position along the intestinal architecture. All these cells
originate from a small population of long-living cells located
at the crypt base, as elegantly shown by clonal analysis. Thanks
to a DNA-labeling method these cells have been recognized as
intestinal stem cells. Exposure to niche signals may induce stem
cells to divide asymmetrically and symmetrically, giving origin
to transient amplifying progenitors (TA) that migrate along the
crypt-villus axis. TA cells are faded to differentiate into three
different mature cell types: enterocytes, entero-endocrine cells and
goblet cells; in a few days these mature cells are entirely replaced.
It has been recently shown that, akin normal tissues, malignant
tissues as well present a hierarchical organization; only a few cells
within the tumor are able to maintain indefinitely the bulk of
cancer, and the term Cancer Stem Cells (CSC) was introduced
for the first time in the ’80s. CSC origin is still a matter of debate;
CSC could originate from genetic or epigenetic mutation(s) that
occur in a normal stem or in a progenitor cell. In the former case,
214
cells isolated from human normal breast tissue and cultured as
mammospheres. Activation of Hedgehog signalling increased
by 57% the mammosphere number and size; these effects
were blocked by treatment with cyclopamine, which reduced
mammospheres formation.
Many of the markers used to identify CSC in different tissues
(such as LGR5/GPR49, CD44, CD24 and Ep-cam) are part of
the Wnt pathway. LGR5/GPR49, recognized as a putative colon
stem cell marker, is overexpressed in the majority of colorectal
cancer samples, compared to normal mucosal tissue; in addition,
LGR5 expression was correlated to lymphatic and vascular
invasion, lymph node metastasis and tumor stage, highlighting
the involvement of aberrant Wnt signals in tumor progression
driven by CSC.
Despite all the work done, several key problems are still
open:
I) since CSC are usually obtained following long-term in vitro
culture, the phenotypic and/or genotypic profile of spheroidderived CSC may not faithfully reflect their original in vivo
properties;
ii) data on surface marker expression by CSC do not always
coincide among the different workers, and different
“cancer stemness” markers have been identified in different
malignancies, or in a same malignant histotype by different
Authors;
iii)assuming that a key property of CSC is their ability to
form tumors when injected at very low cell number into
immunodeficient animals, the estimated number of CSC in a
tumor varies greatly among the Authors, depending on several
factor such as tumor histotype, selection techniques, culture
conditions, as well as the readout chosen for the assay of tumor
generation, as recently elegantly shown in melanoma.
of specific functional features of CSC. In some studies, CSC
have been recognized by dual-wavelength flow cytometry as
the so-called Side Population (SP) on the basis of their ability
to efflux the fluorescent DNA-binding dye Hoechst 33342. In
other studies, CSC have been identified on the basis of their
replicative potential; under standard culture conditions CSC are
poorly or non-proliferating cells compared to the bulk of tumor
cells. By measuring fluorescence intensity following labelling with
membrane-binding dyes such as PKH26, it is possible to identify
cells that proliferate and eventually loose the dye from cells that
remain in a quiescent state hence maintain high intensity of the
dye. In other studies, CSC have been recognized by their ability
to persist in vivo after chemotherapy treatment. It has been
shown that the CD133- fraction of human colorectal cancer
cells showed a dose-dependent sensitivity to oxaliplatin and/or
5-Fluorouracil (5-FU), whereas the CD133+ fraction (recognized
as the CSC subset) did not undergo drug-induced apoptosis, even
by increasing drug concentration. Recent study has demonstrated
that SP/CSC express multidrug resistance genes - including
MDR-1, ABCG2, ABCA3 and BRC1 - that may contribute to
the malignant phenotype and can explain the relative inefficiency
of chemotherapeutic drugs.
Based on the analogies between CSC and their normal
counterpart, much interest has focused on the activation of
certain signalling pathways involved in stem cell maintenance
and proliferation, such as Notch-1, Wnt/β-catenin and Sonic
Hedgehog pathways; it is reasonable that alterations in these
pathways could contribute to neoplastic transformation of
normal stem cells and permit to recognize CSC in different
tissues. Aberrant Notch activation has been demonstrated in
CSC from different tumors, including glioma, breast, colon and
pancreatic cancer. Pancreatic CSC, identified by the expression of
CD44, CD133, CD24, CD34 and ALDH, showed higher levels
of Notch-1 and Notch-2 compared to pancreatic non-CSC. In
colon cancer cells with CSC properties, inhibition of Notch-1
induced a reduction in cell proliferation, a cell cycle arrest in G0G1, and it increased the number of apoptotic cells. Moreover,
Notch inhibition reduced both spheroid formation in vitro and
tumorigenic capacity in mice, two established CSC features. In
contrast, Notch-1 overexpression increased cell proliferation, cell
cycle progression and it reduced apoptotic cells. Likewise, a recent
study has demonstrated that some component of Sonic Hedgehog
pathway are highly expressed in stem/progenitor mammary
Being conscious of all the difficulties to define a specific
profile for CSC, a better understanding of their characteristics,
the key signaling pathways in CSC and their role in the regulation
of CSC quiescence could represent a fundamental point for a
new therapeutic approach capable of improving the efficacy of
established therapeutic approaches to cancer.
215
In the following Section we summarize
the list of the Projects presented to the
Health Ministry for the years 2010-2011
“Ricerca Corrente”, grouped according
to the appropriate Research Line.
Research Activity
Report
RESEARCH ACTIVITY REPORT
217
LINE 1
Tumor Epidemiology
and Prevention
Akin most (if not all) fields of medicine, progress in oncology firmly relies on the
growing body of evidence about the mechanisms underlying neoplastic transformation
and tumor progression. On the other hand, this wealth of knowledge cannot prescind
from the careful consideration of the possible causes that promote cancer generation,
including environmental factors, nor can the incidence of the different cancer forms be
ignored, since its fluctuations over the years may reflect significant variations in the impact
of these factors on the general population. Thus, in-depth knowledge of the prevalence
and incidence of different cancer forms may greatly help in designing primary prevention
strategies addressing exogenous factors or habits causally related to tumor generation.
Secondary prevention as well may strongly impact on cancer morbidity and mortality,
and the importance of appropriate screening strategies for early diagnosis of some tumors
is largely proven. At the IOV, particular attention is paid to primary and secondary
prevention of tumors, and the Institute has the mission of coordinating the three major
cancer screening programs over the entire Veneto region, in strict collaboration with local
health authorities.
RESEARCH ACTIVITY REPORT - LINE 1
218
N° Prog
Titolo
Responsabile
L01P01
Registro Tumori del Veneto, studi di epidemiologia descrittiva ed analitica.
Zambon Paola
L01P02
Prevenzione secondaria dei tumori.
Zambon Paola
L01P03
Valutazioni epidemiologiche sui sarcomi delle parti molli.
Rossi Carlo Riccardo
L01P04
Epidemiologia delle patologie precancerose dell’esofago.
Castoro Carlo
L01P05
Studio delle patologie neoplastiche e delle immunodeficienze associate ad infezione con retrovirus umani
nel bambino.
De Rossi Anita
L01P06
“Prevenire è meglio che curare”: Progetto educativo rivolto ai ragazzi delle scuole medie inferiori di
Padova sui principali fattori di rischio associati al cancro e sull'importanza della prevenzione.
Giacobbo Maria
L01P07
Gravidanza dopo terapia per carcinoma della mammella.
Ghiotto Cristina
L01P08
Sorveglianza diagnostica di donne ad alto rischio genetico-familiare di tumore mammario.
Pescarini Luigi
L01P09
Familiarità e predisposizione genetica nel cancro esofageo e del cardias.
Castoro Carlo
L01P10
Utilizzo del test Papillomavirus Umani (HPV) ad alto rischio nella prevenzione secondaria del carcinoma
della cervice uterina.
Del Mistro Annarosa
L01P11
Analisi della prima recidiva in pazienti affetti da carcinoma mammario operato.
Esperienza monoistituzionale.
Jirillo Antonio
219
LINE 2
Mechanisms
of Cancerogenesis
Neoplastic transformation is a complex process that involves several initiating and/
or promoting events, numerous as yet imperfectly understood molecular changes in
the cell, and bidirectional interactions mediated by soluble or cell-associated molecules
between tumor cells and the microenvironment (endothelial cells, stromal cells, infiltrating
inflammatory cells). Among the causes underlying neoplastic transformation, infectious
agents may play a relevant role, and it is estimated that >20% of human neoplasias are
associated with viral infections. The immunocompromised status, due either to infection
or iatrogenic immunosuppression in transplant recipients, also favors the development of
virus-associated tumors. At the IOV, a great deal of expertise has accumulated over the past
40 years on the pathogenic role of viruses, in particular the human T lymphotropic virus
type 1 (HTLV-1), the Epstein-Barr virus (EBV), the human herpesvirus type 8 (HHV8 or
Kaposi Sarcoma-associated HerpesVirus, KSHV), the human papilloma virus (HPV).
These viruses play a direct role in oncogenesis and behave as causative agents of several
tumors; instead, non-transforming retroviruses, such as the human immunodeficiency
virus (HIV), are involved in the oncogenetic process through indirect mechanisms, by
favoring reactivation of transforming viruses and/or interfering with the physiologic
pathways that regulate cell proliferation and death. Analysis of the mechanisms by which
viruses rearrange the cellular program of senescence/immortalization would shed new light
into cell physiopathology and provide new tools for prevention/treatment strategies.
220
N° Prog
Titolo
Responsabile
L02P01
Analisi dei meccanismi coinvolti nella protezione dall’apoptosi mediata dalla proteina Tax del virus
Saggioro Daniela
Tlinfotropico di tipo 1 (HTLV-1).
L02P02
Melanoma maligno eredo-familiare: analisi funzionale di varianti geniche di CDKN2A.
L02P03
Melanoma maligno: analisi genetica del gene CDKN2A e identificazione di modificatori genetici della
Menin Chiara
penetranza in famiglie ad alto rischio.
L02P04
Analisi funzionali di proteine regolatorie codificate da retrovirus oncogeni umani.
Ciminale Vincenzo
L02P05
Identificazione delle famiglie ad alto rischio di cancro della mammella/ovaio.
D’Andrea Emma
L02P06
Caratterizzazione del fenotipo e studio prospettico della sindrome paraganglioma in una popolazione ad
Opocher Giuseppe
alta prevalenza.
L02P07
Ruolo dell’obesità e dell’insulino-resistenza nella sequenza esofago di Barrett-displasia-adenocarcinoma.
Battaglia Giorgio
L02P08
Role of cancer stem cells in gastrointestinal adenocarcinoma: potential targeted therapy.
Scarpa Marco
L02P09
Linfomagenesi EBV-associata.
De Rossi Anita
L02P10
Modello chirurgico sperimentale di sviluppo di esofago di Barrett e adenocarcinoma indotto da reflusso
Cagol Matteo
biliare nel ratto e nel topo.
L02P11
Il nuovo gene oncosoppressore TMEM127: dalla caratterizzazione del fenotipo associato a mutazioni
Opocher Giuseppe
TMEM al meccanismo d’azione molecolare.
L02P12
Ricerca e tipizzazione HPV (papillomavirus umano) in tumori del capo-collo e dell’esofago, e relazione
Del Mistro Annarosa
con la risposta alla terapia.
L02P13
Definizione della storia naturale della neoplasia endocrina multipla di tipo 1 (MEN1) e del ruolo di menina
nella tumorigenesi a partire dalla caratterizzazione clinica-molecolare della più grande famiglia descritta per Opocher Giuseppe
questa sindrome.
L02P14
Identificazione di nuovi alleli di predisposizione in famiglie con tumore della mammella/ovaio eredoMontagna Marco
familiare non informative al test genetico BRCA.
L02P15
Carcinogenesi in esofago di Barrett: meccanismi di regressione della displasia di basso grado e costruzione
Castoro Carlo
di un vaccino contro l adenocarcinoma esofageo.
L02P16
Studio dei meccanismi patogenetici coinvolti nello sviluppo di tumori correlati all'herpesvirus oncogeno
Calabrò Maria Luisa
HHV8.
L02P17
Imprinting materno nella Sindrome Paraganglioma di tipo 1: basi molecolari e tools diagnostici.
Opocher Giuseppe
L02P18
Tumorigenesi nella sindrome feocromocitoma/paraganglioma.
Opocher Giuseppe
L02P19
Ruolo dell’ipossia nella regolazione di SERPINB3 nell’epatocarcinoma.
Amadori Alberto
L02P20
Studio sugli effetti della soppressione acida sulla carcinogenesi esofagea da reflusso nell’uomo e in un
Castoro Carlo
modello sperimentale di esofago di Barrett e adenocarcinoma indotto da reflusso biliare nel ratto.
L02P21
Tumori ereditari del rene.
Menin Chiara
Opocher Giuseppe
221
LINE 3
Instrumental and Molecular
Approaches for Diagnosis,
Staging and Follow-Up
A large body of evidence on accumulating genetic changes that underlie tumor
development is providing more and more powerful tools for the clinical evaluation of
the neoplastic disease. The characterization of new molecular features is significantly
contributing to redefine both the criteria of tumor diagnosis and the formulation of
prognosis. Indeed, if we only consider mammary tumors, what 20 or 30 years ago we
called a “breast cancer” is now known to be an array of different transformation processes,
each endowed with special phenotypic and genotypic properties, that differentiate this
tumor from tumors apparently similar by conventional histology. As a matter of fact, a
molecular classification of cancer is flanking the classical tumor taxonomy, and patients are
increasingly classified based on the molecular profile of their tumor.
Thus, the definition of new, non-invasive markers for tumor diagnosis, staging and
prognosis is urgently needed. While the identification of new molecular markers (in tumor
cells or in biological fluids) is clearly fundamental to the goal of improving the definition
of prognosis of neoplastic diseases and to help in predicting the response of individual
patients to targeted therapies, progress in tumor diagnosis and monitoring also firmly relies
on the availability of new technological developments in several different fields. In this
frame, the Institute has privileged the development of various instrument-based platforms,
particularly those best suited to neoplastic conditions of major interest to the Institute.
222
N° Prog
Titolo
Responsabile
L03P01
Determinazione seriata delle cellule tumorali circolanti (CTCs) come indicatore di risposta alla terapia
Basso Umberto
antiangiogenetica con Sunitinib (SUTENT®) nel carcinoma renale avanzato.
L03P02
Individuazione di nuove strategie non invasive per la diagnosi e monitoraggio dei tumori: studio della
De Rossi Anita
telomerasi come marcatore molecolare.
L03P03
Confronto tra Tomosintesi Digitale della Mammella e Mammografia Standard in donne sintomatiche.
Gennaro Gisella Maria
L03P04
Protocollo Italiano per i controlli di qualità in mammografia digitale.
L03P05
Automazione controlli di qualità in mammografia digitale: sistemi DR e CR.
L03P06
Tecnica ROLL (Radioguided Occult Lesion Localization) nello studio di piccole lesioni in fase diagnostica
Gregianin Michele
o di ristadiazione in pazienti con sarcoma o altra patologia neoplastica.
L03P07
Approfondimenti diagnostico-prognostici sulla biopsia del linfonodo sentinella del melanoma.
L03P08
Studio multicentrico AIMN. Stadiazione dei Linfomi mediante PET/CT.
Gregianin Michele
L03P09
Accuratezza dell’endomicroscopia confocale nella diagnosi della displasia nell’Esofago di Barrett: studio
Battaglia Giorgio
prospettico in doppio cieco.
L03P10
Valore prognostico incrementale della 18F-FDG-PET/CT nei pazienti con carcinoma della mammella.
Evangelista Laura
L03P11
Confronto tra tomosintesi digitale della mammella e mammografia standard in donne sintomatiche - Fase II.
L03P12
Fattori predittivi della risposta al trattamento e/o della prognosi nel melanoma o nei sarcomi delle parti
molli.
L03P13
PET-CT diagnostica con m.d.c. vs. metodiche standard nella stadiazione del tumore esofageo: diagnosi e
Cervino Anna Rita
management.
L03P14
Determinazione delle Cellule Tumorali Circolanti prima e dopo chirurgia nelle pazienti con nuova diagnosi
Zamarchi Rita
di carcinoma mammario in Stadio I-III.
L03P15
Lesioni infracliniche mammarie e diagnosi precoce di neoplasia.
L03P16
VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic
Lonardi Sara
colorectal cancer patients.
L03P17
Studio della distribuzione del drenaggio linfatico e guida alla biopsia del linfonodo sentinella nel melanoma
Sotti Guido
del tronco. Studio linfoscintigrafico.
L03P18
Ruolo della PET-CT nella valutazione diagnostica precoce della cardiotossicità da chemioterapici in
Evangelista Laura
pazienti con Carcinoma della Mammella.
L03P19
Lo status di BRAF come marcatore prognostico nei pazienti con carcinoma papillare della tiroide (PTC).
L03P20
Valore diagnostico della [18F]-Colina (FCH) PET/CT in pazienti con cancro della prostata al III stadio
Saladini Giorgio
e a rischio di recidiva alto o intermedio.
L03P21
Il ruolo della 18F-DOPA PET-CT total body nella stadiazione e follow-up dei tumori neuroendocrini
vs l imaging convenzionale morfologico (RMN, TC, US) o funzionale (111In-pentetreotide e 123/131I- Cervino Anna Rita
MIBG).
223
Pescarini Luigi
Vianello Federica
L03P22
Ruolo della 18F-FDG PET/CT nel follow-up e nel sospetto di recidiva in pazienti con Cancro del
Gregianin Michele
colonretto operato.
L03P23
Analisi prospettica con TC dei nodi/noduli polmonari nel cancro colon-rettale.
Pomerri Fabio
L03P24
Valutazione dell incidenza dell esofagite sovranastomotica nei pazienti operati di esofagectomia.
Battaglia Giorgio
L03P25
Analisi delle mutazioni dei geni kit e pdgfra in tumori stromali del tratto gastrointestinale (GIST):
Bertorelle Roberta
razionale per la terapia molecolare.
L03P26
Espressione dei fattori di crescita endoteliali dopo chirurgia esofagea.
Castoro Carlo
L03P27
Personalizzazione dei trattamenti per i pazienti con tumori del tratto digestivo.
Amadori Alberto
L03P28
Analisi dell’impatto prognostico delle mutazioni di EGFR e KRAS e della FISH per EGFR nei carcinomi
Favaretto Adolfo Gino
polmonari non a piccole cellule trattati chirurgicamente.
L03P29
18F-FDG-PET/CT vs. CT nella stadiazione post-chirurgica nel carcinoma della mammella ad alto
Evangelista Laura
rischio.
L03P30
Fattori prognostici nel melanoma della coroide metastatico.
Chiarion-Sileni Vanna
L03P31
Marker tumorali nel carcinoma dell’esofago e del cardias. Studio retrospettivo.
L03P32
Studio delle caratteristiche cliniche e dei fattori prognostici delle pazienti con carcinoma della mammella
Ghiotto Cristina
diagnosticato <40 anni. studio retrospettivo.
L03P33
Carcinoma intraduttale della mammella: analisi degli aspetti funzionali mediante Rm e/o Pet.
Pescarini Luigi
L03P34
PET/CT Scanning in the Management of Thyroid Cancer.
Pomerri Fabio
L03P35
Ristadiazione locoregionale del carcinoma del retto dopo terapia neoadiuvante. Risonanza magnetica della
Pomerri Fabio
dinamica vascolare.
L03P36
Valutazione di marcatori prognostici nel melanoma uveale mediante MLPA e FISH.
L03P37
Caratterizzazione fenotipica e genotipica delle CTC, per l'impiego come bio-marcatore prognostico/
Zamarchi Rita
predittivo nei tumori solidi.
L03P38
Valutazione delle cellule tumorali circolanti (CTCs) e dei progenitori delle cellule endoteliali (EPCs) come
fattore prognostico nel carcinoma polmonare localmente avanzato (NSCLC).
L03P39
Identificazione di nuovi target molecolari e agenti biologici per il trattamento chemioterapico del
mesotelioma pleurico maligno.
L03P40
Monitoraggio cardiologico in pazienti affette da carcinoma mammario candidate a terapia adiuvante con
Falci Cristina
Antracicline e Trastuzumab.
L03P41
Sviluppo e validazione di uno strumento per l’estrazione di parametri dosimetrici da immagini radiologiche
digitali da utilizzare per la radioprotezione del paziente.
L03P42
Ruolo del pathway metabolico del glutatione nel trattamento e nella prognosi del tumore dell’esofago.
L03P43
Utilizzo della SPECT con SestaMIBI nella valutazione della risposta in pazienti trattati con antiangiogenetici
Zustovich Fable
(bevacizumab e sorafenib) per glioblastoma multiforme.
224
Bonaldi Laura
Saggioro Daniela
L03P44
Utilizzo della SPECT con SestaMIBI nella valutazione della possibile istologia in pazienti con masse
Zustovich Fable
cerebrali di ndd.
L03P45
Utilizzo della SPECT con SestaMIBI nella valutazione della progressione vera in pazienti trattati
Zustovich Fable
radicalmente per glioblastoma multiforme.
L03P46
Mutazione dei geni IDH1 e IDH2 come fattore predittivo di risposta ai farmaci antiangiogenetici nei
Lombardi Giuseppe
tumori cerebrali.
L03P47
18F-FDG-PET/CT vs. CT nella stadiazione post-chirurgica nei pazienti con carcinoma della mammella
Bezzon Elisabetta
ad alto rischio.
L03P48
Effetto della ormonoterapia sulla accuratezza diagnostica della 18F-FDG PET/CT nei pazienti con
Evangelista Laura
carcinoma della mammella precedentemente trattate.
L03P49
Correlazione tra la presenza della mutazione dei geni IDH1 e IDH2 nei gliomi cerebrali e l’aumento della
Lombardi Giuseppe
espressione del gene HIF-1 e del metabolita 2-HG nell’urina.
L03P50
Correlazione tra la presenza della mutazione dei geni IDH1 e IDH2 nei gliomi cerebrali, l’aumento del
Lombardi Giuseppe
metabolita 2-HG nelle cellule tumorali e la sua rilevazione tramite RMN spettroscopica.
L03P51
Dall’ Endoscopia Confocale all’Endoscopia Mirata: studi clinici e preclinici nel cancro dell’esofago.
L03P52
Metilazione MGMT come fattore predittivo di risposta al trattamento antiangiogenetico nei tumori
Lombardi Giuseppe
cerebrali.
L03P53
Tumori del colon e della mammella: ottimizzazione della sorveglianza tramite analisi clinico-patologica e
Cappetta Alessandro
genetica della loro associazione.
L03P54
Indicazioni all’utilizzo di FDG-PET/CT nelle neoplasie ginecologiche: analisi di una casistica
Dalla Palma Maurizia
retrospettiva.
L03P55
Studio con endoscopia confocale della vascolarizzazione tumorale come “marcatore” di risposta alla terapia
Battaglia Giorgio
antiangiogenetica.
L03P56
L’ecografia endoscopica (EUS) nella ristadiazione dei pazienti chemio-radiotrattati per neoplasie esofagee.
Battaglia Giorgio
L03P57
Analisi delle mutazioni dei geni IDH1 e IDH2 nei gliomi.
Bertorelle Roberta
L03P58
Analisi FISH del riarrangiamento del gene ALK nei tumori non a piccole cellule del polmone.
Bonaldi Laura
L03P59
Imaging con tc multidetettore e ricostruzioni 3d del mesotelioma pleurico: correlazioni con i riscontri
Polverosi Roberta
operatori.
L03P60
Imaging delle Metastasi Pancreatiche da Carcinoma Renale.
225
Battaglia Giorgio
Polverosi Roberta
LINE 4
Innovative Therapeutic
Approaches: Chemotherapy,
Radiotherapy and Surgery
The wealth of knowledge accumulated on the molecular alterations that characterize
tumors has profoundly changed pharmacological approaches to tumor therapy, with
surgery, radiotherapy and chemotherapy now flanked by the so-called “target therapies”,
which rely on the ability of small molecules to more or less specifically and selectively
interfere with abnormal intracellular pathways responsible for the growth advantage of
transformed tumor cells. Thus, several national and international clinical protocols are
active at the Institute, with special attention placed on the possibility of combining small
molecules such as kinase inhibitors with biologically active tools such as monoclonal
antibodies. In any case, all cancer patients are offered an integrated approach to diagnosis
and treatment that involves the expertise of medical oncologists, surgeons, radiotherapists,
psycho-oncologists, and if needed specialists from many other fields, interacting in a
multidisciplinary unit. Of course, the search for new, more active, selective and tolerated
therapies cannot proceed in the absence of continuous exchange with the laboratory, and
laboratory expertise is essential to this integrated approach. Many so-called “intelligent”
drugs are now available, in fact; nothing, however, could be worse than using intelligent
drugs in a stupid manner, that is, administering a drug to patients who cannot benefit from
it due to their constitutional features or the molecular properties of their tumor.
226
N° Prog
Titolo
Responsabile
L04P01
Implementazione ed ottimizzazione dosimetrica della tecnica di irradiazione della mammella con
Reccanello Sonia
posizionamento prono.
L04P02
Radioterapia Stereotassica Frazionata (RSF) nei gliomi a basso grado di malignità in età pediatrica.
L04P03
Studio randomizzato di fase III sull’efficacia dell’Interferone (IFN a2b) intensificato endovenoso vs IFN
a2b secondo ECOG 1684 nel melanoma radicalmente operato.
L04P04
Studio di fase III di valutazione della sicurezza ed efficacia del trattamento con 2 mg di Allovectina-7
intralesionale comparata con DTIC o Temozolomide nei soggetti con melanoma recidivato.
L04P05
Terapia neoadiuvante con Docetaxel,cisplatino e 5-fluorouracile(TPF) seguita da radioterapia e
chemioterapia concomitante o Cetuximab versus radioterapia più chemioterapia concomitante o Koussis Haralabos
Cetuximab in pazienti con carcinoma a cellule squamose della testa e del collo localmente avanzato.
L04P06
Trattamenti innovativi nel melanoma e nei sarcomi delle parti molli.
L04P07
Chirurgia della malattia residua in pazienti con GIST metastatico responsivi ad imatinib (EORTC trial
Basso Umberto
62032).
L04P08
ITACA-S 2: comparison of the efficacy ofa peri-operative versus a post-operative chemotherapy treatment
in patients with operable gastric cancer and assessment of the benefit of a post-operative chemo- Zagonel Vittorina
radiotherapy. Studio multicentrico nazionale randomizzato.
L04P09
Screening for early predictors of Peripheral Neuropathy in Oxaliplatin-Treated patients.
L04P10
Studio multicentrico randomizzato di fase 3 di confronto tra dosaggio fisso e dosaggio modificato
sulla base della tossicità della chemioterapia standard con cisplatino ed etoposide in pazienti affetti da Favaretto Adolfo Gino
microcitoma polmonare avanzato.
L04P11
Supporto metodologico ed informatico nella pianificazione, organizzazione e conduzione di
De Salvo Gian Luca
sperimentazioni cliniche.
L04P12
Progetto “Ufficio di Coordinamento Trials Clinici”: gestione della ricerca clinica no-profit e profit
De Salvo Gian Luca
all’interno dell’Istituto Oncologico Veneto.
L04P13
Attività anti-ossidante del cioccolato fondente in pazienti con carcinoma della mammella in terapia
Ghiotto Cristina
adiuvante.
L04P14
Analisi delle sequenze sorafenib/sunitinib versus sunitinib/sorafenib nel trattamento del tumore renale
Zustovich Fable
avanzato.
L04P15
ASL608LIOM02 (GLIMESOR): Sorafenib (nexavar) in associazione a terapia metronomica con
temozolomide in pazienti con glioblastoma multiforme dopo fallimento di una chemioterapia di prima Zustovich Fable
linea: studio clinico di fase II con valutazione farmacodinamica, farmacocinetica e farmacogenetica.
L04P16
Profilo farmacogenetico e risultati clinici di pazienti con cancro al colon in stadio II ad alto rischio e stadio
Zagonel Vittorina
III trattato con chemioterapia adiuvante Folfox-4 e bevacizumab.
L04P17
Radioterapia con modulazione della dose nel carcinoma dell’esofago cervicale.
Corti Luigi
L04P18
In-use stability dei farmaci oncologici.
Palozzo Angelo Claudio
L04P19
Studio multicentrico nazionale randomizzato di fase II-III di chemioterapia peri o post chirurgica
Zagonel Vittorina
nell’adenocarcinoma pancreatico resecabile-PACT-15.
227
Scarzello Giovanni
Lonardi Sara
L04P20
Studio randomizzato di fase II con taxotere, oxaliplatino, capecitabina (TOX) o epidoxorubicina,
Zagonel Vittorina
oxaliplatino e capecitabina (EOX) in pz con carcinoma gastrico loc avanzato o metastatico.
L04P21
Pemetrexed nel mesotelioma pleurico – un nuovo modello per valutare efficacia, efficienza e appropriatezza
Jirillo Antonio
attraverso il registro AIFA.
L04P22
COMETS: Studio di fase III randomizzato controllato a gruppi paralleli che confronta due differenti
sequenze di terapia (Irinotecan/Cetuximab seguito da FOLFOX-4 vs FOLFOX-4 seguito da Irinotecan/
Lonardi Sara
Cetuximab) in pazienti portatori di tumore del colon-retto metastatico trattati in prima linea di terapia
con FOLFIRI/Bevacizumab.
L04P23
TRIBE: Studio randomizzato di fase III su Folfoxiri + Bevacizumab vs Folfiri + Bevacizumab come prima
Lonardi Sara
linea nel trattamento del tumore colon-retto metastatico.
L04P24
Barrx a completamento di mucosectomia eseguita per HGD e Ca in situ in esofago di Barrett.
Battaglia Giorgio
L04P25
Ablazione di esofago di Barrett mediante radiofrequenza.
Battaglia Giorgio
L04P26
One-arm, multi-center, international prospective pivotal study to assess the safety and efficacy of
Scarzello Giovanni
BioProtect biodegradable implantable balloon in prostate cancer subjects undergoing radiotherapy.
L04P27
Studio retrospettivo sulla cardiotossicità in pazienti con carcinoma della mammella sottoposte a terapia
Ghiotto Cristina
adiuvante con trastuzumab.
L04P28
Studio randomizzato in doppio cieco di PF-804 in pazienti con tumore del polmone non a piccole cellule
in stadio IIIb/IV dopo fallimento di una terapia standard per la malattia avanzata.
L04P29
Doxorubicina peghilata liposomiale (PLD) nella recidiva di carcinoma ovarico: migliore outcome nelle
Nicoletto Maria Ornella
pazienti portatrici di mutazione BRCA?
L04P30
Studio di fase III randomizzato per la valutazione dell’efficacia di cisplatino e gemcitabina come prima
linea di trattamento dei pazienti anziani con tumore del polmone non a piccole cellule (NSCLC) in stadio Favaretto Adolfo Gino
avanzato.
L04P31
Studio multicentrico randomizzato di fase II. Trattamento di pazienti anziani con carcinoma prostatico
Basso Umberto
metastatico non suscettibili di trattamento standard.
L04P32
Valutazione retrospettiva multicentrica dell’attività di sunitinib nei pazienti anziani (70 anni o più) con
Basso Umberto
carcinoma renale metastatico.
L04P33
Studio sull’impiego delle Gemcitabina come terapia di salvataggio nel carcinoma del colon-retto
Lonardi Sara
metastatico.
L04P34
Phase II Trial of Folfoxiri Plus Panitumumab as First-Line Treatment F for Kras and Braf Wild-Type
Lonardi Sara
Metastatic Colorectal Cancer.
L04P35
Boron Neutron Capture Therapy (Bnct) delle Recidive Cutanee da Cancro della Mammella: impiego
Evangelista Laura
della Pet/Ct.
L04P36
Verifica dosimetrica e implementazione della tecnica IMRT e IGRT per il trattamento di patologie del
Simonato Franca
capo-collo e della prostata.
L04P37
Terapia settimanale con Carboplatino e Docetaxel in pazienti con tumore del capo-collo con importante
Koussis Haralabos
comorbidità.
L04P38
Intrabeam project for intraoperative radiotherapy for breast cancer versus whole breast irradiation
Sotti Guido
(TARGIT-A Trial): phase III trial.
228
L04P39
Chemioterapia adiuvante in pazienti Italiani ed Americani con tumore della mammella BRCA-associato. Cappetta Alessandro
L04P40
MITO 8\2011: Doxorubicina Liposomiale Stealth vs Carboplatino + Paclitaxel in pazienti con recidiva
di carcinoma ovarico tra sei e dodici mesi dal precedente trattamento con platino: studio multicentrico Nicoletto Maria Ornella
randomizzato.
L04P41
Studio internazionale multicentrico, randomizzato, in doppio-cieco, di fase III, volto a valutare l’efficacia
e la sicurezza di BIBF 1120 in combinazione con carboplatino e paclitaxel verso placebo più carboplatino Nicoletto Maria Ornella
e paclitaxel in pazienti con cancro ovarico avanzato.
L04P42
Intraoperative radiotherapy as a tumor bed boost (TARGIT−B).
Sotti Guido
L04P43
Studio di Fase I con agenti ditiocarbammici di oro(III) in pazienti oncologici.
Jirillo Antonio
L04P44
Implementazione e ottimizzazione dosimetrica della IORT con IntraBeam System.
Reccanello Sonia
L04P45
Sorafenib nell’epatocarcinoma – un nuovo modello per valutare efficacia, efficienza e appropriatezza
Jirillo Antonio
attraverso il registro AIFA.
L04P46
Pemetrexed nell’adenocarcinoma polmonare – un nuovo modello per valutare efficacia, efficienza e
Jirillo Antonio
appropriatezza attraverso il registro AIFA.
229
LINE 5
Tumor Immunology
and Innovative Therapeutic
Approaches
It is now widely accepted that tumor growth is the result of the very complicated
bidirectional interaction between cells that progressively acquire molecular alterations, a
growth advantage and finally a fully transformed phenotype, and surrounding cells of
the host that may contrast or in some instances also favor their autonomous growth and
expansion. In addition, the interplay between tumor cells and host tissues may change
during the course of tumor development. In a first phase a “sneaking through” situation
may occur, where immune surveillance simply disregards cells on the way to premalignant
or malignant transformation. Later on, an equilibrium may arise between tumor cell
growth and death by apoptosis on the one hand, and active control by immune effectors
on the other, with tumor expansion still in check. The final overt tumor expansion phase
arises when this unstable equilibrium somehow breaks down, during which tumorderived factors often come into play to abate the residual contrasting potential of immune
surveillance. For many years, one of the most popular dreams of tumor immunologists
has been the so-called “magic bullet”; while this goal is close to becoming realized thanks
to monoclonal antibodies and target molecules, the other great dream of potentiating
the immune response against tumors has not lived up to its promise. Notwithstanding,
tumor immunology is currently undergoing a new flare of development, thanks to the
understanding that a combination of different strategies synergizing against all (or most)
the different actors contributing to tumor growth could be a very effective, if not the
ultimate, remedy. While several of these approaches are already in phase I/II clinical trials,
frequently in combination with canonical chemotherapeutic tools, many others are still
in a preclinical, translational research phase; hopefully, some of them will soon move
to the human setting and become a part of the therapeutic armamentarium of clinical
oncologists.
230
N° Prog
Titolo
Responsabile
L05P01
Studio dei meccanismi molecolari che regolano la dormienza tumorale.
Indraccolo Stefano
L05P02
Generazione di linfociti T citotossici survivina-specifici in topi HHD transgenici per HLA-A*0201, per
l’isolamento di TCR utilizzabili nella ingegnerizzazione di cellule T umane per l’immunoterapia adottiva Rosato Antonio
dei tumori.
L05P03
Anticorpi terapeutici verso nuovi antigeni di EBV.
L05P04
Immunoterapia adottiva dei tumori mediante cellule T ingegnerizzate ad esprimere T Cell Receptor (TCR)
Rosato Antonio
transgenici o Recettori Chimerici per l'Antigene (CAR).
L05P05
Ruolo dei microRNA nella maturazione e nel processo di trasformazione neoplastica dei linfociti T.
L05P06
Identificazione di reti regolatorie presenti nelle cellule soppressorie di derivazione mieloide mediante
Mandruzzato Susanna
integrazione di dati di espressione genica e di microRNA.
L05P07
Analisi del profilo dei microRNA come strumento per studiare la biologia delle cellule mieloidi
Bronte Vincenzo
soppressorie.
L05P08
Identificazione di nuove molecole in grado di recuperare l’attività del sistema immunitario contro il tumore:
Bronte Vincenzo
basi molecolari e biologiche per nuove terapie.
L05P09
Chemo-immunoterapia: l’eliminazione selettiva delle cellule soppressorie di origine mieloide tramite
somministrazione del chemioterapico 5-fluorouracile potenzia l’effetto terapeutico dell’immunoterapia Bronte Vincenzo
anti-tumorale.
L05P10
Identificazione di reti regolatorie nelle cellule soppressorie di derivazione mieloide mediante integrazione
Mandruzzato Susanna
di dati di espressione genica e di microRNA.
L05P11
Effetti metabolici della terapia anti-angiogenica nei tumori sperimentali.
Rosato Antonio
231
Zanovello Paola
Indraccolo Stefano
LINE 6
Quality of Life in Cancer Patients
and Geriatric Oncology
Besides the effort spent in translational and clinical research, much attention is paid at
the Institute to the issue of quality of life in cancer patients, with a special focus on geriatric
oncology. Persons over the age of 65 years are the fastest growing segment of the population
and will account for an estimated 20% of Americans and 25% of Europeans by the year
2030. Cancer incidence is 11-fold higher in persons over the age of 65 years than in younger
ones. Treatment of elderly patients with cancer is one of the key areas in which clinical
and scientific activities of our Institute are focused. Close relationship with the Geriatric
Clinics of the University of Padova is a peculiar feature of our Geriatric Oncology Program;
a multidisciplinary team including oncologists, psychologists, geriatricians, cardiologists,
dieticians, endocrinologists and other health professionals is currently involved in the
evaluation and care of elderly patients. Multidimensional geriatric assessment (MGA) is
regarded as an indispensable tool in the management of cancer patients. The Performance
Status (PS) is one of the most useful instruments orienting the therapeutic decision in
adult patients, but it is considered as a rather blunt tool when dealing with the elderly,
for which MGA is much more appropriate, as it covers the multifaceted features of ageassociated conditions. Monthly case-oriented multidisciplinary meetings are organized
in order to share clinical problems and to develop common algorithms of treatment
according to tumor site, stage and MGA parameters. In this occasion a review of pertinent
literature and results of our trials are presented to complete the discussion of clinical cases.
A database containing demographic, clinical and follow-up data of more than 600 patients
evaluated by MGA has been created and has provided data for several communications
to international congresses and scientific articles. Particular attention has been devoted to
proposing clinical trials to elderly patients whenever a national or international protocol is
open at our Institution, because we believe that elderly patients must be enrolled in clinical
trials, even though much more time and effort is needed.
232
Progr.
Titolo
Responsabile
L06P01
Valutazione dei disturbi cognitivi in pazienti con carcinoma mammario sottoposte a terapia con inibitori
Koussis Haralabos
dell aromatasi.
L06P02
Confronto tra il questionario VES-13 (Saliba et al) e la Valutazione Geriatrica Multidimensionale (VGM)
Falci Cristina
standard.
L06P03
Valutazione prospettica del significato prognostico della valutazione geriatrica multidimensionale in
Falci Cristina
pazienti oncologici.
L06P04
L’esperienza terapeutica dello IOV nell utilizzo del Fulvestrant nel carcinoma mammario metastatico
Jirillo Antonio
ormonosensibile:dati a confronto con gli studi registrativi.
L06P05
Studio prospettico sull’analisi dei costi economici reali dei pazienti inseriti all'interno di un trial
Jirillo Antonio
sponsorizzato in rapporto al finanziamento erogato dallo Sponsor.
L06P06
Studio retrospettivo che valuta gli scostamenti dagli studi clinici, in termini di risposta e tossicità dei
Jirillo Antonio
farmaci antitumorali nel registro Onco-AIFA.
L06P07
Studio prospettico sull’impatto prognostico della valutazione geriatrica multidimensionale alla prima visita
Zagonel Vittorina
del paziente oncologico anziano.
L06P08
Analisi retrospettiva dell’utilizzo di Fulvestrant (Faslodex) nel carcinoma mammario metastatico
Trojniak Marta Paulina
ormonosensibile per la valutazione dell’appropriatezza e dell’effectiveness del trattamento.
L06P09
Appropriatezza e costi dei PDTA (Percorsi Diagnostico Terapeutici e Assistenziali).
L06P10
Consumi e costi dei farmaci presso l’Istituto Oncologico Veneto per il trattamento del dolore oncologico. Giacobbo Maria
L06P11
Progetto Atmosfera
Giacobbo Maria
L06P12
Progetto Sole: Ansia, stress ed indagini diagnostiche in oncologia.
Giacobbo Maria
L06P13
Studio retrospettivo di valutazione dell’effectiveness e dell’appropriatezza prescrittiva dei trattamenti
contenenti il farmaco antitumorale pemetrexed (Alimta) sottoposto al monitoraggio Onco-AIFA nel Paganelli Francesco
trattamento delle neoplasie polmonari.
L06P14
Studio retrospettivo osservazionale di valutazione dell’effectiveness verso efficacy e determinazione delle
caratteristiche di sottogruppi dei pazienti responders nel trattamento di neoplasie polmonari con erlotinib Palozzo Angelo Claudio
(Tarceva).
L06P15
Approccio psiconcologico integrato per la comunicazione di “cattive notizie” in pazienti oncologici
ospedalizzati in fase avanzata di malattia: studio randomizzato per valutare l’efficacia nel migliorare la Capovilla Eleonora
gestione del dolore e rispondere ai bisogni informativo-comunicativi.
L06P16
Proposta di un centro di prevenzione, cura e riabilitazione della disfagia grave nei pazienti sottoposti a
Pellegrino Federica
trattamenti radiochemioterapici del capo-collo e dell esofago.
L06P17
Qualità di vita dopo esofagectomia per neoplasia.
Castoro Carlo
L06P18
Medicazioni avanzate e Qualità di Vita in Radioterapia.
Corti Luigi
L06P19
Valutazione della qualità della vita nell’ambito di trial clinici oncologici.
Del Bianco Paola
L06P20
Studio retrospettivo di valutazione dell’effectiveness e dell'apropriatezza prescrittiva dei farmaci antitumorali
sottoposti al monitoraggio Onco-AIFA.
233
Giacobbo Maria
L06P21
La dimensione religiosa e l’ansia di morte in pazienti oncologici. Analisi del fallimento della religione come
Giacobbo Maria
fattore di protezione in base alle rappresentazioni della morte.
L06P22
Epidemiologia delle potenziali interazioni tra farmaci in pazienti oncologici ambulatoriali.
L06P23
Programma multicentrico europeo per la valutazione del servizio di supporto della farmacia per i pazienti
oncologici con rischio di nausea e vomito.
L06P24
Percorso di certificazione della galenica oncologica.
L06P25
Progetto collaborativo per il miglioramento del trattamento antiemetico nel paziente oncologico in
Faoro Sonia
ospedale e nel territorio, realizzando vantaggi farmacoeconomici.
L06P26
Informatizzazione dei processi di farmacia oncologica
L06P27
Quando la coppia incontra la malattia: ricerca-intervento sui ruoli tra i partner e sulla relazione che
Giacobbo Maria
cambia.
L06P28
Prevalenza di neoplasie multiple sincrone o metacrone in pazienti oncologici anziani valutati secondo
Brunello Antonella
“valutazione geriatrica multidimensionale (VGM)”.
L06P29
Prevalenza del dolore, utilizzo degli oppioidi e modifiche del trattamento antalgico in pazienti ricoverati
Brunello Antonella
presso l’Oncologia 1.
L06P30
DAMA - Studio epidemiologico-osservazionale: prevalenza e decorso della Depressione in pazienti
Brunello Antonella
oncologici Adulti-anziani con Malattia in stadio Avanzato.
L06P31
ITACAm: Impatto del Trattamento Adiuvante sulle funzioni Cognitive nelle pazienti affette da Carcinoma
Brunello Antonella
mammario - Studio Pilota.
L06P32
Valutazione della sopravvivenza di pazienti affette da neoplasia ovarica seguite presso l’Istituto Oncologico
Nicoletto Maria Ornella
Veneto (IOV-I.R.C.C.S)
L06P33
Distiroidismo in pazienti affetti da ca rene e GIST sottoposti a target therapy
L06P34
Valutazione indici di metabolismo osseo nelle pazienti affette da ca della mammella trattate con
Zovato Stefania
ormonoterapia.
L06P35
Progetto per la rilevazione e gestione della neurotossicita da chemioterapia.
L06P36
Studio clinico randomizzato multicentrico aperto per la valutazione dell’efficacia del “lock” dei cateteri
Padovan Maria
venosi centrali totalmente impiantabili con soluzione fisiologica verso soluzione eparinata.
L06P37
Medicina di genere e radioterapia: un’indagine retrospettiva in pazienti con tumore dell’orofaringe, della
Groff Elena
cavità orale e del colon-retto.
L06P38
Correlazione tra le alterazioni del metabolismo scheletrico, l’imaging medico nucleare e la comparsa di
Cervino Anna Rita
metastasi scheletriche.
L06P39
Validazione italiana del QUAL-EC per valutare la qualità di vita nei pazienti oncologici in fase avanzata
Capovilla Eleonora
di malattia.
L06P40
Progetto pilota: emozioni in musica - I suoni per dirlo - proposta per una musicoterapia sociale.
Faoro Sonia
Paganelli Francesco
234
Zovato Stefania
Padovan Maria
Giacobbo Maria
CLINICAL RESEARCH
CLINICAL RESEARCH
235
Ethics Committee
PRESIDENT
Renzo Pegoraro
VICE-PRESIDENT
Daniele Rodriguez
MEMBERS
The IOV Ethics Committee (EC) is an independent body that has been formally
designated to review biomedical research involving humans with the aim to protect the
rights and welfare of the research subjects. Members are appointed for a period of three years
and may serve two consecutive terms only. In force of its interdisciplinary composition,
the IOV Ethics Committee also works as an advisory body whose purpose is to facilitate
the discussion and resolution of ethical issues arising in patient care. Moreover, the Ethics
Committee promotes training in Bioethics and working groups on medical ethics in the
field of Oncology.
The number of members is actually sixteen. The Ethics Committee comprises both
healthcare professionals (doctors, nurses and pharmacists) and community representatives.
More than half of the members are unaffiliated with the Institution. Five member are
physicians with a thorough knowledge of the scientific aspects of clinical research. The
Committee includes a biostatistician who is specifically expert of methods of research.
The Ethics Committee’s President in office is a bioethics expert and the vice-President is a
forensic scientist.
CLINICAL RESEARCH
236
Alberto Amadori (ex-officio)
Maria Giacobbo (ex-officio)
Angelo Claudio Palozzo (ex-officio)
Marilena Bertante
Paolo Cadrobbi
Patrizia Debetto
Claudio Drago
Fernando Gaion
Giampiero Giron
Francesco Grigoletto
Daniela Grosso
Roberto Labianca
Carlo Moreschi
Guido Sotti
SCIENTIFIC SECRETARY
Alessandra Bernardi
Clinical Trials
Numerous phase II and III, sponsored and spontaneous clinical
trials are carried out at the IOV, mainly in breast, lung, gastrointestinal and cutaneous (melanoma) neoplasms. Unfortunately,
phase I studies are not a major flag of the Institute, and only one
phase I study addressing the effect of vaccination against Her-2/
Title
neu in patients with head-and-neck cancer, now in progress, is
coordinated by our Institute. The fact that phase I studies are very
scarce nationwide is not a sufficient justification; it is a strong
priority of our Institute to implement these studies in a near
future.
Unit
Type
Sorafenib in association with Metronomic Therapy with Temozolomide
in Glioblastoma patients after first line chemotherapy failure: phase
II clinical trial with pharmacodynamic, pharmacokinetic and
pharmacogenetic evaluation.
Medical
Oncology 1
Phase II
Cilengitide in patients diagnosed with glioblastoma multiform and
methylated MGMT gene promotor plus standard TP (temozolomide
with RT followed by maintenance temozolomide) vs standard
treatment alone. A multicentre open label phase III trial.
Medical
Oncology 1
Cilengitide in patients diagnosed with glioblastoma multiforme and
unmethylated MGMT gene promoter plus standard tp (temozolomide
with radiotherapy followed by maintenance temozolomide). A
multicenter, open-label phase II trial.
Patients
enrolled in
2009
Patients
enrolled in
2010
Total
patients
enrolled
BRAIN
9
18
28
Phase III
0
0
Medical
Oncology 1
Phase II
1
1
Caelyx every 2 weeks in the treatment of metastatic breast carcinoma
in elderly women.
Medical
Oncology 2
Observational
29
0
40
A phase III International Trial on the treatment with adjuvant
Bevacizumab associated with standard CT in “triple negative” breast
carcinoma patients.
Medical
Oncology 2
Phase III
8
0
10
A two-arm randomised open label phase II study of CP-751,871 in
combination with exemestane versus exemestane alone as first line
treatment for postmenopausal patients with hormone receptor positive
advanced breast cancer.
Medical
Oncology 2
Phase II
0
2
2
BREAST
CLINICAL RESEARCH
237
A phase III trial of Vinflunine + Capecitabine vs Capecitabine alone in
previously treated or resistant to Anthracycline/Taxane advanced breast
cancer patients.
Medical
Oncology 1
Phase III
Pilot Study to evaluate the impact of adjuvant treatment on cognitive
function in patients with metastatic breast. cancer. ITACam.
Medical
Oncology 1
A Phase III, randomized, open, two-arm trial with Neratinib in
combination with paclitaxel vs Trastuzumab in Combination with
Paclitaxel as first Line Treatment of Breast Cancer ErbB-2 Positive
Locally Recurrent or Metastatic-3144A2-3005-WW patients.
A randomized, double-blind, controlled trial versus placebo with
Neratinib (HKI-272) after trastuzumab in women with early-stage
Breast Cancer characterized by over-expression/amplification HER-2/
neu- 3144A2-3004-WW.
1
1
Pilot Study
1
1
Medical
Oncology 2
Phase III
0
0
Medical
Oncology 2
Phase III
0
0
Medical
Oncology
1-2
Phase III
2
2
A randomised phase III study of Pemetrexed in combination with
Cisplatin versus Cisplatin monotherapy in Patients with recurrent or
metastatic head and neck cancer.
Medical
Oncology 2
Phase III
3
0
12
A Multicenter, Open-label, Randomised, Phase II/III Study to
Evaluate the Safety and Efficacy of Combretastatin A-4 Phosphate in
Combination with Paclitaxel and Carboplatin in Comparison with
Paclitaxel and Carboplatin for Anaplastic Thyroid Cancer.
Medical
Oncology 2
Phase II-III
4
0
9
Neo-adjuvant docetaxel plus cisplatin and 5-fluorouracil (TPF)
followed by radiotherapy plus concomitant chemo or cetuximab versus
radiotherapy plus concomitant chemo or cetuximab in patients with
locally advanced squamous cell carcinoma of the head and neck.
A randomised phase III factorial study (AVAPO).
Medical
Oncology 2
Phase III
4
3
9
A Phase III randomized controlled parallel group design comparing
two different therapy sequences, (Irinotecan / Cetuximab followed by
FOLFOX- 4 versus FOLFOX-4- followed by Irinotecan / Cetuximab)
in patients with metastatic colorectal cancer treated in first-line therapy
with FOLFIRI / Bevacizumab.
Medical
Oncology 1
Phase III
0
6
6
A randomised trial investigating the role of FOLFOX 4 regimen
duration (3 vs 6 months) and Bevacizumab as adjuvant therapy for
patients with stage II/III colon cancer.
Medical
Oncology 1
Phase III
30
56
114
Randomized study to evaluate the role of the duration of FOLFOX-4
and XELOX (3 vs 6 Months) as adjuvant therapy for patients with
stage II / III colon cancer.
Medical
Oncology 1
Phase III
40
40
Adjuvant anti-estrogen therapy in women with breast cancer: possibility
of a personalized approach. Multicenter study in the Veneto Region.
0
HEAD AND NECK CANCERS
GASTROINTESTINAL CANCER
CLINICAL RESEARCH
238
A Multicenter phase III trial to evaluate neo-adjuvant treatment
with Epirubicine - Oxaliplatin - Xeloda and Oxaliplatin - Xeloda
Radiotherapy in patients with operable gastric carcinoma.
Medical
Oncology 2
Phase III
0
1
1
Randomised phase II study of maintenance therapy with Sunitinib in
pancreatic adenocarcinoma.
Medical
Oncology 1
Phase II
1
0
1
A phase III randomised study evaluating surgery of residual disease in
patients with metastatic gastro-intestinal stromal tumor responding to
mesylated Imatinib.
Medical
Oncology 1
Phase III
3
0
3
A randomised phase II trial to evaluate FOLFOX or FOLFIRI
treatment associated with AG-013736 or Bevacizumab in patients
with metastatic colorectal carcinoma after failure with Irinotecan or
Oxaliplatin as first line therapy.
Medical
Oncology 1
Phase II
2
0
9
Comparison of the efficacy of peri-operative and postoperative
chemotherapy in patients with operable gastric cancer and the
evaluation of the benefit of chemotherapy combined with postoperative
radiation therapy.
Medical
Oncology 1
Phase III
0
0
Intensification Radiotherapy with Accelerated fractionation or
ChemoTherapyAnd Local Excision after 3D External Radiochemotherapy INTE.R.A.CT-LEADER TRIAL.
Medical
Oncology 1
Phase III
20
31
Prospective evaluation of 1498 C/T VEGF polimorphism in the
prediction of benefit from first-line folfiri plus Bevacizumab in
metastatic colorectal cancer patients. Pro.Ve.TT.A Study.
Medical
Oncology 1
Phase II
A phase III randomized trial of Folfoxiri + Bevacizumab versus Folfiri +
Bevacizumab as first-line treatment for metastatic colorectal cancer.
Medical
Oncology 1
Phase III
Phase II study for first-line treatment of colorectal cancer in combination
with FOLFOXIRI + Panitunumab in patients that express “wild type”
KRAS and BRAF - TRIP.
Medical
Oncology 1
Phase I clinical study on intraperitoneal administration of ONCOFID
in patients with peritoneal carcinomatosis from ovarian, stomach,
breast, bladder and colon cancer.
11
85
24
27
Phase II
2
2
Medical
Oncology 1
Phase I
1
1
Open-label multicenter trial to evaluate the efficacy of nilotinib in adult
patients with gastrointestinal stromal tumors resistant to imatinib and
sunitinib.
Medical
Oncology 1
Phase II
0
3
3
Prospective Evaluation of the quality of life (QoL) of patients with locally
advanced rectal cancer after undergoing neoadjuvant radio-chemotherapy
and surgery (performed as part of the INTERACT trial).
Medical
Oncology 1
Phase III
2
8
10
An open-label trial on the efficacy and safety of Bevacizumab (Avastin®)
combined with Xelox (Oxaliplatino + Xeloda®) as first line treatment
of patients with locally advanced or metastatic colorectal cancer OBELIX.
Medical
Oncology 1
Phase III
12
0
23
CLINICAL RESEARCH
239
3
LYMPHOMAS
A 3 arm multicenter phase III trial as first line treatment for patients
with stage II-IV follicular lymphoma.
Medical
Oncology 2
Phase III
Outcome of second-line treatment in patients with relapsed follicular
lymphoma according to the type of first-line treatment received.
Medical
Oncology 2
Phase II
Study to evaluate the prognosis of aggressive B-cell lymphoma treated
with Anthracyclines + Rituximab. Combinations. ProDLBCL
Medical
Oncology 2
Phase II
Phase II multicenter study of rituximab, cyclophosphamide,
doxorubicin liposomal (Myocet®), vincristine, and prednisone
(R-comp) in diffuse large B-cell non-Hodgkin’s disease of the cardiac
patient. Italian Lymphoma Intergroup - Heart01.
Medical
Oncology 2
Phase II
T-Cell Project: Collecting prospective data in patients with peripheral
T lymphoma.
Medical
Oncology 2
Observational
Randomised adjuvant trial on patients with radically operated stage
III malignant melanoma, comparison between different schedules of
Interferon alfa 2B at high doses.
Medical
Oncology 2
Phase III clinical trial to evaluate the safety and efficacy of treatment
with 2 mg of intralesional Allovectina-7® compared to Dacarbazine
(DTIC) or Temozolomide (TMZ) in subjects with recurrent metastatic
melanoma.
3
0
7
13
13
0
11
2
2
0
1
1
Phase III
9
1
75
Medical
Oncology 2
Phase III
16
0
26
A phase III double-blind placebo controlled randomised trial to
evaluate the efficacy of recMAGE-A3 + AS15 as adjuvant therapy in
patients with stage III Mage-A3 positive operable melanoma.
Medical
Oncology 2
Phase III
3
15
18
Analysis of the expression of a specific series of tumor genes and antigens
in patients with non small cell lung carcinoma and melanoma.
Medical
Oncology 2
Observational
13
2
18
Adjuvant immunotherapy with anti-CTLA-4 monoclonal antibody
(Ipililumab) versus placebo after complete resection of high risk
stage III melanoma: A randomised double blind phase III trial of the
EORTC Melanoma Group.
Medical
Oncology 2
Phase III
13
16
36
Treatment and outcome of patients with stage III or IV unresectable
melanoma: a retrospective observational survey.
Medical
Oncology 2
Observational
29
0
29
Open-label multicenter phase III trial of ABI 007 versus dacarbazine in
previously untreated metastatic malignant melanoma patients - CA33
ABRAXIX.
Medical
Oncology 2
Phase III
0
4
4
Open-label, single arm study to evaluate the clinical activity of
recMAGE-A3 + AS15 in inoperable metastatic melanoma, MAGE-A3
positive patients.
Medical
Oncology 2
Observational
0
0
Phase III randomized trial comparing TASISULAM vs. paclitaxel in
previously treated metastatic melanoma patients. H8K-MC-JZAO.
Medical
Oncology 2
Phase III
6
6
11
MELANOMA
CLINICAL RESEARCH
240
0
LUNG
An International multicenter randomised phase III study of first-line
Erlotinib followed by second-line Cisplatin + Gemcitabine versus first
line Cisplatin + Gemcitabine followed by second-line Erlotinib in
advanced non small cell lung cancer - TORCH.
Medical
Oncology 2
Phase III
9
0
32
Phase II, Randomised, double-blind, two-arm, parallel study of Vandetanib
(ZACTIMA™, ZD6474) plus Gemcitabine or Gemcitabine plus Placebo
as first line treatment of advanced (stage IIIB or IV) Non Small Cell Lung
Cancer (NSCLC) in Elderly patients.
Medical
Oncology 2
Phase II
8
0
14
Phase II single arm trial of BIBW 2992 (Tovok) in patients with
NSCLC and EGFR positive at FISH test.
Medical
Oncology 2
Phase II
6
20
26
A single-arm, phase 2 trial of Pemetrexed,Cispatin and Bevacizumab as
induction, followed by Pemetrexed and Bevacizumab as maintenance,in
first-line treatment of Non Squamous Advanced NSCLC H3E-EW-S125.
Medical
Oncology 2
Phase II
0
12
12
NGR015: Randomized double-blind phase III study of NGRhTNF plus best investigator s choice (BIC) versus placebo plus
BIC in previously treated patients with advanced malignant pleural
mesothelioma (MPM) (MOLMED).
Medical
Oncology 2
Phase II
6
6
Open label study of bevacizumab maintenance therapy (AVASTINÒ)
with or without pemetrexed after a first line treatment chemotherapy
with bevacizumab-cisplatin-pemetrexed in patients with advanced,
metastatic or recurrent non-squamous non-small cell lung cancer
(NSCLC)- AVAPERL.
Medical
Oncology 2
Phase III
0
3
3
A Phase III, open-label, randomized trial of CP-751, 871 in combination
with paclitaxel and carboplatin versus paclitaxel and carboplatin in
patients with non-small cell lung cancer. Protocol A4021016.
Medical
Oncology 2
Phase III
7
0
16
Prospective randomised phase II trial of oral vinorelbine and cisplatin
or pemetrexed and cisplatin in first-line metastatic or locally advanced
non-small-cell lung cancer patients with non-squamous histological
type PM 0259 CA227J1. NAVOTRIAL.
Medical
Oncology 2
Phase II
6
6
International, randomized, double-blind trial evaluating Aflibercept vs
placebo in patients treated with docetaxel in second-line after failure with
a platinum-based therapy for locally advanced or metastatic non-small cell
lung cancer (NSCLC). Protocol EFC10261 VITAL STUDY.
Medical
Oncology 2
Phase III
Bevacizumab (Avastin) in combination with gemcitabine or
attenuated doses of gemcitabine and cisplatin as a first line
treatment of elderly patients with advanced or metastatic nonsquamous NSCLC.
Medical
Oncology 2
Phase II
0
3
3
Medical
Oncology 1
Phase II
7
4
15
GENITO-URINARY CANCER
HOPLITE Phase II clinical trial: evaluation of continuous or
intermittent treatment with Docetaxel +/- Extramustine phosphate in
androgen resistant prostate cancer.
CLINICAL RESEARCH
241
Randomised double blind clinical trial comparing Sunitib plus
prednisone versus prednisone alone in patients with progressive
hormone-refractory prostate cancer after failure with a docetaxel based
regimen.
Medical
Oncology 1
Phase III
3
1
4
Phase II open label randomised trial of Sorafenib alone or associated
with Interleukin 2 as first line monotherapy in patients with advanced
renal cancer.
Medical
Oncology 2
Phase II
0
1
1
One-arm, multi-center, international prospective pivotal study to
assess the safety and efficacy of Bio-Protect biodegradable implantable
balloon in prostate cancer subjects undergoing radiotherapy.
Medical
Oncology 1
Observational
10
10
A phase II study of Sunitinib prior to and after or only after cytoreductive
nephrectomy in patients with metastatic renal cell carcinoma.
Medical
Oncology 1
Phase II
0
0
0
An International observational study on the quality of life of patients
with testicular cancer with the aim of developing a questionnaire for
future studies within the EORTC and other research groups.
Medical
Oncology 1
Observational
20
0
20
AXITINIB (AG-013736) as second line therapy for metastatic renal
adenocarcinoma.
Medical
Oncology 1
Phase II
2
0
2
Prospective phase II trial with Sorafenib in patients with locally
advanced or metastatic soft tissue sarcoma following chemotherapy
with anthracycline.
Medical
Oncology 1
Phase II
1
0
9
A study to establish the efficacy and safety of AP23573 administered as
maintenance therapy in patients with soft tissue metastatic sarcoma or
bone metastatic sarcoma.
Medical
Oncology 1
Phase II
4
0
7
Therapeutic regimens for sarcomas and the impact of the disease in
North America and Europe. SABINE.
Medical
Oncology 1
Observational
1
12
13
A Phase III, multicenter, randomized, double-blind trial on the
efficacy of Ramucirumab (IMC-1121B) in combination with the best
supportive care versus placebo plus best supportive care as second-line
treatment in patients with hepatocellular carcinoma after first-line
therapy with Sorafenib.
Medical
Oncology 1
Phase III
0
0
A multicenter randomised trial on Caelix STEALTH versus Carboplatin
+ Paclitaxel in patients with relapsed ovarian carcinoma 6-12 months
after primary treatment with a platinum compound.
Medical
Oncology 1
Phase III
3
3
Multicenter, randomized, double-blind, phase III trial designed to assess
the efficacy and safety of BIBF 1120 in combination with carboplatin
and paclitaxel versus placebo plus carboplatin and paclitaxel in patients
with advanced ovarian cancer.
Medical
Oncology 1
Phase III
7
7
Randomized phase II trial with carboplatin and paclitaxel + / Cetuximab in advanced and / or recurrent cancer of the cervix.
Medical
Oncology 1
Phase II
0
0
SARCOMAS
GYNECOLOGIC CANCER
CLINICAL RESEARCH
242
0
A randomized, double-blind, placebo-controlled, phase 3 study to
assess the efficacy and safety of weekly Farletuzumab (morab-003) in
combination with Carboplatin and Taxane in subjects with platinumsensitive ovarian cancer in first relapse.
Medical
Oncology 2
Phase III
0
0
0
A Prospective randomised controlled trial of hyperfractionated
versus conventionally fractionated radiotherapy in standard risk Radiotherapy
medulloblastoma.(SIOP-PNET 4).
Phase III
3
3
15
Nephroblastoma SIOP 2001.
Radiotherapy
Phase III
International Randomised clinical trial for children and adolescents
Radiotherapy
with low grade glioma (SIOP-LGG 2004).
Phase III
5
15
45
Hodgkin’s Lymphoma - AIEOP - LH-2004.
Radiotherapy
Phase III
12
20
60
Phase III Randomized Study of Ifosfamide, Vincristine, and
Dactinomycin With or Without Doxorubicin in Pediatric Patients Radiotherapy
With Non-Metastatic Rhabdomyosarcoma (EpSSG RMS 2005 trial).
Phase III
16
19
65
PEDIATRIC TUMORS
23
OTHER TOPICS
A case control multicenter observational study on the epidemiology
and risk factors for thromboembolic events in oncologic patients and
the influence the venous thromboembolism has on the prognosis.
Medical
Oncology 1
Observational
12
0
12
Prospective observational study to evaluate the risk management of
neutropenia and anaemia in subjects with solid tumors receiving
mielotoxic chemotherapy.
Medical
Oncology 1
Observational
0
0
15
Open-label, randomized pilot study, to evaluate the change of wellbeing and quality of life induced by the use of a specific room equipped
with complementary therapies, compared to no complementary
therapies at all, in cancer patients facing chemotherapy for the first
time. Atmosphere project.
Medical
Office
Pilot Study
18
126
144
Screening For early predictors of peripheral neuropathy In oxaliplatintreated patients.
Medical
Oncology 1
Observational
24
24
Observational, prospective trial, to assess the intensity of nausea and
vomiting in cancer patients receiving preventive therapy for nausea and
vomiting caused by chemotherapy. Project N & V.
Medical
Office
Observational
179
0
179
Observational, multinational, multicenter, prospective study of adult
patients receiving anti-emetic therapy in concomitance with the start
of moderately or highly emetogenic chemotherapy drugs (HEC or
MEC).
Medical
Office
Observational
13
43
56
Single-arm multicenter study of Denosumab in the treatment of
hypercalcaemia in patients with high serum calcium levels after recent
treatment with bisphosphonates.
Medical
Oncology 2
Observational
0
0
DAMA - Epidemiological - observational study: prevalence and course
of depression elderly patients with advanced disease stage.
Medical
Oncology 1
Observational
2
2
CLINICAL RESEARCH
243
Veneto Oncology
Network
245
Veneto Oncology Network
number of stakeholders possibly involved in tumor prevention
campaigns;
to define rational secondary prevention strategies, by designing
screening plans for colon, mammary and uterine cervix cancer.
A far as the clinical management of patients is concerned, a
preliminary survey of all the Oncology Units will allow to have
an outline of the situation within the Veneto region in order to
better target specific interventions. In particular, the existence of
an efficient network will permit:
availability of a common informatics platform for the sharing of
clinical data and other relevant material;
definition of different levels of assistance, according to the
diagnostic and therapeutic facilities present in different Units;
development of shared guidelines for the different pathologies,
and the identification of centers of excellence for particular
tumors;
careful planning of investments, to allow the access of oncologic
patients to the state-of-the-art diagnostic and therapeutic
facilities without duplication of expensive instrumentation and
resource sparing.
In reference to the research possibilities offered by an Oncologic
Network spread throughout the entire region, it is evident that
collaboration among centers may consent:
promotion of coordinated initiatives in terms of education;
delineation of research programs based on the strict
interconnection of expertise in different fields (laboratory,
medicine, surgery etc);
better exploitation of top facilities, such as genomic and
proteomic platforms;
rapid collection of large case series of patients with a particular
tumor, to allow the performing of in-depth research on their
biological characteristics and adequate clinical trials.
It is evident that careful scrutiny of all research and clinical
resources presently available over the country is a preliminary
step, mandatory for any future strategic planning.
The Istituto Oncologico Veneto has been established in
Padova in view of the excellent background accumulated in this
city over the decades in virtually all the aspects of Oncology.
Notwithstanding, this expertise has slowly but steadily permeated
the entire Veneto region, thanks to the presence in Padova of a
post-graduate Specialty School in Oncology established in the late
’70s and flanked a few years later by a Specialty School in Verona.
A great number of clinical Oncologists now operating in the
different Veneto provinces attended the post-graduate Specialty
School in Padova.
Thus, cancer patients can find elevated diagnosis and cure
standards throughout our region, even though the most specialized
approaches are performed at the major centres.
At present, twenty seven Oncology Units are disseminated
throughout the Veneto region. In most of them, Clinical Oncology
is flanked by diagnostic (such as radiology, pathology and
molecular biology) and therapeutic platforms (such as surgery and
radiotherapy), whereas in some cases only day-hospital structures
are present, offering patients only or mostly pharmacological
treatments according to therapeutic programs discussed and
planned in strict collaboration with major centres.
A major aim of the IOV is to establish and foster an oncological
network throughout our region, in order to improve and optimize
all the aspects of the clinical management of cancer patients, as well
as to implement research potential in an extremely competitive
field.
From an epidemiological point of view, the existence of an
Oncologic Network will permit:
to plan a capillary survey of the entire Veneto region, by
collecting uniform data on the prevalence and incidence of
different types of tumors through the extension of the activities
of the Veneto Tumor Registry;
to standardize primary prevention strategies throughout
the region, in order to achieve the maximum efficacy of the
interventions and avoid duplication of initiatives by the
246
UOC Oncologia, Ospedale di Feltre
Az. ULSS 2
Head: Romana Segati, MD
UOC Oncologia, Ospedale di Belluno
Az. ULSS 1
Head: Mauro Giusto, MD
UO Oncologia,
Bassano del Grappa (VI)
Az. ULSS 3
Head: Luigi Endrizzi, MD
UOC Oncologia, Vicenza
Az. ULSS 6
Head: Paolo Morandi, MD
UOC Oncologia, Ospedale di Thiene
Az. ULSS 4 Alto Vicentino
Head: Franco Bassan, MD
UOC Oncologia, Vittorio Veneto
Az. ULSS 7
Head: Luigi Salvagno, MD
UOC Oncologia, Ospedale di S. Bonifacio (VR)
Az. ULSS 20 / UOC Oncologia
Ospedale Civile Maggiore,
Azienda Ospedaliero-Universitaria.
Verona [Borgo Trento]
Head: Anna Maria Molino, MD
UOC Oncologia, Ospedale Civile Maggiore,
Azienda Ospedaliero-Universitaria, Verona
[Borgo Roma]
Head: Giampaolo Tortora, MD
Ospedale classificato
ed equiparato Sacro Cuore,
Don Calabria - Negrar (Verona)
Head: Marco Venturini, MD
Vittorio
Veneto
Thiene
UOC Oncologia,
Ospedale di San Donà
Az. ULSS 10
Head: Daniele Bernardi, MD
Castelfranco
Treviso
Camposampiero
Bussolengo
Peschiera
San Donà
UOC Oncologia,
Ospedale di Camposampiero
Az. ULSS 15
Head: Fernando Gaion, MD
Vicenza
Negrar
UOC Oncologia,
Ospedale di Montecchio Maggiore
Az. ULSS 5
Head: Cristina Oliani, MD
UOC Oncologia,
Ospedale di Legnago
Az. ULSS 21
Head: Andrea Bonetti, MD
SOC Oncologia, Ospedale di Treviso
Az. ULSS 9
Head: Giovanni Rosti, MD
Feltre
Bassano
del Grappa
UOC Oncologia,
Ospedale di Bussolengo
Az. ULSS 22
Head: Tiziano Franceschi, MD
UO Oncologia
Casa di Cura Pederzoli,
Peschiera del Garda
Head: Annita Lusenti, MD
UOC Oncologia, Ospedale di Castelfranco
Az. ULSS 8
Head: Paolo Manente, MD
Belluno
Montecchio
Maggiore
Mirano
Padova
Mestre
Verona
Este
Legnago
Piove
di Sacco
UOC Oncologia, Venezia Mestre
Az. ULSS 12
Head: Ottorino Nascimben, MD
Rovigo
Adria
Istituto Oncologico Veneto (IRCCS),
Oncologia 1, Padova
Head: Vittorina Zagonel, MD
UOC Oncologia,
Ospedale di Este
Az. ULSS 17
Head: Giorgio Bonciarelli, MD
Medicina Oncologica,
Ospedale Imm. Conc., Piove di Sacco
Az. ULSS 16
Head: Adriano Fornasiero, MD
UOC Oncologia ed Ematologia Oncologica (Mirano)
Az. ULSS 13
Head: Orazio Vinante, MD
Oncologia 2, Padova
Head: Vanna Chiarion-Sileni, MD
SOC Oncologia,
Ospedale di Rovigo
Az. ULSS 18
Head: Felice Pasini, MD
UOC Oncologia,
Ospedale di Adria
Az. ULSS 19
Head: Silvia Toso, MD
UOC Oncologia,
Presidio Ospedaliero Piove di Sacco
Az. ULSS 14
Head: Carlo Gatti, MD
247
Valutazione e Introduzione Nuovi Farmaci
nelle Terapie Oncologiche, Padova
Head: Antonio Jirillo, MD
Building a network is not a trivial job, of course. Over the last
35 years, the interactions among the different Veneto oncology
centers were occasional, and in some instances troublesome, due
to many complex reasons, including the lack of an academic
Oncology chair in Padova. Since 2007, the Scientific Directorate
tried hard to foster communication among all the Oncology
Units, and to overcome the reciprocal difficulties in the interaction
between major and peripheral centers. The Scientific Directorate
is happy to see that these efforts met some significant success
and were able to reconcile different feelings and behaviors; this
allows to foresee even greater advancements in a near future.
For sure, overcoming individualism is an essential ingredient for a
successful recipe in the competition for excellence. In this regard,
thanks to the joint efforts of Dr. Zagonel, Dr. Bonetti, Dr. Gaion,
Dr. Pasini and a few other friends and colleagues, about a half
of the Veneto Clinical Oncology Units will share an electronic
clinical record platform, and other Units are expected to join
this network. This choice will offer the opportunity to share data
among Units, and to compare and study larger case series, thus
rendering collaboration and scientific interactions much more
easy and productive. In addition, two scientific projects have been
recently launched. A first project is centered on the construction
of a network on heredo-familial tumors, modelled according to
a hub-and-spoke model; this network involves about two-thirds
of the Veneto Clinical Oncology Units. A second project will be
focused on the palliative care in non-small cell lung cancer; this
project involves about ten Units of the nascent Veneto Oncology
Network, and it is aimed at formulating shared guidelines on this
important issue.
248
Education
EDUCATION
249
Internal Education & Training
The IOV has an internal Continuous Education and Training
Program, which in the period from 2005 to 2010 has involved over
10,000 participants of the medical, nursing and administrative staff
of both IOV and peripheral oncological Units. The courses, stages
and seminars were centered on both basic/translational topics and
issues of major clinical interest in Oncology; all the personnel
categories and specialties (technicians, nurses, clinical oncologists,
radiotherapists, surgeons, pharmacists etc) were involved. Most
of the formative events were organized according to the national
program of Continuous Medical Education (ECM); overall, more
than 1,000 ECM credits were administered. A list of the 20092011 events is reported here.
2009
Titolo
Responsabile
Scientifico
N.
di partecipanti
Lo Screening del Cervicocarcinoma con il Test Hpv
M. Vettorazzi
25
5
Seminari “From Cloning To Clinic”
G. Opocher
45
0
Applicazioni cliniche e impatto farmacoeconomico dei nuovi farmaci biologici
D. Pastorelli
75
3
Convegno Nazionale Gisma 2009
M. Vettorazzi
200
7
Evoluzione in mammografia digitale: la tomosintesi. Corso per fisici e tecnici
di radiologia
M. Vettorazzi
60
3
Corso pratico di diagnostica mammografica integrata per radiologi
M. Vettorazzi
60
3
Corso teorico pratico di endoscopia operativa
G. Battaglia
15
11
Confronto interistituzionale in patologia mammaria da screening
M. Vettorazzi
45
9
Corso teorico-pratico: pet e linfomi
M. Gregianin
10
21
Psiconcologia: un ponte tra scienza e coscienza
E. Capovilla
200
4
Le terapie di supporto delle tossicità da antiblastici
D. Pastorelli
20
8
Il Carcinoma Ovarico: dalla ricerca di base alle novità terapeutiche
S. Indraccolo
P. Zanovello
80
3
I tumori ereditari del pancreas
G. Opocher
100
4
Sarcomi dei tessuti molli. Aggiornamento delle linee guida regionali e recenti
innovazioni.
C. R. Rossi
100
4
EDUCATION
250
N.
crediti Ecm
Integrative Oncology Care
G. Opocher
60
8
Riunione annuale Screening Colorettale
M. Vettorazzi
90
4
Riunione annuale Screening Citologico
M. Vettorazzi
200
4
Riunione annuale Screening Mammografico
M. Vettorazzi
150
4
Il Carcinoma del Colon: dalla ricerca di base alle novità terapeutiche
S. Indraccolo
P. Zanovello
90
2
Le terapie di supporto nei pazienti oncologici
D. Pastorelli
60
4
La comunicazione tra infermiere e utente nel 2° livello dello screening
colorettale
M. Vettorazzi
25
26
G. Sotti
50
15
M. Padovan
25
28
Titolo
Responsabile
Scientifico
N.
di partecipanti
La colonscopia di screening - Corso Regionale
Il carcinoma della tiroide differenziato aspetti clinico assistenziali
La sperimentazione clinica in oncologia e il nursing avanzato
2010
N.
crediti Ecm
M.Vettorazzi
20
9
Melanoma: novità nell’inquadramento diagnostico e modelli organizzativi
C. R. Rossi
100
9
Qualità della vita nei pazienti oncologici e update sulle terapie di supporto
D. Pastorelli
70
4
Cardioncologia 2010
A. Banzato
90
4
Seminario “Predisposizione genetica al cancro: il problema delle varianti di
incerto significato”
G. Opocher
90
3
Psiconcologia: interventi oncologici evidence-based e medical humanities
E. Capovilla
150
4
Re-ingegnerizzazione della prevenzione individuale e programmi di screening:
efficacia, qualità e sostenibilità
C. Cogo
100
6
Convegno Nazionale Gisci 2010
C. Cogo
250
3
E. Capovilla
50
7
Carcinosi peritoneale: chirurgia citoriduttiva e chemioterapia ipertermica
Mindfulness: una pratica di self care
C. R. Rossi
90
11
Agenti infettivi nella patogenesi dei tumori
P. Zanovello
90
2
Corso di aggiornamento in oncologia toracica
A. Jirillo
20
3
La comunicazione telefonica negli screening oncologici
C. Cogo
25
25
Corso di aggiornamento in oncologia mammaria
Aggiornamento delle linee guida regionali e recenti innovazioni sul melanoma
Il linfonodo sentinella nel carcinoma mammario: realtà e nuove prospettive
EDUCATION
251
F. Bozza
25
26
C. R. Rossi
100
13
F. Bozza
90
4
La comunicazione interpersonale negli screening oncologici
Aggiornamenti in tema di carcinoma dello stomaco
Aggiornamenti sulle neoplasie ginecologiche
C. Cogo
25
4
V. Zagonel
F. Adami
50
26
M. O. Nicoletto
90
5
Riunione annuale screening colorettale
C. Cogo
150
3
Ruolo del Tsrm nell’organizzazione e nella conduzione di uno screening
mammografico di popolazione
C. Cogo
100
4
G. Pinato
80
5
Riunione annuale screening citologico
C. Cogo
200
4
Riunione annuale screening mammografico
C. Cogo
150
4
Comunicare con tutti. 5° Seminario sulla comunicazione nei programmi di screening
C. Cogo
240
4
IX Convegno osservatorio nazionale screening
C. Cogo
240
4
La pratica del primary nursing: la sperimentazione del modello professionale
in area oncologica
B. Burattin,
M. Padovan
50
25
Cartella oncologica informatizzata: sistema innovativo per la gestione dell’attività
clinico assistenziale del malato oncologico, aspetti tecnici e gestionali
V. Zagonel
200
7
Gli strumenti operativi delle sperimentazioni cliniche: il protocollo di ricerca
e la scheda raccolta dati
V. Zagonel
G. L. De Salvo
25
36
La gestione aziendale per la qualità
D. Chiusole
25
20
La sperimentazione clinica in oncologia e il nursing avanzato
M. Padovan
50
33
La sperimentazione clinica in oncologia e il nursing avanzato intensivo
M. Padovan
25
33
M. Cacco
50
20
V Corso di Neuromodulazione: la terapia del dolore
Strumenti diagnostici per la prevenzione e trattamento del tumore alla
mammella
2011
N.
di partecipanti
Titolo
Percorsi integrati in oncologia. Il tumore del polmone
N.
di partecipanti
N.
crediti Ecm
G. Opocher
40
5
F. Bozza
25
13
Percorsi integrati in oncologia. Il tumore del colon retto
G. Opocher
40
5
Percorsi integrati in oncologia. Il tumore della mammella
G. Opocher
40
5
Approccio multidisciplinare nel carcinoma della mammella
EDUCATION
252
Aggiornamento delle linee guida sulle terapie di supporto in chemioterapia
V. Zagonel
35
2
Corso itinerante in oncologia toracica
R. Polverosi
60
6
Approccio multidisciplinare sui gliomi
V. Zagonel
90
3
Percorsi integrati in oncologia. La collaborazione in una rete di relazioni
integrate
G. Opocher
40
5
Melanoma familiare: dal test genetico alla pratica clinica
C. Menin
90
2
Sarcomi delle parti molli e Gist: epidemiologia, clinica e “Network”
C. R. Rossi
150
4
F. Bozza
200
5
A. Favaretto
50
5
1° Congresso Nazionale di Oncologia di genere
V. Zagonel
250
4
Aging and Cancer
A. De Rossi
V. Zagonel
90
4
A. Jirillo
60
3
Corso Teorico - Pratico. La diagnosi e il trattamento endoscopico delle lesioni
“Early” del tratto digestivo
G. Battaglia
12
Nuovi approcci contro il cancro. Elettrochemioterapia: la rete del Nord-Est
C. R. Rossi
100
L’implementazione della qualità e sicurezza dell’assistenza chirurgica del paziente
oncologico
C. Castoro
25
30
Corso di psicologia oncologica. Pazienti, famigliari, operatori: quali strumenti per
una relazione efficace
E. Capovilla
25
15
La sperimentazione clinica in oncologia e il nursing avanzato intensivo
M. Padovan
25
33
M. Cacco
50
20
La gestione aziendale per la qualità
D. Chiusole
25
20
La gestione e verifica del workflow nella diagnostica per immagini con analisi degli
errori comuni e delle possibili soluzioni
M. Giacobbo
75
20
G. Sotti
50
8
Le patologie tiroidee: aspetti dosimetrici della terapia radiometabolica con iodio 131
F. Simonato
50
5
Rilievo e trattamento del dolore cronico nel malato oncologico
M. Giacobbo
V. Zagonel
M. Padovan
G. Sotti
25
20
La neoplasia mammaria nella donna giovane
Systemic treatment selection and target therapies in Nsclc
La storia della nascita di un farmaco
Strumenti diagnostici per la prevenzione e trattamento del tumore alla mammella
Approccio ed assistenza al paziente disfagico
EDUCATION
253
Trattamento del dolore cronico nel malato oncologico
M.Giacobbo
V. Zagonel
M. Padovan
G. Sotti
25
20
La scheda di dimissione ospedaliera: compilazione e codifica icd - 9 - cm 2007
M. Giacobbo
25
6
Prevenzione e gestione delle infezioni ospedaliere nei pazienti oncologici ricoverati
presso l’Istituto Oncologico Veneto
P. Cadrobbi
50
17
Il Sistema BiblioSan: strumenti e metodi per l’implementazione del processo di
ricerca scientifica e documentaristica
A. Rosato
M. Apostolico
50
12
Il Sistema BiblioSan: strumenti e metodi di ricerca finalizzato al miglioramento
della pratica professionale
M. Apostolico
A. Rosato
50
12
C. Rossi
25
15
La gestione del rischio clinico: metodi di analisi
M. Giacobbo
25
15
Tutela della privacy e gestione dei dati sensibili in sanità
M. Padovan
25
10
Sarcomi: valutazione e trattamento multidisciplinare. Studio e discussione di casi
EDUCATION
254
Post-graduate Schools
Doctorate School in Oncology
and Surgical Oncology
The Doctorate School in Oncology
and Surgical Oncology is destined to
physicians and biologists who want
to acquire scientific methodology
and appropriate expertise in basic,
translational and clinical research in
the field of Oncology and Clinical/
Surgical Oncology. The School spans a 3-yr period, and about 10
PhD students are admitted every year on a selective basis.
The major research themes implemented within the Doctorate
School are:
Molecular pathology of tumors;
Virologic oncology;
Tumor immunology and the role of tumor microenvironment;
Animal models of human cancerogenesis;
Genetic predisposition to cancer;
Micro- and nano-biotechnologies in oncology;
Novel therapeutic strategies (vaccination, gene therapy,
immunoregulation);
New molecular tools in onco-hematology.
Post-graduate Specialization School in Clinical Oncology
Post-graduate Specialization School in Medical Radiology
Director: Fausto Adami
The Specialization School in Clinical Oncology is dedicated to
physicians who want to acquire special expertise in the different
fields of Clinical Oncology. About 5 graduates are admitted to the
School every year; during a 4-yr period, the educational program
entails periods of internship in all the clinical Units of the Institute;
the possibility of stages in outstanding Italian or foreign Cancer
Institutes is also strongly encouraged.
Director: Davide Fiore
The Specialization School in Medical Radiology is dedicated
to physicians who want to acquire special expertise in the different
fields of imaging sciences and interventional radiology. A special
attention is dedicated to the neuroradiology. About 10 graduates
are admitted to the School every year.
Director: Paola Zanovello
EDUCATION
255
EDUCATION
256
Meetings and Seminars
2009
Barbara Seliger
How tumor cells fuel the immune system
Peter Siesjö
Immunotherapy of brain tumors: mission impossible?
Graham Le Gros
The differentiation in vitro and its relevance to allergy and parasitic diseases
Maurizio Zanetti
Immunologic aspects of ER stress
Heiko Ihmels
Varations on Annelated Quinzinium Derivatives: How the Shape of a Ligand Determines its Association
with Duplex-, Triplex- and Quadruplex-DNA
Stanley C. Froehner
Nitric Oxide in Skeletal Muscle Function and Disease
Napoleone Ferrara
Regulation of tumor angiogenesis by VEGF- dependent and independent pathways
Klemens Pichler
Virus-mediated stimulation of anti-apoptotic genes as a survival strategy of HTLV-1-transformed
lymphocytes
Andrew Brack
Self renewal of adult muscle stem cells during regeneration
Scientific Conference “Highlights in Oncology: recent Advancements in Oncology”
2010
Veffa Franchini
HTLV – the first human retrovirus to matter
Leonid Margolis
All you wanted to know about HIV but didn’t dare to ask
HIV – A human virus that is much studied but not much understood
War and peace between viruses
Lionel Perrier
Cost- Effectiveness Analysys: Methods and applications in oncology
EDUCATION
257
Charles R M Bangham
How does HTLV-1 persist in vivo?
Raymond White
Genetics and Therapy Dopaminergic System and Addiction: Toward an individually-specific genetically
based therapeutic approach
Oriol Casanovas
Evasive Resistance to Anti-angiogenic Therapies
Joseph Schlessinger
Cell signaling by receptor tyrosine kinases: from molecular mechanism to cancer therapy
David Sassoon
From cell stress responses to stem cells: a common link in muscle, skin and other adult stem cell niches?
Pablo Menendez
Hematopoietic and mesenchymal differentiation from hESC and iPS cells
Luis A. Rokeach
Aging effects of glucose in the model Schizosaccharomyces pombe
Aichi Msaki
Investigating the function of NF-kB subunit RelA
David Y. Graham
Barrett Esophagus: The Graham’s point of view
Adolfo Ferrando
The molecular pathogenesis of T-ALL
Marina Cavazzana-Calvo
Gene therapy: success and failure
Martin Mueller
Papillomavirus L2-based vaccination and high throughput pseudovirion neutralization assay
International Workshop on VIRUSES, GENES AND CANCER – Venice 2010
2011
Rosa Maria Moresco
Antonio Rosato
In Vivo Molecular Imaging in Translational Research
Giovanni Cazzaniga
Minimal residual disease monitoring in childhood ALL. Not only a diagnostic tool
Esteban Czwan
Classification of tumors based on the activity of oncogenic pathways
Mauro Giacca
“How can you mend a broken heart”: Searching for genes that induce myocardial protection, myocardial
repair or neoangiogenesis by in vivo gene transfer using AAV vectors
Marina Lusic
Nuclear structures and chromatin determinants of HIV-1 infected cells
Tim Hoey
Development of new cancer therapeutics that reduce tumor initiating cell frequency
Michael Stuerzl
Molecular Dissection of the Pathogenicity of Kaposi‘s Sarcoma-associated Herpesvirus
EDUCATION
258
Genoveffa Franchini
HTLV-1, the smooth operator of tumor transformation
Ugo Cavallaro
Neural adhesion molecules: old players with new functions in signaling and in cancer
Rafael Rosell
Adolfo Gino Favaretto
Systemic treatment selection and targeted therapies in NSCLC
Beghini Alessandro
Leucemia acuta mieloide con riarrangiamenti del core binding factor: un paradigma senza fine
Giorgio Stanta
Ricerca traslazionale nei tessuti d’archivio: un’opportunità per accelerare l’applicazione della medicina
personalizzata
Francesco Dazzi
The immunoregulatory activity of haemopoietic stem cell transplantation
Giorgio Valle
New generation sequencing:current limits and future perspectives
Piero Dalerba
Cancer Stem Cells: therapeutic implications
Magnus Essand
Viruses and T cells as cancer therapeutics
Oliver Hohn
The rise and fall of HMRV
Vito Pistoia
Nuovi meccanismi immunoregolatori mediati da HLA-G
Marco Dotto
Next Generation Sequencing: current applications for cancer care
EDUCATION
259
AWARDS
VENETO ONCOLOGY
AWARDS NETWORK
261
Awards
In November 2010 Dr. Giulia Pasello received
the ESMO Fellowship Award
for the IDENTIFICATION of NOVEL
MOLECULAR TARGETS and BIOLOGICAL AGENTS
for the CHEMOTHERAPY
of MALIGNANT PLEURAL MESOTHELIOMA
AWARDS
263
Publications
PUBLICATIONS
265
2009 PUBLICATIONS / Journals indexed in ISI-JCR
1 Aapro M, Monfardini S, Jirillo A, Basso U. Management of primary
and advanced breast cancer in older unfit patients (medical treatment)
Cancer treatment reviews; 35:6; 503-508; 2009
2 Abbadessa G, Accolla R, Aiuti F, Albini A, Aldovini A, Alfano M,
Antonelli G, Bartholomew C, Bentwich Z, Bertazzoni U, Berzofsky J A,
Biberfeld P, Boeri E, Buonaguro L, Buonaguro F M, Bukrinsky M Burny
A, Caruso A, Cassol S, Chandra P, Ceccherini-Nelli L, Chieco-Bianchi
L, Clerici M, Colombini-Hatch S, Morghen C D G, De Maria A, De
Rossi A, Dierich M, Della-Favera R, Dolei A, Douek D, Erfle V, Felber
B, Fiorentini S, Franchini G, Gershoni J M, Gotch F, Green P, Greene
W C, Hall W, Haseltine W, Jacobson S, Kallings L O, Kalyanaraman
V S, Katinger H, Khalili K, Klein G, Klein E, Klotman M, Klotman
P, Kotler M, Kurth R, Lafeuillade A, La PlacaM, Lewis J, Lillo F,
Lisziewicz J, Lomonico A, Lopalco L, Lori F, Lusso P, Macchi B, Malim
M, Margolis L, Markham P D, Mcclure M, Miller N, Mingari M C,
Moretta L, Noonan D, O’Brien S, Okamoto T, Pal R, Palese P, Panet
A, Pantaleo G, Pavlakis G, Pistello M, Plotkin S, Poli G, Pomerantz R,
Radaelli A, Robert-Guroff M, Roederer M, Sarngadharan M G, Schols
D, Secchiero P, Shearer G, Siccardi A, Stevenson M, Svoboda J, Tartaglia
J, Torelli G, Tornesello M L, Tschachler E, Vaccarezza M, Vallbracht A,
Van Lunzen J, Varnier O, Vicenzi E, Von Melchner H, Witz I, Zagury
D, Zagury J F, Zauli G, Zipeto D. Unsung hero Robert C. Gallo.
Science; 323:5911; 206- 207; 2009
3 Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann
B, Solari A, Bobisse S, Rondina M B, Guzzardo V, Parenti A R, Rosato
A, Bicciato S, Balmain A, Piccolo S, A Mutant-p53/Smad Complex
Opposes p63 to Empower TGFÎ²-Induced Metastasis. Cell; 137:1;
87-98; 2009
4 Agnelli G, Gussoni G, Bianchini C, Verso M, Mandalà M, Cavanna
L, Barni S, Labianca R, Buzzi F, Scambia G, Passalacqua R, Ricci
S, Gasparini G, Lorusso V, Bonizzoni E, Tonato M, PROTECHT
Investigators [as collab. Falci C, Jirillo A]. Nadroparin for the
prevention of thromboembolic events in ambulatory patients with
metastatic or locally advanced solid cancer receiving chemotherapy:
a randomised, placebo-controlled, double-blind study. Lancet
Oncology; 10:10; 943-949; 2009
5 Alaggio R, Bisogno G, Rosato A, Ninfo V, Coffin C M. Undifferentiated
sarcoma: does it exist? A clinicopathologic study of 7 pediatric cases
and review of literature. Human pathology; 40:11; 1600-1610;
2009
6 Amadori A, Rossi E, Zamarchi R, Carli P, Pastorelli D, Jirillo. A
Circulating and disseminated tumor cells in the clinical management
of breast cancer patients: unanswered questions. Oncology Basel;
76:6; 375-386; 2009
7 Antoniou A C, Sinilnikova O M, McGuffog L, Healey S, Nevanlinna
H, Heikkinen T, Simard J, Spurdle A B, Beesley J, Chen X, Neuhausen
S L, Ding Y C, Couch F J, Wang X, Fredericksen Z, Peterlongo P, Peissel
B, Bonanni B, Viel A, Bernard L, Radice P, Szabo C I, Foretova L,
Zikan M, Claes K, Greene M H, Mai P L, Rennert G, Lejbkowicz
F, Andrulis I L, Ozcelik H, Glendon G, Gerdes A M, Thomassen M,
Sunde L, Caligo M A, Laitman Y, Kontorovich T, Cohen S, Kaufman
B, Dagan E, Baruch R G, Friedman E, Harbst K, Barbany-Bustinza
G, Rantala J, Ehrencrona H, Karlsson P, Domchek S M, Nathanson
K L, Osorio A, Blanco I, Lasa A, Benìtez J, Hamann U, Hogervorst
F B L, Rookus M A, Collee J M, Devilee P, Ligtenberg M J, Van Der
Luijt R. B, Aalfs C M, Waisfisz Q,Wijnen J, Van Roozendaal C E P,
Peock S, Cook M, Frost D, Oliver C, Platte R, Evans D G, Lalloo
F, Eeles R, Izatt L, Davidson R, Chu C, Eccles D, Cole T, Hodgson
S, Godwin A K, Stoppa-Lyonnet D, Buecher B, Léoné M, Bressac-de
Paillerets B, Remenieras A, Caron O, Lenoir G M, Sevenet N, Longy
M, Ferrer S F, Prieur F, Goldgar D, Miron A, John E M, Buys S S,
Daly M B, Hopper J L, Terry M B, Yassin Y, Singer C, GschwantlerKaulich D, Staudigl C, Hansen T V O, Barkardottir R B, Kirchhoff T,
Pal P, Kosarin K, Offit K, Piedmonte M, Rodriguez G C, Wakeley K,
Boggess J F, Basil J, Schwartz P E, Blank S V, Toland A E, Montagna
M, Casella C, Imyanitov E N, Allavena A, Schmutzler R K, Versmold
B, Engel C, Meindl A, Ditsch N, Arnold N, Niederacher D, Deissler
H, Fiebig B, Suttner C, Schönbuchner I, Gadzicki D, Caldes T, De
la Hoya M, Pooley K A, Easton D F, Chenevix-Trench G. Common
variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1
and BRCA2 mutation carriers. Human molecular genetics; 18:22;
4442-4456; 2009
8 Artioli G, Cassaro M, Pedrini L, Borgato L, Corti L, Cappetta A,
Lombardi G, Nicoletto M O. Rare presentation of endometrial
PUBLICATIONS
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9
10
11
12
13
14
15
16
17
18
19
carcinoma with singular bone metastasis. European Journal of Cancer
Care; 19:5; 694-698; 2010 (E-pub 2009)
Aschele C, Bergamo F, Lonardi S. Chemotherapy for operable and
advanced colorectal cancer. Cancer treatment reviews; 35:6; 509-516;
2009
Atwal G S, Kirchhoff T, Bond E E, Montagna M, Menin C, Bertorelle
R, Scaini M C, Bartel F, Böhnke A, Pempe C, Gradhand E, Hauptmann
S, Offit K, Levine A, Bond G L. Altered tumor formation and
evolutionary selection of genetic variants in the human MDM4
oncogene. Proceedings of the National Academy of Sciences of the
United States of America; 106:25; 10236-10241; 2009
Aversa Savina M L, Trentin C, Sorarů M, Bona E D, Marino D,
Canova F, Salvagno L, Adami F. Acute promyelocytic leukemia after
Stanford V plus radiotherapy for advanced Hodgkin lymphoma.
Leukemia & Lymphoma; 50:7; 1214-1216; 2009
Baccarani U, Adani G L, Serraino D, Lorenzin D, Gambato M, Buda
A, Zanus G, Vitale A, Piselli P, De Paoli A, Bresadola V, Risaliti A,
Toniutto P, Cillo U, Bresadola F, Burra P. De Novo Tumors Are a Major
Cause of Late Mortality After Orthotopic Liver Transplantation.
Transplantation proceedings; 41:4; 1303-1305; 2009
Banzato A, Rondina M, Meléndez-Alafort L, Zangoni E, Nadali A,
Renier D, Moschini G, Mazzi U, Zanovello P, Rosato A. Biodistribution
imaging of a paclitaxel-hyaluronan bioconjugate. Nuclear medicine
and biology; 36:5; 525-533; 2009
Baretta Z, Ghiotto C, Marino D, Jirillo A. Aloe-induced hypokalemia
in a patient with breast cancer during chemotherapy. Annals of
Oncology; 20:8; 1445-1446; 2009
Baroncelli S, Ricci E, De Rossi A, Giuliano M. Response to Segat et al.
Are DEFB1 gene polymorphisms associated with HIV-1 infection
and virus replication? AIDS; 23:5; 649-650; 2009
Basso U, Brunello A, Bertuzzi A, Santoro A. Sorafenib is active on
lung metastases from synovial sarcoma. Annals of Oncology; 20:2;
386-387; 2009
Belloni-Fortina A, Piaserico S, Tonin Elena, Alaibac M. Melanoma
and Immunosuppression. Dermatology; 218:1; 88; 2009 (E-pub
2008)
Berrino F, Verdecchia A, Lutz J M, Lombardo C, Micheli A, Capocaccia
R, [as collab. Zambon P, Guzzinati S]. Comparative cancer survival
information in Europe. European Journal of Cancer; 45:6; 901-908;
2009
Bertazza L, Mocellin S, Marchet A, Pilati P, Gabrieli J, Scalerta R,
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27
PUBLICATIONS
267
Nitti D. Survivin gene levels in the peripheral blood of patients with
gastric cancer independently predict survival. Journal of Translational
Medicine; 7; 111; 2009
Biasco G, Velo D, Angriman I, Astorino M, Baldan A, Baseggio M
Basso U, Battaglia G, Bertin M, Bertorelle R, Bocus P, Brosolo P,
Bulzacchi A, Cannizzaro R, Da Dalt G F, Di Battista M, Errante D,
Fedrigo M, Frustaci S, Lionetti I, Massani M, Mencarelli R, Montesco
M C, Norberto L, Pantaleo M A, Pasquali C, Pastorelli D, Rossi C R,
Ruffolo C, Salvagno L, Saponara M S, Vittadello F, Zaccaria F, Zovato
S, Farinati F. Gastrointestinal stromal tumors: Report of an audit
and review of the literature; European Journal of Cancer Prevention.
18:2; 106-116; 2009
Bilora F, Pietrogrande F, Campagnolo E, Rossato A, Polato G, Pomerri
F, Muzzio P C. Are Hodgkin and non-Hodgkin patients at a greater
risk of atherosclerosis? A follow-up of 3 years. European Journal of
Cancer Care; 19:3; 417-419; 2010 (E-pub 2009)
Bisogno G, Ferrari A, Prete A, Messina C, Basso E, Cecchetto G,
Indolfi P, Scarzello G, D’Angelo P, Sio L D, Cataldo A D, Carli M.
Sequential high-dose chemotherapy for children with metastatic
rhabdomyosarcoma. European Journal of Cancer; 45:17; 3035-3041;
2009
Bisogno G, Ferrari A, Rosolen A, Alaggio R, Scarzello G, Garaventa
A, Arcamone G, Carli M. Sequential intensified chemotherapy with
stem cell rescue for children and adolescents with desmoplastic small
round-cell tumor. Bone marrow transplantation; 45; 907-911; 2009
Bobisse S, Rondina M, Merlo A, Tisato V, Mandruzzato S, Amendola
M, Naldini L, Willemsen R. A, Debets R, Zanovello P, Rosato A.
Reprogramming T lymphocytes for melanoma adoptive
immunotherapy by T-cell receptor gene transfer with lentiviral
vectors. Cancer research; 69:24; 9385-9394; 2009
Bordignon M, Belloni-Fortina A, Pigozzi B, Tarantello M, Alaibac M.
Bullous pemphigoid during long-term TNF1-α blocker therapy.
Dermatology; 219:4; 357-358 2009
Boscolo-Rizzo P, Da Mosto M C, Fuson R, Frayle-Salamanca H,
Trevisan R, Del Mistro A. HPV-16 E6 L83V variant in squamous
cell carcinomas of the upper aerodigestive tract. Journal of cancer
research and clinical oncology; 135:4; 559-566 2009 (E-pub 2008)
Brandes A A, Tosoni A, Franceschi E, Sotti G, Frezza G, Amistà P,
Morandi L, Spagnolli F, Ermani M. Recurrence pattern after
temozolomide concomitant with and adjuvant to radiotherapy
in newly diagnosed patients with glioblastoma: Correlation with
28
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31
32
33
34
35
36
37
MGMT promoter methylation status. Journal of Clinical Oncology;
27:8; 1275-1279; 2009
Brenner H, Francisci S, De Angelis R, Marcos-Gragera R, Verdecchia
A, Gatta G, Allemani C, Ciccolallo L, Coleman M, Sant M,
EUROCARE WG [as collab. Guzzinati S, Zambon P]. Long-term
survival expectations of cancer patients in Europe in 2000-2002.
European Journal of Cancer 45:6; 1028-1041; 2009
Bronte V. Myeloid-derived suppressor cells in inflammation:
Uncovering cell subsets with enhanced immunosuppressive
functions. European Journal of Immunology; 39:10; 2670-2672;
2009
Bronte V, Mocellin S. Suppressive influences in the immune response
to cancer. Journal of Immunotherapy; 32:1; 1-11 2009
Brunello A, Loaldi E, Balducci L. Dose adjustment and supportive
care before and during treatment. Cancer treatment reviews; 35:6;
493-498; 2009
Brunello A, Saia G, Bedogni A, Scaglione D, Basso U. Worsening of
osteonecrosis of the jaw during treatment with sunitinib in a patient
with metastatic renal cell carcinoma. Bone; 44:1; 173-175; 2009
(E-pub 2008)
Brunello A, Sandri R, Extermann M. Multidimensional geriatric
evaluation for older cancer patients as a clinical and research tool.
Cancer treatment reviews; 35:6; 487-492; 2009
Bruno W, Ghiorzo P, Battistuzzi L, Ascierto P A, Barile M, Gargiulo
S, Gensini F, Gliori S, Guida M, Lombardo M, Manoukian Menin C,
Nasti S, Origone P, Pasini B, Pastorino L, Peissel B, Pizzichetta M A,
Queirolo P, Rodolfo M, Romanini A, Scaini M C,Testori A,Tibiletti
M G,Turchetti D, Leachman S A, Bianchi Scarrà G. Clinical genetic
testing for familial melanoma in Italy: A cooperative study. Journal
of the American Academy of Dermatology; 61:5; 775-782; 2009
Burra P, Loreno M, Russo F P, Germani G, Galligioni A, Senzolo
M, Cillo U, Zanus G, Fagluoli S, Ruggo M. Donor livers with
steatosis are safe to use in hepatitis C virus-positive recipients. Liver
Transplantation; 15:6; 619-628; 2009
Cagol M, Ruol A, Castoro C, Alfieri R, Michieletto S, Ancona E.
Prophylactic thoracic duct mass ligation prevents chylothorax after
transthoracic esophagectomy for cancer. World journal of surgery;
33:8; 1684-1686; 2009
Calabrese F, Loy M, Lunardi F, Marino D, Aversa Savina M L, Rea
F. Acute cellular rejection and Epstein-Barr virus-related posttransplant lymphoproliferative disorder in a pediatric lung transplant
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PUBLICATIONS
268
with low viral load. Transplant infectious disease; 12:4; 342-346;
2010 (E-pub 2009)
Calabrò L, Gasperini P, Di Gangi I M, Indraccolo S, Barbierato M,
Amadori A, Chieco-Bianchi L. Antineoplastic activity of lentiviral
vectors expressing interferon-αlpha in a preclinical model of primary
effusion lymphoma. Blood; 113:19; 4525-4533; 2009
Campana L G, Mocellin S, Basso M, Puccetti O, De Salvo G L, ChiarionSileni V, Vecchiato A, Corti L, Rossi C R, Nitti D. Bleomycin-based
electrochemotherapy: Clinical outcome from a single institution’s
experience with 52 patients. Annals of Surgical Oncology; 16:1;
191-199; 2009
Capocaccia R, Martina L, Inghelmann R, Croeetti E, De Lisi V, Falcini
F, Guzzinati S, Rosso S, Tagliabue G, Tumino R, Vercelli M, Zanetti
R, De Angelis R. A method to estimate mortality trends when death
certificates are Imprecisely coded: an application to cervical cancer
in Italy. International Journal of Cancer; 124:5; 1200-1205; 2009
Caumo F, Vecchiato F, Pellegrini M, Vettorazzi M, Ciatto S, Montemezzi
S. Analysis of interval cancers observed in an Italian mammography
screening programme (2000-2006). Radiologia Medica; 114:6;
907-914; 2009
Cavallari I, Micol S B, Rende F, Martines A, Fogar P, Basso D, Vella
M D, Pedrazzoli S, Herman J G, Chieco Bianchi L, Esposito G,
Ciminale V, D’Agostino D M. Decreased expression and promoter
methylation of the menin tumor suppressor in pancreatic ductal
Adenocarcinoma. Genes, Chromosomes and Cancer; 48:5; 383-396;
2009
Cecchin D, Chondrogiannis S, Puppa A D, Rotilio A, Zustovich
F, Manara R, Gardiman M, Berti F, Zucchetta P, Carollo C, Bui F.
Presurgical 99mTc-sestamibi brain SPET/CT versus SPET: A
comparison with MRI and histological data in 33 patients with
brain tumors. Nuclear medicine communications 30:9; 660-668;
2009
Chiarelli S, Padoan I, Parenti A, Ninfo V, D’Andrea E. Pathologic
findings in 200 consecutive fallopian tube specimens. Human
pathology; 40:4; 603-604; 2009
Chiarion-Sileni V, Innocente R, Cavina R, Ruol A, Corti L, Pigozzo
J, Del Bianco P, Fumagalli U, Santoro A, Ancona E. Multi-center
phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin
and oxaliplatin in locally advanced esophageal cancer. Cancer
chemotherapy and pharmacology; 63:6; 1111-1119; 2009 (E-pub
2008)
54 De Angelis R, Francisci S, Baili P, Marchesi F, Roazzi P, Belot A,
Crocetti E, Pury P, Knijn A, Coleman M, Capocaccia R, The
EUROCARE-4,WG [as collab. Guzzinati S, Zambon P]. The
EUROCARE-4 database on cancer survival in Europe: data
standardisation, quality control and methods of statistical analysis.
European Journal of Cancer; 45:6; 909-930; 2009
55 De Corti F, Dall’Igna P, Bisogno G, Casara D, Rossi C R, Foletto M,
Alaggio R, Carli M, Cecchetto G. Sentinel node biopsy in pediatric
soft tissue sarcomas of extremities. Pediatric Blood & Cancer; 52:1;
51-54; 2009
56 De Rossi C, Brunello A, Jirillo G, Jirillo A. When an interim analysis
of randomized trial changes the practice in oncology: the lesson of
adjuvant trastuzumab and the HERA trial. Immunopharmacology &
Immunotoxicology; 31:1; 1-4; 2009 (E-pub 2008)
57 Della Puppa A, Dal Pos S, Zovato S, Orvieto E, Ciccarino P, Manara
R, Zustovich F, Berti F, Gardiman M P, Scienza R. Solitary intraventricular brain metastasis from a breast carcinoma. Journal of
Neuro - Oncology; 97:1; 123-126; 2009
58 Di Filippo F, Giacomini P, Rossi C R, Santinami M, Anzà M,
Garinei R, Perri P, Botti C, Di Angelo P, Sofra C, Pasqualoni R,
Sperduti I, Cavaliere F, Di Filippo S, Corrias F, Armenti A, Ferraresi
V, Ginebri A. Prognostic factors influencing tumor response,
locoregional control and survival, in melanoma patients with
multiple limb in-transit metastases treated with TNF1-α based
isolated limb perfusion. In Vivo; 23:2; 347-352; 2009
59 Erlic Z, Rybicki L, Peczkowska M, Golcher H, Kann P H, Brauckhoffm
Müssig K, Muresan M, Schäffler A, Reisch N, Schott M, Fassnacht M,
Opocher G, Klose S, Fottner C, Forrer F, Plöckinger U, Petersenn S,
Zabolotny D, Kollukch O, Yaremchuk S, Januszewicz A, Walz M K,
Eng C, Neumann H P H. Clinical predictors and algorithm for the
genetic diagnosis of pheochromocytoma patients. Clinical Cancer
Research; 15:20; 6378-6385; 2009
60 Falci C, Morello E, Droz J P, Treatment of prostate cancer in unfit
senior adult patients. Cancer treatment reviews; 35:6; 522-527;
2009
61 Fassan M, Castoro C, Saenz A J, Cagol M, Ninfo V, Rugge M.
Inflammatory myofibroblastic tumor as adverse outcome of
eosinophilic esophagitis. Endoscopy; 41: Suppl 2; e95-e96; 2009
62 Favaretto A G, Pasello G, Loreggian L, Breda C, Braccioni F, Marulli
G, Stragliotto S, Magro C, Sotti G, Rea F. Preoperative concomitant
chemo-radiotherapy in superior sulcus tumor: a mono-institutional
46 Ciccolallo L, Licitra L, Cantù G, Gatta G, EUROCARE WG [as collab.
Guzzinati S, Zambon P]. Survival from salivary glands adenoid cystic
carcinoma in European populations. Oral oncology; 45:8; 669-674;
2009
47 Colavito D, Cartei G, Dal Bianco M, Stecca A, Zustovich F, Dalle
Carbonare M, Ragazzi E, Farina M, Colombrino E, Leon A.
Thymidylate synthetase allelic imbalance in clear cell renal carcinoma.
Cancer chemotherapy and pharmacology; 64:6; 1195-1200; 2009
48 Colombatti R, Calò A, Iacopetti T, Rosolen A, Lombardi G, Cesaro
S. Successful treatment of severe iatrogenic calcinosis cutis with
intravenous sodium thiosulfate in a child affected by T-acute
lymphoblastic leukemia. Pediatric dermatology; 26:3; 311-315;
2009
49 Coltrini D, Ronca R, Belleri M, Zardi L, Indraccolo S, Scarlato V,
Giavazzi R, Presta M. Impact of VEGF-dependent tumor microenvironment on EDB fibronectin expression by subcutaneous
human tumor xenografts in nude mice. Journal of Pathology; 219:4;
455-462; 2009
50 Comper F, Antonello D, Beghelli S, Gobbo S, Montagna L, Pederzoli
P, Chilosi M, Scarpa A. Expression pattern of claudins 5 and 7
distinguishes solid-pseudopapillary from pancreatoblastoma, acinar
cell and endocrine tumors of the pancreas. American Journal of
Surgical Pathology; 33:5; 768-774; 2009
51 Dal Maso L, Polesel J, Serraino D, Lise M, Piselli P, Falcini F, Russo
A, Intrieri T, Vercelli M, Zambon P, Tagliabue G, Zanetti R, Federico
M, Limina R M, Mangone L, De Lisi V, Stracci F, Ferretti S, Piffer S,
Budroni M, Donato A, Giacomin A, Bellù F, Fusco M, Madeddu A,
Vitarelli S, Tessandori R, Tumino R, Suligoi B, Franceschi S. Cancer
and AIDS Registries Linkage, (CARL Study). Pattern of cancer risk
in persons with AIDS in Italy in the HAART era. British journal of
cancer; 100:5; 840-847; 2009
52 Dall’Igna P, Cecchetto G, Bisogno G, Conte M, Chiesa P L, D’Angelo
P, De Leonardis F, De Salvo G L, Favini F, Ferrari A. On Behalf of
the TREP Group; Pancreatic tumors in children and adolescents:
the Italian TREP project experience. Pediatric Blood & Cancer; 54:5;
675-680; 2009
53 D’Amico F, Schwartz M, Vitale A, Tabrizian P, Roayaie S, Thung S,
Guido M, Martin J D R, Schiano T, Cillo U. Predicting recurrence
after liver transplantation in patients with hepatocellular carcinoma
exceeding the up-to-seven criteria. Liver Transplantation; 15:10;
1278-1287; 2009
PUBLICATIONS
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68
69
70
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72
786-793; 2009
73 Filen A, Magnavita N, Pescarini L. Analysis of malpractice claims
in mammography: A complex issue. Radiologia Medica; 114:4;
636-644; 2009
74 Franceschi S, Dal Maso L, Zucchetto A, Talamini R, PACE SG [as
collab. Stocco C F, Zambon P]. Alcohol consumption and survival
after breast cancer. Cancer Epidemiology Biomarkers & Prevention;
18:3; 1011-1012; 2009
75 Francisci S, Capocaccia R, Grande E, Santaquilani M, Simonetti A,
Allemani C, Gatta G, Sant M, Zigon G, Bray F, Janssen-Heijnen M,
EUROCARE WG [as collab. Guzzinati S, Zambon P]. The cure of
cancer: A European perspective. European Journal of Cancer; 45:6;
1067-1079; 2009
76 Frego M, Bridda A, Ruffolo C, Scarpa M, Polese L, Bianchera G. The
hostile neck does not increase the risk of carotid endarterectomy.
Journal of Vascular Surgery; 50:1; 40-47; 2009
77 Garoli D, Pelizzo M G, Nicolosi P, Peserico A, Tonin E, Alaibac M.
Effectiveness of different substrate materials for in vitro sunscreen
tests. Journal of dermatological science; 56:2; 89-98; 2009
78 Garolla A, Dinc R, Checchin D, Biagioli A, De Toni L, Nicoletti
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79 Gatta G, Zigon G, Capocaccia R, Coebergh J W, Desandes E, Kaatsch
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80 Gennaro G, Toledano A, Di Maggio C, Baldan E, Bezzon E, La
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81 Gratwohl A, Baldomero H, Schwendener A, Rocha V, Apperley J,
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82 Grazzini G, Visioli C B, Zorzi M, Ciatto S, Banovich F, Bonanomi
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Ficarra V, Novara G. Editorial Comment on: Cytological Punctures
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Ficarra V, Novara G, Artibani W, Cestari A, Galfano A, Graefen M,
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Ficarra V, Novara G, Boscolo-Berto R, Artibani W, Kattan M W.
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Ficarra V, Novara G, Galfano A, Brunelli M, Cavalleri S, Martignoni
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Ficarra V, Novara G, Galfano A. Precursor Isoform of ProstateSpecific Antigen and Human Kallikrein 2: Two New Promising
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Ficarra V, Novara G, Martignoni G. The Use of Simplified Versions of
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Ficarra V, Novara Giacomo, Secco S, D’Elia C, Boscolo-Berto R,
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Ficarra V, Novara G, Secco S, Macchi V, Porzionato A, De Caro R.
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Hersey P, Bastholt L, Chiarion-Sileni V, Cinat G, Dummer R,
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Indraccolo S, Minuzzo S, Masiero M, Pusceddu I, Persano L, Moserle
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Jori G, Soncin M, Friso E, Vicente M G H, Hao E, Miotto G, Colautti
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Luster M, Handkiewicz-Junak D, Grossi A, Zacharin M, Taïeb D, Cruz
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Mammano E, Belluco C, Bonafé M, Olivieri F, Mugianesi E, Barbi
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107 Moserle L, Ghisi M, Amadori A, Indraccolo S. Side population and
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108 Mussolin L, Bonvini P, Ait-Tahar K, Pillon M, Tridello G, Buffardi S,
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109 Neumann H P H, Erlic Z, Boedeker C C, Rybicki L A, Robledo M,
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110 Nicoletto M O, Bertorelle R, Borgato L, De Salvo G L, Artioli G,
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111 Nitti D, Marchet A, Mocellin S, Rossi G M, Ambrosi A, Mencarelli R.
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112 Novara G. Editorial Comment on: Mode-of-Action, Efficacy, and
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98 Mandruzzato S, Solito S, Falisi E, Francescato S, Chiarion-Sileni
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99 Mannelli M, Castellano M, Schiavi F, Filetti S, Giacchè M, Mori L,
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100 Marioni G, Koussis H, Gaio E, Giacomelli L, Bertolin A, D’Alessandro E,
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101 Mazzaferro V, Llovet J M, Miceli R, Bhoori S, Schiavo M, Mariani L,
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103 Mian C, Barollo S, Zambonin L, Pennelli G, Bernante P, Pelizzo M R,
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104 Micheli A, Ciampichini R, Oberaigner W, Ciccolallo L, De Vries E,
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118 Paccagnella A, Ghini M G, Loreggian L, Buffoli A, Koussis H, Mione
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119 Pasello G, Agata S, Bonaldi L, Corradin A, Montagna M, Zamarchi
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120 Pasello G, Favaretto A G. Molecular targets in malignant pleural
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122 Pastore G, De Salvo G L, Bisogno G, Dama E, Inserra A, Cecchetto
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123 Pavesi G, Berlucchi S, Munari M, Manara R, Scienza R, Opocher G.
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124 Persano L, Moserle L, Esposito G, Bronte V, Barbieri V, Iafrate M,
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125 Pierobon M, Calvert V, Belluco C, Garaci E, Deng J, Lise M, Nitti D,
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114 Novara G, Ficarra V. Robotic-assisted laparoscopic radical cystectomy:
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115 Novara G, Galfano A, Secco S, Ficarra V, Artibani W. Impact of surgical
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116 Opocher G, Boaretto F, Pignataro V, Demattè S, Cecchini M E, Erlic
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135 Romanato G, Scarpa M, Angriman I, Faggian D, Ruffolo C, Marin R,
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136 Rossi P G, Zorzi M. Comment on: Efficacy of HPV 16/18 vaccines on
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138 Ruffolo C, Scarpa M, Bassi N, Angriman I. A systematic review
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143 Rustighi A, Tiberi L, Soldano A, Napoli M, Nuciforo P, Rosato A,
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127 Pilati P, Mammano E, Mocellin S, Tessari E, Lise M, Nitti D.
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132 Pucciarelli S, Gagliardi G, Maretto I, Lonardi S, Friso M L, Urso E,
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Annals of Surgical Oncology; 16:4; 893-899; 2009
133 Quaglia A, Tavilla A, Shack L, Brenner H, Janssen-Heijnen M, Allemani
C, Colonna M, Grande E, Grosclaude P, Vercelli M, EUROCARE WG
[as collab. Guzzinati S, Zambon P]. The cancer survival gap between
elderly and middle-aged patients in Europe is widening. European
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134 Ridolfi L, Fiorentini G, Guida M, Michiara M, Freschi A, Aitini E,
Ballardini M, Bichisao E, Ridolfi R, Italian Melanoma Intergroup
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153 Scarpa M, Ruffolo C, Bassi D, Boetto R, D’Incà R, Buda A, Sturniolo
G C, Angriman I. Intestinal surgery for Crohn’s disease: Predictors of
recovery, quality of life, and costs. Journal of Gastrointestinal Surgery;
13:12; 2128-2135; 2009
154 Scarpa M, Victor C J, O’Connor B I, Cohen Z, McLeod R S. Validation
of an English version of the Padova quality of life instrument to
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of Gastrointestinal Surgery; 13:3; 416-422; 2009
155 Silic-Benussi M, Cannizzaro E, Venerando A, Cavallari I, Petronilli
V, La Rocca N, Marin O, Chieco-Bianchi L, Di Lisa F, D’Agostino
D M, Bernardi P, Ciminale V. Modulation of mitochondrial K+
permeability and reactive oxygen species production by the p13
protein of human T-cell leukemia virus type 1. Biochimica et
Biophysica Acta - Bioenergetics; 1787:7; 947-954; 2009
156 Sorgato N, Pennelli G, Boschin I M, Ide E C, Pagetta C, Piott A,
Toniato A, De Salvo G L, Hindié E, Al-Nahhas A, Rubello D, Pelizzo
M R. Can we avoid inadvertent parathyroidectomy during thyroid
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157 Testori A, De Salvo G L, Montesco M C, Trifirò G, Mocellin S,
Landi G, MacRipò G, Carcoforo P, Ricotti G, Giudice G, Picciotto
F, Donner D, Di Filippo F, Soteldo J, Casara D, Schiavon M,
Vecchiato A, Pasquali S, Baldini F, Mazzarol G, Rossi C R. Clinical
considerations on sentinel node biopsy in melanoma from an
Italian multicentric study on 1,313 patients (SOLISM-IMI).
Annals of Surgical Oncology; 16:7; 2018-2027; 2009
158 Testori A, Rutkowski P, Marsden J, Bastholt L, Chiarion-Sileni V,
Hauschild A, Eggermont A M. Surgery and radiotherapy in the
treatment of cutaneous melanoma. Annals of Oncology; 20:Suppl 6;
22-29; 2009
159 Toffoli G, Cecchin E, Gasparini G, D’Andrea M, Azzarello G, Basso
U, Mini E, Pessa S, De Mattia E, Lo Re G, Buonadonna A, Nobili S,
De Paoli A, Innocenti F. Genotype-driven phase I study of irinotecan
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160 Tognazzo S, Bovo E, Fiore A R, Guzzinati S, Monetti D, Stocco C F,
Zambon P. Probabilistic classifiers and automated cancer registration:
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161 Toniato A, Boschin I, Bernante P, Foletto M, Guolo A M, Pelizzo M
R, Opocher G, Ballotta E, Mantero F. Factors influencing the rising
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145 Saggioro D, Silic-Benussi M, Biasiotto R, D’Agostino D M, Ciminale
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146 Sant M, Allemani C, Santaquilani M, Knijn A, Marchesi F,
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147 Sarzo G, Del Mistro A, Finco C, Frayle-Salamanca H, Marino F,
Franzetti M, Ferrara R, Mistrangelo M, Savastano S, Vecchiato M,
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to viral and host factors. Colorectal disease; 12: 7online; e128-e134;
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148 Scaini M C, Rossi E, De Siqueira Torres P L A, Zullato D, Callegaro
M, Casella C, Quaggio M, Agata S, Malacrida S, Chiarion-Sileni V,
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149 Scarpa M, Bortolami M, Morgan S L, Kotsafti A, Ferraro S, Ruffolo C,
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150 Scarpa M, Erroi F, Ruffolo C, Mollica E, Polese L, Pozza G, Norberto L,
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Surgical Endoscopy and Other Interventional Techniques; 23:3;
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151 Scarpa M, Mescoli C, Rugge M, D’Incà R, Ruffolo C, Polese L, D’Amico
D F, Sturniolo G C, Angriman I. Restorative proctocolectomy for
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152 Scarpa M, Pagano D, Ruffolo C, Pozza A, Polese L, Frego M, D’Amico
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171 Vitale A, D’Amico F, Gringeri E, Valmasoni M, Pauletto A, Bonsignore
P, Bassi D, D’Amico F E, Polacco M, Burra P, Russo F, Angeli P, Poci
C, Feltracco P, Romano A, Cillo U. Prognostic Evaluation of the
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Undergoing Liver Transplantation. Transplantation proceedings;
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172 Vitale A, Saracino E, Boccagni P, Brolese A, D’Amico F, Gringeri E,
Neri D, Srsen N, Valmasoni M, Zanus G, Carraro A, Violi P, Pauletto
A, Bassi D, Polacco M, Burra P, Farinati F, Feltracco P, Romano A,
D’Amico D F, Cillo U. Validation of the BCLC Prognostic System in
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173 Vitale A, Saracino E, D’Amico F E, Grigoletto F, Burra P, Angeli
P, Boccagni P, Brolese A, Zanu G, Neri D, Gringeri E, D’Amico F,
Valmasoni M, Carraro A, Gambato M, Feltracco P, Romano A, Buggio
M, D’Amico D F, Cillo U. Prospective Validation of a New Priority
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174 Vitaliani R, Spinazzi M, Del Mistro A, Manara R, Tavolato B,
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175 Zancan M, Galdi F, Di Tonno F, Mazzariol C, Orlando C, Malentacchi
F, Agostini M, Maran M, Del Bianco P, Fabricio A S C, Murer B,
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176 Zanus G, Carraro A, Vitale A, Gringeri E, D’Amico F, Valmasoni M,
D’Amico F E, Brolese A, Boccagni P, Neri D, Srsen N, Burra P, Feltracco
P, Bonsignore P, Scopelliti M, Cillo U. Alcohol Abuse and De Novo
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177 Zattra E, Pigozzi B, Bordignon M, Marino F, Chiarion-Sileni V,
Alaibac M. Anetoderma in cutaneous marginal-zone B-cell
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178 Zattra E, Salmaso R, Montesco M C, Pigozzi B, Forchetti G, Alaibac
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179 Zattra E, Tonin E Fortina A B, Pigozzi B, Alaibac M. Clinical tip:
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162 Toniato A, Merante-Boschin I, Opocher G, Pelizzo M R, Schiavi F,
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163 Tosello V, Zamarchi R, Merlo A, Gorza M, Piovan E, Mandruzzato
S, Bronte V, Wang X, Ferrone S, Amadori A, Zanovello P. Differential
expression of constitutive and inducible proteasome subunits in
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IFN-α or IL-4. European Journal of Immunology; 39:1; 56-66; 2009
164 Turato C, Ruvoletto M G, Biasiolo A, Quarta S, Tono N, Bernardinello
E, Beneduce L, Fassina G, Cavalletto L, Chemello L, Merkel C, Gatta
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165 Ugel S, Delpozzo F, Desantis G, Papalini F, Simonato F, Sonda N,
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166 Ugel S, Scarselli E, Iezzi M, Mennuni C, Pannellini T, Calvaruso
F, Cipriani B, De Palma R, Ricci-Vitiani L, Peranzoni E, Musiani
P, Zanovello P, Bronte V. Autoimmune B-cell lymphopenia after
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Blood; 115:7; 1374-1384; 2010 (E-pub 2009)
167 Ugel S, Zoso A, De Santo C, Li Y, Marigo I, Zanovello P, Cipriani B,
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168 Vajente N, Trevisan R, Saggioro D. HTLV-1 Tax protein cooperates
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169 Verdecchia A, Guzzinati S, Francisci S, De Angelis R, Bray F, Allemani
C, Tavilla A, Santaquilani M, Sant M. Survival trends in European
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170 Vitale A, Boccagni P, Brolese A, Neri D, Srsen N, Zanus G, Pagano D,
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181 Zustovich F, Lombardi G, Della Puppa A, Rotilio A, Scienza R, Pastorelli
D. A phase II study of cisplatin and temozolomide in heavily pre-treated
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182 Zustovich F, Lombardi G, Pastorelli D. Important role of gemcitabine in
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180 Zustovich F, Lombardi G, Cartei G. Paraneoplastic diffuse cutaneous
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2009 PUBLICATIONS / Non indexed in ISI-JCR
9 Mammano E, Pilati P, Tessari E, Cosci M, Mocellin S, Nitti D.
Adjuvant chemotherapy after radical liver resection in the treatment
of metastases from colorectal carcinoma. Minerva chirurgica; 64:5;
457-463; 2009
10 Merante-Boschin I, Fassan M, Pelizzo M R, Ide E C, Rugge M. Neck
emergency due to parathyroid adenoma bleeding: a case report.
Journal of Medical Case Reports; 3:1; 7404; 2009
11 Montrone M, Martorelli D, Rosato A, Dolcetti R. Retinoids as critical
modulators of immune functions: New therapeutic perspectives for
old compounds. Endocrine, Metabolic and Immune Disorders - Drug
Targets; 9:2; 113-131; 2009
12 Morello E, Giordano G, Falci C, Monfardini S. Rehabilitation in older
cancer patients. Aging Health; 5; 3; 369; 384; 2009
13 Opocher G, Schiavi F, Cicala M V, Patalano A, Mariniello B,
Boaretto F, Zovato S, Pignataro V, Macino B, Negro I, Mantero
F. Genetics of adrenal tumors. Minerva endocrinologica; 34:2;
107-121; 2009
14 Palozzo A C, Paganelli F, Faoro S, Trojniak M P, Bertipaglia C.
Registers as evaluation tool of clinical results of antiblastic therapy.
Giornale Italiano di Farmacia Clinica; 23; 3; 128; 130; 2009
15 Ronco G, Giubilato P, Naldoni C, Zorzi M, Anghinoni E, Scalisi A,
Dalla Palma P, Zanier L, Barca A, Gaimo M D, Maglietta R, Mancini
E, Pizzuti R, Iossa A, Segnan N, Zappa M. Extension of organised
cervical cancer screening programmes in Italy and their process
indicators: 2007 activity. Epidemiologia e prevenzione; 33:(3 Suppl 2);
41-56; 2009
16 Ruzza P, Rosato A, Rossi C R, Floreani M, Quintieri L. Glutathione
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1 AIRTUM WG [as collab. Zambon P, Baracco M, Bovo E, Dal Cin A,
Fiore A R, Greco A, Guzzinati S, Monetti D, Rosano A, Stocco C F,
Tognazzo S], Crocetti E, Buzzoni C. New incidence and mortality
data. 2003-2005 Epidemiologia e prevenzione 33:(1-2 Suppl 2); e1\3
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2 Cillo U,Vitale A. Benefit and harm of deceased- or living-donor liver
transplantation for hepatocellular carcinoma. Digestive and Liver
Disease Supplements 3:4 88-92; 2009
3 Diamantis G, Bocus P, Morbin T, Battaglia G. Endoscopic submucosal
dissection of a non-polypoid gastric lesion. Giornale Italiano di
Endoscopia Digestiva 32:3 228-229; 2009
4 Fassan M, Rugge M, Parente P, Tieppo C, Battaglia G. The role of
Helicobacter pylori in the spectrum of Barrett’s carcinogenesis.
Cancer Prevention Research; 2:1; 94; 2009
5 Favaretto A G, Pasello G, Magro C. Second and third line treatment
in advanced non-small cell lung cancer. Discovery medicine; 8:43;
204-209; 2009
6 Ferretti S, Guzzinati S, Zambon P, Manneschi G, Crocetti E, Falcini F.
Cancer incidence estimation by hospital discharge flow as compared
with cancer registries data. Epidemiologia e prevenzione; 33; 4-5;
147-153; 2009
7 Gemelli A, Paciolla A, Oliosi F, Basso A, Moscardin R, Tineo M C,
Romano P, Alaibac M, Aversa S M L, Furian L, D’Angelo A, Bonfante
L. A case of Kaposi’s sarcoma in the rapamycin era. Giornale italiano
di nefrologia; 26:1; 90-93; 2009
8 Lombardi G, Zustovich F, Zovato S, Fiore D, Cappetta A, Pastorelli
D. Characteristics and management of pancreatic lesions in von
Hippel-Lindau disease: A systematic literature review. Oncology
Reviews; 3:2; 103-106; 2009
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19 Vecchiato M, Savastano S, Sarzo G, Cadrobbi R, Gruppo M, Mondi
I, Cavallin F, Bazzolo G, Marcellan E, Merigliano S. Anterior
laparoscopic rectal resection for cancer in the elderly: Long-term
outcome, risk factors and health related quality of life. BMC
Geriatrics; 9:Suppl 1; A43; 2009
20 Zorzi M, Fedato C, Naldoni C, Sassatelli R, Sassoli De’Bianchi P, Senore
C, Visioli C B, Cogo C. Screening for colorectal cancer in Italy: 2007
survey. Epidemiologia e prevenzione; 33:Suppl 2; 57-74; 2009
21 Zustovich F, Shams M, Anselmi P, Lombardi G, Pastorelli D, Cartei
G. Cognitive and emotive state in elderly treatment-naive patients
with advanced cancer compared with an elderly healthy control
population. Cancer Therapy; 7; ISSUE A; 149-152; 2009
17 Savastano S, Vecchiato M, Sarzo G, Gruppo M, Cadrobbi R, Marcellan
E, Mondi I, Cavallin F, Bazzolo G, Merigliano S. Surgery for
obstructed defecation in over 65 year old patients. BMC Geriatrics;
9:Suppl 1; A39; 2009
18 Tomatis M, Mano M P, Baiocchi D, Barca A, Bordon R, Casella D,
Donati G, Berti R, Filippini L, Frigerio A, Furini A, Mantellini P,
Naldoni C, Pagano G, Ramera D, Ravaioli A, Sapino A, Taffurelli
M, Vettorazzi M, Zorzi M, Cataliotti L, Rosselli Del Turco M, Segnan
N, Ponti A. Audit system on Quality of breast cancer diagnosis
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1 Abbate I, Zanchetta M, Gatt M, Gabrielli L, Zanussi S, Milia M G,
Lazzarotto T, Tedeschi R, Ghisetti V, Clementi M, De Rossi A, Baldanti
F, Capobianchi M R. Multicenter comparative study of Epstein-Barr
virus DNA quantification for virological monitoring in transplanted
patients. Journal of clinical virology; 50:3; 224-229; 2011 (E-pub
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2 Adami F, Scarin M, Pescarini L, Binotto G, Pavan L, Sgarabotto D,
Semenzato G. Successful control of Blastoschizomyces capitatus
infection in three consecutive acute leukaemia patients despite
initial unresponsiveness to liposomal amphotericin B. Mycoses; 54:4;
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3 Adeegbe D, Serafini P, Bronte V, Zoso A, Ricordi C, Inverardi L. In vivo
induction of myeloid suppressor cells and CD4Foxp3 T regulatory
cells prolongs skin allograft survival in mice. Cell transplantation;
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4 Agostini M, Pucciarelli S, Calore F, Bedin C, Enzo MV, Nitti D.
miRNAs in colon and rectal cancer: A consensus for their true
clinical value. Clinica Chimica Acta; 411; 17-18; 1181-1186; 2010
5 AIRTUM WG [as collab. Guzzinati S, Zambon P, Baracco M, Bovo E,
Dal Cin A, Fiore A R, Greco A]. Italian cancer figures, report 2010:
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6 Alaggio R, Cecchetto G, Bisogno G, Gambini C, Calabrò M L, Inserra A,
Boldrini R, De Salvo G L, D’Amore E S G, Dall’Igna P. Inflammatory
myofibroblastic tumors in childhood: A report from the italian
cooperative group studies. Cancer; 116:1; 216-226; 2010
7 Albini A, Indraccolo S, Noonan D M, Pfeffer U. Functional genomics
of endothelial cells treated with anti-angiogenic or angiopreventive
drugs Clinical & Experimental Metastasis; 27:6; 419-439; 2010
8 Angeloni G, Alberti S, Romagnoli E, Banzato A, Formichi M,
Cucchini U, Pengo V. Low molecular weight heparin (parnaparin) for
cardioembolic events prevention in patients with atrial fibrillation
undergoing elective electrical cardioversion: a prospective cohort
study. Internal and emergency medicine; 6:2; 117-123; 2011 (E-pub
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9 Angriman I, Scarpa M, Ruffolo C. Health related quality of life
after surgery for colonic diverticular disease. World journal of
gastroenterology : WJG; 16:32; 4013-4018; 2010
10 Antoniou A C, Beesley J, McGuffog L, Sinilnikova O M, Healey S,
Neuhausen S L, Ding Y C, Rebbeck T R, Weitzel J N, Lynch H T, Isaacs
C, Ganz P A, Tomlinson G, Olopade O I, Couch F, J, Wang X, Lindor
N M, Pankratz V S, Radice P, Manoukian S, Peissel B, Zaffaroni D,
Barile M, Viel A, Allavena A, Dall’Olio V, Peterlongo P, Szabo C,
I, Zikan M, Claes K, Poppe B, Foretova L, Mai P L, Greene M H,
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Niederacher D, Sutter C, Domchek S M, Nathanson K L, Rebbeck
T, Blum J L, Piedmonte M, Rodriguez G C, Wakeley K, Boggess J F,
Basil J, Blank S V, Friedman E, Kaufman B, Laitman Y, Milgrom R,
Andrulis I L, Glendon G, Ozcelik H, Kirchhoff T, Vijai J, Gaudet M M,
Altshuler D, Guiducci C, SWE-BRCA, Loman N, Harbst K, Rantala
J, Ehrencrona H, Gerdes A M, Thomassen M, Sunde L, Peterlongo P,
Manoukian S, Bonanni B, Viel A, Radice P, Caldes T, De la Hoya M,
Singer C F, Fink-Retter A, Greene M H, Mai P L, Loud J T, Guidugli
L, Lindor N M, Hansen T V, Nielsen F C, Blanco I, Lazaro C, Garber
J, Ramus S J, Gayther S A, Phelan C, Narod S, Szabo C I, MOD
SQUAD, Benitez J, Osorio A, Nevanlinna H, Heikkinen T, Caligo M
A, Beattie M S, Hamann U, Godwin A K, Montagna M, Casella C,
Neuhausen S L, Karlan B Y, Tung N, Toland A E, Weitzel J, Olopade
O, Simard J, Soucy P, Rubinstein W S, Arason A, Rennert G, Martin
N G, Montgomery G W, Chang-Claude J, Flesch-Janys D, Brauch H,
GENICA, Severi G, Baglietto L, Cox A, Cross S S, Miron P, Gerty S
M, Tapper W, Yannoukakos D, Fountzilas G, Fasching P A, Beckmann
M W, Dos Santos Silva I, Peto J, Lambrechts D, Paridaens R, Rudiger
T, Forsti A, Winqvist R, Pylkas K, Diasio R B, Lee A M, Eckel-Passow
J, Vachon C, Blows F, Driver K, Dunning A, Pharoah P P, Offit K,
Pankratz V S, Hakonarson H, Chenevix-Trench G, Easton D F, Couch
F J. A locus on 19p13 modifies risk of breast cancer in BRCA1
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breast cancer in the general population. Nature genetics; 42:10; 885892; 2010
12 Artioli G, Borgato L, Cappetta A, Wabersich J, Mocellin S, Dalla Palma
M, Nicoletto M O. Overall survival in BRCA-associated ovarian
cancer: case-control study of an Italian series. European journal of
gynaecological oncology; 31:6; 658-661; 2010
13 Artioli G, Mocellin S, Borgato L, Cappetta A, Bozza F, Zavagno G,
Zovato S, Marchet A, Pastorelli D. Phase II Study of Neoadjuvant
Gemcitabine, Pegylated Liposomal Doxorubicin, and Docetaxel
in Locally Advanced Breast Cancer. Anticancer Research; 30:9;
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14 Baccarani U, Piselli P, Serraino D, Adani G L, Lorenzin D, Gambato
M, Buda A, Zanus G, Vitale A, De Paoli A, Cimaglia C, Bresadola
V, Toniutto P, Risaliti A, Cillo U, Bresadola F, Burra P. Comparison
of de novo tumors after liver transplantation with incidence rates
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D, Birk Jensen U, Caligo M, Friedman E, Kaufman B, Laitman Y,
Milgrom R, Dubrovsky M, Cohen S, Borg A, Jernstrom H, Lindblom A,
Rantala J, Stenmark-Askmalm M, Melin B, SWE-BRCA, Nathanson
K, Domchek S, Jakubowska A, Lubinski J, Huzarski T, Osorio A, Lasa
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R, Wappenschmidt B, Engel C, Meindl A, Lochmann M, Arnold N,
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H, Gadzicki D, Preisler-Adams S, Kast K, Schonbuchner I, Calde T,
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Ghoussaini M, Barrowdale D, EMBRACE, Peock S, Cook M, Oliver
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Barollo S, Pennelli G M, Vianello F, Watutantrige Fernando S, Negro
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of endocrinology; 163:4; 659-663; 2010
Bassi D, Ruffolo C, Scarpa M, Mescoli C, Bassi N, Angriman I. Ileal
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Bassi P F, Volpe A, D’Agostino D M, Palermo G, Renier D, Franchini
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Bertazza L, Mocellin S. The Dual Role of Tumor Necrosis Factor
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Bertolin C, Boaretto F, Barbon G, Salviati L, Lapi E, Divizia M T,
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Biasiotto R, Aguiari P, Rizzuto R, Pinton P, D’Agostino D M, Ciminale
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Brunello A, Kapoor R, Extermann M. Hyperglycemia During
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Buja A, Perissinotto E, Compostella A, Tramarin A, Rebba V, Pastorelli
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Burra P, Germani G, Masier A, De Martin E, Gambato M, Salonia
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Caumo F, Vecchiato F, Strabbioli M, Zorzi M, Baracco S, Ciatto S.
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33 Cecchin D, Schiavi F, Fanti S, Favero M, Manara R, Fassina A, Briani
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34 Cecchin E, Agostini M, Pucciarelli S, De Paoli A, Canzonieri V, Sigon
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35 Centonze M, Visconti D, Doratiotto S, Silverio R, Fileni A, Pescarini L,
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36 Ceolotto G, Papparella I, Bortoluzzi A, Strapazzon G, Ragazzo F,
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37 Cillo U, Vitale A, Volk M L, Frigo A C, Grigoletto F, Brolese A, Zanus
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38 Corradin M T, Forcione M, Fiorentino R, Bordignon M, Alaibac M,
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39 Crescenzi M, Persano L, Esposito G, Zulato E, Borsi L, Balza,E.;Ruol
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40 Crocetti E, Buzzoni C, AIRTUM WG [as collab. Zambon P].
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Cucchetti A, Vitale A, Gaudio M D, Ravaioli M, Ercolani G, Cescon
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Dal Maso L, Lise M, Zambon P, Falcini F, Crocetti E, Serraino D,
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Dalla Palma M, Lombardi G, Donach M, Borgato Lucia, Zustovich F,
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Dall’Olmo L, Moja L. Treatment for non-dysplastic Barrett’s
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De Leone A, Tonini M, Dominici P, Grossi E, Pace F, EMERGE
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De Martin E, Senzolo M, Gambato M, Germani G, Vitale A,
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De Palma A, Roveri A, Zaccarin M, Benazzi L, Daminelli S,
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De Rossi A, Zanchetta M, Vitone F, Antonelli G, Bagnarelli P,
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61 Fassan M, Cagol M, Pennelli G, Rizzetto C, Giacomelli L, Battaglia
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62 Fassan M, Pizzi M, Battaglia G, Giacomelli L, Parente P, Bocus P,
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63 Fassan M, Rea F, Clemente R, Rizzardi G, Pizzi M, Giacomelli L, Rugge
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64 Fassan M, Volinia S, Palatini J, Pizzi M, Baffa R, De Bernard M,
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65 Fassina A, Cappellesso R, Schiavi F, Fassan M. Concurrent
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66 Fernandez A, Mesa C, Marigo I, Dolcetti L, Clavell M, Oliver L,
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67 Ferrari A, Miceli R, Rey A, Oberlin O, Orbach D, Brennan B, Mariani
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68 Ferretti A, Simonato F, Zandonà R, Reccanello S, Fabbris R.
Commissioning Siemens Virtual Wedges in the Oncentra
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69 Fogar P, Navaglia F, Basso D, Zambon C-F, Moserle L, Indraccolo
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Di Camillo B, Sanavia T, Iori E, Bronte V, Roncaglia E, Maran A,
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104 Marulli G, Rea F, Nicotra S, Favaretto A G, Perissinotto E, Chizzolini
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105 Massimino M, Gandola L, Barra S, Giangaspero F, Casali C, Potepan
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108 Mercadante S, Zagonel V, Breda E, Arcara C, Gebbia V, Porzio G,
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109 Merlo A, Turrini R, Bobisse S, Zamarchi R, Alaggio R, Dolcetti R,
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110 Merlo A, Turrini R, Dolcetti R, Martorelli D, Muraro E, Comoli P,
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114 Montagnese S, Biancardi A, Schiff S, Carraro P, Carlà V, Mannaioni G,
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115 Nacamulli D, Mian C, Petricca D, Lazzarotto F, Barollo S, Pozza D,
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117 Nicoletto M O, Parenti A, Del Bianco P, Lombardi G, Pedrini L, Pizzi
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119 O’Day S J, Maio M, Chiarion-Sileni V, Gajewski T F, Pehamberger
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120 Opocher G, Schiavi F. Genetics of pheochromocytomas and
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121 Pace F, Riegler G, De Leone A, Pace M, Cestari R, Dominici P, Grossi
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122 Paediatric European Network for Treatment of AIDS [as coord. De Rossi
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126 Pastrello C, Pin E, Marroni F, Bedin C, Fornasarig M, Tibiletti M,
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127 Pelizzo M R, Boschin I M, Barollo S, Pennelli G M, Toniato A,
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135 Pomerri F, Dodi G, Pintacuda G, Amadio L, Muzzio P C. Anal
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136 Pomerri F, Foletto M, Allegro G, Bernante P, Prevedello L, Muzzio P C.
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139 Quarta S, Vidalino L, Turato C, Ruvoletto M, Calabrese F, Valente
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144 Rea F, Marulli G, Di Chiara F, Schiavon M, Perissinotto E, Breda C,
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145 Reni M, Pasetto L M, Passardi A, Milella M, Mambrini A, Cereda
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27 Castelblanco E, Gallel P, Ros S, Gatius S, Valls J, De-Cubas A A,
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28 Castoro C, Scarpa M, Cagol M, Ruol A, Cavallin F, Alfieri R,
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29 Caumo F, Brunelli S, Zorzi M, Baglio I, Ciatto S, Montemezzi S.
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30 Cavallari I, Rende F, D’Agostino D M, Ciminale V. Converging
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32 Chioda M, Peranzoni E, Desantis G, Papalini F, Falisi E, Samantha
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33 Ciccarino P, Rotilio A, Rossetto M, Manara R, Orvieto E, Berti
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34 Cipolletta S, Shams M, Tonello F, Pruneddu A. Caregivers of patients
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Cox D G, Simard J, Sinnett D, Hamdi Y, Soucy P, Ouimet M, Barjhoux
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S S, Borg A, Karlsson P, Stenmark Askmalm M, Barbany Bustinza G,
SWE-BRCA Collaborators, Nathanson K L, Domchek S M, Rebbeck
T R, Benitez J, Hamann U, Rookus M A, van den Ouweland A
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HEBON, EMBRACE, Peock S, Frost D, Evans D G, Eeles R, Izatt L,
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V, Gauthier-Villars M, Lasset C, Giraud S, Hardouin A, Berthet P,
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De Corti F, Bisogno G, Dall’Igna P, Ferrari A, Buffa P, de Paoli A,
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Franceschini L, Realdon S, Marcolongo M, Mirandola S, Bortoletto G,
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Frego M, Scarpa M, Lorenzo N, Iacobone M, Bianchera G. Dysplasia
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Freguja R, Gianesin K, Mosconi I, Zanchetta M, Carmona F, Rampon
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66 Jirillo A, Trentin C. Geriatric evaluation programs and elderly
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67 Kasic T, Colombo P, Soldani C, Wang C M, Miranda E, Roncalli M,
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68 Leali D, Alessi P, Coltrini D, Ronca R, Corsini M, Nardo G, Indraccolo S,
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69 Lionello M, Blandamura S, Loreggian L, Ottaviano G, Giacomelli
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A Pin1/Mutant p53 axis promotes aggressiveness in breast cancer.
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Gridelli C, Gallo C, Morabito A, Iaffaioli R V, Favaretto A G, Isa L,
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Gridelli C, Morgillo F, Favaretto A G, de Marinis F, Chella A, Cerea
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Iacobone M, Schiavi F, Bottussi M, Taschin E, Bobisse S, Fassina A,
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Lombardi G, Nicoletto M O, Gusella M, Fiduccia P, Dalla Palma M,
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Lombardi G, Zustovich F, Farina P, Puppa A D, Manara R, Cecchin D,
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Lorenzi L, Lonardi S, Petrilli G, Tanda F, Bella M, Laurino L, Rossi
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Loupakis F, Cremolini C, Salvatore L, Schirripa M, Lonardi S, Vaccaro
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Lumachi F, Norberto L, Zanella S, Marino F, Basso S M M, Basso U,
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126 Scarpa M, Grillo A, Scarpa M, Brun P, Castoro C, Pozza A, Cavallo D,
Faggian D, Ruffolo C, D’Incà R, Bardini R, Castagliuolo I, Angriman
I. Innate immune environment in ileal pouch mucosa: Α5 defensin
up-regulation as predictor of Chronic/Relapsing pouchitis. Journal
of Gastrointestinal Surgery; E-pub 2011
127 Serafin V, Persano L, Moserle L, Esposito G, Ghisi M, Curtarello M,
PUBLICATIONS
301
hepatocellular carcinoma: A multicentre, cohort study. The lancet
oncology; 12:7; 654-662; 2011
146 Zaninotto G, Parente P, Salvador R, Farinati F, Tieppo C, Passuello N,
Zanatta L, Fassan M, Cavallin F, Costantini M, Mescoli C, Battaglia
G, Ruol A, Ancona E, Rugge M. Long-term follow-up of Barrett’s
epithelium: Medical versus antireflux surgical therapy. Journal of
gastrointestinal surger: official journal of the Society for Surgery of the
Alimentary Tract; Journal of gastrointestinal surgery; E-pub 2011
147 Zappa M, Dardanoni G, Giorgi Rossi P, Grazzini G, Naldoni
C, Paci E, Pirola M E, Pizzuti R, Segnan N, Zorzi M, Federici A.
The diffusion of screening programmes in Italy, year 2009.
Epidemiologia e prevenzione; 35:5-6 Suppl 5; 3-7; 2011
148 Zattra E, Salmaso R, Tonin E, Alaibac M. Achromic superficial
spreading melanoma accidentally treated with imiquimod. Acta
Dermato-Venereologica; E-pub 2011
149 Zattra E, Zambello R, Marino F, Bordignon M, Alaibac M. Primary
cutaneous mantle cell lymphoma. Acta Dermato-Venereologica; 91:4;
474-475; 2011
150 Zorzi M, Baracco S, Fedato C, Grazzini G, Sassoli De’Bianchi P, Senore
C, Visioli C B, Cogo C. Screening for colorectal cancer in Italy, 2009
survey. Epidemiologia e prevenzione; 35:5-6 Suppl 5; 55-77; 2011
151 Zotti P, Del Bianco P, Serpentini S, Trevisanut P, Barba M C, Valentini
V, De Paoli A, Pucciarelli S. Validity and reliability of the MSKCC
bowel function instrument in a sample of italian rectal cancer
patients. European Journal of Surgical Oncology; 37:7; 589-596; 2011
152 Zustovich F, Lombardi G, Nicoletto M O, Pastorelli D. Secondline therapy for refractory renal-cell carcinoma. Critical reviews in
oncology/hematology; E-pub 2011
137 Trojniak M P, Palozzo A C, Mazurek M, Jirillo A. Sorafenib
in hepatocellular carcinoma - a post marketing evaluation.
Immunopharmacology and immunotoxicology; E-pub 2011
138 Turato C, Biasiolo A, Pengo P, Frecer V, Quarta S, Fasolato S, Ruvoletto
M, Beneduce L, Zuin J, Fassina G, Gatta A, Pontisso P. Increased
antiprotease activity of the SERPINB3 polymorphic variant SCCAPD. Experimental biology and medicine (Maywood, N.J.); 236:3;
281-290; 2011
139 Turato C, Buendia M A, Fabre M, Redon M J, Branchereau S, Quarta
S, Ruvoletto M, Perilongo G, Grotzer M A, Gatta A, Pontisso P.
Over-expression of SERPINB3 in hepatoblastoma: A possible
insight into the genesis of this tumour? European journal of cancer;
E-pub 2011
140 Turrini R, Merlo A, Dolcetti R, Zanovello P, Rosato A. Differential
down-modulation of HLA class I and II molecule expression on
human tumor cell lines upon in vivo transfer. Cancer immunology,
immunotherapy:CII; 60:11; 1639-1645; 2011
141 Vianello F, Mazzarotto R, Mian C, Lora O, Saladini G, Servodio O,
Basso M, Pennelli G, Pelizzo M R, Sotti G. Clinical outcome of lowrisk differentiated thyroid cancer patients after radioiodine remnant
ablation and recombinant human thyroid-stimulating hormone
preparation. Clinical oncology (RCR:UK); E-pub 2011
142 Vianello F, Mazzarotto R, Taccaliti A, Lora O, Basso M, Servodio O,
Mian C, Sotti G. Follicular thyroid carcinoma with metastases to the
pituitary causing pituitary insufficiency. Thyroid: official journal of
the American Thyroid Association; 21:8; 921-5; 2011
143 Vitale A, Morales Ramirez R I, dalla Bona E, Scopelliti M, Zanus
G, Neri D, d’Amico F, Gringeri E, Russo F, Burra P, Angeli P, Cillo
U. Donor-model for end-stage liver disease and donor-recipient
matching in liver transplantation. Transplantation proceedings; 43:4;
974-976; 2011
144 Vitale A, Navaglia F, Morales R R, Frigo A, Basso D, D’Amico F, Zanus
G, Bonsignore P, Farinati F, Burra P, Senzolo M, Grigoletto F, Plebani
M, Cillo U. Molecular refinement of clinical staging in hepatocellular
carcinoma patients evaluated for potentially curative therapies. Plos
One; 6:9; e23093; 2011
145 Vitale A, Ramirez Morales R I, Zanus G, Farinati F, Burra P, Angeli P,
Frigo A C, Del Poggio P, Rapaccini G, Di Nolfo M A, Benvegnu L, Zoli
M, Borzio F, Giannini E G, Caturelli E, Chiaramonte M, Trevisani F,
Cillo U, on behalf of the Italian Liver Cancer group. Barcelona clinic
liver cancer staging and transplant survival benefit for patients with
PUBLICATIONS
302
1 Boscolo-Berto R, Raduazzo D I, Vezzaro R, Marino D, Aversa Savina
M L, Gardiman M. Aggressive non-Hodgkin’s lymphoma mimicking
unilateral transitional cell carcinoma of renal pelvis. The risk of making
a diagnostic mistake. Archivio Italiano di Urologia, Andrologia 83: 3;
163-165; 2011
2 Evangelista L, Baretta Z, Vinante L, Sotti G. What are the Best Ways to
Reduce the False-positive Rate of 18F-FDG PET/CT in Patients with
Breast Cancer? Nuclear Medicine and Molecular Imaging 45:1; 85-86; 2011
3 Evangelista L, Sorgato N, Torresan F, Boschin I M, Pennelli G, Saladini
G, Piotto A, Rubello D, Pelizzo M R. FDG-PET/CT and parathyroid
carcinoma: Review of literature and illustrative case series.World journal
of clinical oncology 2:10; 348-354; 2011
4 Kaasa S, Apolone G, Klepstad P, Loge J H, Hjermstad M J, Corli O, Strasser
F, Heiskanen T, Costantini M, Zagonel V, Groenvold M, Fainsinger R,
Jensen M P, Farrar J T, McQuay H, Rothrock N E, Cleary J, Deguines
C, Caraceni A. Expert conference on cancer pain assessment and
classification: the need for international consensus: working proposals
on international standards.BMJ Supportive & Palliative Care 1: 3; 281287; 2011
5 Opocher G, Schiavi F. Functional consequences of succinate
dehydrogenase mutations. Endocrine Practice; 17 Suppl 3; 64-71; 2011
6 Palozzo A C, Di Turi R. Pharmacoeconomic analysis of use of enteral
nutrition in different clinical settings. Part 1: use of an antiinflammatory
feeding formula in critically ill patients with acute lung injury/acute
respiratory distress syndrome (ALI/ARDS). Nutritional Therapy &
Metabolism; 29:2; 81-87; 2011
7 Palozzo A C, Di Turi P. Pharmacoeconomic analysis of use of enteral
nutrition in different clinical settings. Part 2: use of supplemental
feeding in elderly long-term hospitalized patients. Nutritional Therapy
& Metabolism; 29:3; 119-123; 2011
8 Pegoraro R, Bernardi A, Turoldo F. Biobanks and Tissue Research
the Public, the Patient and the Regulation: “Legal and Ethical Aspects of
Biobanks for Research in the European-Mediterranean Area”. International
Library of Ethics, Law and Technology; 8:3; 185-200; 2011
9 Pellicano R, Bocus P, De Angelis C. Adolf Kussmaul, the sword eater and
modern challenges of digestive endoscopy. Minerva gastroenterologica e
dietologica; 57:2; 109-110; 2011
10 Rastrelli M, Soteldo J, Vitali G C, Mazzarol G, Trifiro G, Tosti G, Testori A.
Aggressive digital papillary adenocarcinoma. Indian Journal of Cancer;
48:1; 126-127; 2011
11 Spolverato G, Pucciarelli S, Bertorelle R, De Rossi A, Nitti D.
Predictive Factors of the Response of Rectal Cancer to Neoadjuvant.
Radiochemotherapy Cancers; 3:2; 2176-2194; 2011
12 Stramare R, Scattolin G, Beltrame V, Gerardi M, Sommavilla M, Gatto C,
Mosca P, Rubaltelli L, Rossi C R, Saccavini C. Structured reporting using
a shared indexed multilingual radiology lexicon. International journal of
computer assisted radiology and surgery. E-pub 2011
13 Zustovich F, Lombardi G, Pastorelli D, Farina P, Dal Bianco M, De Zorzi
L, Dalla Palma M, Nicoletto M O, Zagonel V. Clinical experience and
critical evaluation of the role of sorafenib in renal cell carcinoma. Open
Access Journal of Urology; 3:1; 69-82; 2011
PUBLICATIONS
303
Index
Index
305
Index of Names
A
Alaibac Mauro 46, 69
Alfieri Rita 58-59
Aversa Savina M L 47
224, 227
Ciccarese Angelo 83
Ciminale Vincenzo 129, 144, 221
Corti Luigi 46, 58, 109, 227, 233
B
Baldan Enrica 90, 96-97
Banzato Alberto 168-169, 171, 251
Baracco Maddalena 179
Basso Umberto 35, 41, 43, 223, 227-228
Battaglia Giorgio 61, 76-77, 80, 198, 221,
223-225, 228, 250, 253
Berti Franco 108-109
Bertorelle Roberta 128-130, 149, 224-225
Bezzon Elisabetta 90-91, 96-97, 225
Bianchi Alessandra 169
Bocus Paolo 76-77, 80
Bonaldi Laura 129, 152, 224-225
Boso Caterina 109
Bovo Emanuela 178-179
Bozza Fernando 64-65, 67, 96, 202, 251, 253
Bronte Vincenzo 46, 129-130, 199, 231
Buzzaccarini Maria Samaritana 109
D
Dal Bosco Chiara 91, 97
Dal Cin Antonella 179
D’Agostino Donna M. 129, 144
D’Andrea Emma 30, 129, 133
Del Bianco Paola 18, 64, 90, 128, 202-203,
233
Del Mistro Anna Rosa 128-130, 137, 198, 219,
221
De Rossi Anita 128-130, 140, 219, 221, 223,
253
De Salvo Gian Luca 18, 46, 64, 202-203, 227
Di Maggio Antonio 90-91, 172
C
Cagol Matteo 58-59, 76, 221
Calabrò Maria Luisa 129, 141, 221
Canonico Davide 121, 124
Capovilla Eleonora 86, 172-173, 175, 233234, 250-251, 253
Cappellato Sandra 83
Castoro Carlo 58-59, 61, 76, 199, 219, 221,
224, 233, 253
Celentano Connie 83
Ceravolo Renato 35
Cervino Anna Rita 64, 109, 116, 223, 234
Chiarion-Sileni Vanna 46-47, 51-52, 147, 202,
INDEX
306
E
Esposito Giovanni 129
Evangelista Laura 64, 109, 116, 223-225, 228
F
Facchinetti Antonella 129
Falci Cristina 34, 47, 224, 233
Faoro Sonia 163, 165, 234
Favaretto Adolfo Gino 47, 51, 54, 224, 227-228,
253, 259
Fiore Anna Rita 178-179
Fiore Davide 91, 256
Friso Maria Luisa 109
G
Gennaro Gisella Maria 90-91, 96-97, 100-101,
223-224
Ghiotto Cristina 47, 64, 96, 219, 224, 227-228
Granziera Elisa 83, 86-87
Gregianin Michele 64, 109, 116, 223-224,
250
Grigoletto Raffaello 64, 67
Guzzinati Stefano 178-179
I
Indraccolo Stefano 128-129, 148, 198, 231,
250-251
J
Jirillo Antonio 54-55, 219, 228-229, 233,
251, 253
K
Koussis Haralabos 47, 227-228, 233
L
Lonardi Sara 34-35, 39, 223, 227-228
Lora Ornella 108-109
Loreggian Lucio 109
M
Mandruzzato Susanna 46, 128-129, 147, 231
Manfredi Valentina 83
Menin Chiara 30, 129, 134, 221, 253
Meroni Muzio 82-83
Minuzzo Sonia 128-129
Monetti Daniele 179
Montagna Marco 30, 129-130, 133, 221
N
Nardin Margherita 90-91, 172
Nicoletto M. Ornella 35, 64, 90, 172,
228-229, 234
O
Opocher Giuseppe 30, 154-156, 158-159,
199, 221, 250-251, 253
P
Paganelli Francesco 163, 233-234
Paiusco Marta 120-121, 124
Palozzo Angelo Claudio 54, 162-166, 199,
227, 233-234, 236
Pastorelli Davide 34, 39, 47, 64, 250-251
Pescarini Luigi 64, 90, 96-97, 99, 219,
223-224
Pintacuda Giovanna 90-91, 172
Polico Ilaria 90, 96-97
Polverosi Roberta 90-91, 225, 253
Pomerri Fabio 90-91, 93, 224
Proietti Alessandro 90, 96-97
R
Realdon Stefano 76-77, 80
Reccanello Sonia 120-121, 123-124, 227, 229
Riccardi Lucia 121
Rosano Alberto 179
Rosato Antonio 128-129, 151, 193, 231, 254,
259
Rossi Carlo Riccardo 46, 68-69, 147, 202,
219, 223, 227, 250-251, 253
S
Saggioro Daniela 129, 221, 224, 224
Saladini Giorgio 64, 108-109, 223
Scarpa Marco 58-59, 62, 76, 221
Scarzello Giovanni 108-109, 227-229
Shams Malihe 90, 172-173
Simonato Franca 120-121, 123-124, 228,
254
Sommariva Antonio 69
Sotti Guido 108-109, 116, 223, 228-229,
236, 251, 253-254
Stocco Carmen Fiorella 179
T
Tognazzo Sandro 179
V
Vecchiato Antonella 46, 68-69, 202
Vianello Federica 109, 223
INDEX
307
Z
Zagonel Vittorina 34-35, 39, 43, 227-228,
233, 248, 252-254
Zamarchi Rita 129, 145, 223-224
Zambon Paola 178-179, 219
Zandonà Roberto 120-121, 123-124
Zanchetta Marisa 129
Zanovello Paola 46, 128-129, 147, 231,
250-251, 255
Zorzi Manuel 128, 178-179
Zovato Stefania 34, 64, 155, 234
Zustovich Fable 34-35, 43, 227
Analytical Index
A
Acute Lymphoblastic Leukemia 148-149, 257,
259
ALL See Acute Lymphoblastic Leukemia
Angiogenesis 39-41, 73, 148, 199-200, 257258
Apoptosis 50, 73, 141-, 144, 146-149
Erlotinib 164-165, 233, 241
Esophageal Cancer 48, 58, 60-62, 76, 80, 117,
142-144, 200, 206
B
Barrett’s esophagus 76, 78, 79-81, 141
Biostatistics 3, 191, 202
Bone Marrow 49, 51, 108, 112, 145, 147, 152
Boron Neutron Capture Therapy (BNCT) 114,
116, 118, 228
Brachytherapy 111, 114, 122
BRCA 30, 131, 133-134, 199, 210, 221,
228-229
Breast Cancer 36, 38, 43, 45, 48, 51, 56, 64,
66-67, 86, 96, 98-101, 116, 118, 130, 133134, 146-148, 156, 165, 180-182, 202, 205,
213, 222, 228, 237-238
G
Gastro Intestinal Stromal Tumors 36, 49, 74,
149-151, 224, 227, 234
Gefitinib 210, 212
Gene Therapy 141, 192, 200, 255, 259
Geriatric Oncology 4, 45, 232
GIST. See Gastro Intestinal Stromal Tumors
F
FISH 51, 74, 130, 152-153, 212, 224-225,
241
C
Cancerogenesis 3, 60-61, 73, 178, 220, 255
Chromosomes 142
Chronic Lymphocytic Leukemia 140, 152, 153
CLL. See Chronic Lymphocytic Leukemia
Cytogenetics 152, 153, 192
H
HHV-8 132, 199, 210
HIV 128, 132, 199-200, 220, 258
HPV 128, 131, 132, 137-138, 178, 180, 199,
210, 219-221, 250
h-TERT 39, 45, 140-141, 200
HTLV-1 128, 144, 199, 220-221, 258
Human Herpes Virus 8. See HHV-8
Human Immunodeficiency Virus. See HIV
Human Papilloma Virus. See HPV
Human T-Lymphotropic Virus
Type I. See HTLV-1
E
EBV. See Epstein-Barr Virus
EGFR 51, 131, 210, 212, 224, 241
Elderly patients. See Geriatric Oncology
Endoscopy 3, 38, 61, 76, 78, 79, 85, 198
Epidemiology 3, 178, 202, 218
Epstein-Barr Virus 131-132, 199-200, 210,
220-221, 231
I
IL4R 46
Imaging 3, 29, 52, 64, 66, 74, 78, 80, 89-90,
92-93, 96, 98-101, 116-118, 120, 122, 148,
151-152, 192, 221, 223, 225, 234, 256, 259
Imatinib 151, 227, 239
Immunology 3, 4, 29, 38, 42, 45, 61, 71, 128,
130, 132-133, 192, 204, 230, 255
INDEX
308
Immunotherapy 130, 133, 151, 200, 211, 240,
258
125
Iodine 114
K
KIT 149, 150-151, 224
L
Lung tumors 29, 51, 164-165, 210, 212, 224,
228, 241, 253
Lymphadenectomy 67, 205
Lymphoma 48-49, 116-117, 141, 144, 199,
240, 243
M
Mammography 90, 96, 98-102
Melanoma 3, 29-30, 46, 48-49, 52, 68, 70-75,
85, 94, 111, 114, 130-132, 134-137, 147, 151,
174, 200, 202, 204-205, 213, 215, 205, 221,
223-224, 240, 251, 253
Monoclonal antibodies 80, 152, 211, 226, 230
Mutation 43, 113, 134-136, 185-159, 182,
214
N
Neo-adjuvant 40, 80, 181, 238-239
NSCLC. See Lung tumors
P
Paraganglioma 113, 154, 156-159, 221
PDGFRA 149-151, 224
Pediatric tumors 113, 202, 205, 243
Perfusion 46, 68, 71, 75, 94, 111
PET 48, 64, 75, 93, 113, 116-117, 120, 152,
223-225, 228, 250
Prevention 3, 118, 218
R
Registry 3, 76, 79, 104, 164-165, 178, 180182, 192, 246
RET 159, 160
Retrovirus 130, 219, 221, 258
S
Sarcoma 29, 38, 68, 70-75, 85, 90, 94, 117,
132, 178, 199, 202, 204-205, 220, 223, 242243
SCID mice 141, 148, 257
Screening 92, 99-101, 104, 128, 130, 137-139,
142, 145, 159, 178, 180, 198, 218, 227, 243,
246, 250, 251, 250-252
Sentinel Lymphnode 72
Sunitinib 42-43, 146-147, 223, 227-228, 239,
242
T
Telomerase. See h-TERT
Thyroid tumors 29
Tomosynthesis 90, 96, 99, 101-103
Tumor antigens 211
V
VEGF 39, 40, 43, 223, 239, 258
VHL. See Von Hippel Lindau Syndrome
Von Hippel Lindau Syndrome 42, 154, 159,
184
Vulnerability. See Geriatric Oncology
Q
Quality of Life 4, 28, 36, 43,45, 52, 60-62, 7475, 76, 80, 82, 87, 115, 165, 172, 175, 177,
188, 202, 205-206, 210, 232, 239, 242-243
INDEX
309
Colophon
Title:
Scientific Report 2010-2011
Publisher:
Istituto Oncologico Veneto
I.R.C.C.S.
Year / Month:
2012, April
Editorial committee:
Alberto Amadori
Elisabetta Mutto Accordi
Gian Luca De Salvo
Photographer:
Maurizio Peci
Graphic:
Pallino & Co.
Typographer:
La Grafica Faggian
Paper:
Gardamat Art 135gr
April 2012

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