Untitled - Istituto Nazionale dei Tumori

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SCIENTIFIC REPORT 2013
CONTENTS
Introduction 5
Scientific Directorate 8
Ethics Committee
13
Education and Training
14
Clinical Activity Data
22
CLINICAL-SCIENTIFIC DEPARTMENTS
Surgery Department
27
Medical Oncology Department
32
Hematology and Pediatric Onco-Hematology Department
35
Anesthesia, Intensive Care, Pain Therapy, and Palliative Care Department
38
Diagnostic Imaging and Radiotherapy Department
41
Pathology and Laboratory Medicine Department
45
Experimental Oncology and Molecular Medicine Department
47
Preventive and Predictive Medicine Department
53
SHARED RESEARCH RESOURCES
59
RESEARCH ACTIVITY
PREVENTIVE AND PREDICTIVE MEDICINE 65
Prospective observational studies on diet, lifestyle, endocrine/metabolic and genetic factors and cancer risk
66
Rare tumors: creation of an information network and epidemiological surveillance system
68
Clinical interpretation of cancer survival differences in Italy and Europe
70
Study of the molecular determinants of the genetic predisposition to familial-hereditary cancers
72
MOLECULAR CARACTERIZATION OF TUMOR PROGRESSION 75
Involvement of microRNAs in the principal pathways of breast cancer: from biology
to possible therapeutic applications 76
Analysis of circulating markers for monitoring disease progression and treatment response in breast cancer
78
Detection and validation of new genetic/ genomic and metabolic markers of prognosis
or prediction of treatment response and/or early relapse in ovarian cancer
80
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Thyroid cancer: functional studies for the detection of new molecular mechanisms and therapeutic targets
83
Extracellular matrix protein SPARC regulates primary and secondary lymphoid organs homeostasis
and the transition of myeloproliferative or autoimmune spurs toward leukemia and lymphoma
85
INNOVATIVE PROBLEM-ORIENTED APPROACHES TO DIAGNOSIS AND TREATMENT 87
Stroma-derived biomarkers with prognostic value in subjects with polygenic or monogenic inheritance
predisposing to cancer
88
Development of a platform for the pre-clinical evaluation of new anti-tumor drugs and therapeutic combinations
90
Study of immunosuppression mechanisms in patients with solid tumors and their influence
on prognosis and response to drug treatment and immunotherapy
92
Establishing drug and transplant approaches for effective treatment of hematological malignancies
95
Translational project for the development of drugs for personalized cancer treatment 97
MULTIDISCIPLINARY DISEASE-ORIENTED APPROACH 99
Prostate Cancer Program
100
New methodological approaches to the study and personalized treatment of rare tumors and adult sarcomas
102
Biomolecular characterization of rare histological types of ovarian carcinoma and implications
for medical treatment of disease
104
Early diagnosis of lung carcinoma and efficacy of plasma miRNAs as first-line tests
106
PEDIATRIC CANCER 108
Tumors of the central nervous system 109
Adolescents with cancer in Italy: from local projects to a National coordinated program 111
Genetic and biomolecular characterization of Wilms tumor and detection of predictive markers
of poor prognosis
113
New drugs in pediatric oncology 115
PATHWAYS OF RESEARCH/INTERVENTION AND ASSESSMENT OF QUALITY
OF LIFE IN PATIENTS WITH CANCER 118
Assessment and management of symptoms and quality of life in cancer patients receiving palliative care 119
Research and training for the physical, emotional, social, and spiritual support of patients
on active cancer treatment and their caregivers
121
Development of algorithms for nutritional therapy in diseases at high risk of malnutrition 123
PUBLICATIONS125
ONGOING PROJECTS SUPPORTED BY EXTERNAL ORGANIZATIONS
179
ONGOING CLINICAL STUDIES
185
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introduction
SCIENTIFIC DIRECTOR
Marco A. Pierotti
INTRODUCTION
In 2013, the 85th year since the Istituto Nazionale dei Tumori (INT) started its activities, we
felt obliged to offer those who frequent its premises in Via Venezian 1 the opportunity to
learn, or remember, its history. The memorial wall in the entrance hall of the INT is a fitting
tribute to the extraordinary doctors and scientists who have made this institution what it is
today, and who, through their commitment and competence, have allowed Italian oncology
to make an important contribution to the advancement of this science worldwide.
This was also the year of another anniversary: we have celebrated that 40 years ago the
first Italian ethics committee was established at this very Institute. The conference “The
Ethics Committee: Past and Future” was well received, also thanks to the participation of
the illustrious researchers, above all Gianni Bonadonna, who first brought clinical trials to
Italy.
The recollection of our history was not intended as a nostalgic reminder of a brighter past,
but rather as the recognition of the origins of a success story that continues today, as the
contents of this Scientific Report clearly show.
The INT has always been one of the most influential Italian entities in the fight against
cancer, and our efforts to improve the efficiency of our work at all levels (clinical, scientific
and organizational) prompted us to enter the rigorous accreditation procedure of the
Organization of European Cancer Institutes. Even though we still have a long assessment
ahead of us, the Institute has obtained the preliminary designation of Comprehensive
Cancer Center (CCC), a qualification that, when confirmed at the end of the accreditation
procedure, INT will share with world-renowned European institutions such as the
Karolinska Institute of Stockholm and the French Institut Gustave Roussy.
The nature of a CCC is that of a complex organization aimed at the efficient collaboration of
a wide range of specialized professionals, including those who make it possible to carry out
clinical and research activities with the increasingly indispensable technological support
this entails. This year the Istituto Nazionale dei Tumori of Milan won the innovation award
of the ICT Observatory of Health Care of Milan Polytechnic’s School of Management for
the project “Clinical Analytics for Oncology Care Appropriateness”, a computer system
developed in collaboration with IBM. This innovative technological solution offers doctors
a decision-making aid to establish the best treatment for each patient according to the
clinical picture. The system is currently used by clinicians in the medical treatment of adult
sarcomas and tumors of the head and neck, but studies are ongoing for its extension to
other departments of the Institute and other centers of the Lombardy Oncology Network
(Rete Oncologica Lombarda, ROL).
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ROL has completed the third phase of the project this year, and INT has acted as an
implementing agency recognized by the Lombardy Region. This phase included the creation
of a multidisciplinary clinical and research community engaged in the steady production
of guidelines to be shared with regional oncologists. In the meantime the scientific
collaboration with Nerviano Medical Sciences has continued under the supervision of the
Regional Foundation for Biomedical Research. A new collaborative model within ROL that
allows the public and private sectors to interact fruitfully in research facilitation has been
tested with success. Preparations are under way for the creation of an oncology network
aimed at promoting clinical research in multicenter studies, developing personalized
medicine in oncology (through the integrated FRBR platform), and establishing a virtual
research biobank in Lombardy.
INT also contributes in important ways to the knowledge of the numbers that define the
cancer problem, providing health policy decision-makers with useful insights. Examples are
a study published in 2013 on the correlation between the investment in health care among
European countries, the type of health care system in those countries and cancer survival,
and the paper that INT researchers published in the prestigious journal The Lancet,
establishing a causal relationship between particulate matter and certain types of cancer.
Various news items last year have pushed the professionals of the Institute to take a stand
on issues that were the subject of debate – not always well-informed – in the media. For
example, we have responded to the enormous public interest in the fad of the electronic
cigarette with a study (currently in press) on the impact of toxic particles emitted by
electronic cigarettes compared to those present in tobacco smoke.
When the personal choice of a famous actress sparked a lively debate about possible
“extreme” prevention strategies against the risks associated with an inherited
predisposition to certain types of cancer, the Institute could intervene with the knowledge
and experience accumulated over the years thanks to the medical genetics service, which
since 1995 has been identifying and guiding persons who are genetically predisposed to
developing cancers of the breast and ovary. In the context of this service more than 3850
families, for a total of more than 7900 individuals, have been screened, and more than
5300 instances of genetic counseling have been provided (the largest number nationally –
about a third of the total). Based on this extensive experience we were able to articulate a
scientific opinion on this matter, and in a forthcoming publication we make it clear there are
no standard choices that are by definition “better” than others, and the most appropriate
solution is to let every single person decide, as long as they are thoroughly informed.
Over the past years it has become evident that international collaboration is indispensable
for cancer research, which is more and more directed towards exploiting the key scientific
acquirement of our century by pursuing cancer genome projects that identify the
sequences and mutations crucial for the onset and development of cancer. Our Institute
is involved in many global initiatives to explore and experiment with new models of
collaboration through concrete research projects. We are very pleased to announce that
one of the projects approved by the Scientific Advisory Board of the Worldwide Innovative
Networking in personalized cancer medicine (WIN Consortium) has as its principal
investigator a clinical researcher of the Institute, Andrea Necchi.
Lastly, it is worth mentioning that through an internal competition titled “Molecular
Signatures for Diagnosis, Prognosis and Targeted Therapies” the Scientific Directorate,
based on the judgment of an Expert Committee, has financed 15 of the 20 groups that
submitted a project. All groups are multidisciplinary, with projects addressing unsolved
issues of major impact on clinical decision-making and with great prognostic and predictive
significance. The 15 selected projects cover many cancer types and a wide range of issues.
Each is coordinated by a group leader and encompasses different departments of the
Institute.
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introduction
At the time of writing, the crude impact factor (IF) in 2013 had reached a value of 2761.98
for a total of 550 scientific papers published, amounting to an average IF of 4.99. This
means that this year we have again surpassed the already considerable IF of previous years.
Research owes its significance to the clinic, and where there’s good research there will
be clinical excellence; but neither is possible without an effective administration. The
practical implementation of this ideal presents extraordinary complexities that can only
be addressed with a great sense of collaboration: the unity of purpose of the Scientific
Directorate, the Presidency, the General Directorate and the Administration and their
constant interaction have been crucial to the Institute’s achievements.
As in previous years, this Scientific Report offers the most complete documentation of the
many projects designed and conducted at INT Milan.
Marco A. Pierotti
Impact Factor and published papers
2519.29
Impact Factor
2250
2272.32 2274.62
2761.98
2353.98
Published Papers
1559.97
1686.65
1503.55
1349.13 1390.49
1215.17
1188.21
275
287
320
309
293
366
338
415
465
426
450
518
550
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
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SCIENTIFIC
DIRECTORATE
SCIENTIFIC DIRECTOR
Marco A. Pierotti, PhD
+39 02 2390 2300
marco.pierotti@istitutotumori.mi.it
The responsibilities of the Scientific Directorate traditionally include:
• coordination of research and education activities, planning of scientific policy, and
evaluation of scientific projects (Committee of the Scientific Directorate);
• management of institutional relationships with key health authorities at a regional
and national level; support to researchers seeking public and private funding (Grant
Office);
• giving access to information resources in support of ongoing research programs
(Biomedical Library);
• enhancement of communication and collaboration among all cancer-related
institutions in Lombardy (Lombardy Oncologic Network);
• supervision of the Institute’s scientific communication in agreement with the President
of the INT Foundation;
• management of the Clinical Trial Center, a core office to support clinical studies,
especially investigator driven and Phase I and II studies, with the aim of bringing
research results and new treatments to the bedside in the shortest time (see page 61);
Working in tight cooperation with the Technology Transfer Office (TTO), the Scientific
Directorate also facilitates transfer of inventions and knowledge from INT labs to the
public.
Each year the Scientific Directorate organizes a Research Day: the 2013 edition was
held on June 14th at INT. The meeting offers an opportunity to look back to the scientific
accomplishments achieved during the year, and to look forward to future research.
Staff Members
Tiziana Camerini, Maths D; Aurora Costa, Biol Sci D; Cecilia Melani,
MD, PhD
Secretariat
Laura Ballariano Rossi; Eleonora De Palo, MA Mod Lang; Lucia De
Zorzi; Antonio Florita, B Litt
International Relations and Linguistic Consultant
Daniela Majerna, MA Phil
Grant Office
Valeria Anselmi, MA Lett; Marco Asioli; Costanza Bono, MA Pol
Sc; Sabrina Braghieri, MA Mod Lang; Claudia Casoli; Stefania
Didonè;Isabella Russo, MA Econ
Lombardy Oncology Network (ROL)
Rosaria Bufalino; Marco Tricomi, MS Eng
Biomedical Library
Rossella Ballarini; Marina Calderisi
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Editorial Office
Rosaria Parentela
Tumori - Editorial Assistant
Elena Morittu
Clinical Trial Center
Data Manager: Valentina Sinno, BSc (coordinator); Anisa Bermema,
BSc; Liana Bevilacqua, BSc; Ilaria Bossi, BSc; Federica Brunero, BSc;
Laura Concas, BSc; Debora Deglinnocenti, Biol Sci D ;
Federica Favales, BSc; Rosaria Gallucci, BSc ; Elisa Grassi, BSc;
Rosanna Montone, BSc; Paola Pistillo, BSc; Iolanda Pulice, BSc;
Dominique Ronzulli, BSc; Silvia Sesana, BSc;
Eleonora Sparacio, BSc; Irene Vetrano, BSc
Statisticians: Luigi Mariani, MD (coordinator);
Monica Pacifici, Stat D
Scientific and Administrative Secretariat: Paola V. Consonni
Research Nurses: Benedetta Bardazza; Alessandra Castano; Ilaria
Lo Russo; Giulia Saba; Serena Scrudato; Edoardo Tulli Baldoin
Pharmacovigilance: Elena Togliardi, Pharm D
scientific directorate
COMMITTEE OF THE SCIENTIFIC DIRECTORATE
Marco A. Pierotti, Scientific Director
Emilio Bombardieri, Director Diagnostic Imaging and Radiotherapy Department (until August 31)
Paolo Corradini, Deputy Scientific Director, Director Hematology and Pediatric Onco-Hematology
Department
Vito Corrao, Chief Medical Officer
Maria Grazia Daidone, Director Experimental Oncology and Molecular Medicine Department
Filippo de Braud, Director Medical Oncology Department
Alessandro M. Gianni, Deputy Scientific Director
Martin Langer, Anesthesia, Intensive Care, Pain Therapy, and Palliative Care Department
Alfonso Marchianò, Director Diagnostic Imaging and Radiotherapy Department (since September 1st)
Vincenzo Mazzaferro, Deputy Scientific Director
Ugo Pastorino, Director Surgery Department
Giuseppe Pelosi, Director Pathology and Laboratory Medicine Department
Mario Santinami, Deputy Scientific Director
Gustavo Galmozzi, Medical Director
The Committee is the Institutional Reviewer Board and assists the Scientific Director
in defining the Strategic Scientific Program and the contents of correlated educational
activities. Its main objectives are:
• definition of research areas at INT
• approval of multidisciplinary research projects
• approval of the development of research projects at a scientific and administrative level
•evaluation of scientific quality and feasibility of newly-proposed clinical studies prior to
submission to the Independent Ethics Committee
• evaluation of educational programs for residents and non-residents.
In 2013, Emilio Bombardieri, for many years head of the Department of Diagnostic Imaging
and Radiotherapy and a member of the Committee, retired after a successful clinical and
scientific career. The Committee welcomed Alfonso Marchianò who was appointed as new
Director of the Diagnostic Imaging and Radiotherapy Department.
GRANT OFFICE
The Grant Office (GO) has the mission of supporting research activities within the INT,
facilitating access to external financing, both national and international, by looking for
relevant information in the appropriate media, making direct contact with public and
private funding agencies, and swiftly providing information to potentially interested
researchers.
Announcements regarding funding possibilities are constantly updated in the “Calls for
Application” section of the INT IntraNet website on the Scientific Directorate web page.
A section of the website is dedicated to the 7th Framework Program and a new section to
Horizon 2020 (the next EU research and innovation program).
It is the duty of the GO to help investigators in preparing and submitting grant applications,
promote collaborations among researchers at INT and in other public services, and help
them to collaborate on research projects.
At the Scientific Directorate office, databases are continuously updated according to
emerging needs. The database stores information regarding research projects and INT
publications to monitor scientific productivity.
The GO maintains contact with the officers in charge of research at the Ministry of Health
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and at the Health Management offices of the Lombardy Region. The activities of the
GO include management of ongoing Institutional Projects and design of calls aimed at
distributing the funding coming from the Italian 5‰ tax donation.
In 2013, the GO provided support for INT researchers in: 61 applications for public funding
(Ministero della Salute); 135 applications to private national funding agencies (Associazione
Italiana per la Ricerca sul Cancro, Fondazione Berlucchi, Fondazione Cariplo, Fondazione
Monzino, etc.) and 42 international funding bodies (American Institute for Cancer
Research, Chordoma Foundation, European Commission, Mesothelioma Applied Research
Foundation, Swiss Bridge, WIN Consortium, etc.).
LOMBARDY ONCOLOGIC NETWORK (ROL)
The Lombardy Cancer Network (ROL: “Rete Oncologica Lombarda”) provides a network
of organizations and professionals connecting all cancer resources in the region, with
over 10,000,000 citizens, in an effort to improve the quality of cancer care and sharing
patient data. INT has been the implementing body of the ROL and the Scientific Directorate
coordinates all activities since its start-up.
ROL is based on clinical cooperation, exchange of information, and sharing and integration
of existing cancer facilities. The main goal is the assessment of appropriateness of cancer
care on a population level to improve the quality of care by focusing on the cost/efficacy
ratio in order to reduce healthcare costs. ROL aims to organize clinical governance
resorting to an innovative, feasible, measurable model based on networking of services
and providing health benefits to the patient; 58 oncology units are included. ROL designed
evidence-based clinical practice guidelines for all solid tumors developed through a
consensus process among the oncology community to make a comprehensive impact
on clinical oncologic practice. A set of common clinical practice guidelines are annually
updated. For each solid cancer, guidelines list all main clinical presentations (“disease
phases”) along with their “treatment options”. ROL upgraded the existing non-structured
electronic clinical discharge report into a field-based resource, with both free-text and
codified fields. Two codified fields enlist, respectively, disease phases as per guidelines,
and the corresponding treatment options. If they match, the strategic medical decision is
considered tentatively “appropriate”.
In 2013, more than 61,000 reports were released. Started in 2012, a research project to
set up a system that is able to integrate and analyze all available clinical knowledge and
guidelines and correlate this with patient data is ongoing in collaboration with IBM-Italian
team and IBM Research-Haifa, Israel to detect causes of mistakes and mismatches by
automatically analyzing free-text fields. The system, in addition to the analysis of encoded
data, has provided key elements, automatically extracted from text, populating a knowledge
model on clinical decisions.
BIOMEDICAL LIBRARY
The INT Library is affiliated with the European Association for Health Information and
Libraries. It offers on-site access to a large collection of basic science paper journals and
reference books and electronic access to full text journals, bibliographic databases, and
electronic books. The mission of the INT Library, specialized in oncology, is to provide
access and management services aimed at meeting the needs of physicians, researchers,
and students for the efficient retrieval of information needed for best patient care,
advanced research, and postgraduate education.
Through participation to the SBBL and Bibliosan consortia, the Library’s electronic
resources give access to over 9000 titles. Bibliosan also has a “remote access” option
enabling Institute staff to access its services from external sites.
The library also offers access to specialized data banks of bibliographic references and
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scientific directorate
electronic documents such as Medline, Toxnet, Embase, Cochrane Database of Systematic
Review (specialized in EBM), Springer E-book, and Springer Images.
The international nursing literature is covered by CINAHL – The Cumulative Index to
Nursing and Allied Health Literature, with the full text for over 770 journals and 275 books/
monographs in this field.
The Library’s collection is supplemented by interlibrary loan services with access to the
following catalogues:
• GIDIF-RBM: a consortium of key Italian biomedical libraries
• SBBL: Biomedical Library System of Lombardy
• BIBLIOSAN: a network of 50 Italian Research Institutions sponsored by the Italian
Ministry of Health.
The library is also a member of ACNP, the National Archival Collection of Periodicals, and
is thus linked to over 2300 Libraries in Italy and over 110,000 journals and the Italian
framework Nilde (Network for Inter-Library Document Exchange).
Library customers can access RefWorks, which is a personal bibliographic management
software designed to help researchers gather, manage, and store information, as well as
generate citations and bibliographies. To disseminating information via the constantly
updated Intranet Library web page, various courses are held to help researchers gather
information more easily.
EDITORIAL BOARD OF TUMORI
In 2013, the Editorial Board of Tumori received 717 manuscripts for publication. In
the same year, 6 issues containing 183 reviews, original articles, and case reports were
published. For each issue, 5,000 copies were printed.
EDITORIAL OFFICE
The Editorial Office coordinates and manages all activities related to the production of
materials that describe the clinical and scientific activities of the INT. In addition, the
Editorial Office oversees the publication of the annual Scientific Report and Brochure, and
provides support to individual departments for preparation of more specific materials such
as brochures and meeting reports.
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AWARDS AND RECOGNITIONS
• The Comitato Ospedale Donna of the Osservatorio Nazionale sulla Salute della Donna (O.N.Da) awarded the
Fondazione IRCCS INT with three “Bollino Rosa” prizes for its care in the research and treatment of female
diseases and its attention to the specific needs of admitted women.
• The School of Management del Politecnico di Milano awarded the INT for innovation in health care. Recognition
given in the category “Clinical Governance and decision support” for the project “Clinical Analytics for Oncology
Care Appropriateness” computer system developed in collaboration with IBM. This is an innovative technology
solution that provides clinicians with decisional support to evaluate the best treatment for each patient according
to clinical reference. Starting from the clinical data provided by INT, a first prototype of a platform for data analysis
and decision support for clinicians was built. The system also allows retrospective analysis of the effectiveness
of treatment programs already carried out, and compare them with guidelines and decisions made in previous
similar cases. The future development of this system will allow associating the cost of processing in order to obtain
feedback on the appropriateness and sustainability of the care delivered.
• Dr. Egidio Riggio of the Plastic and Reconstructive Unit has named Editor in Chief of the Surgical Techiques
Development, a new scientific journal with eISSN 2038-9582. All contents published in this journal are considered
Open Access.
• Drs. Paolo Bossi and Lisa Licitra of the Head & Neck Cancer Medical Oncology Unit won the Swiss Bridge Award
2013 with the project: “Health and economic outcomes of two different follow-up strategies in effectively cured
advanced head and neck cancer”.
• Dr. Gemma Gatta, Head of the Evaluative Epidemiology Unit, was invited to participate in the selection for the
establishment of the European Union Expert Group on Rare Diseases.
• Dr. Gabriella Sozzi, Head of the Tumor Genomics Unit, became President Elect of the Italian Cancer Society (SIC).
• Dr. Elda Tagliabue, Head of the Molecular Targeting Unit, was named a member of the Scientific Board of the SIC.
• Dr. Carlo Sposito of the Gastrointestinal and Hepatopancreatobiliary Surgery and Liver Transplantation Unit was
conferred the “Giovani Ricercatori” award of the Fondazione IRCCS INT.
• Dr. Veronica Biassoni of the Pediatric Oncology Unit was conferred the “Giovani Ricercatori” award of the
Fondazione IRCCS INT.
• Dr. Elena Tassi of the Immunobiology of Human Tumors Unit was conferred the “Giovani Ricercatori” award of the
Fondazione IRCCS INT.
• Dr. Silvia M. Taverna of the Technology Transfer Office was conferred the “Management Support to Research”
award of the Fondazione IRCCS INT.
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ethics committee
ETHICS
COMMITTEE
The institutional Ethics Committee reviews all new clinical studies submitted by
investigators and approved by the Scientific Institutional Review Board. The Committee
was established in 1973. A public event held on March 18th 2013 marked its 40th
anniversary and was an opportunity to appreciate how some issues discussed as from first
meetings are still open to public debate.
In 2013, 179 new studies received an ethical approval: 96 were prospective interventional
trials, of which 50 were sponsored by pharmaceutical companies and 46 were investigatordriven, while 83 were observational. A total of 468 studies were ongoig in 2013, with a
total of 15,965 cases involved, including 2,343 patients enrolled in interventional trials.
The median time from submission to discussion was in the range of one month (28 days).
This was made possible through an optimized pathway for new study processing, which is
carried out in close cooperation with all other relevant institutional bodies (General and
Legal Affairs Unit, Economic and Financial Resource Management Unit, and the Pharmacy).
These tight institutional collaborations resulted in efficient streamlining of all scientific and
administrative components of the ethical review process.
In September 2013, the Ethics Committee was reshaped and some members substituted,
having already spent two terms. Updated national and regional rules on Ethics Committees
gave the new Ethics Committee the additional role to link the Ethics Committees of the 12
comprehensive cancer centers of Lombardia Region. Thus, activities were planned in order
to harmonize criteria by which they operate and to host public meetings on some of the
most critical aspects pertaining to clinical trials in contemporary oncology.
A project focusing on the information process of patients enrolled in clinical trials is in place
and will provide its first results in 2014. Its aim is to work out practical tools for patient
information in clinical trials, to be based on an analysis of ethical and legal requirements on
one side and clinical and psychological needs on the other.
Chairman
Valter Torri
Scientific Secretariat
Paolo G. Casali, Bianca M. Francucci
Members
Bruno Andreoni, Giuseppe Baiguini, Emilio Bombardieri,
Carlo Celentano, Emanuele Cereda, Vito Corrao,
Francesca Crippa Floriani, Emilio Di Genova, Momcilo Jankovic,
Roberto Labianca, Renato Mantovani, Monica R. Miozzo,
Eugenio Agostino Parati, Roberta E. Pavesi, Marco A. Pierotti,
Tullio Proserpio, Antonio G. Rampoldi, Gabriella Saibene,
Francesco Scaglione, Marta Scorsetti, Rita Vetere
Administratives
Michaela De Palo, Raffaella Didoné, Patrizia Polo
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EDUCATION
AND TRAINING
INT is strongly committed to educating future scientists and clinicians and is directly
engaged in quality education and training. INT offers a wide range of educational activities
for clinical and experimental researchers at different stages of their professional careers.
PhD studentships, postdoctoral research fellowships, graduate student training, medical
residency training, psychology, and social work training, as well as continuing medical
education are all included in the portfolio of educational opportunities offered to staff and
external participants.
Invited lectures, seminars and workshops in a variety of research disciplines related
to cancer are regularly arranged. Participants in education and training programs are
encouraged to attend interdepartmental journal clubs, clinical case discussions, and
grand rounds as well as other multidisciplinary activities aimed to create cross-specialty
knowledge.
ACADEMIC PROGRAMS
INT provides education and training at various levels, including undergraduate, graduate
as well as postgraduate medical and biotechnology students, physicians, nursing
students, and nurses. On the basis of formal agreements with the University of Milan,
INT hosts the Chairs of Medical Oncology (Prof Alessandro M. Gianni), Hematology
(Prof Paolo Corradini, Coordinator of the Experimental Hematology Doctoral Program
at the University of Milan), Medical Statistics and Biometry (Prof Adriano Decarli),
Anesthesiology (Prof Martin Langer), and Pathology (Prof Giuseppe Pelosi). A number of
staff members have joint appointments as professors at the University of Milan. INT hosts
the “Postgraduate School in Oncology”, the “Postgraduate Medical School in Pathology”,
and the 3-year degree in “Nursing Sciences” of the University of Milan. Additionally,
INT participates in the degree in “Biotechnology and Molecular Medicine in Oncology”,
as well as in two PhD programs at the University of Milan (Hematology and Medical
Biotechnology). Every year INT offers a range of highly specialized Master Courses.
DOCTORAL (PHD) TRAINING PROGRAM AT INT
The INT is an Affiliated Research Center of the Open University, Milton Keynes, UK,
providing a PhD Program in Life and Biomolecular Sciences. The program run at INT is
regularly monitored to ensure that it meets the requirements of the Quality Assurance
Agency (QAA) for Higher Education Code of Practice. INT provides direct support for
these training positions and offers fellowship/grants to European Community postgraduate
students holding a degree in Medicine, Biological Sciences or Pharmacy. Students are
involved in several activities, including induction courses, generic skills training, journal club
meetings, and seminars.
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education and training
OPEN UNIVERSITY PHD STUDENTS AND THEIR RESEARCH TOPICS
Mattia Boeri
Exploring the Role of microRNA in Early Lung Cancer
Alessandra Santangelo
SPARC, a Matricellular Protein that Protect Tumors from Therapy
Marianna Sasso
Biomarkers of Aggressive Phenotype in Triple Negative Breast Cancer
Alice Rigoni
Mast Cells at the Interface between External Challenges and Immune Regulation in Colitis and Colorectal
Cancer
Davide Bernareggi
Conversion of AFRA Fab into a Fully Human Monoclonal Antibody directed against a Folate Receptor:
in vitro and in vivo Studies
Daniele Lecis
Inhibitors of Apoptosis Proteins (IAPs) as Targets for Anti-Cancer Treatment
Ilaria Torselli
The Influence of Tumor Microenvironment on Osteosarcoma
Gaia Ghedini
Role of Δ16HER2 Splice Variant in Response to Drug Targeting HER2 Receptor
Sara Ciceri
Molecular Characterisation of Wilms Tumor
Alice Dassano
Expression Networks and Effectors of Genetic Susceptibility to Lung Cancer in Mice
Elvira D’Ippolito
The Role of microRNAs in Triple Negative Breast Cancer
Emanuela Fina
Biological and Clinical Significance of Circulating Tumor Cells in Breast Cancer
Olga Kuchuk
Interference of pH Regulators as an Immunomodulating Therapeutic Strategy for Liver Cancer
Emanuela Minna
miRNA Deregulation in Thyroid Carcinogenesis: in vitro Models to Study Molecular Mechanisms and
Functional Effects.
Valentina Profumo The Role of microRNAs in Triple Negative Breast Cancer
Andrea Tomirotti
Identification of Early Biomarkers of Neoplastic Transformation in Mouse Tumor Models of Breast and
Prostate Carcinogenesis
Emanuela Fina
Biological and Clinical Significance of Circulating Tumor Cells in Breast Cancer
Valeria Maiorana
Analysis of in vitro and in vivo Effects of Metformin Alone or in Combined Treatments in Colorectal
Cancer
Martina Magni
Functional Characterization of the Human Protein Deleted in Breast Cancer 1 (DBC1) Involvement in
the DNA Damage Response
Matteo Dugo
Investigation of Microenvironment Changes in Breast Cancer Patients through Genomic Approaches
and Assessment of their Prognostic Value
15
In addition to the students enrolled in the Open University Program, INT hosts PhD
students from diverse institutional and disciplinary backgrounds, mainly registered in PhD
Courses with Italian Universities:
The Preventive and Predictive Medicine Department hosts PhD Students enrolled in the
School of Biomedical, Clinical and Experimental Sciences, UNIMI: Laura Angelici, Marco
Centola, Chiara Ciniselli, Maria Filomeno, Maria Ghazanfar, Teresa Greco, Elena Landoni,
Alessandra Lugo, Elisabetta Marzo, Valentina Rosato, Annalisa Orenti, Delphine Praud,
Tiziana Rosso, Maria Giovanna Scarale, Antonella Zucchetto.
Attending the Hematology and Pediatric Onco-Hematology Department is Sara Rizzitano
(Experimental Medicine and Medical Biotechnologies).
The Surgery Department hosts PhD Students from the UNIMI PhD Program in
Physiopathological Sciences: Leonardo Duranti, Andrea Billè, and Nicola Rocco (fellowship
granted by the Fondazione Adele e Bruno Onlus).
The Palliative Care, Pain Therapy, and Rehabilitation Unit hosts Cinzia Brunelli, a PhD
student registered in a Program in Palliative Care at the Norwegian University of Science
and Technology (Trondheim).
The Department of Experimental Oncology and Molecular Medicine hosts the following
PhD students: Elena Fusar Poli (Dept BICOM and Neuroscience Center, Insubria
University of Varese), Chiara Alberti, Barbara Frigerio, Anna Granata, Katia Rea, Alessandro
Satta, and Marcella Tazzari (all registered with the UNIMI Ph.D. School in Biological and
Molecular Sciences), Annalisa Conti, Giulia Grazia, Valentina Uva (School of Clinical and
Experimental Biomedical Sciences, UNIMI), Maurizio Callari, (PhD School in Biomedical
Sciences and Oncology, University of Turin), Valeria Musella (School of Clinical and
Experimental Biomedical Sciences, UNIMI).
MASTERS
• Academic Master in Epidemiology. This is a joint appointment with the University of
Turin, ISI Foundation, and INT Unit of Epidemiology and Prevention.
• Master in Rectal Surgery. INT and ARECO (Association for the European Research in
Surgical Oncology) offer a Rectal Surgery Master for medical doctors with a surgery
degree.
• Academic Course in Oncologic Lymphology. The course is designed for physicians and
students graduating in lymphology and oncologic lymphology. The Unit of Palliative
Care, Pain Therapy, and Rehabilitation is the scientific coordinator and is in charge of
educational activities, referred to the Medical Faculty of the University of Milan.
• Master of Palliative Medicine for Nurses. Under the direction of the University of
Milan and in collaboration with INT, this academic course trains graduated nurses to
provide palliative care to patients with cancer diseases.
• Master in Medical Statistics and Statistical Methods for Epidemiological Research.
MSSME is aimed for graduate with Medicine, Biological Sciences, Physics or Statistics
degree. Postgraduate course in biostatistics are also provided. Postgraduate students
are often directly involved in research projects coordinated by MSBB members.
OTHER COURSES
The Pathology Department is involved in the training programs of the Postgraduate
Medical Schools of Pathology, Endocrinology, and Respiratory Medicine (University of
Milan) and of the Soft Tissue Pathology, Postgraduate School of Pathology (Insubria
University of Varese). The Anesthesia Department is involved in the training program and
residency of the Postgraduate School for Anesthesia and Intensive Care, hosting a number
of residents/students and organizing part of teaching in the program of the postgraduate
course of the Medical School, University of Milan. Residents in Anesthesia and Intensive
16
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Care, Cardiology, Nutritional Support (University of Milan and Milano-Bicocca) work within
all the Units of the Department.
Many staff members have teaching positions or are tutors in postgraduate medical
schools or in national/international master programs. Within the Surgery Department,
the Unit of Colorectal Surgery is affiliated with the General Surgery Residency
Programs of the Milano-Bicocca and Pavia Universities; the Unit of Gastrointestinal and
Hepatopancreatobiliary Surgery and Liver Transplantation is a training center for the
University of Milan and the Italian College of Surgeons and is chosen for clinical fellowships
by many visiting clinicians and surgeons every year. In the area of clinical and training
activities, the Plastic and Reconstructive Surgery Unit holds very sought-after weekly and
3-monthly surgery courses for Italian and foreign surgeons. The Gynecologic Oncology
Unit is chosen for clinical fellowships by many visiting surgeons from Italy and abroad
every year. It also organizes a biennial international meeting and a gynecologic oncology
course with more than 50 participants three times a year. The Otorhinolaryngology
Surgery Unit has close links with the University, and is involved in postgraduate teaching
and supervision of junior medical staff. In collaboration with the Human Morphology
Department of the University of Milan, this Unit activated two research doctoral degrees
to develop a new non-invasive method to evaluate the functionality of the mimetic
musculature after iatrogenic damage to the facial nerve. The Unit also collaborates with
the Otorhinolaryngoiatric School of Specialization of the University of Milan, hosting
students for practical training and organizing lessons and courses. The Thoracic Surgery
Unit collaborates with the General Surgery and Thoracic Surgery School of Specialization of
the University of Milan, hosting students for practical training. Many postdoctoral fellows
attend the Melanoma and Sarcoma Unit that collaborates actively with several medical
universities. The Senology Unit collaborates with the University of Milan in teaching and
research projects.
The Medical Staff of the Diagnostic Imaging and Radiotherapy Department is involved
in educational activities cooperating with the University of Milan and Milan-Bicocca in
the Radiology, Radiotherapy, and Medical Oncology Specialization Schools, in the Clinical
Application of Nuclear Medicine of the Nuclear Medicine School of Specialization. The
Radiotherapy Unit also provides tutoring of radiography and radiation technician students.
CONTINUING MEDICAL EDUCATION PROGRAM
The educational and training program promotes professional, cultural and human growth
of INT employees. During 2013, the INT ECM Provider has proposed 196 events in the
main areas (clinical governance, on the job learning, risks prevention, and emergency
management, etc.) of ECM-CPD (174 were accredited), attracting the interest and the
participation of resident and visiting health professionals. In particular, the educational
initiatives included in the Business Formation Plan (BFP) have achieved a total amount of
37,886 formative credits, involving 4,750 individuals.
17
SEMINARS AND CONFERENCES
JANUARY
Giovanni Capranico
Department of Pharmacy and Biotechnology. University of Bologna
Topoisomerase I functions at promoters and genome stability
Rosanna Piccirillo
Laboratory of Cancer Cachexia, AIRC Start-Up. Oncology Department. Istituto di Ricerche
Farmacologiche Mario Negri. Milan
The p97/VCP ATPase complex is critical in muscle atrophy and for the accelerated degradation of
most muscle proteins
FEBRUARY
CONTRIBUTION OF NEW TOOLS TO “OMICS” ANALYSIS IN CANCER RESEARCH
Chair: Silvana Canevari, Molecular Therapies, Istituto Nazionale dei Tumori. Milan
Evaluation of a NGS technologic platform with Health Technology Assessment (HTA) tools
Cecilia Melani, Scientific Directorate, Istituto Nazionale dei Tumori. Milan
BRCA 1-2 genes target re-sequencing: comparison between Sanger methodology and Ion
Semiconductor Sequencing
Loris Bernard, IFOM-IEO Campus. Milan
New software tools for studying the role of miRNAs in complex regulatory circuits
Andrea Bisognin, Laboratory of Computational Genomics, Department of Biology. University of
Padova
Andy Silver
Colorectal Cancer Genetics, Centre for Digestive Diseases, Blizard Institute of Cell and Molecular
Science, Barts and The London School of Medicine and Dentistry. London
A role for Dual oxygenase 2 in intestinal tumourigenesis
Mahvash Tavassoli
Molecular Oncology, Guy’s Hospital. Kings College. London
Stratification biomarkers for the treatment of head and neck cancers
Elia M. Biganzoli
Biostatistics, Section of Medical Statistics, Biometry and Bioinformatics « Giulio A. Maccacaro ».
Department of Clinical Sciences and Community Health, University of Milan. Campus Cascina Rosa,
Istituto Nazionale dei Tumori. Milan
The statistical bioinformatics in the era of “big data”
Raimo Tanzi
NGS Business Development, Lifetechnologies. Europe
Solid Widfire INT users meeting: introduction to the technology, the presentation of applications
and protocols available on the SOLiD 5500WF, feasibility studies and cost
microRNA Workshop
Chair: Franco Martinez, EuroClone. Pero. Milan
Analysis of circulating microRNA biomarkers for cancer
Hazel Pinheiro, Exiqon. Denmark
The miRNA workflow
Laura Monti, EuroClone. Pero. Milan
MARCH
Mario Ciocca
Unit of Medical Physics. CNAO Foundation, Pavia
Hadrontherapy, new infallible weapon: another election promise ?
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MAY
Evi Lianidou
Laboratory of Analytical Chemistry. Analysis of Circulating Tumor Cells (ACTC) Lab. Department of
Chemistry – University of Athens. Athens. Greece
Circulating Tumor Cells: Recent advances in their detection and molecular characterization
Uppugunduri Srinivas
Department of Clinical Chemistry, University Hospital, Linköping. Sweden
Novel anti-infiammatory drug candidates
Robert Clarke
Breast Biology Group. Institute of Cancer Sciences. Paterson Building. University of Manchester.
Wilmslow Road. Manchester
Signalling pathways regulating breast cancer stem cells
Peter K. Rogan
Canada Research Chair in Genome Bioinformatics, Tier I, Biochemistry & Computer Science.
University of Western Ontario
Discovery and predicting impact of non-coding sequence variants that affect gene expression on
a genome scale and in inherited breast cancer
JUNE
Michele Visentin
Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York
Insight the cellular pharmacology of pralatrexate - a new weapon against the Non-Hodgkin
lymphomas
Stefano Cairo
Laboratory of Head R&D Xentech – France
Patient-derived xenografts to assist basic research and clinical practice
Stephanie Dorman
Department of Biochemistry, Schulich School of Medicine and Dentistry Western University, London,
Canada
Graduate studies in cancer genetics: exchanging experiences between Canadian and Italian
Institutions
Augusto Pessina
Department of Biomedical, Surgical and Dental Sciences. University of Milan
Mesenchymal stromal cells for the transportation of paclitaxel: potential applications
Workshop: “Mast cells: host defense or offence?”
Stephen J. Galli - Department of Pathology, Stanford University, CA
Rosetta Pedotti - Neuroimmunology Unit, Istituto Neurologico Besta, Milan
Mario P. Colombo - Molecular Immunology Unit, Experimental Oncology and Molecular Medicine
Department, Istituto Nazionale dei Tumori, Milan
Claudio Tripodo – Department of Human Pathology, University of Palermo
Carlo Pucillo - Department of Biomedical Science and Technology, University of Udine
JULY
Yosef Yarden
Department of Biological Regulation - Weizmann Institute of Science - Rehovot, Israel
HER2 and EGFR: Signalling mechanisms and next generation cancer therapies
Jörg Mages
Field Application Scientist at Partek, Inc
The Ease of Flow: Intuitive and Sophisticated Analysis of Tumor Cell lines using Partek Software
19
Anil K. Sood
Ovarian Cancer Research, Department of Gynecologic Oncology, University; Center for RNA
Interference and Non-Coding RNA, The University of Texas. MD Anderson Cancer Center, Houston,
TX
About Trousseau, Platelets and Ovarian Cancer
Anna Saran
Laboratorio di Biologia delle Radiazioni e Biomedicina, Agenzia Nazionale per le Nuove Tecnologie,
l’Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, Roma
New paradigms in radiobiology: Evidence for radiation induced bystander effects
Diana Eccles
Cancer Genetic Faculty of Medicine Academic Unit of Cancer Sciences. University of Southampton,
University of Southampton Clinical Trials Unit, Clinical Genetics University Hospital Southampton
Foundation Trust – UK
Genetic background determines breast cancer sub-types and prognosis
SEPTEMBER
GENOMICS IN ONCOLOGY: UNDERSTANDING THE PATHOBIOLOGY AND DEVELOPMENT OF
INFORMATIVE ESSAYS FROM THE CLINICAL POINT OF VIEW
Chair: Silvana Canevari, Molecular Therapies, Experimental Oncology and Molecular Medicine
Department, Istituto Nazionale dei Tumori, Milan
Maria Grazia Daidone, Biomarkers, Experimental Oncology and Molecular Medicine Department,
Istituto Nazionale dei Tumori, Milan
Giampaolo Bianchini, Department of Medical Oncology. Ospedale San Raffaele. Milan
Francesca De Michelis, Center for Integrative Biology (CIBIO), University of Trento
Antonino Neri, Department of Clinical Sciences and Community, University of Milan, Hematology
CTMO, Fondazione Cà Granda IRCCS Ospedale Policlinico. Milan
OCTOBER
Andrew R. Reynolds
Tumor Biology Team. The Breakthrough Breast Cancer Research Centre The Institute of Cancer
Research . London
Vessel co-option: an under-appreciated phenomenon with profound consequences for the clinical
translation of anti – angiogenic therapy and Anti – angiogenic therapy: from bench to bedside and
back again
Alessandro Santin
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine,
New Haven, CT-USA
Homing Devices and Microscopic Shuttles-Iron Oxide Nanoparticles functionalized with
Clostridium Perfringens Enterotoxin (CPE) as Novel Agents for Ovarian Cancer Diagnosis and
Therapy
Dèsirèe Bonci
Department of Hematology, Oncology and Molecular Medicine. ISS, Rome
Role of microRNA in primary and metastatic prostate cancer
NOVEMBER
MASS SPECTROMETRY IN THE FIELD OF EXPERIMENTAL AND CLINICAL ONCOLOGY
Chairs: Italia Bongarzone, Rosaria Orlandi, Maria Grazia Daidone, Experimental Oncology and
Molecular Medicine Department, Istituto Nazionale dei Tumori, Milan
Mass spectrometry in the field of proteomics: recent discoveries and projects in progress
Italia Bongarzone, Cancer Proteomics
Mass spectrometry at low and high resolution to analyze peptide and metabolomic profiles of
plasma and breath of patients with breast cancer
Rosaria Orlandi, Molecular Targeting
The new platforms: potential and applications
Giulia Garrone, Samuele Pedraglio e Adalberto Cavalleri, Preventive and Predictive Medicine
Department
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Metabolomics diagnosis by GCMS and LC-MS/MS
Valerio Leoni, Laboratorio di Patologia Clinica e Genetica Medica. Istituto Neurologico “Carlo Besta”
Interpretation of metabolomic profiles in experimental models
Silvana Canevari, Molecular Therapies, Istituto Nazionale dei Tumori, Milan
Matteo Bellone, Cellular Immunology Unit, Istituto Scientifico San Raffaele, Milan &
Maria Grazia Daidone, Experimental Oncology and Molecular Medicine Department, Istituto
Nazionale dei Tumori, Milan
Circulating tumor cells, “not everything that can be counted counts, and not everything that
counts can be counted”
DECEMBER
Massimo Gadina
Translational Immunology Section, Office of Science and Technology, National Institute of Arthritis
Musculoskeletal and Skin diseases, National Institutes of Health. Bethesda
Janus Kinase Inhibitors: from autoimmunity, to inflammation to malignancies
21
CLINICAL
ACTIVITY
DATA
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clinical activity data
INpatients by Geographical Area (overall 14,253)
northwest
6%%
lombardy
northeast
65%
4%
south
11%
center
8%
outside
Number of normal admissions during 2013
divided according to major geographic areas.
The total number of admissions increased
(14,253 in 2013 vs. 13,904 in 2012).
1%
islands
5%
OUTpatients by Geographical Area (overall 7397)
northwest
4%%
northeast
lombardy
4%
78%
south
6%
center
3%
Number of admissions in a Day Hospital
(DH) setting during 2013 in each major
area. The total number of admission
in DH slightly decreased (7397
in 2013 vs. 7727 in 2012) due to the
introduction of a new type of assistance,
namely complex ambulatory activity.
outside
1%
islands
3%
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Inpatients: average length of stay over the years
Medical Oncology
Medical
SurgeryOncology
Average duration of admission in days, both medical and surgical, among
those lasting more than one day. A further decrease in the mean duration
of admission, for both medical and surgical admissions, was observed.
Surgery
9.03
8.95
8.91
9.03
8.95
8.91
5.96
5.96
8.34
8.49
8.49
8.53
8.34
8.49
8.49
8.53
5.47
5.66
5.80
5.47
5.66
5.80
5.90
5.90
5.92
5.90
5.90
5.92
7.42
7.14
7.42
7.14
6.83
6.83
4.93
4.93
4.83
4.53
4.83
4.53
2004
2004
2005
2005
2006
2006
2007
2007
2008
2008
2009
2009
2010
2010
2011
2011
2012
2012
2013
2013
Inpatients: over the years (length of stay >1 DAY)
Medical Oncology
Number of total admissions, medical and surgical, with recovery times
exceeding one day.
Medical
SurgeryOncology
Surgery
6925
6945
6945
6347
6347
5347
5347
2004
2004
24
5959
5959
7145
7145
6250
5965
6174
5987
6250
5965
6174
5987
6705
6802
5994
6705
6802
5994
5786
5574
5508
5452
5594
5804
5427
5574
5508
5452
5594
5804
5427
2005
2005
2006
2006
2007
2007
2008
2008
2009
2009
2010
2010
6925
5786
2011
2011
2012
2012
2013
2013
clinical activity data
outpatient visits (overall 166,387)
Private Patients
18,684
Transfusion Unit
6,188
Anesthesia, Intensive Care, Palliative Care
19,902
Diagnostic Imaging & Radiotherapy
12,691
Surgery
55,500
Medical Oncology
53,422
The graphs are based upon currently used data: on SDO information
and on Budget and Management Control’s Data.
25
CLINICAL
SCIENTIFIC
S
T
N
E
M
T
R
A
P
DE
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clinical-scientific departments
SURGERY
DEPARTMENT
DIRECTOR OF DEPARTMENT: Ugo Pastorino
+39 02 23902906
ugo.pastorino@istitutotumori.mi.it
The Department of Surgery treats oncological diseases that affect all areas of the body except
for the brain, providing elective and emergency surgical activity, in ordinary inpatient and
day hospital regimens, as well as specialist outpatient activity for diagnosis and follow-up.
Routine clinical activity ensures a high standard of care for all surgically-treated patients,
providing conservative surgery (organ/function preserving or minimally invasive) for early
stage disease and combined treatment modalities for advanced disease.
The Department is organized in the following Units:
Gastrointestinal, HepatoPancreatobiliary Surgery, and Liver Transplantation. Has the
goal to improve the standard of care for primary and secondary tumors affecting the liver,
biliary system, pancreas, and gastrointestinal tract. In the field of hepato-oncology, it offers
the complete range of the most up-to-date therapeutic options for liver cancer, including
liver transplantation, minimally-invasive and computer assisted surgery, transarterial
chemo-/radio-embolization, percutaneous and laparoscopic tumor ablation, and targeted
molecular therapies. The Unit is a pioneer in computed-assisted liver surgery performed
using an ultrasound navigation system that allows localization of tumors deep in the liver
that are not visible with conventional ultrasound.
Colorectal Surgery. Devotes special attention to tumors of the distal rectum and has
established high standards of care for the management of this subset of patients.
Conservative, function-preserving surgical techniques to avoid extensive resection
an definitive colostomy have been perfected. The Peritoneal Surface Malignancies
(PSM) program is responsible for the treatment of pseudomyxoma peritonei, peritoneal
mesothelioma, and peritoneal carcinomatosis from colorectal cancers. In 2013, an
important study was published on the role of perioperative systemic chemotherapy in
diffuse malignant peritoneal mesothelioma patients treated with cytoreductive surgery and
hyperthermic intraperitoneal chemotherapy.
Breast Surgery. Clinical activity includes all aspects of breast cancer treatment, i.e.
diagnosis, primary and adjuvant therapy, and follow-up. Enhanced understanding of the
pathogenesis of breast cancer coupled with a growing interest in improved esthetic results
led to the investigation of skin- and nipple-sparing mastectomy as a potential improvement
over conventional mastectomy. In 2013, the longstanding experience on breast conserving
surgical treatment was further strengthened by the publication of the final results of a
randomized controlled clinical trial on breast cancer treatment without axillary surgery.
27
Melanoma and Sarcoma. Comprises all aspects of melanoma and sarcoma treatment, i.e.
diagnosis, primary and adjuvant therapy, and follow-up. The Unit conducts clinical trials in
the field of adjuvant therapy for melanoma and pre-operative therapy for sarcoma. The Unit
is the referring center for melanoma and sarcoma guidelines.
Diagnostic Endoscopy and Endoscopic Surgery. Includes activities of the multidisciplinary
endoscopy, i.e., diagnostic and therapeutic procedures of the gastrointestinal,
biliopancreatic, respiratory, and urinary tracts. The Unit is particularly committed to cancer
prevention and diagnosis and treatment of early cancers.
Otolaryngology Surgery and Maxillo-Facial Surgery. Specialized in the treatment of
benign and malignant tumors of the head and neck area. State-of-the-art surgical treatment
for patients with head and neck tumors is guaranteed by experts from across disciplines:
otolaryngologists and maxillofacial surgeons.
Gynecologic Oncology. Deals mainly with primary and secondary tumors of the female
genital tract. Surgical research was conducted on the following techniques: nerve
sparing radical surgery, debulking surgery, mini-invasive surgery, laparoscopic surgery in
diagnosis, staging and treatment of early gynecological tumors; sentinel node detection in
endometrial cancer.
Thoracic Surgery. Covers all aspects of thoracic oncology, focusing on pulmonary,
mediastinal, chest wall, and esophageal tumors. In the management of lung cancer, the
mainstay of surgical treatment is maximal functional sparing. Innovative techniques
for tridimensional chest wall reconstruction have been developed (rib-like technique),
permitting appropriate reconstruction even in case of removal of an entire hemithorax. In
mediastinal surgery, superior vena cava (SVC) replacement is performed by procedures
not requiring SVC cross-clamping, avoiding intraoperative hemodynamic instability.
Pleuro-pneumonectomy is proposed in limited malignant mesothelioma, after induction
chemotherapy.
Plastic and Reconstructive Surgery. Performs reconstructive surgical procedures related
to extensive breast and head and neck surgery, soft-tissue tumors, chest-wall surgery, and
other types of aggressive oncologic surgery, as well as surgical treatment and repair of skin
cancer. Oncoplastic surgery represents a new standard for reconstructive procedures after
tumor excision.
Urologic Surgery. Strengthens multidisciplinary care and clinical trials in difficult to treat
diseases. In particular, a number of phase II clinical trials have been approved in different
clinical settings of urothelial, testicular, and penile cancer and are initiating in 2014.
Most importantly, a primary objective of the Unit is to develop a modern framework for
clinical research, and with this aim the collaboration with EORTC was fulfilled, together
with the establishment of an urothelial cancer patient advocacy group. The multicentric
international cooperation for next generation sequencing analyses was another endpoint,
and collaboration with MSKCC as well as with UAB Comprehensive Cancer Center of
Alabama has been established in urothelial and penile cancers, respectively. The objective
of these collaborations will be to characterize extreme responders to specific targeted
drugs as well as conventional therapy from a molecular standpoint in order to provide
information to design informed clinical trials in multiple urological cancers.
Pediatric Surgery. Collaborates with pediatric oncologists and provides a high standard of
treatment for the most frequent solid – non-CNS – tumors in children and adolescents. The
role of surgery is established according to ongoing European treatment protocols.
Laser Therapy Unit. Uses high-quality instrumentation including four lasers for a total
of 20 wavelengths. It allows conservative and ablative therapies in diseases where laser
therapy is the first or only treatment choice. Selective photothermolysis laser treatment is
performed for keloids as well as pigmented and vascular lesions, and laser ablation is used
for mucosal and skin cancer lesions requiring histological evaluation.
Day Surgery Unit. Devoted to surgical procedures performed in ambulatory and day
hospital settings. The clinical activity covers many aspects of oncologic surgery, and in
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particular includes the treatment of different lesions involving skin, soft tissues, breast,
as well lesions in gynecologic, urologic, and head and neck areas. This activity involves the
collaboration of physicians from Units within the Surgical Department.
HIGHLIGHTS
The Liver Transplant Program is mainly focused on establishing oncological guidelines and plays a leading role worldwide in defining
consistent indications and prospective lines of research.
INT is a referral center for soft-tissue sarcomas of the limbs and trunk, as well as retroperitoneal sarcomas, GIST, and axial bone
sarcomas.
A special effort is dedicated to the Regional Colorectal Cancer Screening Program as well as to endoscopic surveillance of patients
affected by familial adenomatous polyposis (FAP) or Lynch syndrome.
Lung cancer early detection program: at INT a large prospective study in heavy smokers volunteers is ongoing, based on plasma miRNA profiling to assess its efficacy as a first line screening test for lung cancer detection (www.biomild.org).
INT is certified as a Center of Excellence by the European Society Neuroendocrine Tumors (ENET).
KEYWORDS
liver transplantation, peritoneal carcinomatosis, locoregional therapy, immunotherapy, cancer prevention, laser therapy, skin cancer,
lung cancer, screening
GASTROINTESTINAL,
HEPATOPANCREATOBILIARY SURGERY,
AND LIVER TRANSPLANTATION
Head
Vincenzo Mazzaferro, MD
Clinical Research Staff
Carlo Battiston, MD; Sherrie Bhoori, MD (hepatogastroenterologist); Jorgelina C. Coppa, MD; Christian Cotsoglou, MD;
Alessandro Germini, MD; Andrea Pulvirenti, MD;
Enrico Regalia, MD; Raffaele Romito, MD; Carlo F. Sposito MD
COLORECTAL SURGERY
Head
Ermanno Leo, MD
Dario Baratti, MD; Luigi Battaglia, MD; Filiberto Belli, MD;
Giuliano Bonfanti, MD; Alessandro Cesa Bianchi, MD; Marcello
Deraco, MD; Shigeki Kusamura, MD, PhD; Marco Vitellaro, MD
Residents
Marcello Guaglio, MD; Mario Moschita, MD;
Giovanni Piscitelli, MD; Vincenzo Pruiti, MD; Monica Zisa, MD
Research Staff
Marco A. Bongini, MD; Maria F. Reyes, MD; Daniela Sia, MD;
Elisa Sottotetti, MD
Administrative Personnel
Roberta Aceto
Residents
Davide Citterio, MD; Glenda Grossi, MD; Cecilia Muscarà, MD;
Marco Nencioni, MD; Matteo Origi, MD
Nurses
Fabiana Bettoni, Lucia Caracciolo, Rut Cittadin, Angela Colamonaco,
Stefania Labori, Magdalena-Alonso Manuel, Marica Melis,
Vanessa Neri, Palma, Mirtha Ybazeta Ramos, Riccardo Vacca
Elisa Giavari and Francesco Roncacci (Unit secretaries);
Daniela Guarneri and Nela Zito (scientific secretaries);
Simona G. Marchesi (data manager)
Healthcare Assistants
Monica Anzaghi, Isabella Damasi, Nunzia Di Perna, Fabio Lizzano,
Maria Petrosina
Nurses
Paola Serafin (coordinator), Adriana Blanco, Salvatore Bonafede,
Annateresa Bugada, Morena De Santis, Milda Di Giacomo,
Angela Mihaela Farcas, Stefania Fici, Francesca Maiorano,
Antonella Masiello, Monica Mitarotonda, Nadia Nicoletti,
Patrizia Perotto Ghi, Patrizia Rota, Rossina Sitta, Stefania
Sperandio, Cristina Stracquadaini, Patrizia Valentini
BREAST SURGERY
Head
Roberto Agresti, MD (until 30 November)
Marco Greco, MD (since 1 December)
Nicoletta Damiani, Rosa De Felice, Mariangela Lopriore,
Annamaria Pancari, Angela Restaini, Enza Spina, Anna Vecchio
Silvia Bohm, MD; Alberto Rudy Conti, MD; Cristina Ferraris, MD;
Massimiliano Gennaro, MD; Maria Ilaria Grosso, MD;
Gabriele Martelli, MD; Cristina Pellitteri MD (until 30 November);
Domenico Piromalli, MD, Gianbattista Spatti MD
Research Fellows
Mario Rampa, MD; Alessandra Moscaroli, MD (until August 30th),
Ilaria Maugeri, MD
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Angela Allegri
Nurses
Irene Alessandrini, Giovanni Cavaliere, Miriam P. Conti, Stefano
Licata, Bruna Nuscis, Maria C. Puddu, Michele Rossello, Gelsomina
Sasso, Francesco A. Spagnolo, Liliane Venafra
Maria C. Fadda, Luigi Magnifico, Caterina Pianu
MELANOMA AND SARCOMA
Head
Mario Santinami, MD
Melanoma
Francesco Gallino, MD; Andrea Maurichi, MD; Daniele Moglia, MD;
Roberto Patuzzo, MD; Roberta Ruggeri, MD
Surgery of Sarcoma
Alessandro Gronchi, MD (Head); Marco Fiore, MD; Chiara
Colombo, MD, Stefano Redaelli, MD
Research Staff
Valentina Girgenti, MD; Roberto Grillo, MD; Elena Tolomio, MD
Residents
Consuelo Barbieri, MD; Federica Marazza, MD
OTOLARYNGOLOGY SURGERY
Head
Gabriele Scaramellini, MD
Roberto Bianchi, MD; Sarah Colombo, MD; Walter Fontanella,
MD; Marco Guzzo, MD; Tullio M. Ibba, MD, PhD; Natalia R. E. Pizzi,
MD; Madia Pompilio, MD; Stefano Riccio, MD
Nurses
Vincenzo Spanò (coordinator), Giovanna V. Bello, Petronilla
D’Agostino, Elena Cotellessa, Angelo Di Caro, Giorgio Fumi,
Giorgio Inverni, Carmen Minio, Rosita A. Nanna, Laura Ongari,
Daniele Pezzera, Francesca Pisano, Federica Prudenzano, Raffaella
Repetto, Maura Rimoldi, Maria S. Selva
Technicians
Pablita Endaya, Vincenzo Marotta, Giuseppe Messana, Laura
Somma
Sabrina Zazzera
GYNECOLOGIC ONCOLOGY
Head
Francesco Raspagliesi, MD
Antonella Vescera
Antonino Ditto, MD; Rosanna Fontanelli, MD; Barbara Grijuela,
MD; Domenica Lorusso, MD; Marina Merola, MD; Andrea Papadia,
MD; Eugenio Solima, MD; Flavia Zanaboni, MD
Data Managers
Annabella Di Florio, Adele Di Fazio, Giulia Bonarini
Research Fellows
Fabio Martinelli, Stefano Ramondino, Maria Mancini, Italo Sarno
Research Nurse
Gabriella Nicolò
Nurses
Patricia A. Costa, Alice Casali, Francesco Crugliano, Floriana Dimo,
Lorenza Greco, Eva Guitti, Antonio Micello, Marianna Miranda,
Claudio Oppido, Rossana Penasa, Ylenia Ponti, Paolo Re, Patrizia
Valente
Nurses and Healthcare Assistants
Giovanna Lomartire (coordinator), Nicola Abatangelo, Roberta
Allenza, Annamaria Biondo, Sonia Cappellini, Annarita Carluccio,
Alessio Cremonesi, Nello Curatolo, Floarea Dorca, Loridana
Marino, Silvana Mirante, Erica Panigada, Giusy Pede, Lucia
Preto, Esther Reinoso Crespo, Francesca Ruiu, Claudia Sonzogni,
Antonella Tomasicchio, Monica Ullio, Addolorata Volpe
DIAGNOSTIC ENDOSCOPY AND ENDOSCOPIC
SURGERY
Head
Emanuele Meroni, MD
Giovanni Ballardini, MD; Giuseppe Calarco, MD; Gabriele
Delconte, MD; Gianfranco Di Felice, MD; Massimo Falsitta, MD;
Andrea Mancini, MD
Nurses
Vittorio Mauro (coordinator), Francesco Bottani, Raffaele Calò,
Roberto Fiocco, Daniele Lo Curcio, Francesca Mannai, Giovanni
Sammartino, Raffaele Quagliolo
Technicians
Silvia Cara, Rosanna Loi, Salvatore Morfeo
Concetta Di Quattro, Annamaria Mercuri
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Health Care Assistants
Rosa Farro, Alessia Formicola, Natalia Munante, Cecilia
Muzzupappa
Cinzia Marretta, Rosella Zennoni, Stefano Ramondino, Maria
Mancini, Italo Sarno
THORACIC SURGERY
Head
Ugo Pastorino, MD
Andrea Billè, MD, PhD student; Leonardo Duranti, MD, PhD student; Riccardo Giovannetti, MD; Francesco Leo, MD, (until March
2013); Paolo Scanagatta, MD; Luca D. Tavecchio, MD
Fellows
Giuseppe Garofalo, MD; Mara Gisabella, MD; Stefano Sestini, MD
Resident
Lara Girelli, MD
Nurses
Federica Pirovano (coordinator), Brice Atiomeguim, Francesco
Auletta, Marcella Bernardo, Claudia Costa, Yesica Del Rio Mendez,
Antonino De Vita, Raffaele Di Nino, Margherita Fersurella, Hilda A.
Martinez, Daniele Marino, Maria L. Quitadamo, Anna M. Panareo,
Antonio Pantano, Antonella Prete, Antonino Proto
Technicians Oss
Nekpen Eguavoen, Angela Di Luglio, Diego Risuglia, Svitlana
Shulzhenko, Pamela K. Soto Fernandez
Tiziana Negri (Unit secretary)
Research Staff
Elena Bertocchi (Research Coordinator) Anna Maria Calanca,
Carolina Ninni (Scientific secretaries), Claudio Jacomelli
(Informatics); Paola Suatoni (Biol Sci D)
External Collaborator
Nicola Sverzellati (Radiologist)
Testicular Cancer Surgery
Nicola Nicolai, MD (Coordinator)
Pediatric Surgery
Luigi Piva, MD (Coordinator)
Nurses
Graziella Russo (coordinator), Rosanna Candigliota, Maria
L. Cennamo, Anna M. Cercaci, Zino Ferro, Francesca Marelli,
Lucia Mesiano, Arturo Monetta, Valentina Musarò, Giuseppa
Napoli, Veronica P. Rojas, Annalisa Simone, Raffaella Rossi, Rita
Sciancalepore
Maria G. Bodini
PLASTIC AND RECONSTRUCTIVE SURGERY
Head
Maurizio B. Nava, MD
Technicians
Elena Cristiani, De La Cruz, Velesmoro Rocio Del Pilar, Olimpia
Liberatore, Anna Mastroianni, Isabella Vurchio,
Novella Bruno, MD; Pierfrancesco Cadenelli, MD; Umberto
Cortinovis, MD; Joseph Ottolenghi, MD; Angela E. Pennati, MD;
Egidio Riggio, MD; Andrea Spano, MD
LASER THERAPY
Head
Anna Colombetti, MD
Nurses
Maria Saracino (coordinator), Samantha F. Castelli, Cinzia Gentilini,
Giusppe L’Abbate, Marisa Labò, Giovanna Melia, Caterina Pireddu,
Irene Rossi, Raffaella Tupputi
Technicians
Nadia Casati, Provvidenza Peci, Nomi Ibazeta Ramos, Iolanda
Panipucci, Annunziata Rugolo
Luisa Morandi
UROLOGIC SURGERY
Head
Roberto Salvioni, MD
Davide Biasoni, MD; Mario A. Catanzaro, MD; Alessandro Crestani,
MD (Fellow, University of Padua School of Urology); MD; Elena
Farè, MD (Fellow, University of Milan School of Medicine); Patrizia
Giannatempo, MD (Resident, Department of Medical Oncology,
Medical Oncology Unit 2); Andrea Guttilla, MD (Fellow, University
of Padua School of Urology); Massimo Maffezzini, MD; Andrea
Necchi, MD (Faculty, Department of Medical Oncology, Medical
Oncology Unit 2); Daniele Raggi, MD (Fellow, University of Milan
School of Medicine); Silvia Stagni, MD; Tullio Torelli, MD
Silvia Aiello, MD; Mario Z. Raso, MD
Nurses
Maria Saracino (coordinator), Emilia D’Arrigo
Healthcare Assistant
Domenica Lo Prete
M. Rosaria Aceto
DAY SURGERY
Head
Aldo E. Bono, MD
Nurses
Giovanna R. Colaci, Mariangela Lena, Mara D. Luisoni, Pina P. Mele,
Anna Picciallo, Domenica Violi, Marina Zocchi
Antonella Bordoni, Silvia Cara, Rosa Selvati
Maria R. Bignamini, Anna Corella, Loredana Orezzi
FOR MORE INFORMATION ABOUT THE UNITS, VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT
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MEDICAL
ONCOLOGY
DEPARTMENT
DIRECTOR OF DEPARTMENT: Filippo de Braud
+39 02 2390 3066
filippo.debraud@istitutotumori.mi.it
The Department carries out comprehensive cancer treatments in adults with solid tumors and
performs research focusing on new drug development and treatment strategies. Opportunities
are maximized for inter-departmental and inter-institutional collaborations to ensure the
forefront of patient care and oncology research. The Medical Oncology Department comprises
various clinical medical units and a centralized day hospital; outpatients visits are performed
in dedicated rooms.
Medical Oncology 1. New drug development (phase I, early phase II), breast cancer,
gastrointestinal tumors (gastric, colorectal, neuroendocrine, pancreatic and biliary tract),
melanoma, thoracic tumors (lung cancer, mesothelioma, thymoma), urogenital tumors
(renal and prostatic cancer).
Medical Oncology 2. Preclinical and clinical activities mainly for malignant lymphomas,
germ cell tumors and bladder cancer.
Medical Day Hospital. Deals with adult patients referred by the clinical Units of the
Department, as well as diagnosis, treatment, and follow-up of neuroendocrine tumors.
Adult Mesenchymal Tumor Medical Oncology. Clinical research and care in sarcomas and
peritoneal mesothelioma.
Head and Neck Cancer Medical Oncology. Clinical research and care in cancer, thyroid,
and salivary gland cancer.
Cardiology. Evaluation of patients subjected to surgery and medical treatments. Followup of cardiovascular toxicities due to antineoplastic treatments (see Shared Research
Resources page 59)
Respiratory Pathophysiology. Evaluates patients addressed to surgery and medical
treatments. Follow-up of pulmonary toxicities due to chemo-radiotherapy. Hospitalbased tobacco control policies as well as outpatient and inpatient smoking cessation clinic
activities (see Shared Research Resources page 59).
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HIGHLIGHTS
Overall, 58 studies ranging from Phase I to an antismoking campaign [Phase I (8), Phase II (19), Phase III (15), Observational (16)] were
activated in 2013.
New drug development (Phase I and Ib studies) and the promotion of translational research projects. An entire unit is fully dedicated
to Phase I and early Phase II studies.
Translational research on prognostic and/or predictive biomarkers to investigate new therapeutic strategies for all solid tumors (upper
and lower gastrointestinal tract cancer, non-small cell lung cancer, malignant pleural mesothelioma, thymoma, breast cancer, and
genitourinary tumors).
New generation targeted therapy and immunotherapy for malignant melanoma, lung cancer, gastrointestinal tumors, and prostate
cancer.
Translational research on poor prognosis relapsed/refractory lymphoma with the development of new chemotherapy approaches and
combinations of targeted therapeutics.
Health organization and networking in rare tumors: coordination of the Italian Network on Rare Cancers (about 800 new sarcoma patients shared clinically within the project; activation of an educational Web site); coordination of the rare cancer area of the
Rete Oncologica Lombarda (ROL, the cancer network of Lombardy Region); involvement in the European RareCareNet project
(“Information network on rare cancers”).
Translational research on predictive biomarkers, new drug development including rare head and neck cancer and thyroid cancer,
studies in supportive care.
Cardiologic surveillance to assess the cardiotoxicity of new experimental drugs (monoclonal antibodies, receptor tyrosine kinase
inhibitors, BRAF inhibitors, MEK inhibitors).
Preclinical studies on the pharmacogenetics of smoking cessation drugs as well as the safety of new electronic cigarette devices in
terms of second-hand vapor exposure.
INT is certified as a Center of Excellence by the European Society Neuroendocrine Tumors (ENET).
KEYWORDS
new drug development, personalized medicine, high-dose chemotherapy, immunotherapy, rare cancers, pharmacovigilance, neuroendocrine tumors, smoking cessation clinic, cardiotoxicity
MEDICAL ONCOLOGY 1
Head
Filippo de Braud, MD
Giulia V. Bianchi, MD; Giuseppe Capri, MD; Luigi Celio, MD;
Sara Cresta, MD; Michele Del Vecchio, MD; Maria Di Bartolomeo,
MD; Serena Di Cosimo MD; Marina Garassino, MD; Gabriella
Mariani, MD; Angela Moliterni, MD; Marco Platania, MD; Giuseppe
Procopio, MD; Elena Verzoni, MD; Nicoletta Zilembo, MD
Postdoctoral Fellows
Valentina Colonna, MD; Silvia Damian, MD; Elena De Benedictis,
MD; Lorenza Di Guardo, MD; K. Fiorella Dotti, MD; Francesco
Gelsomino, MD; Paolo Grassi, MD; Eva R. Haspinger, MD; Roberto
Iacovelli, MD; Paola Mariani, MD; Filomena Panzone, MD; Filippo
Pietrantonio, MD; Lorenzo Pilla, MD; Sara Pusceddu, MD; Danila
Serpico, MD; Vitali Milena, MD; Elisa Zanardi, MD
Research Staff
Benedetta Bardazza and Alessandra Castano (Research Nurses);
Antonia Martinetti, Biol Sci D; Elisa Sottotetti, Biol Sci D
Residents
Francesco Agustoni, MD; Pamela Biondani, MD; Matteo Duca,
MD; Arpine Gevorgyan, MD; Alice Indini, MD; Claudia Maggi, MD;
Alessia Mennitto, MD; Monica Niger, MD; Francesca Ricchini, MD;
Lorenzo Sica, MD; Anna Tessari, MD; Isabella Testa, MD
Barbara Formisano, Giuseppa Iannaci, Sabrina Lanterna, Susanna
Maggi
Data Managers
Valentina Sinno, DSc (coordinator); Ilaria Bossi, DSc; Rosaria
Gallucci, DSc; Silvia Sesana DSc; Alessandra Siliprandi, DSc;
Eleonora Sparacio DSc; Irene Vetrano, DSc
MEDICAL ONCOLOGY 2
Head
Alessandro M. Gianni, MD
Liliana F. Devizzi, MD; Massimo A. Di Nicola, MD; Anna Guidetti,
MD; Michele Magni, MD; Paola Matteucci, MD; Andrea Necchi,
MD; Simonetta Viviani, MD
Research Staff
Anna Rossini, Fellow; Giusi Ruggero, Fellow; Roberta Zappasodi,
PhD
Postdoctoral Fellow
Patrizia Giannatempo, MD
Residents
Barbara Bocci, MD; Emanuela Paternò, MD
Antonietta M. Maglione, Agnese Lasala, Loredana Costa, Mauro L.
Pedretti, Antonella Di Perna
Maria Luisa Longhi
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Data Manager
Liana Bevilacqua
ADULT MESENCHYMAL TUMOR MEDICAL
ONCOLOGY
Head
Paolo G. Casali, MD
Rossella M. Bertulli, MD; Elena R. Fumagalli, MD; Michela Libertini,
MD; Elena Palassini, MD; Roberta G. Sanfilippo, MD; Silvia
Stacchiotti, MD
Residents
Vittoria Colia, MD; Salvatore Provenzano, MD
Stefania Cimbari, Anabela Di Giovanni, Paola Esposti, Elisabetta
Prati
Data Managers
Federica Favales, Paola Pistillo
HEAD AND NECK CANCER MEDICAL ONCOLOGY
Head
Lisa Licitra, MD
Cristiana Bergamini, MD; Paolo Bossi, MD; Roberta Granata, MD;
Laura Locati, MD; Aurora Mirabile, MD
Residents
Martina Imbimbo MD; Carlo Resteghini, MD
Stefania Cimbari, Anabela Di Giovanni, Paola Esposti, Elisabetta
Prati
Data Managers
Camilla Cassani (coordinator), Federica Favales
MEDICAL DAY HOSPITAL
Head
Roberto Buzzoni, MD
Laura A.M. Ferrari, MD
Clinical Fellow
Cristina Bregant, MD
Anna R. Cabiddu, Antonella Bifano
Vincenzina Arnone, Fabio Di Bartolo, Lucia A. Di Murro, Maria
Rosa Forte, Anna Maria Meloni, Rita Trovato
Data Manager
Laura Concas
CARDIOLOGY
Head
Patrizia Piotti, MD
Patrizia Greco, MD; Costanza Mantovani, MD; Carlo Materazzo,
MD
Postdoctoral Fellow
Iryna Arendar, MD
Nurses
Sabrina Barrotta, Graziella Borlenghi, Rosella Murru, Luisa Sala
Maria Grazia Marchetti, Rosanna Villani
RESPIRATORY PATHOPHYSIOLOGY
Head
Roberto Boffi, MD
Alessandra Busia, MD
Paolo Pozzi, MD; Elena Munarini, Psy D; Chiara Marabelli, Psy D
Technicians
Maria Chiricosta, Simona Montalti, Fabio Valente
Sara Santoro
Administratives Personnel
Maria Grazia Marchetti, Rosanna Villani
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HEMATOLOGY
AND PEDIATRIC
ONCO-HEMATOLOGY
DEPARTMENT
DIRECTOR OF DEPARTMENT: Paolo Corradini
Professor of Hematology, University of Milan
+39 02 2390 2950
paolo.corradini@istitutotumori.mi.it
The Department of Hematology and Pediatric Onco-Hematology comprises two clinical
divisions, the Hematology Unit, a leader in hematological malignancies care and research,
and the Pediatric Oncology Unit devoted to the care of children with solid tumors and
hematological disorders. The Units participate in national and international clinical research
studies, providing patients access to new therapies including new combinations of drugs
and monoclonal antibodies and new modalities for autologous or allogeneic stem cell
transplantation. The Department has a strong commitment to clinical and basic science
research and to advancing the field of stem cell transplants. It maintains an advanced cell
processing laboratory that is dedicated to preparing safe and effective hematologic cells for
transplantation and a laboratory devoted to translational research to rapidly turn scientific
discoveries into more effective and personalized treatment modalities.
In 2013, following organizational changes at INT, the Supportive Care In Cancer Unit,
responsible for treatment of chronic pain and supportive care in cancer patients, was
assigned to this Department. The Unit pursues clinical, educational, and research objectives
aimed at the prevention assessment, treatment, and study of side effects or toxicity
resulting from cancer therapy, as well as the cure of emotional, social, and spiritual patient
needs through global care of patients starting from diagnosis. The treatments offered are
compliant with guidelines of the WHO, MASCC, ESMO, and AIOM.
The Immunohematology and Transfusion Medicine (SIMT) Unit, responsible for
laboratory diagnosis as well as donation, testing, processing, preservation, storage,
distribution, and transfusion safety of blood components, was also assigned to the
Department. A donor center, apheresis center, and HLA typing laboratory are part of this
Unit.
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HIGHLIGHTS
Integrating Next Generation Sequencing in the molecular diagnosis and monitoring of lymphoproliferative disorders
Development of new clinical trials integrating Next Generation Sequencing data
KEYWORDS
hematopoietic stem cell transplantation, hematological malignancies, pediatric tumors, supportive care, international trials, combination of conventional chemotherapy and targeted agents, transfusion medicine.
HEMATOLOGY AND ALLOGENEIC BONE
MARROW TRANSPLANTATION (ETMO)
Head
Paolo Corradini, MD
Michela Casanova, MD, Andrea Ferrari, MD; Roberto Luksch, MD,
Cristina Meazza, MD; Daniela Polastri, MD, Filippo Spreafico, MD;
Monica Terenziani, MD
Anna Dodero, MD; Lucia Farina, MD; Giulia Perrone, MD; Vittorio
Montefusco, MD; Francesco Spina, MD
Research Staff
Luca Bergamaschi, resident; Veronica Biassoni, MD; Serena
Catania, MD; Stefano Chiaravalli, MD; Marco Vajna de Pava, MD;
Francesca Favini, resident; Barbara Giacon, Psy D; Giacomo Gotti
MD; Carla Moscheo MD; Marta Podda, MD; Nadia Puma, MD;
Elisabetta Schiavello, MD; Fabio Simonetti, MD
Research Staff
Cristiana Carniti, PhD
Residents
Serena Dalto, MD; Chiara De Philippis, MD; Francesco Maura, MD;
Alberto Mussetti, MD; Tommaso Radice, MD; Francesca Rezzonico,
MD; Luisa Roncari, MD; Martina Soldarini, MD
Postdoctoral Fellow
Antonio Vendramin, PhD
PhD Students
Silvia Gimondi, Med Biotech D; Sara Rizzitano, Med Biotech D
Clinical Studies Coordinator
Debora Degl’Innocenti, PhD
Data Manager
Anisa Bermema, Med Biotech D
Marialuisa Longhi, Elena Maggioni
Nurses
Giorgia Gobbi (coordinator), Rosa Abate, Sonia Citro, Riccardo
De Stefano, David Guiote Pertierra, Donatella Luongo, Elisabetta
Martinelli, Simona Mazzella, Francesco Murana, Leonardo Orsini,
Alfonso Parisi, Rita Russo, Rita Sciancalepore, Serafina Tomasicchio,
Giuseppe Torregrossa, Anna Vernone
Research Nurse
Ilaria Lo Russo
Nunzio Bovello, Carmelo Fedele, Evelina Palella, Jose Noboa
Velasco
Cell Processing Tecnicians
Pietro A. Di Nuzzi, Paolo D. Longoni
PEDIATRIC ONCOLOGY
Head
Maura Massimino, MD
36
Elena Barzanò, Liana Bevilacqua, Luna Boschetti, Mattia Bussi,
Chiara Secco, Gabriella Vighi
Social Worker
Giovanna Casiraghi
Teachers
Stefania Benedetti, Anna Bernasconi, Franca Bertola, Antonia Biasi,
Cinzia Cassanelli, Silvia Dragone, Manuela Farina, Andrea Gazzi,
Lucia Toniolo, Immacolata Volpe
Nurses
Mariangela Armiraglio (coordinator), Iris Baranella, Morena Berti,
Daniela Bruno, Cristina Comelli, Patrizia Conti, Domenica Costeri,
Lucia Curelli, Laura De Porras, Ruggero Fauro, Marta Ferrante,
Carmelo Fiorello, Giuseppe Forzini, Marinella Gaidolfi, Rossana
Ghezzi, Laura Lottaroli, Simone Macchi, Rossana Marra, Manuela
Oriani, Elisa Procopio, Silvana Saverino, Elisa Triglia
Annamaria Bilanzuoli, Gisella Cancedda, Rita Carulli, Silvana
Celauro, Rita Marina Tamburro, Stella Uzzardi
SUPPORTIVE CARE IN CANCER
Head
Carla I. Ripamonti, MD
Maria A. Pessi, MD; Gloria Barone, MD
Nurses
Pietro Toma , Laura De Taddei, Giuseppina Bottigliero,
Technicians
Chiarina Pireddu, Fabio Lizzano
Anna Aquilini, Adriana Cremagnani, Anna Cremonesi, Renata
Nobili, Antonella Puntieri, Fulvia Sangermani, Ivana Zaglio, Silvia
Sala, Elisabetta Tandoja
SIMT, IMMUNOHEMATOLOGY AND
TRANSFUSION MEDICINE
Head
Fernando Ravagnani, MD
Clinical Staff
Flavio Arienti, MD; Annalisa Birolini, MD; Paola Coluccia, MD;
Carmela Guarino, MD; Laura R. Terranova, MD; Elisabetta Di
Giuseppe, Biol Sci D; Claudia Lombardo, Biol Sci D; Arabella
Mazzocchi, Biol Sci D
Fellow
Francesca R. Taverna, Biol Sci D
Orietta C. Polisena, Elide Spinelli, Maria C. Zanetti, Giovanni
Veronese
Technicians
Mario Avella, Cinzia L. Biasuz, Alvaro Bompadre, Laura M.
Bonizzoni, Antonella Falanga, Daniela Ferrari, Marina Galbiati,
Annamaria Gorla, Silvia Larghi, Roberto Losa, Antonia Morleo,
Ernestina Pigliafreddo, Lara Pusterla, Roberta Serpi, Lorena
Sfreddo, Barbara Strada, Tiziano P. Tattanelli, Ornella Zanaboni
Nurses
Marisa Dentella, Filomena Fedele, Rita Fiorito, Cristina I. Lasala,
Monica Pedretti, Pietrina Sanna, Carmela Santolla
Antonella Atzeni, Carmela Gizzi, Maria A. Somma, Maria
Tamburriello
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ANESTHESIA,
INTENSIVE CARE,
PAIN THERAPY, AND
PALLIATIVE CARE
DEPARTMENT
DIRECTOR OF DEPARTMENT: Martin Langer
Professor of Anesthesia and Critical Care Medicine
University of Milan
martin.langer@istitutotumori.mi.it
The Department has a key position in the hospital, and is involved in medical and surgical
treatment of cancer patients involving very close collaboration between surgeons, medical
oncologists, radiologists, and pediatricians for many interventional treatments. The main
missions of the Department are peri-operative medicine, palliative care, and terminal support
in the hospice and in-home care for patients with advanced cancer after failure of aggressive
treatments and safety in the hospital. The provision of palliative care and supportive
treatments to cancer patients is recognized as a defining characteristic of a comprehensive
cancer center.
Clinical Anesthesia. INT runs an intense surgical program supported by the Anesthesia
Team, also participating in demanding surgical procedures such as liver transplantation,
major liver resection, peritonectomy-HIPEC, and resection of tumors in the thorax
and retroperitoneum. INT is a referral center for solid tumors in pediatric patients, and
anesthesiologists are also involved in practical techniques such as long-term central venous
catheter placement and administration of anesthesia for diagnostics and radiotherapy.
Intensive Care Unit (ICU). Mainly functions as a surgical ICU and post-anesthesia care
unit, but occasionally treats patients from other medical wards for complications during
chemotherapy. Monitoring and surveillance of high-risk surgical patients and intensive
treatment of patients with life-threatening postoperative complications and/or organ
failure of different origins is the mission of the ICU.
Palliative Care, Pain Therapy, and Rehabilitation. Addressed to the needs of patients in all
stages of disease with the aim of improving quality of life, and provide a system of care and
fully integrated support for the overall program of cancer diagnosis, therapy, and research.
Rehabilitative interventions address or reduce acute and chronic complications after
38
cancer surgery, radiation-therapy, and medical treatments as well as manage complications
in advanced cases. The Unit has a fully dedicated lymphedema clinic that is open 5 days a
week, is linked with the palliative care team service in the hospice, and organizes home care
programs.
Clinical Nutrition. Prevention and early treatment of malnutrition are the main goals of
the Unit. Nutritional intervention should be considered during the different phases of
oncologic therapy: diagnosis, surgery, chemo, and radiotherapy. In accordance with the
recommendations of the European Society of Clinical Nutrition, nutritional screening is
undertaken in all patients with a high risk of malnutrition. Patients affected by any form
of malnutrition are included in a comprehensive nutrition program, which consists of
nutritional status monitoring and personalized nutrition therapy mainly with artificial
nutrition, both enteral and parenteral, nutritional counseling, and diet therapy.
HIGHLIGHTS
The training program for residents in the Anesthesia and Intensive Care Program at the University of Milan is established and allows
5-7 young doctors/year to specialize in clinical anesthesia and acute postoperative pain therapy.
Federico Piccioni is active member of the Working Group in Anesthesia for Thoracic Surgery.
Partecipation in Italian multicenter studies in Anesthesia and Postoperative Care: “Gestione delle vie aeree in chirurgia toracica” and
“Complicanze postoperatorie polmonari in chirurgia addominale maggiore: studio osservazionale prospettico multicentrico”. In both
data collections, our Institution is top contributor.
A research project on prevention of surgical site infection in breast cancer surgery started enroling patients in 2013: by April 2014,
about 1000 patients were enrolled reaching nearly 50% of the planned enrollment.
The “Acute Pain Service” caring for patients after surgery, coordinated by Rossella Brambilla, RN, has nearly completed a dedicated
software program to improve clinical support and research opportunities.
From August 2013, Daniela Codazzi, MD is the new director of our ICU.
Since 2008, the ICU is part of the GiViTI network, part of PROSAFE, a collaborative project aimed at improving the quality of intensive
care medicine.
The research program “European Palliative Care Research Center” (PRC), founded as a collaboration between the Palliative Care, Pain
Therapy, and Rehabilitation Unit and the Cancer Department at the University of Science and Technology in Trondheim (Norway), is
active.
A noteworthy innovation was the establishment of the Master Course (Master Universitario di II° livello di Alta Formazione e
Qualificazione in Cure Palliative) of the University of Milan in Palliative Medicine, one of the first of its kind in Italy, chaired by Prof.
Martin Langer. Our specialists in palliative care as well as several INT clinicians are involved.
The Hospice at INT provides palliative care to any terminally-ill patient, without regard to the patient’s ability to pay for any services
rendered.
KEYWORDS
anesthesia, postoperative treatment, acute pain service, surgical day hospital, palliative care, rehabilitation, nutritional status, artificial
nutrition
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CLINICAL ANESTHESIA
Head
Martin Langer, MD
Mario Ammatuna, MD; Maria Grazia Bonalumi, MD; Anna
Cardani, MD; Roberta Casirani, MD; Pasqualina Costanzo, MD;
Ilaria Donati, MD; Luca Fumagalli, MD; Edward A. Haeusler, MD;
Antonio Maucione, MD; Silvana Migliavacca, MD; Lucia Miradoli,
MD; Marta Negri, MD; Federico Piccioni, MD; Andrea Poli, MD;
Paola Previtali, MD; Giacomino Rebuffoni, MD; Giuseppe Rigillo,
MD; Mara G. Roberto, MD; Emiliano Tognoli, MD; Alessandro
Zanon, MD
Residents
Jacopo Colombo, MD; Valentina Colosio Lombardi, MD; Valeria
Donghi, MD; Giuditta Fallabrino, MD; Silvia Guenzani, MD; Sergio
Lassola, MD; Beatrice Motti, MD; Rosalia Paternò, MD; Noemi
Sacchi, MD
Stefania Bettinardi, Fiorina Cantisani
Nurses
Romano Castellari (coordinator), Elisabetta Anchora, Stefania Soleil
Andreoli, Laura E. Anselmi, Marina Balbi, Marco Balconi, Gilda
Barletta, Silvana Bertoli, Gabriella Bianchessi, Renata Bordonali,
Katia Botrugno, Rossella Brambilla, Debora Buenaventura Boada,
Julia D. Burgos Baena, Silvia Cuccaro, Antonella Chiesa, Liviu D.
Corbu, Maria B. Corbu, Matrona De Felice, Maria Della Croce,
Simonetta Delrio, Andrea Dibiase, Maria A. DiTano, Marina Djokic,
Luca G. Falcone, Federica Fiorini, Claudio Gasparro, Angelo
Giannuzzi, Rosanna Giumbo, Marcella Gozzo, Elisabetyta Kertez,
Mara G. Longo, Ezio Luzzi, Maria P. Maienza, Margherita A. Marzo,
Anna R. Mazzotta, Annamaria Morricella, Tatiana M. Monfredini,
Antonella Nieddu, Nagore Nieto, Lucia Orru, Hippolito Otani,
Barbara Ottonello, Maria R. Pezone, Cecilia Pifarotti, Flavia F. C.
Ravasi, Stefania Ronca, Maria A. J. Rosso, Massimo Sanseverino,
Renato Santini, Salvatore Santucciu, Sara Sciamanna, Paola Striglia,
Adriana Valentini, Filippo Venezia, Silvia Zanotto
Rosa M. Benevento, Pierangela Carrino, Denise de Bastiani, Mario
Castronovo, Vincenzo Dellaquila, Annuccia Delrio, Antonietta
Fantilli, Antonio Labori, Anna Lorenti, Maria Maestri, Francesca
Maiorana, Stefania Massella, Monica Mastrogiovanni, Maria
C. Pirrotta, Maria C. Pisasale, Elisabetta Saccaggi, Elena Scotti,
Carmelo Scrofani, Rosa Selvati, Rosa M. Tirone, Dario Tonelli,
Veronica Valentino, Lucia Velotti
Technicians
Maria I. Cipolletta, Giovanni Di Bari, Gerardo Gizzi, Gianbattista
Grazioli, Monica Mastrogiacomo
VASCULAR ACCESS TEAM: Maria Chiara Allemano, RN
ACUTE PAIN SERVICE: Rossella Brambilla, RN
PRE-ANESTHESIA CLINIC: Andrea Dibase,
INTENSIVE CARE UNIT (ICU)
Head
Daniela Codazzi, MD
Nurses
Katia Masala (coordinator), Salvatore Alcamo, Maria C. Allemano,
Maria P. Augello, Marcantonio Boccola, Alice Casali, Armando
Cofone, Francesco Filippazzo, Michele Gasparini, Masha Kintaba,
Emilia Lonetti, Katia Masala, Flavia Montalto, Laura Morsenti,
Andrea Mulas, Sonia Romero Lemos, Achille Simonetti, Salvatore
Sirigu, Martina Zoanni
J. D. Carmen Garzon, Nadia Duca, Erik Papa, Elisabetta Zedda
PALLIATIVE CARE, PAIN THERAPY,
AND REHABILITATION
Head
Augusto T. Caraceni, MD
Augusta Balzarini, MD; Paola Bracchi, MD; Cinzia Brunelli, MSc;
Tiziana Campa, MD; Laura Campanello, PsyD; Daniela Ermolli,
MD; Fulvia Gariboldi, MD; Silvia Grecchi, MD; Andrea Magni, MD;
Cecilia Mandelli, PsyD; Cinzia Martini, MD; Alessandra Pigni MD;
Luigi Saita, MD; Carmela Sigari, MD; Fabio Simonetti, MD; Ernesto
Zecca, MD; Marco Carminati, Shiatsu Master; Gianluigi Cislaghi,
Shiatsu Master; Giovanni Sala, Chaplain
Physical Therapists
Livia Bedodi, Maria G. Blandini, Chiara Bottani, Simona Breggiè,
Paola Campanini, Lucia Cavallini, Bruna Cotza, Liviana Craba, Heike
Feddersen, Cinzia A. Ficcarelli, Donato Ficchì, Alida Grossi, Chiara
Piazza, Patrizia Placucci, Raffaella Sensi, Beatrice Simoncini
Nurses
Barbara Acquisto, Giuseppe Baiguini, Sara Bianchi, Anna Biondo,
Giuseppina Bottigliero, Rosa A. Candigliota, Renato Della Vittoria,
Olmina Di Florio, Massimo Di Francesco, Vincenzina Ferraro,
Antonella Ferraresi, Anna M. Mazzucchelli, Nives Porta, Edoardo
Rossetti, Arianna Rossi, Federica Sara Rusconi, Annunziata
Sammarro, Gianluigi Schena, Elisabetta Volpato
Marco Andreon, Maria L. Cipolletti, Raffaella Diaferio, Maria R.
Lia, Nataliya Maksymova, Roberta B. Martinelli, Anna Mastroianni,
Teresa Natali, Teresa Pace, Nicola Paternoster
Manuela Brusati, Loredana D’Urso, Chiara Vinuzzi
CLINICAL NUTRITION
Head
Cecilia Gavazzi, MD
Serena Della Valle, MD; Michela Fiscella, MD
Fellow
Jessica Lops
Nurses
Anna Armonti, Franca Filincieri, Carmen Maiorana, Lorena Riva
Silvia Colatruglio, RD
Fortunato D’Elia, MD; Marco Faustini, MD; Renato Manzi, MD;
Laura Persiani, MD; Maurillia Rizzi, MD; Edda Merola, MD, Paola
Previtali, MD
40
DIAGNOSTIC
IMAGING AND
RADIOTHERAPY
DEPARTMENT
DIRECTOR OF DEPARTMENT: Emilio Bombardieri (until 31 August 2013) – Alfonso Marchianò (since 1 September 2013)
+39 02 2390 3144
alfonso.marchianò@istitutotumori.mi.it
The Department is a large multidisciplinary structure comprising different areas of clinical
activity and research, where many disciplines work together in very close interaction. The
Department is equipped with a large number of high-technology facilities and supports the
implementation of biologic imaging and image-guided contouring radiotherapy at INT. The
development and study of several specific radiopharmaceuticals has led to the improvement
of targeted radiotherapy. These achievements are possible thanks to the strong collaboration
of many experts from the fields of physics, biotechnology, biology, radiopharmacy,
instrumentation, and medical sciences.
Radiology and Diagnostic Imaging 1 (Functional Imaging). Carries out conventional
radiologic tests (X-rays), magnetic resonance imaging (MRI), and breast cancer diagnosis
(mammography, US, radioguided biopsies).
Radiology and Diagnostic Imaging 2 (CT and Interventional Imaging). Provides computed
tomography (CT), US, angiography, interventional radiology, intralesional treatments, and
radiological tests for the gastrointestinal tract.
Nuclear Medicine Unit. Provides multidisciplinary clinical and research activities.
It is equipped with a 17 MeV cyclotron and radiochemistry labs for the synthesis of
radiopharmaceuticals for diagnosis and therapy, a bone densitometry scanner, three
gamma-cameras, two PET/CT scanners, and a protective ward for radionuclide therapies.
The Unit performs routinely bone densitometry scans, conventional scintigraphic and
SPECT studies, PET/CT examinations, and radionuclide treatments. In collaboration with
the Experimental Oncology and Molecular Medicine Department, small animal tumor
models can be evaluated with a dedicated micro-PET system.
Radiation Oncology 1. Carries out external beam radiotherapy [3D conformal radiation
therapy, intensity modulated radiotherapy (IMRT), Rapid Arc, image guided radiation
therapy (IGRT), volumetric modulated arc therapy (VMAT), Calypso 4D localization
system].
Radiation Oncology 2. Provides treatments of external beam radiotherapy for head and
neck and gynecologic cancer and high-dose rate brachytherapy (HDR-BT) treatments
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mainly for gynecologic and prostate cancer. Combination of chemo- and radiotherapy and
supportive care are delivered in an inpatient setting.
Medical Physics. Supports the Radiation Oncology Units in planning radiotherapy
treatments and dosimetric calculations. This Unit also takes care of quality control of
instruments for diagnostic imaging. A personal dosimetry laboratory is present in the unit
as a part of the radioprotection activity.
HIGHLIGHTS
DWI (diffusion-weighted imaging) and MRS (MR spectroscopy) have been validated as emerging functional tools to improve information about the vitality or aggressiveness of cancer tissue.
Breast MRI and pre-operative staging of cancer are performed as part of a surveillance program of high risk and BRCA mutation
carriers.
A dosimetric study of digital mammography combined with tomosynthesis exams was performed in order to assess benefits and related harms.
In liver cancer, we evaluated the use of radiofrequency hyperthermia therapy combined with the arterial stop flow procedure to
achieve maximum effectiveness with minimal invasiveness. This procedure has been formally endorsed by the Italian Society of
Interventional Radiology.
Original experience of percutaneous cryoblation continued in selected patients with small renal tumors.
Intra-arterial treatment of HCC with 90Y loaded glass microspheres (in collaboration with Gastrointestinal, Hepatopancreatobiliary
Surgery and Liver Transplantations Unit).
PET/CT studies using different PET radiopharmaceuticals (18F-FDG, 11C-Methionine, 68Ga- DOTATOC, 18F-FLT).
Preclinical studies in animal tumor models with a micro-PET system (in collaboration with the Experimental Oncology and Molecular
Medicine Department).
Radionuclide therapy with 90Y-Zevalin in non-Hodgkin’s lymphomas. Novel approaches for the treatment of neuroendocrine tumors
with tandem radiolabeled somatostatin analogues (111Lu and 90Y DOTA-TATE).
Implementation of partial breast irradiation: “SHARE - Cyberknife Partial Breast Irradiation for Early Stage Breast Cancer”, a study
performed in conjunction with the IRCCS Istituto Neurologico Besta of Milan.
Prediction of acute and late toxicity (rectal, erectile, bladder, skin toxicity) after high dose radiotherapy, correlation with plasma levels
of inflammatory markers and acute and late toxicity after prostate cancer irradiation, quality of life new fractionation schemes, and
treatment modalities.
High-dose rate brachytherapy (HDR BCT) is given as endocavitary treatment in uterine cancers, as endoluminal BCT in biliary tract
cancers, and as interstitial BCT in prostate cancer with HDR equipment (Selectron®). In collaboration with the Centre for Medical
Radiation Physics (University of Wollongong, Australia) and the Materials Science Department (University of Milan Bicocca, Italy) new
detectors were studied and applied to perform in vivo dosimetry during highly hypo-fractionated prostate HDR BCT treatments.
In collaboration with the Politecnico di Milano, software to merge CT and MR imaging was developed. The software is able to deform
the images to take into account the growth of children. This work is a part of a research where correlations between white and gray
matter changes, evaluated by magnetic resonance diffusion tensor imaging (DTI), RT dose, and neurocognitive damages in children
who underwent focal brain RT for malignant brain tumors will be studied.
KEYWORDS
breast imaging, MRI, radiology, functional imaging, diffusion imaging, radiofrequency, percutaneous thermal ablation, tumor cryoblation ablation, pediatric radiotherapy, external beam radiotherapy, brachytherapy, dosimetry, spectrophotometry
42
RADIOLOGY 1 (FUNCTIONAL IMAGING)
Head
Pietro Panizza, MD
Nurses
Piero Ciccarese, Laura Fagnani, Addolorata Mauro, Nadia Nicoletti,
Roberta Populin, Marinella Porceddu
Claudio Ferranti, MD; Alberto Laffranchi, MD; Monica Marchesini,
MD; Antonella Messina, MD; Laura Suman, MD;
Giovanna Trecate, MD
Ornella Venegoni
Magnetic Resonance
Daniele Vergnaghi, MD (Head)
Radiology and Magnetic Resonance GI Tract
Davide Scaramuzza, MD (Head),
Pediatric Magnetic Resonance
Paolo Potepan, MD (Head), Roberta Cherubini (Data Manager)
Breast Imaging Unit
Gianfranco Scaperrotta, MD (Head)
Alessandra Casale, MD; Marta Vaiani, MD
Residents
Emanuela Capalbo, MD; Maria Cosentino, MD; Sara Viganò, MD
Technicians
Cristina Folini (coordinator), Gaetano Annunziata, Luisa Colombo,
Luciana Dedei, Cinzia Fossaceca, Antonella Laturra,
Maria Pia Mannella, Tina Mastrostefano, Luca Musumeci,
Carmelina Pannone, Nicola Pulerà, Stefania Sala, Anna Tavola,
Valeria Tosi, Maurizio Zattoni
Nurses
Mirella Ferruccio, Loredana Palella
Guglielmina Riccio
Giuseppa Pacicca
RADIOLOGY 2 (DIAGNOSTIC AND
INTERVENTIONAL RADIOLOGY)
Head
Alfonso Marchianò, MD
Enrico Civelli, MD; Giuseppe Di Tolla, MD; Laura F. Frigerio, MD;
Rodolfo Lanocita, MD; Marco Milella, MD; Carlo Morosi, MD;
Monica Salvetti, MD; Carlo Spreafico, MD
NUCLEAR MEDICINE
Head
Emilio Bombardieri, MD (until 31 August);
Flavio Crippa, MD (since 1 September)
Alessandra Alessi, MD; Gianluca Aliberti, MD;
Anna Bogni, Biol Sci D; Maria R. Castellani, MD;
Carlo Chiesa, Physicist; Alice Lorenzoni, MD Marco Maccauro, MD;
Claudio Pascali, Radiochemist; Gianluca Serafini, MD
Clinical Pet
Flavio Crippa, MD (Head)
Nuclear Medicine Therapy and Endocrinology
Ettore Seregni, MD (Head)
Claudio Cucchi, Chemist; Barbara Padovano, MD;
Federica Pallotti, MD; Elisa Galli, Chemist
Technicians
Monica Testoni (coordinator), Grazia Aprigliano, Davide Bassani,
Gianenrico Cucchetti, Carlotta Edera, Maria Di Francesco,
Martino Faedi, Rita Filieri, Deborah Mansi, Rossana Pavesi,
Matteo Ragazzoni, Lidia Spano, Roberto Segreti
Nurses
Rita Sicari (coordinator), Cristina De Somma, Carmela Fallacara,
Dario Longo, Calogero Oliveri, Aurelio Scarabelli
Rosangela Ghilardi
RADIATION ONCOLOGY 1
Head
Riccardo Valdagni, MD
Nice Bedini, MD; Anna Di Russo, MD; Claudia Sangalli, MD;
Fulvia Soncini, MD; Sergio Villa, MD
Gastrointestinal Radiotherapy
Francesca Valvo, MD (Head)
Diagnostic and Interventional Gastroenterology
Guido Cozzi, MD (Head)
Breast Cancer Radiotherapy
Laura Lozza, MD (Head)
Intralesional Treatment Unit
Francesco Garbagnati, MD (Head)
Pediatric Radiotherapy
Lorenza Gandola, MD (Head)
Tommaso Cascella, MD; Giuseppina Calareso, MD
Clinical and Research Fellows
Barbara Avuzzi, MD; Maria Carmen De Santis, MD;
Marzia Franceschini, MD; Sara Morlino, MD; Emilia Pecori, MD;
Elisa Ciurlia, MD; Mulugeta Haile Techlemichael, MD
Residents
Guglielmo Cannella, MD; Tien T.U. Van, MD
Technicians
Antonio Perchinunno (coordinator), Pietro Basile,
Enrico De Pedri, Maria Ferrarello, Roberto Gallo,
Giuseppina Gentile, Maria Giovanna Grossi, Luca Lanzillotti,
Roberto Nioi, Luciana Tanzini, Vanni Tirella
Resident
Chiara Chiruzzi, MD
Technicians
Franca Gaetano (coordinator), Claudio Boccadamo,
Giuseppina Bonanno, Alberto Buzzetti, Carmelo Campolo,
Federica Caputo, Gabriele Carabelli, Pasquale Contessa,
Lucio Donatone, Rosa Fortunato, Sarah Frasca, Emanuela Gatti,
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Manuela Guerra, Antonio Spartano, Francesca Spartano,
Carla Valenti, Luca Zappa
Nurses
Pasquale Brunacci, Flavia Montalto, Emanuela Visentin
Grazia Arpaia, Manuel Cornelli, Paola Fiolo, Luca Pedone,
Sebastiano Sicilia, Cristina Terenghi
Donatella Orlandi, Patrizia Riva
Data Manager
Laura Andreoli
RADIATION ONCOLOGY 2
Head
Carlo Fallai, MD
Annamaria Cerrotta, MD; Ester Orlandi, MD; Silvia Tana, MD
Eva Iannacone, MD; Anna Maria Mileo MD, Garcia Monica, MD
Resident
Pappalardi Brigida, MD
Technicians
Ciro Pintaudi, (coordinator), Sergio Bavusi, Paolo D’Agnese,
Carmelo Di Marco, Dayana Pignata, Piera Fusar Poli
Nurses
Elena Omati (coordinator), Roberta Albasini, Rosa Attolino,
Antonella Causio, Luigia Cerra, Cinzia Cocca, Fabrizio D’Amico,
Patrizia Galantin, Carmen R. Garcia Cuesta, Carmen Greco,
Yuliya Kovhan, Antonio Lucenti, Filippo Monno, Erminia Nardo,
Vincenza Natola, Samanta Palmisano, Michela Saracino,
Luigi Tamburrino
Angela Abatangelo, Fabrizio D’Amico, Marlene Fuentes Delgado,
Giuseppe Gaglio, Virginia Marini, Gianluca Severgnini,
Claudia Soave
MEDICAL PHYSICS
Head
Emanuele Pignoli, Med Phys D
Marta Borroni, Med Phys D; Mauro Carrara, Med Phys D;
Valeria Mongioj, Med Phys D; Claudio G. Stucchi, Med Phys D
Fellows
Manuela Lualdi, Med Phys D; Claudia Cavatorta Phys D
Residents
Francesca Bonfantini, Phys D; Anna Cavallo Phys D,
Tommaso Giandini, Phys D; Silvia Meroni, Phys D;
Chiara Tenconi, Phys D
Technicians
Vito Cosentino, Luca Marrone, Ester Mazzarella, Dario Posté
Giuseppina Esposito
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PATHOLOGY
AND LABORATORY
MEDICINE
DEPARTMENT
DIRECTOR OF DEPARTMENT: Giuseppe Pelosi
Professor of Pathology, University of Milan
+39 02 2390 3017
giuseppe.pelosi@istitutotumori.mi.it
The mission of the Department is to provide accurate diagnoses and information of prognostic
and therapeutic value to clinicians. The activities of Surgical Pathology, Diagnostic Molecular
Pathology, Cytopathology, and Autopsy Pathology are carried out in the two Anatomic
Pathology Units, while laboratory tests and microbiological investigations are carried out at
the Laboratory Medicine Unit, all using state-of-the-art techniques and quality certification
(ISO9001; 2000-2015).
HIGHLIGHTS
The Department is engaged in the Institutional human frozen tumor tissue bank, a project aimed at the creation of an extensive collection of human tissues that is not restricted to a specific organ or disease type, as well as in a telepathology project involving several
Italian cancer Institutes.
Extensive pheno-genotyping and assessment of predictive and/or prognostic factors are an integral part of diagnosis and research
activities aiming at the best clinical management of patients, as well as developing diverse research in several human cancers.
KEYWORDS
therapeutic pathology, immunohistochemistry, diagnosis, molecular assay, mutation, in situ hybridization, cytofluorimetry, clinical
chemistry, hematology, microbiology
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ANATOMIC PATHOLOGY UNITS 1 AND 2
Heads
Maria Luisa Carcangiu, MD: Anatomic Pathology Unit 1
Giuseppe Pelosi, MD: Anatomic Pathology Units 2
Marta Barisella, MD; Antonello D. Cabras, MD; Paola Collini, MD;
Maurizio Colecchia, MD; Alessandra Fabbri, MD; Massimo Milione,
MD; Biagio Paolini, MD; Alessandro Pellegrinelli, MD; Pasquale
Quattrone, MD; Gabrina Tragni, MD; Barbara Valeri, MD; Antonella
Aiello, Biol Sci D; Annunziata Gloghini, Biol Sci D; Federica Perrone,
Biol Sci D; Carla Riva, Biol Sci D (Coordinator of Cytopathology),
Mario Ruggeri, Biol Sci D; Elena Tamborini, Biol Sci D; Adele Testi,
Biol Sci D
Fellows
Manuela Bimbatti, MD; Giorgia Leone, MD; Ester Antelmi, Biol Sci
D; Enrica Bovio, Biol Sci D; Adele Busico, Biol Sci D; Elena De Paoli,
Biol Sci D; Ambra Gualeni, Biol Sci D; Gabriella Montemurro, Biol
Sci D; Giulio Settanni, Biol Sci D; Francesca Testa, Biol Sci D; Chiara
Volpi, Biol Sci D
Technicians
Claudia Alphandery (Cytotechnologist); Maria Grazia Bonora;
Renata Borchini; Rita A. Carminati; Giovanni Centonze; Luca
Cesana; Alessandra Chinosi; Marilena Colantuono; Silvia Colombo
(Cytotechnologist); Daniela De Bari; Francesca Dominoni (Chief
Technician); Alessandra Elli; Maria Grazia Facciorusso; Elena
Fomiatti; Angelo Gaito; Daniela Galbiati; Morena Gobbo; Rosangela
Intorre; Teresa Labella; Matteo Marcuzzo; Alessia Mietta; Marzia
Mietta; Loretta Missiato; Maria Luisa Moiraghi; Margherita Mondini;
Paola Murè; Marta Orsenigo; Desirè Parimbelli; Katia Ponzoni
(Cytotechnologist); Silvia Redaelli; Consiglia Sgura
Administrative personnel
Patrizia Cangioli; Margherita Cariglia; Maria Teresa Codecasa; Maria
Cristina Di Bartolomeo; Mariangela Girotti; Maria Morelli; Alda Tosi;
Enrica Colzani (volunteer)
Paolo Castioni, Cosima Ciccarese, Massimo Festa, Paola Tonielli,
Anna Urbano
Personnel involved in specific research activities
Silvana Pilotti, MD (responsible for selected research projects)
Research Fellows
Antonino Belfiore, Biol Sci D; Fabio Bozzi, Biol Sci D; Tiziana Negri,
Biol Sci; D; Gian Paolo Dagrada, Biol Sci D; Claudia Bertan, Biol Sci
D; Silvia Brich, Biol Sci D; Elena Conca, Biol Sci D; Barbara Cortelazzi,
Biol Sci D; Valentina Mauro, Biol Sci D; Rosalin Dolores Spagnuolo,
Biol Sci D
LABORATORY MEDICINE
Head
Daniele Morelli, Biol Sci D
Mariachiara Bonini, Biol Sci D; Eutilia Conte, Biol Sci D; Antonio
Mastroianni, Biol Sci D; Roberta Rossi, Biol Sci D; Loredana Simoni,
MD; Giovanna Viola, Biol Sci D
Technicians
Giuseppina Ballabio, Rosella Bonfanti, Chiara Brusati, Maria R.
Carati, Maria R. Cattaneo, Maria V. Corengia, Teresa Fontana, Carlo
Maggi, Roberta Marchetti, Valerio Motta, Giuseppa Perrucci, Pia S.
M. Picco, Marco Ranzani, Nicola Salvatore, Federica Sozzani
Santa Zingone
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EXPERIMENTAL
ONCOLOGY
AND MOLECULAR
MEDICINE
DEPARTMENT
DIRECTOR OF DEPARTMENT: Maria Grazia Daidone
+39 02 2390 2238
mariagrazia.daidone@istitutotumori.mi.it
This Department includes 10 Research Units and one AIRC-awarded start-up Unit dedicated
to preclinical investigations. Its primary goal is to serve as an important conduit through which
new discoveries are applied to cancer diagnosis, prognosis, and treatment. This is fostered
by a collaborative environment and strong interaction among physicians and basic scientists
working in different disciplines, as well as by collaborations with research groups in Italy and
abroad.
The activity of the Research Units is addressed:
• to identify and validate biomolecular features associated with tumor development and
progression as diagnostic, prognostic, and treatment response/resistance markers,
and as molecular targets to develop new treatment approaches;
• to investigate the tumor microenvironment and extracellular matrix at a molecular and
functional level;
• to elucidate the interactions between tumor cells and the immune system;
with the final aims of:
• developing highly sensitive tests (which utilize a panel of novel biomolecular markers)
for a possible clinical application;
• preclinical testing of novel drug combinations, and to develop novel therapeutic
agents;
• identifying novel therapeutic strategies based on immunomodulation, and to develop
vaccination strategies, also taking advantage of the acquired competence in developing
new generation recombinant antibodies.
Such studies involve multidisciplinary approaches, statistical and bioinformatic
methodologies, and integration among the different high-throughput and high-resolution
methodologies and functional tests. Investigations are carried out using different preclinical
experimental models and validated on large series of human biospecimens.
47
The Department supports investigators with state-of-the-art core facilities, with shared
instrumentation and trained specialists.
• Molecular Mechanisms of Cell Cycle Control. Research of the Unit is oriented towards:
i) analysis of the ATM-dependent pathway in the cellular DNA damage response to double
strand breaks and alterations of this response in tumor cells and in cancer-predisposing
neurodegenerative syndrome; ii) development of pro-apoptotic SMAC-mimetic compounds
with anticancer activity targeting the BIR3 domain of the inhibitor of apoptosis XIAP,
frequently upregulated in tumors.
• Molecular Mechanisms. The Unit is involved in studies of the molecular mechanisms
of thyroid carcinogenesis. The final goal of ongoing studies is the identification of markers
useful for early detection, prognosis, and follow-up, as well as novel therapeutic targets
through: i) the generation of in vitro models of thyroid carcinogenesis; ii) analysis of the
role of selected pathways and molecules; iii) mRNA and microRNA expression analysis; iv)
characterization of a thyroid tumor case collection, used both for discovery and validation
studies.
• Tumor Genomics. The research activity covers all aspects of lung cancer with the
final aim of making an impact on a disease that is a major health-care burden in terms of
morbidity and mortality. The Unit uses an integrated approach that combines cellular and
molecular biology, biochemistry, and pharmacology to gain new insights in the pathogenesis
of lung cancer and to find novel ways to provide early diagnosis and new treatment options.
The goal of translational studies is the implementation of highly sensitive molecular
tests that can be included in screening programs to improve both detection and clinical
management of lung cancers.
• Immunobiology of Human Tumors. The research activity focuses mainly on cutaneous
melanoma. The main goals are: i) to understand how the adaptive immune response
developed by cancer patients or promoted by immunotherapy can contribute to control
tumor growth; ii) to identify new molecular targets to overcome melanoma resistance to
target-specific therapy; iii) to understand the mechanisms of interaction of the tumor with
its microenvironment; iv) to develop a functional classification of melanoma based on RTK
expression and intracellular signaling pathway activation.
• Molecular Immunology. This Unit investigates the complex interplay between cells
of the immune system, the extracellular matrix, and transforming tissues, following the
hypothesis that the evolving microenvironment is crucial for the fate of incipient tumors
and might therefore offer new therapeutic targets within stroma components. Taking
advantage of knock out and transgenic mouse models, the role of immune cells (such as
mastocytes, T regulatory cells, neutrophils and myeloid derived suppressor cells) and their
cross-talk in the context of the tumor stroma embedded in the ECM are elucidated to
understand tumor and metastasis development in different neoplasms (prostate, breast,
colitis-associated cancer, osteosarcoma, lymphoma and myeloid malignancies).
• Immunotherapy of Human Tumors. The major goal is to investigate the cross-talk
between tumor cells and the host immune systems in cancer patients, to understand their
impact on disease course and response to treatments, and to identify novel therapeutic
strategies based on immune manipulation. Towards this aim, the Unit includes both clinical
and experimental expertise, to focus on: i) clinical and immunological effects of immunebased cancer therapies; ii) cancer-related immune regulatory pathways; iii) molecular
studies on melanoma progression markers.
• Biomarkers. Research in this Unit is aimed at identifying and validating cancer-related
and actionable biomarkers relevant for cancer progression, using molecular and cell
biology, high-throughput techniques, and bioinformatic tools. Studies are mainly focused on
breast cancer to investigate: i) gene expression profiles on “critical” samples (formalin-fixed
paraffin-embedded material and/or limited amount of cells, such as circulating tumor cells
and tumor-initiating cells); ii) microRNA as blood-derived biomarkers that are potentially
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useful for early detection and risk assessment through non-invasive approaches. In order
to develop sensitive and specific tests for clinical application, particular efforts have
been spent in the last years to understand pre-analytical and analytical confounders for
circulating markers.
• Molecular Targeting Unit. This Unit is currently focused on identifying new molecular
targets against which to design drugs against molecular pathways sustaining breast cancer
progression without disrupting normal cell functions. Research activities are directed
to investigate: i) the patho-biological role of extracellular matrix components in disease
progression and response to therapy; ii) therapeutic targets in triple-negative breast
tumors, and mechanisms involved in the early metastatic capability; iii) activity of resistance
mechanisms to HER2-targeted therapies.
• Molecular Therapies. Through a multidisciplinary approach and the integration of
functional and analytical methodologies, the Unit aims: i) to gain insight into the molecular
events involved in tumor progression; ii) identify and validate new potential targets and
prognostic/predictive markers; iii) develop and validate new diagnostic/therapeutic
strategies, mainly based on new generation recombinant antibodies, to target ovarian and
prostate cancers.
• Molecular Pharmacology. The research activity is focused on: i) identification and
validation of novel therapeutic targets, (i.e. G-quadruplex structures and heparanase);
ii) dissection of drug resistance mechanisms in tumor cells; iii) rational design of novel
anticancer drug combinations; iv) preclinical development of novel therapeutic agents,
based on the availability of a large number of preclinical models of human tumors of
different histologic type; v) identification and functional validation of microRNAs as novel
therapeutic targets/tools.
• AIRC Start Up Unit. The goal is the identification and study of microRNAs involved in
the most important pathways activated in human breast cancer through investigations
on: i) microRNAs involved in molecular pathways associated with the different molecular
subtypes; ii) biological effects of the microRNAs of interest identified in the previous
task and validation of putative targets; iii) prognostic/predictive significance of selected
microRNAs on series of primary breast carcinomas; iv) identification of the mechanisms
regulating the expression of candidate microRNAs.
HIGHLIGHTS
In sentinel nodes of melanoma patients with progressing disease, CD30/TNFRSF8 is upregulated and a higher number of CD30(+) lymphocytes can be detected in nodes and peripheral blood lymphocytes from these patients. These findings reinforce the concept that
sentinel nodes act as pivotal sites for determining progression patterns, revealing that the presence of CD30(+) lymphocytes at those
sites correlates with melanoma progression.
Unsupervised clustering analyses in independent datasets of invasive breast tumors profiled by using different platforms segregated
ECM3 tumors as an independent subset in all datasets. ECM3 showed a homogeneous gene pattern, consisting of 58 genes encoding
43 structural ECM proteins. Both stromal and breast carcinoma cells can coordinately express ECM3 genes, contributing to an extracellular matrix gene expression profile defining a molecular subtype that is likely to progress.
The diagnostic performance of a noninvasive plasma microRNA signature classifier (MSC) was retrospectively evaluated in samples prospectively collected from smokers within the randomized Multicenter Italian Lung Detection (MILD) trial. The diagnostic
performance of MSC for lung cancer detection was 87% for sensitivity and 81% for specificity across both arms, and 88% and 80%,
respectively, in the LDCT arm. This large validation study indicates that MSC has predictive, diagnostic, and prognostic value and could
reduce the false-positive rate of LDCT.
miR-205 showed to be the most down-modulated miRNA in prostate cancer (PCa) cells upon CAF stimulation, due to transcriptional
repression by HIF-1, a redox- sensitive transcription factor. miR-215 replacement in PCa cells is able not only to prevent but also to revert the oxidative/pro-inflammatory axis leading to EMT induced by CAFs. Such finding sets the rationale for developing miRNA-based
approaches to prevent and treat metastatic disease. Moreover, miR-205 proved to impair the autophagic flux and to enhance cisplatin
cytotoxicity in castration-resistant prostate cancer cells.
Acidification proved to induce reversible anergy in both human and mouse CD8+ T lymphocytes in vivo and in the tumor microenvironment, and the administration of proton pump inhibitors, which buffer tumor acidity, can revert T-cell anergy and increase the
efficacy of immunotherapy. Such findings show that acidification of the tumor microenvironment may represent a novel mechanism of
immune escape that can be overcome by drugs targeting pH-regulatory pathways.
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The anti-tumor activity of CpG oligodeoxynucleotides (CpG-ODN) aerosol was demonstrated in mouse lung metastases. In particular, aerosolized CpG-ODN activated a local immune response, while tumor immunogenicity and tumor-induced immunosuppressive
environment represent critical factors for the success of CpG therapy in the lung. Combination of CpG-ODN, cetuximab, and cisplatin
displayed high efficacy for advanced ovarian xenograft tumors. CpG-ODN combination therapies that enhance the immune response
in the tumor microenvironment and concomitantly target tumor cells are highly active even in experimental advanced malignancies.
Using mouse tumor and cellular models, trabectedin, a recently approved chemotherapeutic agent, proved to induce rapid apoptosis
exclusively in mononuclear phagocytes.
SM83, a newly synthesized dimeric SMAC mimetic, modulates in vivo the immune system within the tumor microenvironment and,
through its pro-inflammatory action, induces cancer cells to die by necrosis. Our work provides evidence that SMAC mimetics could be
more therapeutically active than expected by stimulating the immune system.
The heparanase inhibitor SST0001, alone and in combination with antiangiogenic agents, showed antitumor efficacy in human pediatric sarcoma models.
Cisplatin or oxaliplatin, in combination with the MEK1/2 inhibitor CI-1040, resulted in a synergistic effect associated with enhanced
apoptotic response in platinum-sensitive cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors
(BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6).
KEYWORDS
antibody-based therapy, apoptosis, blood-derived biomarkers, cancer vaccines, circulating tumor cells, drug resistance, exosomes,
extracellular matrix, microRNA, preclinical drug development, regulatory T cells, solid tumors, target-specific therapy, translational
medicine, tumor genetics, tumor microenvironment.
MOLECULAR MECHANISMS OF CELL CYCLE
CONTROL
Head
Domenico Delia, Biol Sci D
Benjamin Nachimuthu, Biol Sci D, PhD; Clara Ricci, Med Biotech,
PhD; Laura Zannini, Biol Sci D, PhD
Research Fellows
Luigi Carlessi, Biol Sci D; Federico Lorenzetti, Med Biotech D;
Vincenzo Ruscica, Mol Biol Sci D
PhD Students
Daniele Lecis, Biol Sci D; Annalisa Conti, Biol Sci D; Elena FusarPoli, Biol Sci D, Martina Magni, Biol Sci D
Technician
Enrico Fontanella
MOLECULAR MECHANISMS
Head
Maria Angela Greco, Biol Sci D
Research Staff
Maria Grazia Borrello, Biol Sci D; Italia Bongarzone, Biol Sci D
Maria Grazia Vizioli, Med Biotech D; Maria Chiara Anania, Biol Sci
D; Mara Mazzoni, Biol Sci D; Paola Romeo, Med Biotech D; Cetti
Elena Med Biotech D, Dario Caccia, Med Biotech D, Luca Varinelli,
Med Biotech D.
PhD Student
Emanuela Minna, Biol Sci D
Technicians
Maida De Bortoli, Sonia Pagliardini, Maria Grazia Rizzetti, Elena
Taverna
50
TUMOR GENOMICS
Head
Gabriella Sozzi, PhD
Research Staff
Luca Roz, Pharm Sci D
Francesca Andriani, Pharm Sci D; Giulia Bertolini, Med Biotech D,
PhD; Patrizia Gasparini, Biol Sci D; Massimo Moro, Biol Sci D, PhD;
Carla Verri, Biol Sci D
PhD Students
Mattia Boeri, Biotech D, Tiziana Caputo, Pharm Biotech D
Technicians
Roberto Caserini, Davide Conte; Federica Facchinetti, Mavis
Mensah
IMMUNOBIOLOGY OF HUMAN TUMORS
Head
Andrea Anichini, Biol Sci D
Research Staff
Roberta Mortarini, Biol Sci D; Marialuisa Sensi, Biol Sci D
Fellows
Giulia Grazia, Biotechnol Sci D; Ilaria Penna, Biol Sci D; Valentina
Perotti, Biol Sci D; Elena Tassi, Biotechnol Sci D
Technicians
Paola L. Baldassari, Ilaria Bersani, Alessandra Molla, Gabriella
Nicolini, Claudia Vegetti
MOLECULAR IMMUNOLOGY
Head
Mario P. Colombo, Biol Sci D
Research Staff
Silvia Miotti, Biol Sci D; Claudia Chiodoni, Biol Sci D
Agniezka Chronowska, Biol Sci D, PhD; Giorgio Mauri, Med
Biotech D;Sabina Sangaletti, Biol Sci D, PhD; Caterina Vitali, Pharm
Biotech D, PhD; Alessia Burocchi, Biol Sci D
PhD Students
Alice Rigoni, Biol Sci D; Andrea Tomirotti, Med Biotech D, Ilaria
Torselli, Biol Sci D
Technicians
Ivano Arioli, Barbara Cappetti, Ileana Facetti, Renata Ferri, Mariella
Parenza, Claudia Bassani, Laura Botti, Biol Sci D; Chiara Ratti
IMMUNOTHERAPY OF HUMAN TUMORS
Head
Licia Rivoltini, MD
Research Staff
Chiara Castelli, Biol Sci D; Monica Rodolfo, Biol Sci D
Maja Burdek, PhD (Fellowship from DFG, German Research
Association); Chiara Camisaschi, Biol Sci D, PhD; Annamaria De
Filippo, Biol Sci D, PhD; Paola Filipazzi, Biol Sci D; Veronica Huber
MD, PhD; Viviana Vallacchi, Biotechnol Sci D, PhD; Elisabetta
Vergani, Biol Sci D, PhD
PhD Students
Olga Kuchuk Biol Sci D; Marcella Tazzari, Pharm Sci D
Fellows
Sara Rigoletto, Biol Sci D; Alessandra Tuccitto, Biol Sci D
Technicians
Valeria Beretta, Agata Cova, Paola Deho, Simona Frigerio,
Francesca Rini, Paola Squarcina
Research Nurses
Felicetta Giardino, Gianluigi Rigamonti
Data Manager
Paola Frati
BIOMARKERS
Head
Maria Grazia Daidone, Biol Sci D, PhD
Research Staff
Vera Cappelletti, Biol Sci D; Silvia Veneroni, Biol Sci D; Raffaella
Villa, Biol Sci D
Valentina Appierto, Biol Sci D, PhD; Valentina Angeloni, Biol Sci D,
PhD
PhD Students
Maurizio Callari, Med Biotech D; Emanuela Fina, Biol Sci D; Valeria
Musella, Med Biotech D
Research Fellows
Eleonora Di Buduo, Med Biotech D; Giuseppe Merlino, Med
Biotech D; Paola Tiberio, Biol Sci D
Technicians
Cinzia De Marco, Chiara Iacona, Patrizia Miodini, Biol Sci D; Gloria
Morandi, Rosita Motta
MOLECULAR TARGETING UNIT
Head
Elda Tagliabue, Biol Sci D
Research Staff
Rosaria Orlandi, Biol Sci D; Serenella Pupa, Biol Sci D
Postdoctoral Fellow
Manuela Campiglio, Biol Sci D
PhD Students
Gaia C. Ghedini, Biotech Sci D; Marta Giussani, Biotech Sci D;
Alessandra Meini, Biol Sci D; Marianna Sasso, Biol Sci D; Tiziana
Triulzi, Biotech Sci D
Fellows
Lorenzo Castagnoli, Biotech Sci D; Valentina Ciravolo, Biotech Sci
D; Viola Regondi, Biotech Sci D; Anna Rossini, Biol Sci D; Federica
Turdo, Biol Sci D
Consultants
Sylvie Ménard, Biol Sci D; Marco Sandri, Stat Sci D
Technicians
Pierangela Aiello, Patrizia Casalini, Cristina Ghirelli
MOLECULAR THERAPIES
Head
Silvana Canevari, Biol Sci D
Research Staff
Mariangela Figini, Biol Sci D; Delia Mezzanzanica, Biol Sci D;
Antonella Tomassetti, Pharmacol Sci D
Fabio Benigni, Biol Sci D; Marina Bagnoli, Biol Sci D
Fellows
Chiara Alberti, Biol Sci D; Davide Bernareggi, Biol Sci D; Barbara
Frigerio, Biol Sci D; Anna Granata, Biol Sci D; Roberta Nicoletti,
Med Biotech D; Patrizia Pinciroli, Biol Sci D; Katia Rea, Med
Biotech D; Alessandro Satta, Vet Biotech D; Valentina Tinaglia, Sci
Biotech D
Technicians
Paola Alberti, Francesco Caroli, Anna Maria Invernizzi, Elena
Luison, Cristina Luna
MOLECULAR PHARMACOLOGY
Head
Nadia Zaffaroni, Biol Sci D, PhD
Research Staff
Marco Folini, Biol Sci D, PhD; Cinzia Lanzi, Biol Sci D; Paola Perego,
Biol Sci D, PhD
Giovanni l. Beretta, Biol Sci D, PhD; Joanna Bidzinska, Biotech Sci
D, PhD; Giuliana Cassinelli, Pharm D, PhD; Graziella Cimino Reale,
Biol Sci D, PhD; Michelandrea De Cesare, Vet D; Paolo Gandellini,
Biotech Sci D, PhD; Laura Gatti, Biol Sci D, PhD; Alessia Lopergolo,
Biotech Sci D, PhD; Marzia Pennati, Biol Sci D, PhD; Valentina
Zuco, Biol Sci D
PhD Student
Valentina Profumo, Biol Sci D
Fellows
Denis Cominetti, Biol Sci D; Nicola Fenderico, Biotech Sci D;
Francesca Santambrogio, Biol Sci D; Stefania Sbarra, Biol Sci D
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Technicians
Elisa Campi, Nives Carenini, Elena Cavadini, Elisabetta Corna,
Laura Delbo, Enrica Favini, Maria Stella Tinelli, Monica Tortoreto
AIRC START UP UNIT
Head
Marilena V. Iorio, Biotech Sci D
The following core facilities are available.
Immunohistochemistry (Technical Specialists: Lorena
Ventura and Lucia Gioiosa): histological and cytological
processing, including tissue microarrays, a wide range of
histological techniques, immunohistochemistry, in situ
hybridization, and autoradiography.
Cell imaging facility (Technical Specialist: Patrizia Casalini,
Biol Sci D): provides access to BioRad Radiance 2000 and
Leica SP8 AFC AOBS WLL HyD laser confocal microscopes
allowing for a wide range of fluorescent dye use, sequential,
and simultaneous 3 channel bright field image collection,
and live cell imaging.
Flow cytometry and cell sorting (Technical Specialist:
Gabriella Abolafio; Research Fellow: Andrea Vecchi, Biol
Sci D): state-of-the-art flow cytometric and cell sorting
instrumentations, and software analysis.
Microbiology (Technical Specialist: Maria Teresa Radice):
core services include media preparation; bacterial
transformation; purification of plasmid DNA, BAC, YAC;
freezing and storage of recombinant plasmids and bacterial
strains.
Cytogenetics and molecular cytogenetics (Specialist:
Patrizia Gasparini, Biol Sci D): with state-of-the-art
instruments, approaches of classic and molecular
cytogenetics (fluorescent in situ hybridization and
karyotype analysis using spectral karyotyping) and
dedicated software allows identification of specific
chromosomal alterations that are potentially useful for
cancer diagnosis and as targets for novel treatments and/or
associated with drug resistance in several solid tumor types
(in particular, lung, colon and breast cancers, and soft tissue
sarcomas).
Functional genomics and Bioinformatics (Marina Bagnoli,
Biol Sci D; Vera Cappelletti, Biol Sci D; Loris De Cecco,
Biol Sci D; Rosaria Orlandi, Biol Sci D; Marialuisa Sensi,
Biol Sci D; Maurizio Callari, Biotech D, Bioinformatician;
Ilaria Plantamura, Biol Sci D, PhD; Claudia Piovan, Pharm Biotech
D, PhD
Phd Student
Elvira D’Ippolito, Biotech Sci D
Gaetano De Feo, Biol Sci D; Matteo Dugo, Biotech D,
Bioinformatician; Patrizia Pinciroli, Biol Sci D and Technical
Specialists: Edoardo Marchesi, Donata Penso): see Shared
Research Resources, page 62.
Proteomics/mass spectrometry laboratory (Dario Caccia,
Biotech Med D, PhD; Ruben Magni, Biotech Med D, PhD
and Technical Specialist: Maida De Bortoli): see Shared
Research Resources, page 63.
Tissue and cell repository (Silvia Veneroni, Biol Sci D and
Technical Specialists: Antonio Scavo, Francesco Pastore,
Gloria Morandi): see Shared Research Resources, page 62.
Laboratory animal facility
Administrative Personnel: Claudia Miranda Biol Sci D, and
Grazia Convertino, Simona Galluzzi, Ester Grande, Silvia
Grassi, Laura Mameli, Silvia Portincasa, Luisa Rivetta,
Daniela Silva, Laura Zanesi, Cristina Zanini. This team
facilitates the activity of the Department by providing
administrative support to research unit leaders and core
facilities, coordinating the activities of graduate students
and fellows, handling purchasing requests for laboratory
consumables, and finance administration.
Laboratory Management Team: Enrico Ronchi, Domenico
Di Fazio, Angelo Labori, Salvatore Venturino. This team
plays an essential role in supporting the research units in
the Department for maintenance of instrumentation, and
management and supervision of areas for cryopreservation
of stored tissues/cells/cell extracts and reagents. In
addition, the team – in association with the administrative
team – also oversees a cost-effective and efficient
centralized system of ordering and stock control for the
most widely used items.
Supporting Personnel: Antonietta Calcagno, Linda Cimaglia,
Antonio Illuminato, Giuseppina Liguori, Agata Mancuso,
Luisa Mona, David Penni, Gisella Rivadossi, Pasquale Russo,
Claudio Santagostini.
52
PREVENTIVE
AND PREDICTIVE
MEDICINE
DEPARTMENT
DIRECTOR OF DEPARTMENT: Marco A. Pierotti (interim)
+39 02 23902300
marco.pierotti@istitutotumori.mi.it
The department focuses primarily on epidemiological and translational research. This
comprises knowledge of lifestyle and genetic risk factors in order to take preventive action
(i.e. from prediction to prevention), and knowledge of inequalities in cancer prevention and
treatment in order to take corrective actions. The research relies on extensive interaction
between researchers in the fields of basic experimental science, epidemiology, genetics, and
clinical medicine.
The priorities of the Department are:
•promotion of healthy diet and lifestyle: to proceed from large cohort studies, in which
the INT has been actively involved for more than 20 years, to dietary intervention
studies targeting the general population, high-risk subgroups, and cancer patients to
minimize the risk of recurrence (facilities include a hormonal laboratory and a teaching
kitchen);
•inequalities in survival and cure rates of cancer patients: from the systematic description
of cancer incidence, prevalence, and survival to research on the interpretation of
survival differences between and within countries, and promote actions to minimize
such inequalities;
•environmental and occupational risk factors: this research ranges from standard
epidemiological designs to the systematic monitoring of occupational risk through
linkage of cancer registry data and occupational history files;
•hereditary cancer prevention in high-risk families: to go beyond clinical surveillance
and prophylactic surgery, and promote research on environmental and lifestyle factors
as well as genetic characteristics that may affect the penetrance of hereditary cancer
genes;
•in the field of low penetrance cancer genes and polygenic inheritance: to classify the
complex genetics of risk and prognosis of lung and breast cancer.
Epidemiology and Prevention. The Unit is involved in large prospective and intervention
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studies on the association between diet, hormones, nutrition, lifestyle, genetic factors, and
cancer risk.
Analytical Epidemiology and Health Impact. The Unit investigates patterns of care and
cancer patient survival, promotes research in the field of public health, and conducts
studies for planning cancer control. Scientific activities are carried out in collaboration with
the Istituto Superiore di Sanità.
Evaluative Epidemiology. The Unit is mainly involved in assessing the burden of cancer
in populations. Several projects are focused on rare cancers and tumors diagnosed in
children, adolescents, and young adults (AYA). However, major cancers like prostate, breast,
colorectal, lung, cervix, and skin melanoma are considered for estimations of mortality,
incidence and prevalence.
Cancer Registry and Environmental Epidemiology. The Unit activity focuses on
information systems and disease registries for epidemiological research and on the
evaluation of the environmental, territorial, and prognostic risks. In July 2013, Dr Paolo
Crosignani, for many years head of this Unit, retired after a successful scientific career.
Since 1st October following organizational changes, two Units were derived.
Medical Genetics. This Unit offers genetic counseling for several hereditary
predispositions to cancer syndromes. The main focus is the study of hereditary breast
and ovarian cancer syndrome (HBOC), but other inherited predispositions to cancer such
as Li-Fraumeni Syndrome and familial melanoma are investigated. The principal goal is to
identify individuals with an increased genetic risk of cancer in order to offer a targeted
clinical management strategy including integrated and multidisciplinary healthcare service
for prevention and treatment.
Hereditary Digestive Tract Tumors. The Unit is devoted to the counseling, molecular
testing, and clinical management of individuals with genetic predisposition to the major
hereditary gastrointestinal cancer syndromes. These include Lynch syndrome (or
hereditary non-polyposis colorectal cancer, HNPCC), familial adenomatous polyposis (FAP)
and its phenotypic variant, attenuated-FAP, Peutz-Jeghers syndrome, juvenile polyposis,
and hereditary gastric cancer. Individuals with evidence of hereditary susceptibility
to cancer are counseled and informed about personal risk and that of their relatives.
Depending on the fulfillment of defined criteria, individuals who receive genetic counseling
are offered the possibility to undergo molecular testing for identification of specific genetic
alteration(s) that may be associated with the increased risk of cancer in their families.
These criteria include personal and family history of cancer, presence of specific clinical
phenotypes, and tumor characteristics.
Molecular Basis of Genetic Risk and Genetic Testing. This research Unit is devoted to the
identification and characterization of genetic elements associated with predisposition to
cancer and cancer progression. Studies are mainly focused on breast carcinoma and Wilms
tumor.
Genetic Epidemiology and Pharmacogenomics. The research group conducts studies to
identify genetic factors associated with the risk and prognosis of individual cancer. The
main study model is lung cancer, a ‘big killer’ characterized by a strong environmental risk
factor formed by cigarette smoke.
HIGHLIGHTS
The European Prospective Investigation into Cancer and Nutrition (EPIC) study (http://epic.iarc.fr) was designed to investigate the relationships between diet, lifestyle, genetic, and environmental factors and the incidence of cancer and other chronic disease in 23 centers across 10 European countries: Denmark, France, Germany, Greece, Italy, The Netherlands, Norway, Spain, Sweden, and the United
Kingdom. Over 520,000 healthy volunteers, characterized by large variations in dietary habits and cancer risk, have been recruited.
The study centers were chosen in order to increase the power to detect diet and cancer associations by increasing the heterogeneity
of exposure levels and the variations in the frequency of the cancers of interest.
Clinical interpretation of cancer survival differences in Italy and Europe across regions and groups of patients through the collection
and analyses of data in population cancer registries (CR) and hospital based cohorts of patients. Survival time trends and geographic
54
differences in cancer survival are being analyzed using the EUROCARE data base - the largest European data base on survival and
care of cancer patients- which presently centralizes data from 116 European CRs in 21 countries, with diagnoses from 1995 to 2007.
The results of these analyses provide a measure of the efficacy of European health systems in cancer control, contributing to identify
regions with low survival, where actions should be implemented to improve cancer diagnosis and treatment and to reduce inequalities
in outcomes.
Rare diseases including rare cancers are a priority for action in the European Public Health Program (2008-2013). The importance
of providing accurate information on rare diseases to all European citizens is clearly stated in the Communication of the European
Commission on Rare Diseases: Europe’s challenges, and in the Recommendations from the Council.
Data from INT registry, the oldest still active in Italy, are validated and accepted by the IARC for the publication of Cancer Incidence in
Five Continents. The registry participates in collaborative studies such as Epic, Ordet, Eurocare, RareCare, Accis, and Caremore, and
supports the evaluation of screening programs in the Province of Varese.
For more than 20 years, clinical units dedicated to counseling, genetic testing, and clinical management of individuals with evidence
of genetic susceptibility to cancer have been operating at INT, mainly on familial breast, ovarian, and colorectal carcinomas. These
activities fuel research projects aimed at increasing our current knowledge on the molecular basis of these diseases and our ability to
diagnose individuals who are at higher risk of cancer development due to a genetic predisposition.
The process of tumor progression and metastatic dissemination can involve germline polymorphisms and individual gene expression
signatures in normal tissue. Our project is aimed to integrate genome and transcriptome data across multiple individuals, thus allowing
identification of genetic biomarkers that are predictive of clinical phenotypes of colorectal or lung cancer.
KEYWORDS
prospective studies, diet, hormones, metformin, breast cancer, intervention studies, cancer epidemiology, health indicators, cancer
burden, rare cancers, occupation, environment, familial and hereditary cancer, genetic counseling, cancer genetics, single nucleotide
polymorphisms, experimental models, in vitro assays.
EPIDEMIOLOGY AND PREVENTION
Head
Vittorio Krogh, MD, MSc
Research Staff
Claudia Agnoli, Nutrition Tech D, MSc; Manuela Bellegotti, BSc;
Eleonora Bruno, Nutrition Tech D, MSc; Patrizia Cogliati, Biol Sci
D; M. Gaetana Di Mauro, MD; Giuliana Gargano, Biol Sci D;
Giulia Garrone, Chemist D; Sara Grioni, Nutrition Tech BSc; M.
Valeria Pala, Agronomy D; Patrizia Pasanisi, MD, MSc;
Samuele Pedraglio, Chemist D; Giuseppina Saragò, Biol Sci D;
Sabina Sieri, Biol Sci D; Elisabetta Venturelli, Biol Sci D;
Anna Villarini, Biol Sci D
Technicians
Simone Bonfarnuzzo, Alberto Turco
Agatina A. Cifalà, Chiara Margutti, Stefania Saltarelli
EVALUATIVE EPIDEMIOLOGY
Head
Gemma Gatta, MD
Research Staff
Laura Botta, BioStatistics D; Roberto Foschi, Math D, Msc;
Annalisa Trama, MD PhD
Resident
Marilena M. Vece, MD
Rossana Berruti, Lucia Buratti
Technicians
Adalberto Cavalleri, Daniela Del Sette Cerulli
ENVIRONMENTAL EPIDEMIOLOGY
(SINCE 1ST OCTOBER)
Head
Paolo Contiero, DSc, PhD
Aministrative Personnel
Alberto Evangelista, Paola Consorti, Patrizia Curtosi,
Fabrizia Genoni, M. Grazia Guerrini, Maria Larossa
Consultant
Franco Berrino
ANALYTICAL EPIDEMIOLOGY AND HEALTH
IMPACT
Head
Milena Sant, MD
Research Staff
Hade Amash, MD; Camilla Amati, BA; Paolo Baili, Statistician, PhD;
Francesca Bella, MD; Paolo Bonaiuti, Mathematics D, PhD;
Ilaria Casella, Economist; Ilaria Cavallo, Informatics D;
Francesca Di Salvo, Statistics D; Francesco L. Funaro, Informatics
D; Elisabetta Meneghini, Physics, PhD; Pamela Minicozzi,
Mathematics D, PhD
Research Staff
Martina Bertoldi, DSc
Fellows
Alessandro Borgini, DSc; Maria E. Sanoja Gonzalez, DSc
Technician
Alessandra Scaburri
Immacolata Favia, Alessandro Cau
CANCER REGISTRY (SINCE 1ST OCTOBER)
Head
Giovanna Tagliabue, MD, PhD
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Research Staff
Laura Di Grazia, DSc; Emanuela Frassoldi, DSc; Daniela Gada, DSc;
Mariarosa Ruzza, DSc
Fellows
Edoardo Bai, MD, PhD; Enrico Oddone, MD, PhD; Milena Calati,
DH; Lucia Preto, DSc
Technicians
Sabrina Fabiano, Andrea Tittarelli
Tiziana Codazzi, Anna Maghini
MEDICAL GENETICS
Head
Siranoush Manoukian, MD, PhD
Clinical Staff
Bernard Peissel, MD, PhD
Data Manager
Daniela Zaffaroni, Biol Sci D, PhD
Residents
Giulia Melloni, MD; Giulietta Scuvera, MD
Alex Sandra Masioli Dos Santos, Caterina Spina
HEREDITARY DIGESTIVE TRACT TUMORS
Head
Lucio Bertario, MD
Research Staff
Paola Sala, Biol Sci D; Stefano Signoroni, Biol Sci D
Mariangela Di Ceglie, Ornella Galuppo
MOLECULAR BASES OF GENETIC RISK AND
GENETIC TESTING
Head
Paolo Radice, Biol Sci D
Research Staff
Daniela Perotti, PhD
Laura Caleca, PhD; Mara Colombo, PhD; Giovanna De Vecchi, Biol
Sci D; Antonio Fiorino, Biol Sci D; Carla B. Ripamonti, MD
PhD Students
Sara Ciceri, Med Biotech D
Fellow
Claudia Foglia, Biol Sci D
Technician
Patrizia Mondini
Silvia Grassi
GENETIC EPIDEMIOLOGY AND
PHARMACOGENOMICS
Head
Tommaso A. Dragani, PhD
Research Staff
Giacomo Manenti, PhD; Paola Orsini, PhD
Francesca Colombo, PhD; Antonella Galvan, PhD; Marco
Giannoccaro, MSc; Sara Noci, PhD; Marco Anderlini, MSc
PhD Student
Alice Dassano, MSc
Technician
Angela Pettinicchio
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shared research resources
SHARED
RESEARCH
RESOURCES
Core Facilities at the INT provide clinicians and researchers with centralized centers of
expertise and state-of-the-art technologies. The INT core facilities include clinical resources
supporting the physical, social, and emotional needs of cancer patients, in addition to research
resources to extend the capabilities and accelerate the research progress of our clinical and
experimental researchers.
The INT supports core facilities, including: Cardiology, Respiratory Pathophysiology,
Clinical Psychology, Medical Statistics, Biometry and Bioinformatics, Clinical Epidemiology
and Trial Organization, Clinical Trials Center, Human Tissue Bank, Functional Genomics,
and Cancer Proteomics.
CARDIOLOGY
Director: Patrizia Piotti, MD
The Cardiology Unit is mainly concerned with the preoperative evaluation of surgical
patients. Working in close collaboration with anesthesiologists and thoracic and abdominal
surgeons, the Unit aims to reduce preoperative risk and manage complications. The Unit
also provides evaluations and consultations for patients from the Fondazione IRCCS
Istituto Neurologico C. Besta.
Among the main duties of the Cardiology Unit are evaluation of the general cardiac status
of all candidates for chemo-radiotherapy treatment to monitor potential cardiovascular
toxicity related to antineoplastic treatments from early recognition to diagnosis and
therapy. All of the Phase I, II, and III clinical studies carried out at INT require regular
cardiologic surveillance to assess the cardiotoxicity of new experimental drugs (monoclonal
antibodies, receptor tyrosine kinase inhibitors, BRAF inhibitors, MEK inhibitors).
RESPIRATORY PATHOPHYSIOLOGY
Director: Roberto Boffi, MD
The Unit provides a broad range of respiratory consultations as well as pulmonary function
tests.
Inpatient activity is mainly focused on:
• preoperative evaluation of patients planned for thoracic surgery;
•short- and long-term follow-up of pulmonary toxicities due to chemotherapy and/or
radiotherapy;
59
• pharmacological aid to smoker inpatients;
• healthcare associated pneumonia and/or pulmonary graft-versus-host disease.
Outpatient activity is focused on:
• asthma and COPD patients;
• interstitial lung diseases and evaluation of sarcoidosis;
• smoker outpatients with a dedicated anti-tobacco clinic.
The clinical research activity stems from productive collaborations with:
•Department of Predictive and Preventive Medicine (pharmacogenetic of smoking
cessation drugs)
• Thoracic Surgery (smoking cessation within a lung cancer screening trial)
• Clinical Psychology (smoking cessation counseling for inpatient smokers)
•Società Italiana di Medicina Generale (indoor and outdoor pollution from cigarette
smoke).
CLINICAL PSYCHOLOGY
Director: Claudia Borreani, Psy D
The Unit supports patients with life-threatening illnesses, along with their families, and is
aimed to improve the quality of life and well-being, and relieve mental suffering throughout
the course of illness and survivorship. Psycho-Oncology covers the whole range of mental
and emotional difficulties related to cancer, stimulates research, and develops training
so that psychosocial care may be integrated with clinical oncology specialties for holistic
patient care. The research activity aims to assess the subjective impact of cancer and
cancer treatments on patients’ quality of life and the psychosocial aspects related to
the various phases of the oncologic disease. The clinical activity includes: psychological
assessment, individual psychological counseling, short psychotherapies, family therapies,
and psycho-educational groups.
Collaboration with other clinical Units on specific issues includes:
•Multidisciplinary clinical project to support cancer patients undergoing liver transplant
surgery (Liver Transplantation Unit)
•Multidisciplinary clinical project to support decision-making in BRCA1/2 carriers
(Medical Genetics Unit)
•Clinical decision making counseling, psychological support, and psychosexual counseling
for prostate cancer patients (Prostate Program)
• Multidisciplinary smoking cessation project for inpatients (Tobacco Control Laboratory).
MEDICAL STATISTICS, BIOMETRY,
AND BIOINFORMATICS (MSBB)
Director: Adriano Decarli, PhD
The MSBB provides quantitative support to research activity across various Departments
at INT, and maintains collaborative relationships with other national or international
research groups. The activity of the INT group is governed by a convention with the
University of Milan.
Biostatistics for Oriented Basic Research and Quality Control (Paolo Verderio, Biol Sci
D, PhD; Sara Pizzamiglio, Msc). The team applies statistical methods to different phases of
the biomarker development process in oncology. It provides implementation and statistical
analysis of quality control studies for tumor biomarkers and in vitro diagnostic tools,
evaluation of inherited diseases in oncology, establishment and validation of biological
assays, preclinical pharmacology and testing new molecular detection strategies based on
innovative technologies. As partner of the FP7 EU Project SPIDIA, the team is involved in
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the planning, implementation, and statistical analysis of ring trials, and contributes to the
setup and validation of biological assays and testing new molecular detection strategies
based on innovative technologies.
Biostatistics for Bioinformatics and Translational Research (Elia M. Biganzoli, PhD; Ilaria
Ardoino, PhD; Matteo Malvezzi, PhD). In the context of analytical molecular epidemiology,
the team supports the transfer of basic preclinical research to clinics using quantitative
approaches to assess the impact of new technologies in oncology according to cost-benefit
principles and sustainability perspectives. Within the framework of collaborative projects,
the team is involved in research concerning the assessment of high-throughput and next
generation sequencing (NGS) platforms for DNA and RNA analysis, qRT-PCR, and highthroughput assays in cancer. Statistical bioinformatics research supports the design and
analysis of NGS experiments. Studies on follow-up data with reference to the analysis of
risk patterns related to metastatic dormancy are conducted in cooperation with clinical
Units.
CLINICAL EPIDEMIOLOGY
AND TRIAL ORGANIZATION
Director: Luigi Mariani, MD PhD
Research Staff: Rosalba Miceli, PhD; Elena Landoni, PhD
The Unit provides statistical support relating to the design, conduct, and analysis of clinical
trials, observational and population-based studies, mainly in the areas of surgical, medical
or hematological oncology.
CLINICAL TRIALS CENTER
Coordinators: Valentina Sinno and Luigi Mariani
The operative Clinical Trial Center (CTC) has been re-established in January 2012 by the
Scientific Director to support clinical studies, especially investigator driven and Phase I
and II studies, with the aim of bringing research results and new treatments to the bedside
in the shortest time. The CTC supports Clinical Researchers in managing many aspects of
investigational clinical studies, such as study design and statistical validation, submission
to the Ethics Committee and regulatory authorities (AIFA for Phase I studies), budget and
contract related issues, as well as data management and statistical analysis, thanks to 16
data managers, two medical statisticians, and an administrative and legal specialist. The
CTC also provides pharmacovigilance through an “ad hoc” trained pharmacist, employs
six qualified Research Nurses to improve patient care in the various steps of the study
(scheduling of treatments, blood sampling, exams, controls, etc.), and two laboratory
biologists to handle tissue and blood samples for pharmacokinetics and molecular studies.
CTC works through validated and updated SOP and electronic CRF customized for each
specific study; personnel education and training is coordinated by the Scientific Directorate.
The CTC is also improving the organization of sponsored clinical trials, speeding up
administrative processes, budget definition, patient recruitment and data management,
organizing a centralized record of all radio-diagnostic exams, and assisting Clinical Monitors
in their visits.
Up to the end of 2013, the CTC managed 21 investigator driven monocentric/multicentric
clinical trials, and provided statistic support to 44 studies; among the “for-profit” clinical
studies activated in 2013 at INT, 50 were administered by the CTC data managers.
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TISSUE AND CELL REPOSITORY
Directors: Giuseppe Pelosi, MD and Maria Grazia Daidone, Biol Sci D, PhD
Since 2002, the INT Tissue Bank (ITB) has been dedicated to the collection and distribution
of neoplastic, preneoplastic, and normal tissues from human subjects for research projects.
This resource is a project of INT Scientific Directorate, with day-to-day staff supervision
provided by personnel from the Departments of Pathology and Experimental Oncology &
Molecular Medicine.
The activities are overseen by an interdepartmental advisory committee, which also
evaluates and approves research projects depending on the availability of tissue
specimens. Adopting TUBAFROST procedures, although slightly modified to comply
with local conditions, the ITB stores frozen samples (primary and metastatic lesions,
with corresponding normal tissues) and contributes specimens to a large number of
specific research projects dealing with almost all tumor types. All patients/subjects sign an
informed consent document (approved by the Independent Ethics Committee and filed
in the patients’ records) to donate leftover tissue/biological specimens from diagnostic
procedures to the ITB for future studies. It is a one-time general consent with a twostep decision process that allows patients to control the use of their samples and foster
important research. Guidelines have been proposed to define responsibilities for ITB
management, policies and procedures to protect patient confidentiality and privacy, and
establish priorities for specimen distribution.
FUNCTIONAL GENOMICS
AND BIOINFORMATICS CORE FACILITY (FGBCF)
Coordinator: Silvana Canevari, Biol Sci D
The activities of the FGBCF are conducted using the following instruments: QIAcube
for nucleic acid purification; Agilent Bioanalyzer, Nanodrop, Qubit for quantity and
quality control of nucleic acids; Illumina and Agilent platforms for microarray analysis
of mRNA expression, miRNA and lncRNA expression, ChIP-on-chip, DNA methylation,
CGH and CNV, SNPs; Quantstudio 12K for quantitative real-time PCR; automated liquid
handling MultiProbe II; Next Generation Sequencing SOLiD™ 5500xl Wildfire and 3130
Sequencer for Sanger Sequencing; dedicated servers, work-stations, and up-to-date
software, hardware and web-based databases. The research group comprises full time
personnel involved in wet analyses and personnel dedicating part of their institutional
activity to computational analysis using wet and in silico data. The FGBCF performs: study
design; RNA and DNA extraction and quality controls; all the labeling and hybridization
methodologies required for high quality analysis; data processing and statistical analysis.
Full computational analyses are performed using open-source software and dedicated
licenses. Identification and bio-functional interpretation of promising biomarkers are based
on differential expression analysis, pathway analysis with over-representation or gene set
enrichment approaches (GO and GSEA), and integration of different kinds of data. The
FGBCF also provides certification of identity of cell lines adhering to ATCC guidelines and
sample processing on a 3130 capillary genetic analyzer.
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PROTEOMICS/MASS SPECTROMETRY
LABORATORY (PMSL)
Coordinator: Italia Bongarzone, Biol Sci D
The INT PMSL uses proteomics to analyze cell lines, tissue biopsies, and biofluid samples.
A combination of proteomics profiling - aimed to characterize as many proteins as possible
from cell line secretomes, body fluids, or extracts - and bioinformatic analyses allow us to
reveal critical biological information. The PMSL studies suggest new tumor classification
strategies and lines of therapeutic intervention. In addition to cataloging proteins, the
PMSL analytical approach and statistical workflow has the potential to improve the
accuracy of patient classification with the aim to better understand pathway-related genes
and proteins associated with prognosis.
FOR MORE INFORMATION VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT
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RESEARCH
ACTIVITY
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research activity
PREVENTIVE
AND PREDICTIVE
MEDICINE
COORDINATOR: Marco A. Pierotti
The research activity focuses on epidemiology and prevention through prospective
epidemiological studies, case-control studies and survival studies. Our Institute is involved
in the coordination of national and international multicenter studies including projects on
rare tumors coordinated at a European level as well as interventional prevention projects.
In our research on families with a high genetic risk, where a series of interventions has been
developed aimed at people with a genetic predisposition to cancer, we intend to continue with
the clinical and molecular characterization.
AIMS: Organization and implementation of interventional prevention projects, and
management of the related biobanks. Creation of information networks directed
at all stakeholders through the use of data of population-based cancer registries.
Identification of the causes of survival differences between populations of different
countries and within the same country; production of health indicators; promotion
of information on health and healthy lifestyles; distribution of knowledge in the field
of cancer epidemiology.In the setting of familial-hereditary cancer: detection of
individuals at increased genetic risk; detection of the predisposing gene(s); provision
of appropriate surveillance programs and possible options for prevention; provision
of adequate treatment in case disease develops.
PROJECTS
• Prospective observational studies on diet, lifestyle, endocrine/metabolic
and genetic factors and cancer risk (Vittorio Krogh)
• Rare tumors: creation of an information network and an epidemiological
surveillance system (Gemma Gatta)
• Clinical interpretation of cancer survival differences in Italy and Europe
(Milena Sant)
• Study of the molecular determinants of the genetic predisposition
to familial-hereditary cancers (Paolo Radice, Siranoush Manoukian and Lucio Bertario)
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.Vittorio Krogh.
PROSPECTIVE OBSERVATIONAL STUDIES
ON DIET, LIFESTYLE, ENDOCRINE/METABOLIC
AND GENETIC FACTORS AND CANCER RISK
OVERVIEW AND SCIENTIFIC GOALS
The Epidemiology and Prevention Unit is involved in large prospective and intervention studies on the association between
diet, hormones, nutrition, lifestyle, genetic factors, and cancer risk. The European Prospective Investigation into Cancer
and Nutrition (EPIC) study (http://epic.iarc.fr) was designed to investigate the relationships between diet, lifestyle, genetic,
and environmental factors and the incidence of cancer and other chronic disease in 23 centers across 10 European
countries: Denmark, France, Germany, Greece, Italy, The Netherlands, Norway, Spain, Sweden, and the United Kingdom.
Over 520,000 healthy volunteers, characterized by large variations in dietary habits and cancer risk, have been recruited.
The study centers were chosen in order to increase the power to detect diet and cancer associations by increasing the
heterogeneity of exposure levels and the variations in the frequency of the cancers of interest. Data were collected on
diet, physical activity, sexual maturation and reproductive history, lifetime consumption of alcohol and tobacco, previous
and current illnesses, and current medication. Following a common protocol and using identical equipment, blood samples
were collected, separated into plasma, serum, white blood cells and erythrocytes, and stored in liquid nitrogen at –196°C
for future laboratory analyses on cancer cases and matched healthy controls. Anthropometric measurements were
taken according to a standard protocol. Follow-up is based on linkage with population cancer registries or a combination
of methods including health insurance records, cancer and pathology registries, and active follow-up through study
participants and their next-of-kin.
The ORDET study is one of the first prospective European studies on the role of hORmones and DiET in the etiology
of cancer. A total of 10,786 healthy women, ages 35–69 years, residents of the Varese province in northern Italy, were
recruited for this prospective study of hormones, diet, and breast cancer risk. Information on lifestyle characteristics,
menstrual and reproductive history, dietary habits, and anthropometric measurements were collected at baseline.
Moreover, blood samples were collected, after 12 hours fasting, between 7:30 and 9:00 a.m. from all of the participants
in the study. For premenopausal women, blood was collected in the luteal phase of the menstrual cycle. All of the blood
samples were processed and stored at –80°C. Women are followed through the local cancer registry (Lombardy Cancer
Registry, Varese Province) characterized by high completeness and quality.
The ORDET study is participating in the “Pooling project”, a collaborative project that involves major European and North
American cohort studies coordinated by Harvard University.
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PROGRAM HIGHLIGHTS
The EPIC project represents an ideal natural laboratory thanks to the very heterogeneous dietary habits still found in different
European populations, ranging from the Mediterranean diets of Greece, southern Italy, Spain, and the south of France to the central
European food patterns of Germany, Netherlands, and north of France, to the Nordic style diet of Norway, Sweden, and Denmark. At
the same time, incidence of several major cancer sites varies substantially across countries and even more across regions. In addition
to the variations in risk and dietary habits, a crucial element of the statistical power, which was central in the design of EPIC, is study
size.
The ORDET study was designed to evaluate the association between endogenous hormones with breast cancer risk, therefore at
recruitment several sources of hormone variability were controlled for by both inclusion criteria and highly standardized conditions
at blood drawing. Women with bilateral ovariectomy, those currently pregnant or breast-feeding, those on oral contraceptives or
hormone replacement therapy, or affected by metabolic diseases influencing the endocrine profile (i.e. liver disease) were not eligible
for the study. This allowed to control for or eliminate several sources of bias and undesired variability that have probably blurred the
results of some previous studies on prediagnostic sex steroids level and breast cancer risk.
PROGRAM MEMBERSHIP
Vittorio Krogh. Head of Unit, is an experienced chronic disease
epidemiologist with an interest in the link between environment and
genetic factors in the etiology of Cancer and Cardiovascular Disease.
His main and long standing focus of research interest is the role of diet
and nutrition, and its interaction with individual and familial factors,
in disease etiology and prevention. He has directed a number of
epidemiological studies and participated since 1991 in the EPIC Study.
Dr. Krogh’s papers have attracted >15,000 citations to date, and his
H-Index is 64.
Valeria Pala. Dr Pala is a senior epidemiologist, working since 1995 as
researcher at the Department of Preventive and Predictive Medicine. Dr.
Pala has been working on longitudinal cohorts (ORDET, EPIC) for about
20 years and her main focus has been on diet, genetic susceptibility, and
cancer and other chronic disease etiology. Dr. Pala publications have
attracted over 3500 citations to date and her H-index is 35.
Sabina Sieri. Dr. Sieri is a senior epidemiologist working in the field
of cancer and cardiovascular diseases since 1996. Her main focus of
research interest is the role of diet, nutrition, endocrinological and
metabolic factors in the etiology of chronic diseases. Dr. Sieri’s papers
have attracted >5900 citations and her H-Index is 41.
Sara Grioni. Dr. Grioni is a young researcher with interest in
nutritional and lifestyle related risk factors in the etiology and
prevention of cancer and cardiovascular diseases since 2004. Dr.
Grioni is also involved in the continuous update of the EPIC and
ORDET follow-up databases. Dr. Grioni’s papers have attracted
>1300 citations to date and her H-Index is 24.
Claudia Agnoli. Dr. Agnoli is a young researcher who works in the field
of cancer and cardiovascular disease epidemiology since 2006. Her
main research interests include the role of metabolic syndrome in
cancer etiology, with special focus on breast cancer, and the association
between dietary patterns and risk of chronic disease. Dr. Agnoli’s
papers have attracted >1,200 citations to date and her H-Index is 20.
SELECTED RECENT PUBLICATIONS
Key T.J., Appleby P.N., Reeves G.K., Travis R.C., Alberg A.J., Barricarte
A., Berrino F., Krogh V., Sieri S., Brinton L.A., Dorgan J.F., Dossus L.,
Dowsett M., Eliassen A.H., Fortner R.T., Hankinson S.E., Helzlsouer
K.J., Hoffman-Bolton J., Comstock G.W., Kaaks R., Kahle L.L., Muti P.,
Overvad K., Peeters P.H., Riboli E., Rinaldi S., Rollison D.E., Stanczyk
F.Z., Trichopoulos D., Tworoger S.S., Vineis P.: Sex hormones and risk
of breast cancer in premenopausal women: a collaborative reanalysis
of individual participant data from seven prospective studies. Lancet
Oncol 2013; 14: 1009-1019
Raaschou-Nielsen O., Andersen Z.J., Beelen R., Samoli E., Stafoggia M.,
Weinmayr G., Hoffmann B., Fischer P., Nieuwenhuijsen M.J., Brunekreef
B., Xun W.W., Katsouyanni K., Dimakopoulou K., Sommar J., Forsberg
B., Modig L., Oudin A., Oftedal B., Schwarze P.E., Nafstad P., De F.U.,
Pedersen N.L., Ostenson C.G., Fratiglioni L., Penell J., Korek
M., Pershagen G., Eriksen K.T., Sorensen M., Tjonneland A., Ellermann
T., Eeftens M., Peeters P.H., Meliefste K., Wang M., Bueno-de-Mesquita
B., Key T.J., de Hoogh K., Concin H., Nagel G., Vilier A., Grioni S., Krogh
V., Tsai M.Y., Ricceri F., Sacerdote C., Galassi C., Migliore E., Ranzi A.,
Cesaroni G., Badaloni C., Forastiere F., Tamayo I., Amiano P., Dorronsoro
M., Trichopoulou A., Bamia C., Vineis P., Hoek G.: Air pollution and lung
cancer incidence in 17 European cohorts: prospective analyses from
the European Study of Cohorts for Air Pollution Effects (ESCAPE).
Lancet Oncol 2013; 14: 813-822
Kreimer A.R., Johansson M., Waterboer T., Kaaks R., Chang-Claude
J., Drogen D., Tjonneland A., Overvad K., Quiros J.R., Gonzalez C.A.,
Sanchez M.J., Larranaga N., Navarro C., Barricarte A., Travis R.C., Khaw
K.T., Wareham N., Trichopoulou A., Lagiou P., Trichopoulos D., Peeters
P.H., Panico S., Masala G., Grioni S., Tumino R., Vineis P., Bueno-deMesquita H.B., Laurell G., Hallmans G., Manjer J., Ekstrom J., Skeie
G., Lund E., Weiderpass E., Ferrari P., Byrnes G., Romieu I., Riboli E.,
Hildesheim A., Boeing H., Pawlita M., Brennan P.: Evaluation of human
papillomavirus antibodies and risk of subsequent head and neck
cancer. J Clin Oncol 2013; 31: 2708-2715
Agnoli C., Grioni S., Sieri S., Palli D., Masala G., Sacerdote C., Vineis P.,
Tumino R., Giurdanella M.C., Pala V., Berrino F., Mattiello A., Panico S.,
Krogh V.: Italian Mediterranean index and risk of colorectal cancer
in the Italian section of the EPIC cohort. Int J Cancer 2013; 132:
1404-1411
Sieri S., Pala V., Brighenti F., Agnoli C., Grioni S., Berrino F., Scazzina F.,
Palli D., Masala G., Vineis P., Sacerdote C., Tumino R., Giurdanella M.C.,
Mattiello A., Panico S., Krogh V.: High glycemic diet and breast cancer
occurrence in the Italian EPIC cohort. Nutr Metab Cardiovasc Dis 2013;
23: 628-634
SELECTED RECENT MAJOR GRANTS
“Role of nutrients involved in one-carbon metabolism in the
development of different molecular subtypes of BC in the ORDET
cohort”, funded by Ministry of Health in 2011. Local PI: Sabina Sieri.
“Changes in weight and inflammation markers in relation to breast
cancer risk: a nested case-control study”, funded by Associazione
Italiana per la Ricerca sul Cancro (AIRC) in 2012. Local PI: Vittorio
Krogh.
“Is the protective effect of Mediterranean Diet on cancer mediated by a
methylation pattern?”, funded by Associazione Italiana per la Ricerca sul
Cancro (AIRC) in 2013. Local PI: Vittorio Krogh.
“ENVIROGENOMARKERS – Genomics biomarkers of environmental
health”, funded by European Commission, Seventh Framework Program
(Grant Agreement n. 226756), in 2009. Local PI: Vittorio Krogh.
KEYWORDS
prospective studies, diet, hormones, breast cancer
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.Gemma Gatta.
RARE TUMORS: CREATION OF AN INFORMATION
NETWORK AND EPIDEMIOLOGICAL
SURVEILLANCE SYSTEM
Rare diseases including rare cancers are a priority for action in the European Public Health Program (2008-2013).
The importance of providing accurate information on rare diseases to all European citizens is clearly stated in the
Communication of the European Commission on Rare Diseases: Europe’s challenges, and in the Recommendations from
the Council.
The project Surveillance of Rare Cancers in Europe (RARECARE) estimated the burden of rare cancers in Europe by
providing the first indication of the size of the public health problem due to these diseases and constitutes a useful basis
for implementing public health actions and further research. According to RARECARE, around 4 million individuals in the
European Union (EU) are affected by rare cancers. Despite the rarity of each of the 186 identified rare cancers, together
they represent about 22% of all cancer cases diagnosed in the EU27 each year. Five-year relative survival is significantly
worse for rare cancers (47%) than for common cancers (65%), and differences in survival exist across European regions
(Gatta G. Lancet Oncology 2006). There is general agreement that treatment of rare cancers should be concentrated in
specialist multidisciplinary centers, and that international collaboration is needed to undertake research in this group
of patients. However, there is no evidence on the impact of such initiatives on survival. Due to their low frequency, rare
cancers pose particular challenges such as late or incorrect diagnosis, lack of access to appropriate therapies and clinical
expertise, limited information about the disease and a scarcity of clinical trials. In responses to these challenges, Rare
Cancers Europe (RCE) has launched a Call to Action that urges policymakers and stakeholders to give priority to rare
cancers. In particular, it is campaigning to: 1) foster the creation of reference networks for the treatment of patients
with rare cancers, 2) spread knowledge and clinical guidelines on rare cancers, 3) promote the establishment of clinical
databases and registries, and 4) empower patients. Against the background described, a key goal is to build on a network of
organizations collaborating in research, promotion, and implementation of appropriate solutions to address the challenges
posed by rare cancers.
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PROGRAM HIGHLIGHTS
The overall goal is to serve as the reference source of information on rare cancers in Europe and contribute to ameliorate diagnosis and treatment of rare cancers, foster research on rare cancers, support the establishment of centers of expertise and empower
patients. The list of continuously updated rare cancers promotes better classification. The list complements the EU dynamic inventory
of rare diseases developed by Orphanet by providing information on rare cancers and contributing to identify which cancers are rare.
Information on health care pathways and estimates of survival differences by European region contribute to identify determinants of
variations in survival across Europe and to develop recommendations to improve the situation by reducing health inequalities across
Europe. Updated incidence and prevalence data support better healthcare planning and resource allocation for rare cancers. The availability of prevalence data updated to 2007 for rare cancers also facilitate application of the EU orphan drug directive. Monitoring time
trends of rare cancers improves information for healthcare planning, from primary prevention to care. The availability of criteria for
centers of expertise for rare cancers are essential for their identification, establish networks of such centers in Europe and harmonize
practices across EU countries. Networks of reference centers are essential to increase knowledge on rare cancers, define and share
best practice, put expert knowledge at disposal of physicians, and improve diagnosis of rare cancers as well as their treatment and research. Knowledge of centers to which rare cancer patients are most frequently referred will help patients and their GPs in finding an
appropriate hospital for treatment. Information on diagnosis and treatment of rare cancers support clinical oncologists and physicians
in everyday oncology practice. This will contribute to improving the timeliness and appropriateness of diagnoses as well as overall disease management. The clinical database supporting the pooling of cases of very rare cancers leads to the development of new knowledge and to the definition of more homogeneous clinical management of such rare diseases. It also contributes to the development of
international collaborative groups to foster research on rare cancers. Empowerment of rare cancer patients requires both information
and education. The network contributes to inform, educate, and motivate patients. Information flows, not only towards patients but
also from them, are essential so that their needs can be known and enable them to take responsibility, understand their own disease,
and know who can manage it. In general, patients can contribute by participating in the definition of a healthcare agenda and becoming
empowered patients. The outcomes described contribute to ameliorating survival of patients with rare cancers.
PROGRAM MEMBERSHIP
The University of Edinburgh (Ian Kunkler)
Dissemination of the project
Survival of Cancer Patients in Europe (EUROCARE) (Franco Berrino),
Milan, Italy
Information on epidemiology of rare cancers
Institut de CancÈrologie Gustave Roussy (Ellen Benhamou)
Evaluation of the project
Oncological Societies (ESMO, ESSO, ECCO)
Information on centers of expertise for rare cancers and clinical
management of rare cancers
Istituto Superiore di Sanità (Riccardo Capocaccia)
Information on epidemiology of rare cancers
Integraal Kankercentrum Nederland (Sabine Siesling)
Information on centers of expertise for rare cancers
Gatta G., Rossi S., Foschi R., Trama A., Marcos-Gragera R., Pastore G.,
Peris-Bonet R., Stiller C., Capocaccia R.: Survival and cure trends for
European children, adolescents and young adults diagnosed with
acute lymphoblastic leukemia from 1982 to 2002. Haematologica
2013; 98: 744-752
Fondazione IRCCS, Istituto Nazionale dei Tumori, Italy (Lisa Licitra)
Information on clinical management of rare cancers
European Cancer Patient Coalition (Jana Pelouchov· – Francesco De
Lorenzo)
Information for patients with rare cancers
National Oncology Hospital, Bulgaria (Nadya Dimitrova)
Contributing to all the above activities
National Cancer Registry, Ireland (Harry Comber)
Cancer Society of Finland − Institute for Statistical and Epidemiological
Cancer Research, Finland (Eero Pukkala)
Institute of Oncology Ljubljana (Maja Primic Žakelj)
Rare Cancer Europe (Paolo Casali)
Information on epidemiology of rare cancers and Information on
centers of expertise for rare cancers
European Partnership for Action Against Cancer (Josep M Borras),
Barcelona, Spain
Information on centers of expertise for rare cancers
European School of Oncology (Alberto Costa), Milan, Italy
Dissemination of the project
Mallone S., De Angelis R., van der Zwan J.M., Trama A., Siesling S.,
Gatta G., Capocaccia R., RARECARE WG.: Methodological aspects of
estimating rare cancer prevalence in Europe: The experience of the
RARECARE project. Cancer Epidemiol 2013; 37: 850-856
Stiller C.A., Trama A., Serraino D., Rossi S., Navarro C., Chirlaque M.D.,
Casali P.G.: Descriptive epidemiology of sarcomas in Europe: Report
from the RARECARE project. Eur J Cancer 2013; 49: 684-695
Van Der Zwan J.M., Trama A., Otter R., LarraÒaga N., Tavilla A.,
Marcos-Gragera R., Dei Tos A.P., Baudin E., Poston G., Links T.: Rare
neuroendocrine tumours: Results of the surveillance of rare cancers
in Europe project. Eur J Cancer 2013; 49: 2565-2578
Gatta G., van der Zwan J.M., Casali P.G., Siesling S., Dei Tos A.P., Kunkler
I., Otter R., Licitra L., Mallone S., Tavilla A., Trama A., Capocaccia R.;
RARECARE working group. Rare cancers are not so rare: the rare
cancer burden in Europe. Eur J Cancer 2011; 47(17): 2493-2511
Projects supported by the EC DG Sanco and Italian Ministry of Health
(for rare diseases)
KEYWORDS
Europe, rare cancers, network, center of excellence
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.Milena Sant.
CLINICAL INTERPRETATION OF CANCER SURVIVAL
DIFFERENCES IN ITALY AND EUROPE
The project investigates differences in cancer outcomes and survival across regions and groups of patients, in Europe and
Italy, through the collection and analyses of data in population cancer registries (CR) and hospital based cohorts of patients.
Survival time trends and geographic differences in cancer survival are being analyzed using the EUROCARE data base - the
largest European data base on survival and care of cancer patients- which presently centralizes data from 116 European
CRs in 21 countries, with diagnoses from 1995 to 2007. The results of these analyses provide a measure of the efficacy
of European health systems in cancer control, contributing to identify regions with low survival, where actions should be
implemented to improve cancer diagnosis and treatment and to reduce inequalities in outcomes.
These analyses can also evaluate, in current clinical practice, the impact of innovative treatments validated in controlled
clinical studies (i.e. comparing “effectiveness” and “efficacy”). For instance, the large improvement in survival for
many hematological malignancies in most European countries, at the population level, is generally attributable to the
dissemination of new and effective treatments. However, the EUROCARE analyses show how these improvements are less
evident in eastern European countries.
Specific studies on patient’s samples are carried out to understand the reasons for these inequalities: “High resolution
studies” (HR) are being conducted by collecting data with greater detail than that available for population-based CR, i.e. on
diagnostic investigation, stage at diagnosis, treatment, bio-molecular tumor characteristics, and follow-up.
The HR studies describe and compare patterns of cancer care across areas between groups of patients and over time; they
also study the frequency of adhesion to clinical guidelines and their effect on cancer outcomes.
Further insights on mechanisms of tumor progression and metastatic dissemination, as well as differences in clinical
outcome, are provided by the INT in-house breast cancer registry, which uses routine administrative files (e.g. hospital
discharge records) as well as ad hoc information from clinical records obtained by dedicated personnel. Linkage with
INT biological and tissue banks have been established to correlate experimental research results with clinical data. The
possibility of extending the adopted clinical registration methodology to other cancers will be tested. Data from the
Lombardy Region Oncologic Network (ROL) – covering all oncology departments in the Region – is used to compare
patterns of cancer care analyses with adhesion to clinical guidelines between hospitals.
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PROGRAM HIGHLIGHTS
EUROCARE is the largest European population based program monitoring cancer survival in Europe; since its beginning in the late
1980s, it has progressively become a well established program for surveillance of cancer survival in Europe. The latest EUROCARE
results show that, over the EUROCARE-5 study period, survival increased steadily in all countries, for practically all cancers, possibly
because of improved treatment and probably in relation to earlier diagnosis. However, differences between countries remain large
within Europe, with a large gap between eastern Europe and the rest of Europe. Survival in the UK, Ireland and Denmark remains low
for many solid cancers. Possible explanations for persistent international differences in survival include use of diagnostic tests and
screening, stage at diagnosis, access to high-quality care, and differences in cancer biology. Although distribution of stage at diagnosis
remains the main factor affecting between-area survival differences, past HR studies also indicate that adhesion to treatment guidelines affects cancer survival inequalities. The HR studies have therefore contributed to the identification of factors associated with
cancer outcome, and provide the basis for future progress and assessing appropriate actions to reduce inequalities and improve cancer
outcomes. In addition to the above aspects, which are mainly related to public health services and delivery of healthcare, the collection
of biomolecular characteristics allows us to investigate the distribution and prognostic influence of breast cancer molecular subtypes
in population-based cohorts of patients. For instance, the HR Italian study on breast cancer has shown that in ER+PR+ patients high
blood glucose and high BMI are independently associated with an increased risk of breast cancer death, indicating that detection and
correction of these factors patients may improve prognosis.
Based on past experiences, we launched a new round of HR studies in the framework of the EC Funded European Action Against cancer (EPAAC) Joint Action on breast, colorectal and lung cancer, melanoma, and non-Hodgkin’s Lymphoma.
Beside staging, treatment and recurrences, the new HR studies are collecting data on co-morbidities and undesired effects of treatment, as well as on tumor biomarkers of clinical relevance.
Population based studies are supplemented by INT’s clinical registry and related biological repositories, which help investigating the
relation of the molecular characteristics of the tumor with clinical outcome and comorbidity.
PROGRAM MEMBERSHIP
Milena Sant (MD): project leader
Pamela Minicozzi (Mathematician, PhD): Statistical analyses on
EUROCARE and HR databases. Centralization and management of
population based HR data.
Paolo Baili (Statistician, MSc): coordination and management of INT inhouse clinical registries and ROL data
Hade Amash (MD): collection of HR data in INT, medical advice on
technical registration activities
Francesca Di Salvo (Statistician, PhD): support for statistical analyses of
EUROCARE survival data and HR data)
Elisabetta Meneghini (Physicist, MSc): statistical analyses on the INT inhouse clinical breast cancer registry.
Camilla Amati (Humanities BA): EUROCARE Secretariat, scientific
secretariat in research projects
Simone Bonfarnuzzo: IT support for the clinical registry
Agata Cifalà: secretarial support for research projects
Chiara Margutti: EUROCARE secretariat, administrative secretariat in
research projects
Stefania Saltarelli (Political Science MSc): dissemination of results and
research activities through www.tumori.net
Alberto Turco: HR data collection in INT, support to management of INT
in-house clinical registry and ROL data
Ilaria Cavallo (IT degree): IT activity of the clinical registries
Francesco Funaro (IT degree): IT activity of the clinical registry
Allemani C., Sant M., Weir HK., Richardson L.C., Baili P., Storm H.,
Siesling S., Torrella-Ramos A., Voogd A.C., Aareleid T., Ardanaz E.,
Berrino F., Bielska-Lasota M., Bolick S., Cirilli C., Colonna M., Contiero
P., Cress R., Crocetti E., Fulton J.P., Grosclaude P., Hakulinen T.,
Izarzugaza M.I., Malmström P., Peignaux K., Primic-Žakelj M., Rachtan
J., Safaei Diba C., Sánchez M.J., Schymura M.J., Shen T., Traina A.,
Tryggvadottir L., Tumino R., Velten M., Vercelli M., Wolf H.J., Woronoff
A.S., Wu X., Coleman M.P.: Breast cancer survival in the US and
Europe: a CONCORD high-resolution study. Int J Cancer 2013;
132(5): 1170-1181
Minicozzi P., Berrino F., Sebastiani F., Falcini F., Vattiato R., Cioccoloni
F., Calagreti G., Fusco M., Vitale M.F., Tumino R., Sigona A., Budroni
M., Cesaraccio R., Candela G., Scuderi T., Zarcone M., Campisi I.,
Sant M.: High fasting blood glucose and obesity significantly and
independently increase risk of breast cancer death in hormone
receptor-positive disease. Eur J Cancer 2013; 49(18): 3881-3888
Bouvier A.M., Minicozzi P., Grosclaude P., Bouvier V., Faivre J., Sant M.:
Patterns of adjuvant chemotherapy for stage II and III colon cancer in
France and Italy. Dig Liver Dis 2013; 45(8): 687-691
Bella F., Minicozzi P., Giacomin A., Crocetti E., Federico M., Ponz de
Leon M., Fusco M., Tumino R., Mangone L., Giuliani O., Budroni M.,
Sant M.: Impact of diabetes on overall and cancer-specific mortality
in colorectal cancer patients. J Cancer Res Clin Oncol 2013; 139(8):
1303-1310
Mangone L., Minicozzi P., Vicentini M., Giacomin A., Caldarella A.,
Cirilli C., Falcini F., Giorgi Rossi P., Sant M.: Key factors influencing
lung cancer survival in northern Italy. Cancer Epidemiol 2013; 37(3):
226-232
EUROCARE-6 disuguaglianze di sopravvivenza e cure in Europa
(financed by Compagnia di San Paolo) (April 2011-October 2014)
High resolution Eurocare - clinical data collection and statistical analysis
for interpretation of inequalities in prognosis observed in Italy (financed
by the Cariplo Foundation) (August 2011-August 2014)
European Partnership for Action Against Cancer: WP-9 “Health
information and data” (financed by the EU) (March 2011-February
2014)
Cancer survival comparisons: a global perspective (financed by the
Istituto Superiore di Sanità) (July2013-December 2013)
Survival and management of tumors in Italy and Europe (financed by
the Ministry of Health for prevention and control of disease (CCM)(September 2011-September 2013)
KEYWORDS
Tumors, survival and prognosis, care, diagnostic and therapeutic
procedures, cancer registry
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...Siranoush Manoukian...
............Paolo Radice............
..........Lucio Bertario...........
STUDY OF THE MOLECULAR DETERMINANTS
OF THE GENETIC PREDISPOSITION TO
FAMILIAL-HEREDITARY CANCERS
In recent years, several genetic factors associated with hereditary susceptibility to cancer have been identified, and
genetic testing is routinely applied in clinical practice to search for germline cancer predisposing alleles. This allows for
identification of, within cancer prone families, at-risk individuals and to offer them appropriate surveillance programs and/
or other measures of risk reduction, such as chemoprevention or prophylactic surgery. Conversely, family members who
are not found to be carriers of the disease-related gene variants observed in their relatives may be advised to follow the
same recommendations offered to the general population.
However, at present only a fraction of cancer families benefit from genetic testing. In fact, a large fraction of familial cancer
risk remains still molecularly unexplained (so-called “missing hereditability”). In addition, molecular analyses in a diagnostic
context are limited to only a subset of genes associated with cancer susceptibility, i.e. those whose mutations confer
much higher risks than those of the general population (high penetrance alleles). In fact, the clinical relevance of cancer
susceptibility genetic markers that are relatively common and individually associated with marginal risk increase (low
penetrance alleles) is still debated. The same applies to hereditary cancer associated genes in which only a small number of
mutations have been identified, and for which there is still a degree of uncertainty about the clinical consequences of such
mutations. Finally, while loss-of-function mutations are generally considered as deleterious, the pathogenicity of a sizable
fraction of variants identified in hereditary cancer genes, such as missense mutations and variants in introns and regulatory
sequences, still remains undetermined (unclassified variants, UVs).
For more than 20 years, clinical units dedicated to counseling, genetic testing, and clinical management of individuals with
evidence of genetic susceptibility to cancer have been operating at INT, mainly on familial breast, ovarian, and colorectal
carcinomas. These activities fuel research projects aimed at increasing our current knowledge on the molecular basis
of these diseases and our ability to diagnose individuals who are at higher risk of cancer development due to a genetic
predisposition.
The main goals of our research projects are:
1.Definition of the mutational spectra of known cancer associated genes, with particular reference to those occurring
in non-coding regions that are usually not investigated in diagnostic laboratories, and the identification of pathogenic
variants that are recurrent in high-risk Italian families.
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research activity
2.Development of experimental assays for functional characterization of allelic variants of cancer predisposing genes, and
their employment for the clinical classification of UVs.
3.Identification of novel genetic markers of cancer susceptibility.
These objectives are also pursued through the participation of national and international collaborative consortia.
PROGRAM HIGHLIGHTS
This research program takes advantage of the continuous recruitment of individuals and families with evidence of genetic predisposition to cancer who are counseled at the involved clinical units.
In particular, the consolidated and long-lasting clinical activity of the Medical Genetics unit has assembled the largest Italian collection
of HBOC patients and their relatives, including more than 8150 individuals from 3950 different families, of whom approximately 1200,
from some 650 families, are BRCA1/BRCA2 gene carriers. As for the unit of Hereditary Digestive Tract Tumors, in the course of 2013
approximately 600 individuals were screened for germline mutations in genes associated with hereditary susceptibility to gastrointestinal cancers.
Main achievements of 2013 include the following.
1.The effect on mRNA of 24 variants ascertained in HBOC families at splicing regions of the BRCA1 and BRCA2 genes has been
investigated. Overall, 19 were found to lead to aberrant mRNA splicing. The results of experimental assays were compared with the
outcomes of bioinformatic analyses using algorithms developed to predict the consequences of genetic variants at the transcript
level, demonstrating that in silico tools can be used for prioritizing variants that are more likely to be pathogenic (Colombo et al.,
PLoS One. 2013;8:e57173).
2.A case of acinic cell carcinoma of the breast, a rare malignancy diagnosed in a woman carrying a BRCA1 mutation, has been characterized molecularly and immunohistochemically. The observed tumor features suggest involvement of the patient’s germline
mutation in the disease. This broadens the spectrum of BRCA1-associated breast malignancies (Ripamonti et al., BMC Cancer.
2013;13:46).
3.A study carried out in collaboration with the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan on 450 women
with mutations in BRCA genes did not confirm a previously reported association of preferential X chromosome inactivation (XCI)
with BRCA status and breast/ovarian cancer risk. However, an increase in the frequency of XCI with ageing and in cancer patients
submitted to chemotherapy was observed (Manoukian et al., Eur J Cancer. 2013;49:1136-41).
4. The units involved in the present project have actively contributed to studies of collaborative national groups and international
consortia. Among the most relevant, it is worth mentioning: a) genome-wide analysis carried out on 10,052 breast cancer cases and
12,575 controls that led to the discovery of 41 new loci associated with breast cancer risk (Michailidou et al., Nat Genet. 2013;45:35361); b) an integrative analyses on 132 patients affected with hereditary non-polyposis colorectal cancer, demonstrating the wide
genetic and allelic heterogeneity associated with this disease and enlightening the role of allelic-specific gene expression (De Lellis et
al., Plos One 2013; 8:e81194); c) an Italian multicenter survey on cancer risk in carries of STK11/LKB1 germline mutations (Resta et
al., Dig Liver Dis. 2013; 45:606-11).
PROGRAM MEMBERSHIP
Paolo Radice, PhD
Head of Molecular basis of genetic risk and genetic testing research
unit.
Principal investigator of research projects on the identification
and characterization of genetic factors responsible for hereditary
predisposition to cancer.
Siranoush Manoukian, MD
Head of Medical Genetics clinical and research unit.
Identification of hereditary breast and ovarian cancer (HBOC) families,
genetic counseling, and collection of blood withdrawal for genetic
testing and research purposes.
Collection of genetic, clinical, and pathological data of high-risk
individuals.
Lucio Bertario, MD
Head of Hereditary Digestive Tract Tumors unit.
Counseling, molecular testing, and clinical management of individuals
with predisposition to major hereditary gastrointestinal cancer
syndromes: Lynch syndrome, familial adenomatous polyposis (FAP)
and its phenotypic variant attenuated-FAP, Peutz-Jeghers syndrome,
juvenile polyposis and hereditary gastric cancer.
Data collection on high-risk individuals.
Maria Luisa Carcangiu, MD
Head of Anatomic Pathology Unit 1 and Reference pathologist.
Paolo Verderio, PhD and Sara Pizzamiglio, Msc
Research staff scientists at the Medical statistics, biometry, and
bioinformatics unit.
Reference statisticians.
Colombo M., De Vecchi G., Caleca L., Foglia C., Ripamonti C.B.,
Ficarazzi F., Barile M., Varesco L., Peissel B., Manoukian S., Radice P.:
Comparative in vitro and in Silico analyses of variants in splicing
regions of BRCA1 and BRCA2 genes and characterization of novel
pathogenic mutations. PLoS One 2013; 8(2): e57173
Manoukian S., Verderio P., Tabano S., Colapietro P., Pizzamiglio S., Grati
F.R., Calvello M., Peissel B., Burn J., Pensotti V., Allemani C., Sirchia S.M.,
Radice P., Miozzo M.: X chromosome inactivation pattern in BRCA
gene mutation carriers. Eur J Cancer 2013; 49(5): 1136-1141 De Lellis
L., Aceto G.M., Curia M.C., Catalano T., Mammarella S., Veschi S., Fantini
F., Battista P., Stigliano V., Messerini L., Mareni C., Sala P., Bertario L.,
Radice P., Cama A.: Integrative analysis of hereditary nonpolyposis
colorectal cancer: the contribution of allele-specific expression and
other assays to diagnostic algorithms. Plos One 2013; 8(11): e81194
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Resta N., Pierannunzio D., Lenato G.M., Stella A., Capocaccia R., Bagnulo
R., Lastella P., Susca F.C., Bozzao C., Loconte D.C., Sabbà C., Urso E., Sala
P., Fornasarig M., Grammatico P., Piepoli A., Host C., Turchetti D., Viel
A., Memo L., Giunti L., Stigliano V., Varesco L., Bertario L., Genuardi M.,
Lucci Cordisco E., Tibiletti M.G., Di Gregorio C., Andriulli A., Ponz de
Leon M.; AIFEG. Cancer risk associated with STK11/LKB1 germline
mutations in Peutz-Jeghers syndrome patients: results of an Italian
multicenter study. Dig Liver Dis 2013; 45(7): 606-611
Michailidou K., Hall P., Gonzalez-Neira A., Ghoussaini M., Dennis J.,
Milne R.L., Schmidt M.K., Chang-Claude J., Bojesen S.E., Bolla M.K.,
Wang Q., Dicks E., Lee A., Turnbull C., Rahman N.; Breast and Ovarian
Cancer Susceptibility Collaboration, Fletcher O., Peto J., Gibson L., Dos
Santos Silva I., Nevanlinna H., Muranen T.A., Aittomäki K., Blomqvist C.,
Czene K., Irwanto A., Liu J., Waisfisz Q., Meijers-Heijboer H., Adank M.;
Hereditary Breast and Ovarian Cancer Research Group Netherlands
(HEBON), van der Luijt R.B., Hein R., Dahmen N., Beckman L., Meindl
A., Schmutzler R.K., Müller-Myhsok B., Lichtner P., Hopper J.L., Southey
M.C., Makalic E., Schmidt D.F., Uitterlinden A.G., Hofman A., Hunter
D.J., Chanock S.J., Vincent D., Bacot F., Tessier D.C., Canisius S., Wessels
L.F., Haiman C.A., Shah M., Luben R., Brown J., Luccarini C., Schoof N.,
Humphreys K., Li J., Nordestgaard B.G., Nielsen S.F., Flyger H., Couch
F.J., Wang X., Vachon C., Stevens K.N., Lambrechts D., Moisse M.,
Paridaens R., Christiaens M.R., Rudolph A., Nickels S., Flesch-Janys D.,
Johnson N., Aitken Z., Aaltonen K., Heikkinen T., Broeks A., Veer L.J.,
van der Schoot C.E., Guénel P., Truong T., Laurent-Puig P., Menegaux F.,
Marme F., Schneeweiss A., Sohn C., Burwinkel B., Zamora M.P., Perez J.I.,
Pita G., Alonso M.R., Cox A., Brock I.W., Cross S.S., Reed M.W., Sawyer
E.J., Tomlinson I., Kerin M.J., Miller N., Henderson B.E.,
Schumacher F., Le Marchand L., Andrulis I.L., Knight J.A., Glendon G.,
Mulligan A.M.; kConFab Investigators; Australian Ovarian Cancer
Study Group, Lindblom A., Margolin S., Hooning M.J., Hollestelle A., van
den Ouweland A.M., Jager A., Bui Q.M., Stone J., Dite G.S., Apicella C.,
Tsimiklis H., Giles G.G., Severi G., Baglietto L., Fasching P.A., Haeberle L.,
Ekici A.B., Beckmann M.W., Brenner H., Müller H., Arndt V., Stegmaier
C., Swerdlow A., Ashworth A., Orr N., Jones M., Figueroa J., Lissowska
J., Brinton L., Goldberg M.S., Labrèche F., Dumont M., Winqvist R.,
Pylkäs K., Jukkola-Vuorinen A., Grip M., Brauch H., Hamann U., Brüning
T.; GENICA (Gene Environment Interaction and Breast Cancer in
Germany) Network, Radice P., Peterlongo P., Manoukian S., et al.: Largescale genotyping identifies 41 new loci associated with breast cancer
risk. Nat Genet 2013; 45(4): 353-361
Associazione Italiana per la Ricerca sul Cancro
Novel approaches for the assessment of the functional effects of
unclassified variants in BRCA genes (Jan 2012 – Dec 2014)
Principal investigator: Paolo Radice
INT- Institutional strategic projects “5x1000” of the Scientific Directorate.
Novel molecular mechanisms of genetic predisposition to early-onset
breast cancer (Jun 2013 – May 2014)
Principal investigator: Paolo Radice
KEYWORDS
hereditary cancer, risk alleles, mutation testing, functional assays
Figure: RT-PCR analyses of BRCA1
and BRCA2 variants affecting mRNA
splicing. For each variant, the RTPCR products were characterized
by agarose gel electrophoresis and
sequencing. Gel images: lane 1, no
template; lane 2, genomic DNA used
as negative control of the RT-PCR
reaction; lane 3, cDNA from the
BRCA1/BRCA2 wild-type LCL used as
positive control; lane 4, cDNA from
LCL carrying the UV. M, molecular
marker (ΦX-174 HaeIII digest). The
size of the full-length (FL) and aberrant
transcripts are reported. Sequencing
electropherogram data: (B-G) the RTPCR products were directly sequenced;
(A, H) the sequencing was performed
after band excision or cloning step. (H)
An additional band due to improper
annealing of full-length and aberrant
transcripts is shown by the asterisk.
The Ex5del, visible in both sample and
control is a naturally occurring isoform
lacking exon 5. (A) In addition to the
full-length and the Ex14del aberrant
transcript, the naturally occurring
isoform lacking the first 3 bp of exon 14
(Ex14_3bp del) was observed. Ex, exon;
I, intron. (reproduced from Colombo et
al., PLoS One. 2013;8:e57173).
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MOLECULAR
CARACTERIZATION
OF TUMOR
PROGRESSION
COORDINATOR: Maria Grazia Daidone
Study of molecular mechanisms (and their alterations) responsible for the origin, growth and
progression of solid tumors to develop treatment approaches selectively targeting those
mechanisms; study of tumor interactions with the surrounding stroma, the cells of the immune
system, and the extracellular matrix in order to elucidate biological events (such as tolerance
of and resistance against tumor development) and investigate the link between inflammation
and cancer. Definition of new therapeutic targets, diagnostic and prognostic biomarkers, and
markers predictive of the response to conventional treatments.
AIMS: Identification of molecular defects associated with cell transformation and
tumor progression, to be used as markers for diagnosis, prognosis and disease
monitoring. Creation of highly sensitive molecular tests for possible clinical
application. Detection and assessment of molecular targets against which to
develop innovative treatments. Development of new drug combinations in models
and experimental systems. Identification of mechanisms of interaction with the
microenvironment during cancer progression.
PROJECTS
• Involvement of microRNAs in the principal pathways of breast cancer:
from biology to possible therapeutic applications (Marilena Iorio)
• Analysis of circulating markers for prognosis and treatment response
monitoring in breast cancer (Maria Grazia Daidone)
• Detection and validation of new genetic/genomic and metabolic markers of prognosis
or prediction of treatment response and/or early relapse in ovarian cancer (Delia Mezzanzanica)
• Thyroid cancer: functional studies for the detection of new molecular
mechanisms and therapeutic targets (Angela Greco)
• Extracellular matrix protein SPARC regulates primary and secondary lymphoid organs homeostasis and the
transition of myeloproliferative or autoimmune spurs toward leukemia and lymphoma (Mario P. Colombo)
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.Marilena V. Iorio.
INVOLVEMENT OF microRNAs IN THE PRINCIPAL
PATHWAYS OF BREAST CANCER: FROM BIOLOGY
TO POSSIBLE THERAPEUTIC APPLICATIONS
In the last years new players have been revealed in cancer biology, namely microRNAs, a class of small non-coding RNAs
that are able to regulate gene expression at the post-transcriptional level. Several studies have demonstrated that
microRNAs, highly specific for tissue and developmental stages, and playing important roles in essential processes, are
involved in several human diseases, including cancer.
Our group (Iorio MV et al., 2005) described the first breast cancer-specific microRNA signature obtained by genome wide
microRNA expression analysis in a large set of normal and tumor breast tissues, identifying a list of microRNAs able to
classify tumors and normal tissues with an accuracy of 100% and signatures associated to specific biopathological features.
Breast cancer is a complex and heterogeneous disease, where survival and proliferation of a cancerous cell might depend
on the activation of different pathways. In addition to breast tumors depending on ER activation or HER2 overexpression,
the third major subgroup of breast cancer includes the so-called Triple Negative Tumors (TNBC), which are negative for
ER, PgR, and HER2 expression. Very aggressive from a clinical point of view, they are characterized by an undifferentiated
phenotype and lack specific markers for an effective targeted therapy. These tumors still represent a relatively unknown
area in breast cancer biology. microRNAs could both provide the missing information to explain the behavior of this class of
breast carcinoma, and represent possible tools or targets for a specific therapy.
The goal of our project is the identification and the study of microRNAs involved in the most important pathways activated
in human breast cancer, with the aim to better define the role of these small but powerful molecules in this neoplasia, and to
provide the experimental bases for their possible use as targets or tools of specific therapies.
The most recent results of this study include the description of the oncosuppressive role of miR-205 in TNBC (Piovan C
et al., 2012); a regulatory loop involving miR-191 and ER in collaboration with Dr Di Leva (Di Leva et al., 2013); a recently
accepted manuscript in collaboration with Dr. Tagliabue on PDGFRbeta involvement in vascular mimicry properties of
TNBC (Plantamura I et al., 2014), in addition to preliminary data on two microRNAs involved in this phenomenon; the
production of two KO mouse models for miR-205; preliminary data on miR-205 and responsiveness to trastuzumab in
HER2+ breast cancer.
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PROGRAM HIGHLIGHTS
This is a translational project with the overall goal to increase knowledge about the involvement of miRNAs in breast cancer, and to
evaluate their possible use as markers of diagnosis and prognosis, and eventually as new targets or tools of a specific, future therapy.
Even though different groups are investigating miRNAs in different subtypes of breast cancer, instead of starting from the expression
profile of different subgroups of breast cancer to find the relevant miRNAs, we are dissecting the main pathways driving proliferation/
survival in different breast cancer models to discover microRNAs that may be crucial for the biology of this neoplasm.
Moreover, the availability at INT of a series of specimens from breast cancer patients make this project a combination of discovery,
validation, and clinical applications.
Finally, during last year we generated ubiquitous, conditional, miR-205 KO mice (through a Cre-LoxP system). Even though the
technique is not innovative per se, just a few experimental models have been developed to date concerning microRNAs. A KO mouse
certainly represents a valuable genetic model that will allow not only more accurate demonstration of the causal role of miR-205 in
the occurrence of breast cancer, but also investigation of the function of this microRNA in development of the normal breast gland and
other tissues.
The PI has reached the expertise to carry out the proposed experiments working both at the INT and in Dr. Croce’s laboratories, where
she participated in pioneering studies in the miRNA field. Moreover, collaboration with different experts and scientists at the INT
guarantees fruitful and reciprocal interaction.
PROGRAM MEMBERSHIP
Marilena V. Iorio, PI. Coordinates the project.
Ilaria Plantamura, Fellow. Mainly focused on the study of miRNAs
involved in vascular mimicry properties of TNBC.
Sara Baroni, Post-doc fellow. Focused on miRNAs involved in HER2mediated pathway.
Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics,
monitoring and therapeutics. A comprehensive review. EMBO Mol
Med. 2012 Mar;4(3):143-59.
Piovan C, Palmieri D, Di Leva G, Braccioli L, Casalini P, Nuovo G,
Tortoreto M, Sasso M, Plantamura I, Triulzi T, Taccioli C, Tagliabue E,
Iorio MV, Croce CM. Oncosuppressive role of p53-induced miR-205 in
triple negative breast cancer. Mol Oncol. 2012;6(4):458-72.
Claudia Piovan, Post-doc, collaborator. In charge of the miR-205/
trastuzumab study and miR-205 KO mice.
AND AWARDS
Elvira D’Ippolito, PhD student. Mainly focused in the study of miRNAs
involved in vascular mimicry properties of TNBC.
AIRC Start Up Grant (2011);
Annalisa Elefante, Graduate student. Her thesis is on miRNAs in TNBC.
Di Leva G, Piovan C, Gasparini P, Ngankeu A, Taccioli C, Briskin D,
Cheung DG, Bolon B, Anderlucci L, Alder H, Nuovo G, Li M, Iorio MV,
Galasso M, Santhanam R, Marcucci G, Perrotti D, Powell KA, Bratasz A,
Garofalo M, Nephew KP, Croce CM. Estrogen mediated-activation of
miR-191/425 cluster modulates tumorigenicity of breast cancer cells
depending on estrogen receptor status. PLoS Genet. 2013;9(3).
Young Researcher Grant from the Italian Ministry of Health (2012)
Young Researcher Award at INT (2008)
KEYWORDS
Breast Cancer, microRNA, therapeutics
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.Maria Grazia Daidone.
ANALYSIS OF CIRCULATING MARKERS FOR
MONITORING DISEASE PROGRESSION AND
TREATMENT RESPONSE IN BREAST CANCER
The identification of reliable circulating biomarkers tracking tumor behaviour and allowing to discover novel alterations
in cancer cells represents a paradigm shift in the personalized clinical care of different solid tumors, including breast
cancer (BC). Blood-based biomarkers as circulating tumor cells (CTCs) and free nucleic acids (circulating tumor DNA,
ct-DNA, and circulating microRNAs, miRNAs) represent ideal non-invasive tools since they may allow: 1) multiple
“liquid biopsies” over time, when primary tumor and metastatic lesions are not available; 2) longitudinal analyses of the
molecular features of cancer cells to understand in real time changes occurring within the tumor; 3) monitoring response
to systemic treatments in neoadjuvant, adjuvant and advanced settings, and detecting minimal residual disease in the
early disease. Overall, information obtained by liquid biopsies could represent means to address the challenges raised by
phenotypic and functional heterogeneity and may provide insights into some of the fundamental processes that led to
an aggressive and treatment-refractory phenotype. During the last decade, studies carried out in BC on CTCs, miRNAs
and ct-DNA showed promising results. However, despite encouraging results and the development of novel and sensitive
technologies to detect molecular changes at the single-cell-level, some weaknesses of the new generation of biomarkers
still outperform their strengths. In addition, notwithstanding the growing interest on a molecular characterization of liquid
biopsies, ct-DNA, miRNA and CTC molecular features have been mostly investigated singly, on relatively limited case
series and convenience samples, without integrative approaches to comparatively analyse the informative contribution
provided by each of them to BC biology and clinical outcome. We are performing an extensive molecular characterization
of liquid biopsies, in terms of evaluation of ct-DNA, circulating miRNA and CTC profiles (transcriptome, DNA mutations
and miRNAs), in blood samples prospectively collected from a consecutive series of BC patients undergoing surgery to
assess the clinical implications of biomarkers derived from liquid biopsies and of their dynamic changes as tumor trackers
in different clinical scenarios. This step could allow us to monitor the different aspects of tumor heterogeneity, in terms of
emergence of new somatic alterations within a patient and occurrence of treatment-related plasticity of cancer cells. In
parallel with these translational steps, also pre-clinical in vivo and in vitro studies will be carried out to identify molecular
profiles of metastasis-initiating cells and features associated with resistance to targeted therapies. We base our work on
biospecimens collected from clinical tumors, established BC cell lines in vitro cultured or injected in the mammary fat pad
of NOD/SCID mice, and on highly sensitive technologies able to detect molecular alterations at the single-cell-level.
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PROGRAM HIGHLIGHTS
In this study we plan to define a molecular portrait of liquid biopsies from women with BC, taking also in consideration the molecular
subtype of the primary tumor and the clinical setting of the patients with the aim to monitor the different aspects of tumor heterogeneity, in terms of emergence of new somatic alterations within a patient and occurrence of alterations in cancer cell plasticity following
specific systemic treatments. Since the molecular characterization will become part of chemotherapy protocols of systemic therapy
for resectable and advanced tumors, it might provide insights into some of the fundamental processes that led to metastasis and
treatment resistance.
During 2013 our group addressed some critical points (such as presence of hemolysis, choice of the most appropriate technique
for discovery, lack of established miRNA reference) related to evaluation and analysis of circulating miRNAs from blood specimens.
Specifically, we:
•by using experiments of controlled hemolysis and lipemia in plasma from cancer patients, developed and validated a simple, robust,
sensitive, cost-effective, reproducible, lipemia-independent spectrophotometrically-based system to identify hemolyzed plasma/
serum specimens, which is suitable for limited serum/plasma aliquots (and thus useful for studies on archival material);
•critically evaluated strengths and weaknesses of the available analytical tools for circulating miRNA profiling and, once assessed
the adequate intra- and inter-array reproducibility of miRNA profiling and the feasibility of using archival plasma samples stored
for an extended period of time and available in limited amounts, demonstrated the feasibility of using archival plasma samples with
high-throughput microarray-based strategies;
•routinely analyzed experimental results using different approaches (raw data, normalization approaches ratio-based or using
housekeeping miRNAs).
Taking into consideration all these warnings, we profiled long-term stored plasma samples from node-negative BC patients entering
from 1987 to 1993 a randomized clinical study of chemoprevention and identified a signature of circulating miRNAs associated with
the development of distant metastasis. Candidate miRNAs, proved to be associated with distant metastasis even when evaluated on
tumor tissue (Fig.1) and, when added to culture medium, increase BC cell migration.
As regards to CTC profiling, we set up a technical protocol to measure by the WG-DASL HT assay the expression of more than 29,000
genes in CTCs captured from whole blood with immune beads linked with antibodies against EpCAM and MUC1, designed to be used
for clinical samples. Our approach allows obtaining technically reliable gene expression profiles (GEPs) from isolated CTCs and distinguishing unique features thus providing biologically useful information. It is reproducible and suitable to be challenged in prospective
studies, provided that at least 25 CTCs can be isolated.
PROGRAM MEMBERSHIP
Biomarkers Unit, DOSMM
Maria Grazia Daidone, Biol Sci D PhD (PI of the project)
Valentina Appierto, Biol Sci D, PhD, and Paola Tiberio, Biol Sci D (Fellows
involved in miRNA and ct-DNA studies)
Vera Cappelletti, Staff, Biol Sci D, Emanuela Fina, Biol Sci D, PhD student
(involved in CTC isolation and molecular characterization)
Silvia Veneroni, Staff, Biol Sci D (coordinating the collection of
biospecimens)
Elena Cavadini, Staff technician involved in miRNA studies
Maurizio Callari, Med Biotech D, PhD (Fellow involved in bioinformatic
analyses)
DOSMM core facilities
Loredana Cleris, Staff technician involved in in vivo studies
Senology Unit
Roberto Agresti, MD (clinical partnership and patient follow-up)
Medical Oncology 1 Unit
Giulia Bianchi, MD, Serena di Cosimo, MD (clinical partnership and
treatment of patients)
Medical Statistics Unit
Rosalba Miceli, MSc Stats, PhD and Elena Landoni, MSc Stats, PhD
(statistical support)
Callari M, Tiberio P, De Cecco L, Cavadini E, Dugo M, Ghimenti C,
Daidone MG, Canevari S, Appierto V. Feasibility of circulating miRNA
microarray analysis from archival plasma samples. Anal Biochem.
2013 Jun 15;437(2):123-5. doi:10.1016/j.ab.2013.03.002
Tiberio P, De Cecco L, Callari M, Cavadini E, Daidone MG, Appierto V.
MicroRNA detection in plasma samples: how to treat heparinized
plasma. J Mol Diagn. 2013 Jan;15(1):138-9. doi: 10.1016/j.
jmoldx.2012.08.009
Bisso A, Faleschini M, Zampa F, Capaci V, De Santa J, Santarpia L, Piazza
S, Cappelletti V, Daidone M, Agami R, Del Sal G. Oncogenic miR-181a/b
affect the DNA damage response in aggressive breast cancer. Cell
Cycle. 2013 June 1; 12(11): 1679–1687. doi: 10.4161/cc.24757
De Cecco L, Dugo M, Canevari S, Daidone MG, Callari M. Measuring
microRNA expression levels in oncology: from samples to data
analysis. Crit Rev Oncog. 2013;18(4):273-87. Review. PubMed PMID:
23614615
Daidone MG, Zaffaroni N, Cappelletti V. Strategies to translate
preclinical information to breast cancer patient benefit. J Natl Cancer
Inst Monogr. 2011;2011(43):55-9. doi: 10.1093/jncimonographs/
lgr033. PubMed PMID: 22043041
ASSOCIATED CLINICAL TRIALS
4-HPR INT study: chemoprevention of stage I breast cancer patients
with fenretinide; Neo ALTTO (Neoadjuvant Lapatinib and/or
Trastuzumab Treatment Optimisation)
Associazione Italiana per la Ricerca sul Cancro (AIRC, Special program
“Innovative tools for cancer risk assessment and early diagnosis,
5x1000, PI M.A. Pierotti, and MFAG to SdC), EurocanPlatform, FIRBNewton, Nanomax-MIUR and other MIUR-supported grants.
KEYWORDS
Liquid biopsy, circulating biomarkers, circulating tumor cells, circulating
mutant ct-DNA, circulating miRNAs
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.Delia Mezzanzanica.
DETECTION AND VALIDATION OF NEW GENETIC/
GENOMIC AND METABOLIC MARKERS OF PROGNOSIS
OR PREDICTION OF TREATMENT RESPONSE AND/
OR EARLY RELAPSE IN OVARIAN CANCER
Although the incidence is quite low, ovarian cancer (OC) is a highly lethal malignancy and is the leading cause of
gynecological cancer death. Factors contributing to its unfavourable prognosis include late diagnosis, frequent relapse
after front-line treatment, and development of chemoresistance. In spite of many efforts, to date no reliable clinical
measures for prediction of response to treatment are available and survival rates have changed little in the last 30 years,
with an overall 5-year survival rate for advanced stage patients of approximately 30%.
The analysis of differential gene expression, and more recently of non-coding RNAs, while having contributed to identify
diagnostic and prognostic markers in different pathologies, have not yet been sufficiently developed and validated in the
case of OC. Our research group has significantly contributed in this area with the identification and characterization of a
cluster of microRNAs (miRNAs) that are down-modulated in patients with early relapsing OC and involved in regulation of
cellular plasticity and drug sensitivity. Indeed, we demonstrated that one of these miRNAs, when re-expressed, sensitizes
OC cells to treatment with platinum compounds. Resistance to apoptotic stimuli is only one of the tumor “hallmarks”, a
series of biological properties acquired by tumor cells during transformation and disease progression that also includes the
ability to modify/reprogram cellular metabolism.
Abnormal choline (Cho) metabolism is an emerging hallmark associated with oncogenesis and tumor progression. We
recently reported alterations of the Cho-metabolite magnetic resonance spectral (MRS) profile in OC, characterized by an
increased content of phosphocholine (PCho). We showed that choline kinase (ChoK) has a primary role in sustaining the
aberrant PCho content of OC as its activity and expression is significantly increased in cancer cells compared to normal
counterparts.
The overall aim of this project is the definition of new prognostic and predictive markers that take into account tumor
biology and its heterogeneity, and will eventually help in identifying patients with an increased risk of disease recurrence.
The specific aims are:
•Mapping chemoresistance using an integrated transcriptomic approach on clinically homogeneous OC patients with
different prognoses and identification of miRNAs driving disease recurrence by matched analyses on primary tumor,
omental secondary localization, and tumor at relapse.
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research activity
•Assessment of clinical and biological relevance of increased ChoK expression and activity in OC and to focus attention
on a possible prognostic role and druggability, as ChoK has a primary role in sustaining the EOC cholinic phenotype. The
effect of ChoK-targeted treatments either alone or combined with conventional therapy will be followed by quantitative
MRS and MRI characterization of EOC xenotransplant models. The potential prognostic impact of ChoK will also be
explored.
PROGRAM HIGHLIGHTS
It is well known that resistance to chemotherapeutic treatments is the result of multiple molecular aberrations. We hypothesize that
an integrated transcriptomic and metabolomic approach, by considering at the same time genetic, epigenetic and metabolic alterations, could be more informative than single-transcriptome analysis for identification of patients with poor prognosis. We expect that
integration of these distinct but complementary levels of information might resemble more precisely the complexity of tumor aberrations that drive recurrence of disease and drug resistance, and improve the effectiveness of outcome prediction procedures, possibly
allowing the development of ‘’clinically-useful measures’’. Indeed, the use of metabolic markers as a diagnostic tool has the potential to
influence clinical oncology affecting patient care with significant benefit. Metabolic and molecular imaging techniques, in fact, offer the
possibility to monitor and discriminate metabolic markers in a non-invasive manner in vivo. The overall expected outcome is to identify
prognostic factors tailored to the molecular/metabolic features of patients. This should allow a more accurate identification of patients
experiencing early relapse and/or chemoresistance, and significantly help to select the best therapeutic and follow-up modalities.
PROGRAM MEMBERSHIP
Internal collaborators
Unit of Molecular Therapies: Dr. Marina Bagnoli (signaling pathways and
statistical/bioinformatic analyses); Dr. Anna Granata (in vitro and in vivo
characterization of ChoK silenced cells); Dr. Roberta Nicoletti (biological
characterization of miRNAs/genes identified by OC samples profiling).
Technical support by Mrs. Paola Alberti.
Unit of Functional Genomics: Dr. Loris De Cecco and Dr. Silvana Canevari
(genetic/genomic profiling and bioinformatic analysis).
Unit of Gynecological Oncology: Dr. Francesco Raspagliesi and Dr.
Domenica Lorusso (clinical samples collection and pathological and
follow-up data).
Anatomic Pathology Unit 1: Dr. Maria Luisa Carcangiu (pathological
revision of selected tumor specimens).
External collaborators
Istituto Superiore Sanità Rome: Dr. Egidio Iorio and Dr. Rossella Canese
(characterization of NMR-detectable metabolites and MRI/MRS
profiles for early detection of treatment response in preclinical EOC
models).
Istituto Italiano di Tecnologia, Genoa: (development of nanomaterial and
their functionalization with antibodies for specific tumor targeting).
Fondazione G. Pascale Naples: Dr. Sandro Pignata, Dr. Daniela Califano, Dr.
Stefano Greggi, Dr. Simona Losito (samples and clinical data collection at
Pascale, nucleic acid extraction and quality control).
Johns Hopkins University - Baltimore, USA: Dr. Zaver M. Bhujwalla (expert
in choline metabolism and MRS/MRI imaging).
MD Anderson Cancer Center, Houston, USA: Dr. Anil K. Sood and Dr. Wei
Zhang (miRNAs functional characterization).
Sonego M., Schiappacassi M., Lovisa S., Dall’Acqua A., Bagnoli M., Lovat
F., Libra M., D’Andrea S., Canzonieri V., Militello L., Napoli M., Giorda
G., Pivetta B., Mezzanzanica D., Barbareschi M., Valeri B., Canevari S.,
Colombatti A., Belletti B., Del Sal G., Baldassarre G.: Stathmin regulates
mutant p53 stability and transcriptional activity in ovarian cancer.
EMBO Mol Med 2013; 5: 707-722
De Cecco L., Berardi M., Sommariva M., Cataldo A., Canevari S.,
Mezzanzanica D., Iorio M.V., Tagliabue E., Balsari A.: Increased
sensitivity to chemotherapy induced by CpG-ODN treatment is
mediated by microRNA modulation. PLoS One 2013; 8: e58849
Bagnoli M., De Cecco L., Granata A., Nicoletti R., Marchesi E., Alberti
P., Valeri B., Libra M., Barbareschi M., Raspagliesi F., Mezzanzanica
D., Canevari S.: Identification of a chrXq27.3 microRNA cluster
associated with early relapse in advanced stage ovarian cancer
patients. Oncotarget 2011; 2: 1265-1278
AND AWARDS
AIRC IG-grant 12976 (2013-2016; PI Delia Mezzanzanica): The
ovarian cancer cholinic phenotype: exploring possible theragnostic
windows.
Fondazione CARIPLO grant 2013-0865 (2014-2017; PI Delia
Mezzanzanica): Disease recurrence in epithelial ovarian cancer:
deciphering miRNA-driven regulatory networks related to drug
sensitivity/cellular plasticity and exploring nanomaterial-based targeted
delivery of identified key molecules for therapeutic purposes.
Winner of the ROL/REL call for pre-clinical research (2012-2013
PI Delia Mezzanzanica/Marina Bagnoli): Selection and functional
characterization of Choline kinase-alpha inhibitors for a new targeted
therapy approach.
KEYWORDS
Ovarian cancer, resistance to chemotherapy, genomic/metabolic
alterations
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Figure: The virtuous circle of OC characterization: potential translational applications for a personalized approach to disease treatment.
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research activity
.Angela Greco.
THYROID CANCER: FUNCTIONAL STUDIES
FOR THE DETECTION OF NEW MOLECULAR
MECHANISMS AND THERAPEUTIC TARGETS
Thyroid carcinoma is the most frequent endocrine cancer with an incidence that is rapidly increasing. The majority of
thyroid tumors arise from follicular cells and consist of well differentiated papillary (PTC), the most frequent histotype, in
addition to follicular (FTC) carcinomas, and poorly differentiated (PDTC) and undifferentiated anaplastic carcinomas (ATC).
Generally, PTC and FTC have a good prognosis. Standard therapy, based on total thyroidectomy, ablation with radioiodine
and suppressive therapy, is generally successful. Nevertheless, in about 20% of patients with well-differentiated thyroid
cancer, the tumor develops resistance to therapy, or tends to dedifferentiate, leading to recurrent disease and death.
Furthermore, patients with ATC have a very poor prognosis. Therefore, a better understanding of thyroid carcinogenesis
and novel therapeutic opportunities are needed.
This need is being approached by different functional approaches.
1) The identification of molecules governing oncogene-induced senescence (OIS) in thyrocytes, a mechanism
demonstrated to be involved in thyroid tumor progression. We have recently proposed that OIS may restrain the evolution
of early to late tumor stages, as well as the transition of well differentiated to more aggressive variants. We are interested
in the characterization of secreted molecules, in particular inflammatory cytokines, produced by senescent thyrocytes,
which model in vitro thyroid tumor in the early phase.
2) Dissection of the role, in the process of thyroid carcinogenesis, of genes differentially expressed in PTC, by investigating
the effect of their modulation on different aspects of the transformed phenotype of PTC-derived cell lines.
3) Identification of genes whose inactivation selectively promotes lethality of tumor cells but do not affect normal thyroid
cells (non-oncogene addiction, NOA). Through the screening of a synthetic small interfering RNA (siRNA) library targeting
the human druggable genome a panel of 13 genes whose inhibition interferes with tumor, but not normal thyroid, cell
viability has been identified. The effect of their inhibition in several thyroid tumor cell lines, as well as the identification of
the affected pathways, will unveil their possible use as therapeutic targets.
4) Characterization of the interaction between tumor microenvironment components, in particular macrophages, and
thyroid tumor cells representative of early (senescent thyrocytes) and late (tumor-derived cell lines) thyroid tumor stages.
5) Investigation through functional studies of the biological relevance and possible use as therapeutic tool of selected,
under-estimated miRNA, which are under-expressed in PTC. These miRNAs have been identified through our integrated
analysis of in vitro PTC models and clinical case list expression profiles.
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PROGRAM HIGHLIGHTS
•The proposed studies allow the identification of novel players in PTC carcinogenesis. Targeting identified genes, miRNAs, and
molecules, as well as thyroid associated oncogenes, may represent novel therapeutic options for patients who are not curable by
standard therapy.
•OIS is a mechanism proposed as a barrier to cancer. Notably, we have demonstrated that it occurs in thyroid tumor early phase, for
which senescent thyrocytes represent an in vitro model. Moreover, we have produced an in vitro inducible model of thyrocytes OIS.
•Integrated expression profiles of genes and miRNA, combining clinical tumors with in vitro cell models, may lead to identification of
novel players in PTC cancerogenesis. This approach allowed us to identify miR-199a-3p as a novel oncosuppressor miRNA in PTC.
•The ability of miRNAs to target multiple genes, frequently in the context of a network, makes these molecules very efficient in
regulating whole cell functions, more than the single genes they target.
•The tumorigenic state, besides the activity of oncogenic pathways, also depends on the activity of various genes and pathways that
are not oncogenic themselves, but which are essential to support the oncogenic phenotype of cancer cells and not required to the
same degree for viability of normal cells. This phenomenon is referred to as ‘Non-Oncogene Addiction’ (NOA). NOA genes may be
identified by loss of function, RNA interference-based genetic approaches, which have not yet been applied to thyroid tumor cells.
•The role of tumor microenvironment, and particularly macrophages, is a major issue in cancer. Macrophage infiltration has been
reported in thyroid tumors; however, no functional studies dissecting the interplay between macrophages and thyroid tumor cells
(representative of different tumor stages) are available.
PROGRAM MEMBERSHIP
A Greco: Coordinator of the project
Cariplo 2013-0893: “Role of tumor microenvironment in thyroid
carcinogenesis onset and progression: thyroid cells cross-talk with
macrophages” (2014- 2016; PI: A Greco)
MG Borrello: Coordinator of studies involving miRNA
MCA Anania, E Cetti: studies related to NOA
M Mazzoni: studies related to OIS and senescent thyrocytes and
macrophage interaction
P Romeo: studies related to thyroid tumor cells and macrophage
interaction; collaboration in miRNA studies
E Minna: miRNA studies
S Pagliardini, MG Rizzetti: technical collaboration
Vizioli M.G., Possik P.A., Tarantino E., Meissl K., Borrello M.G., Miranda
C., Anania M.C., Pagliardini S., Seregni E., Pierotti M.A., Pilotti S., Peeper
D.S., and Greco A.: Evidence of oncogene-induced senescence in
thyroid carcinogenesis. Endocr Relat Cancer 2011; 18(6): 743-757
Anania M.C., Miranda C., Vizioli M.G., Mazzoni M., Cleris L., Pagliardini
S., Manenti G., Borrello M.G., Pierotti M.A., Greco A.: S100A11
overexpression contributes to the malignant phenotype of
papillary thyroid carcinoma. J Clin Endocrinol Metab 2013; 98 (10)
E1591-E1600
Degl’innocenti D., Romeo P., Tarantino E., Sensi M., Cassinelli G.,
Catalano V., Lanzi C., Perrone F., Pilotti S., Seregni E., Pierotti M.A.,
Greco A., Borrello MG.: DUSP6/MKP3 is over-expressed in papillary
and poorly-differentiated thyroid carcinoma and contributes to the
neoplastic properties of thyroid cancer cells. Endocr Relat Cancer.
2013; 20(1): 23-37
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AIRC IG 11347 “Role of ‘oncogene-induced senescence’ and ‘nononcogene addiction’ in thyroid carcinogenesis” (2012-2014; PI: A
Greco)
AIRC IG 10366: ìMicroRNAs in papillary thyroid carcinoma: pathways
involved and possible therapeutic targetsî (2010-2013; PI: MG
Borrello)
2013 AIRC annual fellowship ‘Giavanna Ciani’ to MG Vizioli
2013 Fondazione Umberto Veronesi Fellowship to MC Anania
KEY WORDS
Thyroid tumors, miRNA, oncogene-induced senescence, non-oncogene
addiction
research activity
.Mario P. Colombo.
EXTRACELLULAR MATRIX PROTEIN SPARC
REGULATES PRIMARY AND SECONDARY LYMPHOID
ORGANS HOMEOSTASIS AND THE TRANSITION
OF MYELOPROLIFERATIVE OR AUTOIMMUNE
SPURS TOWARD LEUKEMIA AND LYMPHOMA
Upon induction of immune responses (either physiological or autoimmune), lymphoid tissues undergo dynamic
changes in number, distribution, and phenotype of immune cell populations, which require substantial and concomitant
remodeling of tissue architecture (e.g. secondary follicle formation, marginal zone expansion). These modifications
normally occur within the fringes of the functionally compartmentalized stroma of secondary lymphoid organs, which is
composed by cellular elements (e.g. follicular dendritic cells, reticular cells) and an extracellular matrix that contributes
to the regulation of trafficking and activation of immune cells. Our project is challenging the hypothesis that biasing the
stromal microenvironment through defective expression of a matricellular protein could be sufficient to drive malignant
transformation in the presence of a lymphoproliferative spur such as that occurring under autoimmune conditions.
To demonstrate this hypothesis, we have focused on SPARC, a non-structural pleiotropic matricellular protein involved as
key regulator of tissue remodeling in physiological conditions such as embryogenesis-associated epithelial mesenchymal
transition, lymph-node swelling, and germinal center formation during adaptive immune responses. SPARC also plays a role
in the profound changes occurring in the tissue architecture of solid and hematological neoplasms. The SPARC produced
by innate immune cells influences the crosstalk between cancer cells and extracellular matrix at the invasive edge of
primary tumors and regulates pro-inflammatory TNF production in response to tissue damage. Moreover, bone marrow
stroma-derived SPARC has been reported to regulate the expansion of myeloid cell populations under myeloproliferative
stress. Experimentally, cell death receptor mutant Fas deficient mice that have unrested lymphoproliferation were
crossed with Sparc deficient mice to obtain double mutants. The human validation of mouse findings was obtained by
screening SPARC expression in a series of human non-Hodgkin’s B cell lymphomas (NHL) by gene expression profiling and
immunohistochemistry.
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PROGRAM HIGHLIGHTS
The working hypothesis is that aberrant changes in ECM organization might participate in the pathogenic events leading to malignancies of lymphoid tissues other than affecting development and function of immune cells. Among the relevant modifications occurring in
the stromal compartment of BM and SLO, we have uncovered the relevance of the matricellular protein SPARC in the homeostatic and
pathogenic modifications of hematopoietic and immunological settings. Specifically, the high expression of SPARC in stroma leads to
the aberrant osteoblastic niche expansion towards myelofibrosis under the pressure of a myeloproliferative spur (Tripodo, 2012). On
the contrary, the absence of stromal SPARC alters the hematopoietic niche favoring myeloid precursor expansion in the BM (Tripodo,
2012). In SLO, SPARC deficiency alters the mesenchymal follicular dendritic cells (FDC) networking (Piconese, 2011) and impairs humoral immunity while promoting lymphomagenesis in the case of persistent perturbation of lymphoid tissue homeostasis. In this latter
case, the absence of SPARC results in defective collagen assembly and lack of inhibitory signals through the collagen receptor LAIR-1
on myeloid cells, particularly neutrophils. Hyper-activated neutrophils acquire an IFN-related signature and eventually die through
NETosis that promotes CD5+ B cell transformation via NF-kB. The emerging scenario indicates that stromal SPARC expression has an
effect on lymphomagenesis by controlling the behavior of bystander immune cells rather than influencing CD5+ B cells directly. These
data correlate with human B-CLL, which shows reduced microenvironmental SPARC expression and ECM deposition as well as signs
of NETotic neutrophil among the activated infiltrating myeloid cells. Overall, these data allow the hypothesis that stromal SPARC may
represent a common regulatory trait linking hematopoietic and lymphopoietic homeostasis in both BM and SLO niches. This also lends
support to the idea of targeting matricellular proteins to impinge on the efficacy of other agents in combination therapies.
PROGRAM MEMBERSHIP
Mario P. Colombo, PI and program coordinator.
Sabina Sangaletti, Project leader, responsible for experiments and data
collection.
Caterina Vitali, Post-doctoral fellow, responsible for FACS analysis.
Silvia Miotti, Senior scientist, responsible for biochemistry.
Paola Portararo and Barbara Cappetti, Lab. Technicians.
Collaborators: Claudio Tripodo, University of Palermo, Lead Pathologist;
PierPaolo Piccaluga, University of Bologna, Lead for bioinformatics.
MP.: Neutrophil extracellular traps mediate transfer of cytoplasmic
neutrophil antigens to myeloid dendritic cells toward ANCA induction
and associated autoimmunity. Blood 2012; 120: 3007-3018
Sangaletti S., Tripodo C., Cappetti B., Casalini P., Chiodoni C., Piconese
P., Santangelo A:, Parenza M., Arioli I., Miotti S., Colombo MP. SPARC
oppositely regulates inflammation and fibrosis in bleomycin-induced
lung damage. Am J Pathol 2011; 179: 3000-3010
Tripodo C., Sangaletti S., Piccaluga P.P., Prakash S., Franco G., Borrello
I., Orazi A., Colombo M.P., Pileri S.A.: The bone marrow stroma in
hematological neoplasms-a guilty bystander. Nature Review Clin
Oncol 2011; 8: 456-466
Tripodo C., Sangaletti S., Guarnotta C., Piccaluga P.P., Cacciatore M.,
Giuliano M., Franco G., Chiodoni C., Sciandra M., Miotti S., Calvaruso
G., Carè A., Florena A.M., Scotlandi K., Orazi A., Pileri S.A., Colombo
M.P.: Stromal SPARC contributes to the detrimental fibrotic changes
associated with myeloproliferation whereas its deficiency favors
myeloid cell expansion. Blood 2012; 120: 3541-3554
Supported by grants from the Association for International Cancer
Research (AICR UK, grant n° 11-0595), Associazione Italiana per la
Ricerca sul Cancro (AIRC: Investigator Grants n° 10137 to MPC and
My First Grant n° 12810 to SS) and the Italian Ministry of Health.
Sangaletti S., Tripodo C., Chiodoni C., Guarnotta C., Cappetti B., Casalini
P., Piconese S., Parenza M., Guiducci C., Vitali C., Colombo
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KEYWORDS
Leukemia/lymphoma, extracellular matrix, autoimmunity, neutrophil
extracellular traps
research activity
INNOVATIVE
PROBLEM-ORIENTED
APPROACHES
TO DIAGNOSIS
AND TREATMENT
COORDINATOR: Paolo Corradini
Research into the interaction between a tumor and its microenvironment and identification
of molecular and genetic characteristics that can be translated into biomarkers for diagnosis
of cancer at its earliest stages. Studies relative to the development of: i) radiopharmaceuticals
for tumor characterization in molecular imaging and treatment; ii) new drugs and/or treatment
approaches for solid tumors, including clinical-translational studies prompted by the need
for a) the prognostic characterization of rare tumors, which resemble the “big killers” and
constitute an as yet unsolved problem both from a diagnostic and therapeutic point of view; b)
knowledge of the mechanisms responsible for the different degrees of toxicity of radiotherapy
in different tumor types; c) anticancer vaccines, genetic and biological therapies in certain
tumors for the clinical testing of new substances.
AIMS: Selection of biomarkers for early diagnosis or cancer risk assessment;
development of radiopharmaceuticals for biological characterization and use in
imaging and treatment; detection of biomarkers that can be used as indicators of
treatment response; testing and development of targeted molecular therapies;
stratification of radiotoxicity by degree of severity and assessment of its potential
indicators.
PROJECTS
• Stroma-derived biomarkers with prognostic value in subjects with polygenic
or monogenic inheritance predisposing to cancer (Tommaso Dragani)
• Development of a platform for the pre-clinic evaluation of new anti-tumor
drugs and new therapeutic combinations (Nadia Zaffaroni)
• Study of immunosuppression mechanisms in patients with solid tumors and their influence
on prognosis and response to drug treatment and immunotherapy (Licia Rivoltini)
• Establishing drug and transplant approaches for effective treatment
of hematological malignancies (Paolo Corradini)
• Translational project for the development of drugs for personalized
cancer treatment (Filippo de Braud)
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.Tommaso A. Dragani.
STROMA-DERIVED BIOMARKERS
WITH PROGNOSTIC VALUE IN SUBJECTS
WITH POLYGENIC OR MONOGENIC
INHERITANCE PREDISPOSING TO CANCER
The process of tumor progression and metastatic dissemination can involve germline polymorphisms and individual gene
expression signatures in normal tissue. Our project is aimed to integrate genome and transcriptome data across multiple
individuals, thus allowing identification of genetic biomarkers that are predictive of clinical phenotypes of colorectal (CRC)
or lung cancer (LC). Importantly, the availability of RNA levels and genotype data on the same subjects will allow to define
cis- and trans-controls of genes expressed in normal tissues, thus revealing the architecture of gene regulation in the
microenvironment of CRC and LC.
We have carried out a transcriptome study of non-involved lung tissue, excised from a discovery series of 204 lung
adenocarcinoma patients, evaluated using whole-genome expression microarrays. Genes associated with survival status
at 60 months were identified by Cox regression analysis (adjusted for gender, age and clinical stage) and re-tested in a
validation series of 78 additional cases. RNA-Seq analysis from non-involved lung tissue of 12 patients was performed to
characterize the different isoforms of candidate genes. Gene expression signatures associated with survival comprised 10
genes: CNTNAP1, PKNOX1, FAM156A, FRMD8, GALNTL1, TXNDC12, SNTB1, PPP3R1, SNX10, and SERPINH1.
In CRC patients, we have carried out a study to test the possible role of known SNPs that have been reported to affect
risk or other aspects of disease in the modulation of clinical parameters. We have investigated the possible influence
of 86 informative SNPs on overall survival and time to recurrence (TTR) in a series of 770 colorectal adenocarcinoma
patients with follow-up to 84 months. In Cox multivariate analysis, adjusted for gender, age at surgery, pathological stage,
and adjuvant chemotherapy, SNPs rs1801133 (MTHFR), rs4939827 (SMAD7) and rs2306283 (SLCO1B1), showed
the highest statistically significant association with overall survival. The highest association with TTR was observed for
rs16892766, which maps downstream of the EIF3H gene.
By crossing mouse strains that are resistant or susceptible to lung tumorigenesis, it has been observed that mice
susceptible to lung tumors express, in normal lung tissue, higher levels of the Kras-4A transcript isoform, compared to mice
resistant. This difference is modulated by genetic polymorphisms located near or within this same locus Pas1 where the
K-ras gene maps and which modulates susceptibility to lung tumorigenesis in mice.
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research activity
PROGRAM HIGHLIGHTS
Our findings support the hypothesis that individual genetic characteristics, as shown by the expression pattern of non-involved tissue,
can influence the outcome of lung adenocarcinoma patients. We have also found that a set of genetic variants (SNPs) previously found
associated with risk of CRC was also associated with overall survival and TTR. The identification of alleles affecting subgroups of cancer patients with worse clinical outcome may have clinical application in future pharmacogenetic strategies to personalize treatment.
PROGRAM MEMBERSHIP
Tommaso A. Dragani, principal investigator.
Giacomo Manenti, researcher, staff.
Antonella Galvan, researcher.
Francesca Colombo, researcher.
Sara Noci, researcher.
Alice Dassano, PhD student.
Angela Pettinicchio, laboratory technician.
Galvan A., Cabrera W., Vorraro F., Jensen J.R., Borrego A., Starobinas N.,
Ribeiro O.G., De Franco M., Knott S., Dragani T.A., Manenti G., Ibañez
OC.: Genetic linkage analysis identifies Pas1 as the common locus
modulating lung tumorigenesis and acute inflammatory response in
mice. Genes Immun 2013; 14(8): 512-517
Galvan A., Frullanti E., Anderlini M., Manenti G., Noci S., Dugo M.,
Ambrogi F., De Cecco L., Spinelli R., Piazza R., Pirola A., GambacortiPasserini C., Incarbone M., Alloisio M., Tosi D., Nosotti M., Santambrogio
L., Pastorino U., Dragani T.A.: Gene expression signature of noninvolved lung tissue associated with survival in lung adenocarcinoma
patients. Carcinogenesis 2013; 34(12): 2767-2773
Falvella F.S., Alberio T., Noci S., Santambrogio L., Nosotti M., Incarbone
M., Pastorino U., Fasano M., Dragani T.A.: Multiple isoforms and
differential allelic expression of CHRNA5 in lung tissue and lung
adenocarcinoma. Carcinogenesis 2013; 34(6): 1281-1285
Frullanti E., Colombo F., Falvella F.S., Galvan A., Noci S., De Cecco
L., Incarbone M., Alloisio M., Santambrogio L., Nosotti M., Tosi D.,
Pastorino U., Dragani T.A.: Association of lung adenocarcinoma clinical
stage with gene expression pattern in noninvolved lung tissue. Int J
Cancer 2012; 131(5): E643-8
Dassano A., Noci S., Galbiati F., Colombo F., Trincucci G., Pettinicchio A.,
Dragani T.A., Manenti G.: Multigenic nature of the mouse pulmonary
adenoma progression 1 locus. BMC Genomics 2013; 14: 152
AIRC-2014, PI Dr. Tommaso A. Dragani
AIRC 5x1000, PI Dr. Marco A. Pierotti
KEYWORDS
Single nucleotide polymorphisms, transcriptome, lung cancer,
expression quantitative trait locus.
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.Nadia Zaffaroni.
DEVELOPMENT OF A PLATFORM FOR THE
PRE-CLINICAL EVALUATION OF NEW ANTI-TUMOR
DRUGS AND THERAPEUTIC COMBINATIONS
The possibility to evaluate the preclinical effectiveness of new anticancer drugs, as well as novel therapeutic combinations,
is strongly associated with the availability of appropriate preclinical models, which are representative of clinically relevant
phenotypes. In this context, over the years, we generated a large panel of human tumor xenografts of different histological
origin in immunodeficient mice. These models have been extensively characterized in terms of: i) frequency of mutations in
genes involved in master pathways; ii) constitutive activation of the main mitogenic and cell survival signaling pathways; iii)
gene and microRNA expression profiles. In addition, for models with spontaneous or experimentally induced resistance to
specific drugs, the molecular determinants of drug resistance have been identified.
These models constitute the platform for the study of new therapeutic agents, including newly designed analogues of
cytotoxic drugs, targeted drugs, and therapeutic nucleic acids (i.e. siRNA, miRNA mimics). Specifically, our research is
focused on: 1) evaluation of effectiveness of new compounds as a function of histological type, genetic background and,
more generally, molecular profile of tumor models; 2) the identification of new therapeutic combinations designed to target
specific molecular alterations in tumor models. In addition, the availability of specific preclinical models will allow us to
investigate new possible therapeutic indications for drugs already used in a clinical setting.
Overall, the results of these studies should allow us to define new therapies for clinical development, as well as identify
potential predictors of response (such as specific molecular alterations in tumors) that should be useful for patient
selection.
At the beginning of the study, both optimal route and schedule of administration will be determined. The antitumor
efficacy of drugs, administered alone or in combination (i.e. contemporary or sequentially) will be evaluated in terms of
tumor volume percentage reduction, induction of complete responses, and increased survival of animals. The modulation
of putative molecular targets and specific pathways will be determined on tumor samples obtained after treatment.
For promising drugs and/or combinations, the changes induced by treatment in the different signaling networks will be
evaluated to obtain more accurate characterization of the mechanism of action.
Finally, the histopathological evaluation of material, combined with morphometric and immunohistochemical techniques,
will allow us to quantify the effects of treatment on angiogenesis, as well as to determine the infiltration of inflammatory
and/or immune system cells and quantify the presence of apoptosis/necrosis.
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PROGRAM HIGHLIGHTS
The project is making progress towards the improvement of therapeutic options for treatment of different tumor types, including rare
diseases poorly responsive to conventional therapies, such as diffuse malignant peritoneal mesothelioma (DMPM) and solitary fibrous
tumors (SFT). Specifically, concerning the preclinical development of new drugs, we evaluated the activities of: 1) new nortopsentin
analogues (1H-pyrrolo[2,3-b]pyridine derivatives) in experimental models of diffuse DMPM. We demonstrated that the three most
active compounds (shown to act as cyclin-dependent kinase 1 inhibitors) consistently reduced DMPM cell proliferation and induced
a caspase-dependent apoptotic response, with concomitant reduction of the activation of the antiapoptotic protein survivin. In
the mouse model, i.p. administration of these derivatives was effective, resulting in a significant tumor volume inhibition of DMPM
xenografts at well-tolerated doses, and two complete responses were observed in each treatment group, suggesting a possible clinical
relevance of these drugs for the treatment of DMPM; 2) hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and
diaminedichloro-platinum (II) complex. The compounds (which produced platinum-DNA adducts and topoisomerase I-mediated
DNA damage with a cleavage pattern and persistence similar to SN38, the active principle of irinotecan) showed growth inhibitory
activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The most active
compound also exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, in the absence of toxicity,
comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support these conjugates as a
new class of anticancer agents of potential clinical interest.
As far as the identification of new therapeutic combinations is concerned, through collaboration with other research groups at INT,
we reported the antitumor activity of CpG oligonucleotides (synthetic DNA sequences recognized by Toll-like receptor 9 and able to
induce innate/adaptive immune responses) administered alone or in combination with chemotherapy in preclinical models of human
cancer.
Considering preclinical experiments performed on xenografts generated from biopsies of patients with rare tumors, we explored
the activity of conventional and targeted agents on a human high-grade dedifferentiated SFT characterized by overexpression and
activation of PDGFRB and VEGFR1. In a xenograft model, dacarbazine and temozolomide were found to have a high and superimposable antitumor activity and to induce almost complete tumor volume inhibition, which was maintained after treatment interruption
and confirmed pathologically. In contrast, sunitinib, pazopanib, and bevacizumab were found to be less active, with appreciable tumor
relapse immediately after drug withdrawal.
PROGRAM MEMBERSHIP
Nadia Zaffaroni (PI), planning and coordination of experiments.
Andrea De Cesare (Veterinarian), Denis Cominetti (junior researcher)
and Monica Tortoreto (technician) will be involved in: i) subcutaneous
and orthotopic xenotransplantation of cancer cells into nude, SCID,
and NOD/SCID mice; ii) treatment with new therapeutic agents
(alone or in combination); iii) assessment of tumorigenic potential and
chemosensitivity profiles of different models; iv) tumor tissue collection
and storage; and v) general animal care.
Giovanni Beretta (senior researcher), Marzia Pennati (senior
researcher), Valentina Zuco (senior researcher), Alessia Lopergolo
(junior researcher) will be involved in: i) cell culture maintenance
for xenotransplants; ii) molecular and biochemical assays in tumor
specimens; and iii) immunohistochemical assessment of proliferation,
apoptosis/necrosis, and microvessel density-related markers in
explanted tumor xenografts.
Carbone A., Pennati M., Parrino B., Lopergolo A., Barraja P., Montalbano
A., SpanÚ V., Sbarra S., Doldi V., De Cesare M., Cirrincione G., Diana
P., Zaffaroni N.: Novel 1H-pyrrolo[2,3-b]pyridine derivatives
nortopsentin analogues: synthesis and antitumor activity in
peritoneal mesothelioma experimental models. J Med Chem 2013;
56: 7060-7072
Sfondrini L., Sommariva M., Tortoreto M., Meini A., Piconese S.,
Calvaruso M., Van Rooijen N., Bonecchi R., Zaffaroni N., Colombo M.P.,
Tagliabue E., Balsari A.: Anti-tumor activity of CpG-ODN aerosol in
mouse lung metastases. Int. J. Cancer 2013; 133: 383-93
Sommariva M., De Cesare M., Meini A., Cataldo A., Zaffaroni N.,
Tagliabue E., Balsari A. High efficacy of CpG-ODN, cetuximab and
cisplatin combination for very advanced ovarian xenograft tumors. J
Transl Med 2013; 11: 25
Stacchiotti S., Tortoreto M., Bozzi F., Morosi A., Messina A., Libertini
M., Palassini E., Cominetti D., Negri T., Gronchi A., Pilotti S., Zaffaroni
N., Casali P.G.: Dacarbazine in solitary fibrous tumor: a case
series retrospective analysis and preclinical evidence vis-a-vis
temozolomide and antiangiogenics. Clin Cancer Res 2013; 19:
5192-5201
AIRC
Ministero dello Sviluppo Economico
Mesothelioma Applied Research Foundation
KEYWORDS
Experimental models of human tumors, new drugs, new therapeutic
combinations
Cincinelli R., Musso L., Dallavalle S., Artali R., Tinelli S., Colangelo D.,
Zunino F., De Cesare M., Beretta GL, Zaffaroni N.: Design, modeling,
synthesis and biological activity evaluation of camptothecin-linked
platinum anticancer agents. Eur J Med Chem 2013; 63C: 387-400
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.Licia Rivoltini.
STUDY OF IMMUNOSUPPRESSION MECHANISMS
IN PATIENTS WITH SOLID TUMORS AND THEIR
INFLUENCE ON PROGNOSIS AND RESPONSE TO
DRUG TREATMENT AND IMMUNOTHERAPY
This project is aimed at characterizing interactions between tumor cells and the immune system to search for novel
predicting/prognostic factors or therapeutic targets. Immunological studies are performed on peripheral blood, saliva,
draining lymph nodes, and tumor lesions from patients with different stages of disease and undergoing specific drug
treatments. A major focus is devoted to melanoma, sarcoma, liver carcinoma, and head and neck (H&N) cancer. The goal
is to perform comprehensive and standardized immune profiling based on multiparametric assays for the visualization of
immune cells and circulating factors. Gene-expression and miRNA profiling is also performed to identify immune-related
signatures. Specific attention is paid to regulatory cell subsets (including myeloid-derived suppressor cells – MDSC -,
regulatory T cells, and plasmocytoid dendritic cells) and plasma content of cyto- and chemokines. We also investigate
tumor or immune exosomes to understand their impact on tumor immunity and the potential as source of biomarkers.
Applying these strategies, we found that:
1.Multiparametric cytofluorimetry allows the simultaneous visualization of different immune cell subsets present in
peripheral blood and lymph nodes, providing a reliable “immune profile” that differs substantially from that detected in
age and sex-matched healthy donors.
2.MDSC frequency and activation state are associated with disease progression in melanoma and sarcoma patients, and
with insensitivity to different therapeutic strategies including target therapies.
3.Drugs such as ipilimumab and BRAF-inhibitors have an impact on the frequency and function of MDSC, Treg and
effector/helper T cells. The role of immune profile in the sensitivity or resistance to treatment is under investigation.
4.MDSC accrual involves the conditioning activity of tumor exosomes on myeloid cells through the delivery of selected
chemokines and miRNA affecting HLA-DR, IL-6, HIF1-alpha, and TGF-beta pathways. The presence of exosomes bearing
a myeloid-modulating signature is under evaluation in plasma samples from melanoma patients with different disease
stage.
5.Salivary cytokines, detected by cytokine-bead array assay, accumulate in H&N cancer patients upon chemoradiotherapy
and predict the severity of treatment-induced mucosites.
6.Gene expression profiling of sentinel nodes provides information about immune pathways that are associated with
recurrence and poor prognosis.
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7.Acidity is a powerful tool for tumor microenviroment to anergize immune responses in melanoma. A clinical trial
investigating the ability of anti-acid drugs to improve tumor immunity and control tumor growth is ongoing in melanoma
patients. Altogether, these data strongly confirm the potentiality of immune-related pathways as novel source of
biomarkers for patient selection and management in cancer
PROGRAM HIGHLIGHTS
The recent success of novel cancer therapeutics based on immunomodulation has finally shown the key role of the immune system in
controlling tumor growth. Evidence is also emerging regarding the influence that immunity exerts on disease progression and on the
response to cancer treatment including targeted therapies. Hence, the study of immune-tumor interactions aimed at characterizing
the “immune profile” at the single patient level represents a promising tool for the identification of novel predicting/prognostic factors
and new therapeutic targets. Thanks to our long-standing experience in tumor immunology, continuously updated at the scientific
and technological levels through collaboration with several national and international groups and networks, we are collecting a broad
and comprehensive picture of immune-cancer cross-talk and its outcome in patients. Immunomonitoring is performed according to
standardized protocols and SOPs, including sample collection and immunological testing. The active and productive collaboration
with several clinical units allows the design of studies that meet specific and relevant clinical needs as well as timely patient selection
and accrual. Based on these features, we are dissecting the mechanisms of cancer-mediated immunosuppression, possibly finding
common features and patterns across different tumor histologies. Focusing on patients and defined questions, we are committed to
verify whether investigating the immune system can provide relevant information about patient prognosis and response to treatment.
Understanding the pathways regulating tumor immunity may also contribute to the identification of novel therapeutic strategies for
cancer patients.
PROGRAM MEMBERSHIP
Unit of Immunotherapy of Human Tumors
Study design and management, immunological and genetic analyses,
data interpretation.
Melanoma Unit
Patient selection, collaboration in study design.
Liver Unit
Collaboration in study design, patient selection, result discussion and
Sarcoma Unit
Patient selection, collaboration in study design.
Head and Neck Oncology
Patient selection, collaboration in study design, result discussion and
Unit of Functional Genomics
Genetic profiling, data analysis
MIA consortium
Imaging studies
Unit of Statistics and Epidemiology
Collaboration in study design, data analysis
Camisaschi C., Filipazzi P., Tazzari M., Casati C., Beretta V., Pilla L.,
Patuzzo R., Maurichi A., Cova A., Maio M., Chiarion-Sileni V., Tragni
G., Santinami M., Vergani B., Villa A., Berti E., Umansky L., Beckhove
P., Umansky V., Parmiani G., Rivoltini L., Castelli C.: Effects of
cyclophosphamide and IL-2 on regulatory CD4+ T cell frequency and
function in melanoma patients vaccinated with HLA-class I peptides:
impact on the antigen-specific T cell response. Cancer Immunol
Immunother 2013; 62(5): 897-908
Castelli C., Tazzari M., Negri T., Vergani B., Rivoltini L., Stacchiotti S.,
Pilotti S.: Structured myeloid cells and anti-angiogenic therapy in
alveolar soft part sarcoma. J Transl Med 2013; 11:237
Filipazzi P., Pilla L., Mariani L., Patuzzo R., Castelli C., Camisaschi C.,
Maurichi A., Cova A., Rigamonti G., Giardino F., Di Florio A., Asioli M.,
Frati P., Sovena G., Squarcina P., Maio M., Danielli R., Chiarion-Sileni
V., Villa A., Lombardo C., Tragni G., Santinami M., Parmiani G., Rivoltini
L.: Limited induction of tumor cross-reactive T cells without a
measurable clinical benefit in early melanoma patients vaccinated
with human leukocyte antigen class I-modified peptides. Clin Cancer
Res 2012; 18(23): 6485-6496
Calcinotto A., Filipazzi P., Grioni M., Iero M., De Milito A., Ricupito
A., Cova A., Canese R., Jachetti E., Rossetti M., Huber V., Parmiani G.,
Generoso L., Santinami M., Borghi M., Fais S., Bellone M., Rivoltini L.:
Modulation of microenvironment acidity reverses anergy in human
and murine tumor-infiltrating T lymphocytes. Cancer Res 2012;
72(11): 2746-2756
Experimental Clinical Study no Profit
AdESOM: Effetto immunomodulatorio e antitumorale dell’
esomeprazolo ad alte dosi in regime neoadiuvante e adiuvante in
pazienti con melanoma in stadio III. Studio pilota randomizzato
trattamento vs controllo
PROVAX: Studio di vaccinazione, in aperto, di fase II con peptidi di
survivina emulsionati in Montanide® ISA 51VG dopo somministrazione
di IMP321TM, in pazienti con carcinoma prostatico in recidiva
biochimica
MULTIMELMARKERS: Identificazione di marcatori molecolari del
melanoma multiplo
NIBIT-001: A Phase II Study of the Combination of Ipilimumab and
Fotemustine in Patients with Unresectable Locally Advanced or
Metastatic Malignant Melanoma
Experimental Clinical Study Profit
GINGER: Studio multicentrico, randomizzato, in doppio cieco,
controllato verso placebo per valutare l’attività di un integratore
alimentare a base di Ginger (Zingiber officinalis) nella gestione della
nausea in pazienti che ricevono trattamenti altamente emetizzanti e la
terapia antiemetica standard
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METRIC/MEK114267: Studio di Fase III randomizzato, in aperto,
per confrontare GSK1120212 verso chemioterapia in soggetti con
melanoma avanzato o metastatico positivo alle mutazioni di BRAF
V600E/K
NYESO-1: An open Phase I study of immunization with the recNY ESO
1 + AS15 Antigen-Specific Cancer Immunotherapeutic in patients with
NY-ESO-1 positive unresectable and progressive metastatic cutaneous
melanoma
PRAME: An open, dose-escalation Phase I/II study to assess the safety,
immunogenicity and clinical activity of recPRAME + AS15 AntigenSpecific Cancer Immunotherapeutic as first-line treatment of patients
with PRAME-positive metastatic melanoma
Observational Clinical Studies (Non-profit)
EPApHIL-6: Analisi dell’infiltrato infiammatorio come fattore
prognostico e target terapeutico in pazienti con carcinoma epatico.
Ruolo della componente mieloide e dei pathway coinvolti nella
regolazione del pH
miRNA: Identificazione di microRNA circolanti quali potenziali
indicatori di progressione nel melanoma metastatico
BRAF-MEK: Studio dell’effetto immunomodulatorio degli inibitori di
BRAF e MEK in pazienti con melanoma
Target Therapy: Valutazione del ruolo dei meccanismi
immunosoppressivi nella prognosi e nella risposta al trattamento con
farmaci ‘targeted therapy’ in pazienti affetti da sarcoma
Project MCO-9998 Special Program Molecular Clinical Oncology, AIRC
5 per Mille “Cell therapy with TRAIL-armed, genetically engineered or
phenotypically redirected, effectors”
Duration: 01/07/2010 - 30/06/2015
Project n. 12162 - AIRC 5 per Mille “Tumor-Microenvironment related
changes as new tools for early detection and assessment of high-risk
disease”
Duration: 31/12/2011 - 30/12/2016
Project AIRC IG-14285 “Modulation of melanoma immunosuppressive
microenvironment by proton pump inhibitors”.
Duration: 02/01/2014 - 01/01/2015
Project AIRC IG-13335 “From regional node to systemic immunity
suppression in melanoma metastatic progression”
Duration: 02.01.2014 - 01.01.2015
MINISTERO della SALUTE convenzione n. 52/RF-2010-2312620
“IL-6-related inflammation signatures as a predictive marker of
recurrence in liver cancer patients”
Duration: 03/12/2012 - 02/12/2015
Harry J Lloyd Charitable Trust “Study of microRNA related to myeloid
derived suppressor cells in early melanoma patients” Duration:
14/06/2013 - 30/06/2015
KEYWORDS
Immune suppression, myeloid-derived suppressor cells, exosomes,
miRNA
Figure: Immunosuppressive and exhausted lymphocytes in metastatic sentinel node from melanoma patients with unfavorable disease course at 5
years follow-up. Double staining for CD30 and CD147, Foxp3, and PD1 in a representative PP sample showing cells expressing one or both markers
(magnification, ×100). Confocal images of sections stained for CD30 in green and for CD147 or PD1 in red are shown (merge). In the CD30-Foxp3 double
staining, CD30+ cells are indicated by red, and nuclear staining for Foxp3 is indicated by brown. From Vallacchi V et al. Cancer Res 2014;74:130-140
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.Paolo Corradini.
ESTABLISHING DRUG AND TRANSPLANT
APPROACHES FOR EFFECTIVE TREATMENT
OF HEMATOLOGICAL MALIGNANCIES
Treatment options for patients with hematological malignancies include chemotherapy, radiotherapy, immunotherapy,
and high-dose chemotherapy followed by autologous and allogeneic stem cell transplantation (auto- and allo-SCT).
These therapeutic strategies have an established role in the management of patients at diagnosis, with cure rates ranging
between 30% and 90% depending on histology. However, a significant proportion of patients affected by aggressive
lymphomas display primary chemo-refractoriness or early relapse and have dismal long-term disease control, and thus
represent an unmet medical need. In addition, the mechanisms driving chemo-refractoriness still remain largely unclear.
Also, new biomarkers for upfront identification of refractory patients or those requiring intensified approaches (auto- or
allo-SCT) as first-line treatment are mandatory. New treatments tailored to overcome aggressiveness and refractorinessdriving lesions are required. Ongoing clinical and biological studies in the field of multiple myeloma (MM), indolent and
aggressive non-Hodgkin’s lymphoma (NHL), acute myeloid leukemia (AML), myelodysplastic and myeloproliferative
disorders, and graft-versus-host disease (GVHD) are aimed at:
•Evaluating the efficacy of new, targeted therapies alone or in combination with standard chemotherapy to allow
individualized treatment options designed to target each patient’s specific genetic lesions, thereby reducing toxicity and
increasing effectiveness. Massive sequencing technologies will help in identifying genetic lesions/mechanism(s) driving
lymphoma aggressiveness and/or chemo-refractoriness and to define new targets for treatment.
•Exploiting the role of potential genes/proteins as diagnostic tools and novel biomarkers for the early recognition/
stratification of patients requiring intensified treatment options or those unlikely to respond to standard chemoimmunotherapies. The discovery of biological and/or molecular biomarker(s) of aggressiveness or chemo-refractoriness
will lead to the development of innovative clinical programs with substantial impact in clinical practice
•Introducing new molecular methods for diagnosis of hematological malignancies. In B cell malignancies, several methods
have been developed for the detection of minimal residual disease (MRD). We are now applying a new, next generation
sequencing technology strategy based on the use of Ion Torrent Personal Genome Machine (PGM, Life Technologies)
to monitor MRD in B cell malignancies and clonal evolution in MM patients. We have also introduced and developed
molecular tests for the detection of mutation with diagnostic impact (BRAF V600E in hairy cell leukemia, MYD88
L265P in Waldenstrom macroglobulinemia, TET2 and IDH mutations in peripheral T cell lymphomas, and JAK2 V617F
in myeloproliferative disorders).
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PROGRAM HIGHLIGHTS
This project will address currently unmet clinical needs in the management of hematological malignancies. New biomarkers for the
upfront identification of patients with aggressive disease, refractory and/or relapsing and new treatments tailored to target cancer-driving lesions are mandatory. Although a variety of genetic and epigenetic lesions as well as microenvironmental features have
been mechanistically implicated in the pathogenesis and progression of hematological malignancies, the pathogenesis of chemo-refractoriness remains unclear. Major improvements in sequencing technologies could provide the opportunity to discover genomic
alterations and therapeutic targets accounting for chemo-refractoriness and early relapse. This project will also define preclinical
models mainly for PTCLs that reliably predict the clinical activity of novel compounds specifically targeting the key genetic lesions
identified. The potential role of genes/proteins as diagnostic tools and novel biomarkers with prognostic and predictive value will be
assessed. Our research project has the clear goal of a rapid translation in the clinical setting by: i) improving the early identification of
chemo-refractory/relapsing patients and patients requiring auto- or allo-SCT as first line treatment with novel biomarkers; ii) designing
phase 1/2 clinical studies aimed at exploring the clinical activity of rationale combinations of targeted drugs that have been previously
tested in in-vitro models.
PROGRAM MEMBERSHIP
The goals of this project will be achieved by integrating the
complementary and synergistic skills and facilities of members
(clinicians, researchers and data managers) of the Hematology Unit.
The clinical staff (Prof Paolo Corradini, Dr. Anna Dodero, Dr. Vittorio
Montefusco, Dr. Lucia Farina, Dr. Francesco Spina) has been working in
the field of hematological malignancies and stem cell transplantation
for many years and will be instrumental in designing clinical studies
and selecting patients for biological analysis. All clinical information
necessary to correlate the biological results with outcome will be
collected by or data managers (Dr. Debora Degli Innocenti, Dr. Anisa
Bermema). Well-characterized bio-repositories of biospecimens (blood,
plasma, biopsies) from patients enrolled in several clinical trials are
available to the research team as a biobanking system, which is ongoing
within the Unit and coordinated by Dr. Cristiana Carniti. The biobank
will provide a sufficient number of samples for analysis and validation
of results. The expertise for the use of new sequencing technologies is
increasing in our Unit. Specifically Dr. Silvia Gimondi of the Hematology
Branch has recently attended the Ion PGM teaching course at Life
Technologies laboratories, Darmstadt, Germany to learn the use of this
technology and complement her existing bioinformatic skills. Other
members of the team include researchers (Dr. Antonio Vendramin, Dr.
Alessandra Cavanè, Dr. Sara Rizzitano) with different but synergistic
expertise that have been selected according to their proven welldefined scientific and technical skills.
INT 118/13 - Protocol COEB071X2103: An open-label, singlearm, Phase Ib/II study of AEB071 (a protein kinase C inhibitor) and
everolimus (mTOR inhibitor) in patients with CD79-mutant or ABC
subtype diffuse large B-cell lymphoma
Perrone G., Farina L., Corradini P.: Current state of art for
transplantation paradigms in peripheral T-cell lymphomas. Expert Rev
Hematol 2013; 6(4): 465-474
Larocca A., Montefusco V., Bringhen S., Rossi D., Crippa C., Mina
R., Galli M., Marcatti M., La Verde G., Giuliani N., Magarotto V.,
Guglielmelli T., Rota-Scalabrini D., Omedé P., Santagostino A., Baldi I.,
Carella A.M., Boccadoro M., Corradini P., Palumbo A.: Pomalidomide,
cyclophosphamide, and prednisone for relapsed/refractory multiple
myeloma: a multicenter phase 1/2 open-label study. Blood 2013;
122(16): 2799-2806
Gay F., Magarotto V., Crippa C., Pescosta N., Guglielmelli T., Cavallo
F., Pezzatti S., Ferrari S., Liberati A.M., Oliva S., Patriarca F., Offidani
M., Omedé P., Montefusco V., Petrucci M.T., Giuliani N., Passera R.,
Pietrantuono G., Boccadoro M., Corradini P., Palumbo A.: Bortezomib
induction, reduced-intensity transplantation, and lenalidomide
consolidation-maintenance for myeloma: updated results. Blood
2013; 122(8): 1376-1383
Montefusco V., Spina F., Patriarca F., Offidani M., Bruno B., Montanari
M., Mussetti A., Sperotto A., Scortechini I., Dodero A., Fanin R.,
Valagussa P., Corradini P.: Bortezomib plus dexamethasone followed
by escalating donor lymphocyte infusions for patients with multiple
myeloma relapsing or progressing after allogeneic stem cell
transplantation. Biol Blood Marrow Transplant 2013; 19(3): 424-428
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INT 134/13 - Protocol CC-122-DLBCL-001: A PHASE 1B, MULTICENTER, OPEN-LABEL STUDY OF NOVEL COMBINATIONS OF
CC-122, CC-223, CC-292, AND RITUXIMAB IN DIFFUSE LARGE
B-CELL LYMPHOMA
INT 31/13 – IST-CAR-561: A MULTICENTER, OPEN LABEL
STUDY OF WEEKLY CARFILZOMIB, CYCLOPHOSPHAMIDE AND
DEXAMETHASONE (wCCyd) IN NEWLY DIAGNOSED MULTIPLE
MYELOMA (MM) PATIENTS
INT 19/13: Studio dei meccanismi molecolari di chemio-resistenza
nei linfomi a cellule T periferiche (PTCL) mediante sequenziamento
massivo del genoma
INT 86/13: Identificazione delle cause genetiche responsabili di una
forma famigliare di mieloma
INT 149/13: Studio retrospettivo osservazionale sul monitoraggio dei
livelli sierici di TARC e i risultati PET dei pazienti con linfoma di Hodgkin
sottoposti a trapianto allogenico di cellule staminali emopoietiche
GRANTS
AIRC IG 2013 Prof Paolo Corradini UNDERSTANDING THE
BIOLOGICAL BASIS OF CHEMOREFRACTORINESS IN PERIPHERAL
T-CELL LYMPHOMA TO DEVELOP NOVEL TREATMENTS
MFAG Mariotti Identifying new molecular pathways and predictor
biomarkers of GVHD after allogeneic-HSCT
FP7 PEOPLE 2010 RG Role and Modulation of Jak and STAT signaling
in Graft Rejection and Graft versus
KEYWORDS
Hematological malignancies; Drug response and/or resistance;
Targeted therapy; Next Generation Sequencing
research activity
.Filippo de Braud.
TRANSLATIONAL PROJECT
FOR THE DEVELOPMENT OF DRUGS
FOR PERSONALIZED CANCER TREATMENT
The Division of Medical Oncology 1 has the mission to develop methodology and evidences to bring personalized medicine
and the most active drugs to treat cancer into clinical practice. Therefore, it is involved in several phase I and II studies with
solid rationales and preclinical background.
In the very early phase of new drug development, information about patients screened, but not included in studies, as well
as evidence of efficacy for small subgroups of patients are frequently missing. Nevertheless, much data becomes available
because of the availability of systematic blood sample collections, used for pharmacodynamics and pharmacokinetics, and
tumor samples for biomarker screening.
The Pathology Department has implemented diagnostic procedures with the most up to date approaches using
immunohistochemistry, molecular diagnostics with PCR, and next generation sequencing (Ion Torrent) to screen tumor
specimens from patients who may be candidates for clinical trials. Together we have designed molecular panels that are
being investigated within subgroups of solid tumors to study the individual steps of several pathways, gene mutations,
signal transduction, and response to TKIs, cell cycle checkpoints, and expression of single genes expression.
The Experimental Department applies high-throughput technologies of transcriptomics (microarrays for gene expression,
exome sequencing) to understand molecular pathways within cancer tissues on paraffin embedded samples.
Through collection of clinical data, clinical observations, medical history, acute and chronic adverse events , drug
interaction data, and sharing of personal views, clinicians can bring researchers together to correlate clinical behavior with
pathological, pathophysiological, molecular, and genetic information. Through astute clinical observation, we are posing key
questions to collaborating scientists to help answer the clinical unmet needs, and gathering information on pharmacological
targets and histological, molecular or/and mutational characteristics of tumors.
Our methodology is simple and consists in systematic collection of all data available on outpatient first access lists,
considering the pathology and inclusion or not into a clinical trial. Whenever possible, patients also receive a molecular
diagnosis by identifying targets for available phase I/ first in human drugs. Thanks to the support of the data management,
several database have been implemented that can be consulted according to disease, molecular target, mutational status,
and clinical response to therapy. Collections are also planned on retrospective material.
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PROGRAM HIGHLIGHTS
The strength of this project is represented by systematic data collection organized since the first visit of a patient to our Outpatient
Department. This collection enables identification of possible target populations for further phase I studies, but also collects information about the distributions of molecular targets and their expression in a specific population. This implies that first access of patients
becomes a resource for future research.
Analyzing past treatments, we can rapidly obtain information on toxicities or responses to specific drugs, that, when collected in a
database, can be retreived by seeking for molecular target or drug (e.g. data are available on TKI treatments, gathering cross sectional
experience from clinical trials).
Furthermore, through clinical experience on specific target inhibitors we can compare classes of drugs on different solid tumors and
address our efforts to new research programs based on a solid clinical background, optimizing the investments of time, patients, and
researchers.
The different role of detected mutations, classified as “driver”, “passenger”, or “addictive” with regards to tumor development may
guide the use of a wide spectrum of available targeted therapies in phase I, Ib, and early phase II clinical trials, as well as provide a solid
rationale to plan single or double targeted treatment from the onset of therapy or forecast a multiple step sequential treatment at
disease progression.
PROGRAM MEMBERSHIP
Filippo de Braud, Project Coordinator
Clinical researchers: Sara Cresta, MD, Silvia Damian, MD, Anna Tessari,
MD, Lorenzo Pilla, MD, Luigi Celio, MD, Filippo Pietrantonio, MD
Pietrantonio F., Biondani P., Ciurlia E., Fanetti G., Tessari A., Bertarelli G.,
Bossi I., Musella V., Melotti F., Di Bartolomeo M., Valvo F., Pellegrinelli A.,
Milione M., Perrone F., de Braud F.: Role of BAX for outcome prediction
in gastrointestinal malignancies. Med Oncol 2013; 30: 610
Clinical data management: Valentina Sinno
Pietrantonio F., Biondani P., Milione M., Melotti F., Bertarelli G., Perrone
F., De Braud F., Mariani L., Fanetti G., Cortinovis D., Di Bartolomeo M.:
Lack of Bax expression is associated with irinotecan-based treatment
activity in advanced colorectal cancer patients. Clin Transl Oncol
2013; 15: 582-586
Tessari A., Palmieri D., Di Cosimo S.: Overview of diagnostic/targeted
treatment combinations in personalized medicine for breast cancer
patients. Pharmgenomics Pers Med 2013; 7: 1-19
Prospective observational study of the genetic polymorphisms role
in the development of chemotherapy related toxicity in gastroenteric
tumors.
INT126/13 PI: F. de Braud 29/11/2013
Translational researchers: Manuela Iorio, PhD, Antonia Martinetti,
Biologist
Tessari A., Pilla L., Paolini B., Carcangiu M.L., Mariani L., Moliterni A:, de
Braud F., Cresta S.: Expression of NY-ESO-1, MAGE-A3, PRAME and
WT1 in different subgroups of breast cancer. AACR Annual Meeting
2013, Abstract number LB-320
Plantamura I., D’Ippolito E., Tessari A., Cresta S., Orlandi R., Moliterni
A., Carcangiu M.L., De Braud F., Tagliabue E., Iorio M.V.: PDGFR-betainduced miR-9 is up-regulated in triple negative breast cancer. SABCS
2013; P4-07-18
Pilot study to identify miRNA predictive for response to gemcitabine
treatment in metastatic breast cancer.
INT115/13 PI: S. Cresta 09/08/2013
Retrospective multicentric analysis of the prognostic role of cMet
mutations in GE tumors.
INT163/13 PI: L: Celio 23/12/2013
KEYWORDS
Personalized medicine, biomarkers, target therapy, solid tumors
Figure: Molecular target database
outpatient visit
screening for target mutations
amplification
“positive” molecular
screening
target therapy
“negative” Molecular
screening
standard therapy
(eg. trial screening failure)
analysis prognostic
predictive factors “driver” vs
“passenger” mutation, etc
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standard therapy
research activity
MULTIDISCIPLINARY
DISEASE-ORIENTED
APPROACH
COORDINATOR: Vincenzo Mazzaferro
Organ disease-focused interdisciplinary studies including lung carcinoma, hepatocellular
carcinoma, soft tissue sarcomas, tumors of the adult lymphohematopoietic system, and
possibly other tumor types. To create added value between preclinical and clinical research
based on novel molecular characterization, for new treatment approaches and a wider use
of targeted molecular therapies. Translational project development in the context of single
diseases with operational support for the design and conduct of non-profit institutional clinical
trials. To promote the development of a multidisciplinary disease-oriented approach across
different types of cancer.
AIMS: Focal areas of study will be chemoprevention and the treatment of preinvasive
disease; early diagnosis; molecular characterization and staging; conservative and
minimally invasive treatment; targeted, biologically based therapies. Additional areas
will include assessing the potential of therapies tailored to the individual patient
(personalized medicine) using both conventional cytotoxic drugs and new molecular
compounds to minimize toxicity.
PROJECTS
• Prostate cancer program (Riccardo Valdagni)
• New methodological approaches to the study and personalized treatment of rare tumors
and adult sarcomas (Paolo Casali)
• Biomolecular characterization of rare histological types of ovarian carcinoma and implications for the medical
treatment of the disease (Francesco Raspagliesi)
• Early diagnosis of lung carcinoma and efficacy of plasma miRNAs as first-line tests (Ugo Pastorino)
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.Riccardo Valdagni.
PROSTATE CANCER PROGRAM
The Prostate Cancer (PC) Program is a translational multidisciplinary (MD) and multi-professional (MP) program started
in September 2004. Endorsed by the Scientific Director, the PC Program has expertise in epidemiology, experimental
oncology, molecular pharmacology, pathology, imaging, urologic surgery, radiotherapy, medical oncology, palliative care,
and psychology. Its goals are to outline and implement research strategies in PC, including the study of mechanisms of
PC development and progression; to promote clinical and experimental studies, also in collaboration with national and
international partners; to offer PC patients a MD management of their disease; to run MD clinical activities; to organize
educational activities (i.e. Grand Rounds, Multidisciplinary Team Meetings, conferences for clinicians, general practitioners,
patients); and to optimize the human and technological resources within a disease-focused translational MD framework.
More than 20 research projects are currently on-going.
The rationale at the basis of the PC clinical program is that, depending on the state of disease, there are several therapeutic
options. Although the therapies show no clear differences in cancer control rates in the same state, they can induce adverse
effects and affect patients’ quality of life. In addition, selected patients can be addressed to observational strategies,
namely active surveillance (AS) and watchful waiting. For this reason, patients should receive objective, comprehensive
information about the disease, therapeutic and observational options, therapy-induced side effects, and be accompanied in
the decision-making process.
Within this framework, several MD clinical activities are organized:
•First Consultations (350 MD visits in 2013) with the synchronous participation of the urologist, radiation oncologist, and
psychologist; the medical oncologist is on call for patients with locally advanced, hormone-refractory and metastatic PC;
supportive care, rehabilitation, and specialist palliative care interventions are available on demand; PC patients are offered
psychological support (decision-making support, counseling for individuals, couples, families, and self-help groups);
•Follow-up visits for patients on AS or watchful waiting (600 visits in 2013): the urologist or the radiation oncologist
meet patients continuing in the observation in a mono-disciplinary setting; a psychologist is on demand; if patients have
to discontinue the observational setting and be addressed to treatment, a MD setting is undertaken;
•Multidisciplinary Team Meetings, a CME activity aimed to share decisions and paths of care on PC patients, tailor
therapeutic and observational strategies, enroll patients in trials, and verify adherence to guidelines and quality
assurance. In this process, great attention is paid to quality of life and psychological issues.
The PC Program is acknowledged worldwide as an important experience in managing AS protocols. This observational option
is being offered to patients with low and very low risk PC as an alternative to radical treatment since March 2005. The PC
Program is the top recruiting center in the PRIAS (Prostate cancer Research International: Active Surveillance) consortium
(327 patients) and is the coordinator of the Italian institutions participating in PRIAS under the name of SIUrO PRIAS ITA.
The PC Program has been running a biobank and collects blood, urine, and tissue from different categories of patients to
obtain biological material for research.
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PROGRAM HIGHLIGHTS
Research is focused in multiple areas, such as interpretation of survival differences and improvement over time in Italy, development
of novel approaches for the inhibition of cell survival factors in preclinical models, identification of epithelial and stromal/microenvironmental microRNAs regulating PC progression and metastasis, identification of long non-coding RNAs governing prostate epithelial
biology and tumor development, molecular characterization of indolent PCs, quality of life of patients on AS, toxicity and quality of life
in patients treated with radiotherapy.
An urgent need is related to the improvement of selection criteria for AS, which is currently suboptimal and relies exclusively on clinical and pathological parameters, with the addition of novel biological markers for early identification of occult high-risk PC. We plan
to evaluate microRNA profiles in plasma from patients on AS and correlate these with patient outcomes to assess whether specific
microRNAs are able to better predict disease behavior and/or earlier compared to conventional markers. Upon confirmation of results
in an independent patient cohort, the final aim of this study will be the integration of selected microRNAs in an updated and improved
model for the prediction of indolent PC.
More generally, the current understanding of low-risk, potentially indolent tumors is very limited, due to a number of technical hurdles
inherent in the analysis of these lesions. Because of their very favorable prognosis, a matter of debate is the possibility that they could
be regarded as non-malignant. In this regard, it can be hypothesized that molecular alterations characteristic of indolent PC may be
different from those previously detected in clinically-significant tumors. We will use Whole Exome Sequencing (WES) technology to
detect DNA alterations in positive core biopsies from a subset of AS patients (60), with the aim:
1. Compare such genomic alterations with those characteristic of clinically significant PC;
2.Shed light on the nature of such tumors (clinically insignificant disease, early lesions preceding the development of aggressive
cancer - versus indolent cancer - which do not progress during the patient’s lifetime);
3. Identify specific DNA alterations associated to disease progression during AS.
In the same subset of AS patients, the presence of TMPRSS2-ERG gene fusion transcripts will be assessed in urine.
Information derived from these analyses will be integrated with miRNA expression and WES data to generate a more complete molecular profile for each individual patient.
We have initiated research aimed to develop a non-invasive innovating diagnostic method to detect PC on urine samples measuring
urinary volatiles. This will enable to identify and distinguish emission spectra in urine from patients with PC from healthy specimens. If
this preliminary evaluation is positive, substances contained in PC patients urine will be more specifically identified in a larger group in
order to implement the technique and produce low cost and non-invasive diagnostic kits.
PROGRAM MEMBERSHIP
Riccardo Valdagni, Group Leader
Nadia Zaffaroni, Preclinical activities and protocols Group Leader
Participating Departments and Units
Scientific Director’s Office
Diagnostic Imaging and Radiotherapy
Experimental Oncology and Molecular Medicine
Medical Oncology
Medical Statistics and Biometry
Palliative Care, Pain Therapy, and Rehabilitation
Pathology and Laboratory Medicine
Preventive and Predictive Medicine
Psychology
Supportive Care in Cancer
Urologic Surgery
Mauri G., Chiodoni C., Parenza M., Arioli I., Tripodo C., Colombo
M.P.: Ultrasound-guided intra-tumor injection of combined
immunotherapy cures mice from orthotopic prostate cancer. Cancer
Immunol Immunother 2013; 62(12): 1811-1819
Valdagni R., Procopio G., Nicolai N., Gruppo Multidisciplinare del
Programma Prostata. Neoplasie della Prostata. In: Labianca R., Cascinu
S., La Medicina Oncologica - Diagnosi Terapia e gestione clinica, Edra –
Masson Ed., 2013
Non-invasive diagnosis of PC based on urine samples test. PI: Cristina
Marenghi
Predictive models of genitourinary toxicity and erectile dysfunction
after external high dose radiotherapy in PC. PI: Riccardo Valdagni
PC Patient’s choice after the MD First Consultation. PI: Riccardo
Valdagni
Quality of life of men on Active Surveillance. PI: Riccardo Valdagni
Bellardita L., Rancati T., Alvisi M.F., Villani D., Magnani T., Marenghi
C., Nicolai N., Procopio G., Villa S., Salvioni R., Valdagni R.: Predictors
of health-related quality of life and adjustment to prostate cancer
during active surveillance. Eur Urol 2013; 64(1): 30-36
Phase Ib/II study comparing GDC-0068 or GDC-0980 associated
with abiraterone acetate versus abiraterone acetate in patients
with castration resistant PC already treated with docetaxel based
chemotherapy. PI: Giuseppe Procopio
Bul M., Zhu X., Valdagni R., Pickles T., Kakehi Y., Rannikko A., Bjartell
A., van der Schoot D.K., Cornel E.B., Conti G.N., Boevé E.R., Staerman
F., Vis-Maters J.J., Vergunst H., Jaspars J.J., Strölin P., van Muilekom
E., Schröder F.H., Bangma C.H., Roobol M.J.: Active surveillance for
low-risk prostate cancer worldwide: The PRIAS study. Eur Urol 2013;
64(4): 597-603
Fenderico N., Casamichele A., Profumo V., Zaffaroni N., Gandellini
P.: MicroRNA-mediated control of prostate cancer metastasis:
implications for the identification of novel biomarkers and
therapeutic targets. Curr Med Chem 2013; 20(12): 1566-1584
AIRC (My First AIRC Grant)
Fondazione Italo Monzino
Fondazione ProADAMO
KEYWORDS
Translational research, multidisciplinary approach, experimental
therapeutics
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.Paolo G. Casali.
NEW METHODOLOGICAL APPROACHES TO
THE STUDY AND PERSONALIZED TREATMENT
OF RARE TUMORS AND ADULT SARCOMAS
Soft tissue and bone sarcomas, including GISTs, are rare and highly heterogeneous tumors, which related to their
ubiquitous anatomic origin. In this regard, it is well known that application of good surgical principles to all sarcoma
primary sites is not feasible. It is realized that new therapeutic avenues should be explored for these tumors, exploiting
all disciplines, from surgery to radiation and medical therapy. Heterogeneity is also related to the pathology of these
tumors. It is well-known that the natural history of sarcomas differs substantially depending on the histological subtype.
It has also become clear that histologic subtypes possess distinct cytogenetic and molecular profiles that affect sensitivity
to medical therapies, including cytotoxic and targeted agents. These latter have mechanisms of action that are more
specifically dependent on the molecular profile of the tumor. This poses new challenges to medical therapy of sarcomas,
reinforcing the need to personalize medical treatment, mainly by exploiting knowledge of deregulated molecular profiles.
In particular, it is clear that the current approach to sarcomas should be highly personalized, on a highly multidisciplinary
basis. GISTs constitute an advanced platform, but other sarcomas are catching up rapidly as new targeted agents are
becoming available at a steady pace. The aim of this project is to strengthen the institutional research platform aimed
at gaining new insights on the antitumor activity of cytotoxics and molecular targeted agents in selected types of
sarcoma, including the rarest ones. New insights will also be gained on how to incorporate these medical therapies into
multidisciplinary treatment strategies, with insights in the most challenging clinical presentations of sarcoma. New avenues
in the methodology of clinical research will be attempted, so that an additional value of the project will be the assessment
of new strategies for clinical research, potentially serving as a model for other rare tumors. From a healthcare perspective,
new organizational tools are being experimented, which are aimed at diminishing healthcare migration in the field of rare
cancers in Italy. Distant “shared” patient care is carried out within the Italian Network for Rare Cancers (RTR). This is a
collaborative project aimed to improve quality of care, let institutions share clinical cases, define clinical practice guidelines,
and rationalize patient access to health facilities. Finally, clinical observations shared within the RTR project could allow
a shared national database, also aimed to encourage clinical research on rare tumors. The patient populations involved in
this project include those affected by sarcoma: soft tissue sarcoma, GIST, small blue round cell sarcoma, osteosarcoma,
chordoma and chondrosarcoma, and rare histological types.
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PROGRAM HIGHLIGHTS
Within the project, the global international collaboration among sarcoma centers was strengthened. The ESMO International
Conference on Sarcoma & GIST was organized by INT and planned for February 2014. The event has important educational intent and
is a crucial moment for the sarcoma community, aimed to share new investigational trials and methodologies in sarcomas.
Several rare sarcoma subtypes are the target of on-going or just completed clinical trials:
•pigmented villonodular tenosynovitis (PVNS); a rare condition in which tumor growth is sustained by CSF1R/CSF1 through an
autocrine/paracrine loop. A phase II trial on nilotinib was completed. Role of nilotinib in imatinib resistant-PVNS was published.
•imatinib-pretreated chordoma: a phase II trial on the activity of lapatinib, an EGFR inhibitor, was published. A phase II study to test
the activity of combined targeted therapy with everolimus (mTOR inhibitor) and imatinib in first line is on-going .
•GIST: an effort was made to activate an international phase II trial on sunitinib in first line therapy for advanced disease in a pediatric population. From a clinical point of view, pediatric GISTs have mostly wild-type genotype, an indolent course, and are related to
syndromic conditions.
•solitary fibrous tumor: activity of dacarbazine was reported in a case series on a preclinical evidence vis-a-vis temozolomide and
antiangiogenic. Role of pazopanib was presented at CTOS 2013 and response to chemotherapy was retrospectively analyzed in an INT
series. Furthermore, outcomes of late recurrences in a small series was published within the National Rare Cancer Network project.
•osteosarcoma: an Italian Sarcoma Group observational trial was activated to assess the natural history of osteosarcoma arising
from atypical sites.
• myxoid extraskeletal chondrosarcoma: a retrospective study on the activity of anthracycline-based chemotherapy was reported.
The role of sunitinib was observed and an international phase II trial was planned.
Intriguing patterns of response to trabectedin were observed, especially in myxoid liposarcoma. Tumor shrinkage was seen, but
changes in tumor density suggested a type of ‘targeted’ activity of trabectedin in this histotype, which may be related to the drug’s
ability to target the FUS-CHOP-mediated transcriptional block. Uterine leiomyosarcoma may show similar patterns of response to
trabectedin. The assessment of tumor response is a goal in an on-going trial in patients affected by high-grade limb and superficial soft
tissue sarcoma, within a prospective European randomized trial aimed to compare the efficacy of full dose standard chemotherapy vs.
histotype-tailored chemotherapy. In 2013, about 800 new cases were shared within the National Rare Cancer Network, confirming
the increasing activity of the project. An educational Web site was activated in collaboration with Accademia Nazionale di Medicina: a
“Journal Club” section and a “Case Report” section are monthly dedicated to each solid rare tumor.
PROGRAM MEMBERSHIP
Adult Mesenchymal Tumour Medical Oncology
Paolo G. Casali, Coordinator of the project
Clinical researchers: Rossella Bertulli, MD, Silvia Stacchiotti, MD, Elena
Fumagalli, MD, Michela Libertini, MD, Elena Palassini, MD, Roberta
Sanfilippo, MD
Surgery Sarcoma Unit
Clinical researchers: Alessandro Gronchi, MD, Chiara Colombo, MD,
Marco Fiore, MD, Stefano Redaelli, MD
Molecular Pathology Laboratory
Chief of translational research: Silvana Pilotti, MD
Researchers: Elena Tamborini, Biol Sci D, Federica Perrone, Biol Sci D,
Tiziana Negri, Biol Sci D, Fabio Bozzi, Biol Sci D., Paolo Dagrada, Biol Sci D,
Elena Conca, Biol Sci D
Tos A.P., Pilotti S., Casali P.G.: Anthracycline-based chemotherapy in
extraskeletal myxoid chondrosarcoma: a retrospective study. Clin
Sarcoma Res 2013; 3(1): 16
Sanfilippo R., Casali P.G.: The intriguing patterns of tumor response to
trabectedin. Expert Rev Anticancer Ther 2013; 13(6 Suppl 1): 21-24
Casali P.G.: Improving methodology to go beyond histology in rare
cancers. Lancet Oncol 2013; 14(4): 276-277
Bozzi F., Manenti G., Conca E., Stacchiotti S., Messina A., Dagrada
G., Gronchi A., Panizza P., Pierotti M.A., Tamborini E., Pilotti S.:
Development of transplantable human chordoma xenograft for
preclinical assessment of novel therapeutic strategies. Neuro Oncol
2013; 16(1):72-80
Immunotherapy Laboratory
Researchers: Marcella Tazzari, Biol Sci D, Chiara Castelli, Biol Sci D
Phase II study on imatinib in combination with RAD001 in advanced
chordoma.
PET Unit. Response assessment: Flavio Crippa, MD
A phase I/II study of sunitinib in young patients with advanced
gastrointestinal stromal tumor (GISTs)
Radiology Unit. Response assessment: Antonella Messina, MD, Carlo
Morosi, MD
Stacchiotti S., Tortoreto M., Bozzi F., Tamborini E., Morosi C., Messina
A., Libertini M., Palassini E., Cominetti D., Negri T., Gronchi A., Pilotti S.,
Zaffaroni N., Casali P.G.: Dacarbazine in solitary fibrous tumor: a case
series analysis and preclinical evidence vis-a-vis temozolomide and
antiangiogenics. Clin Cancer Res 2013; 19(18): 5192-5201
Stacchiotti S., Tamborini E., Lo Vullo S., Bozzi F., Messina A., Morosi
C., Casale A., Crippa F., Conca E., Negri T., Palassini E., Marrari A.,
Palmerini E., Mariani L., Gronchi A., Pilotti S., Casali P.G.: Phase II study
on lapatinib in advanced EGFR-positive chordoma. Ann Oncol. 2013;
24(7): 1931-1936
Stacchiotti S., Dagrada G.P., Sanfilippo R., Negri T., Vittimberga I., Ferrari
S., Grosso F., Apice G., Tricomi M., Colombo C., Gronchi A., Dei
A phase II, open label study to evaluate the activity and safety of
everolimus in association to imatinib in PDGFRA-D842V unresectable
or metastatic gastrointestinal stromal tumors (GISTs) as first-line
treatment.
Localized high-risk soft tissue sarcomas of the extremities and trunk
wall in adults: an integrating approach comprising standard vs.
histotype-tailored neoadjuvant chemotherapy.
Phase II randomized, non-comparative study on the activity of
trabectedin or gemcitabine + docetaxel in metastatic or locally relapsed
uterine leyomiosarcoma pre-treated with conventional chemotherapy.
Osteosarcoma arising from atypical site: an observational Italian
Sarcoma Group study.
KEYWORDS
Rare tumors, sarcoma, translational research, methodology
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.Francesco Raspagliesi.
BIOMOLECULAR CHARACTERIZATION
OF RARE HISTOLOGICAL TYPES OF OVARIAN
CARCINOMA AND IMPLICATIONS
FOR MEDICAL TREATMENT OF DISEASE
Ovarian cancer is the second most common gynecologic malignancy and by far the most dreadful for its dismal prognosis.
In fact, about 5000 women are diagnosed with ovarian cancer every year in Italy alone, and more than 3000 die from
disease. The standard treatment for ovarian cancer is surgery followed by adjuvant chemotherapy with carboplatin and
paclitaxel. This chemotherapeutic regimen was defined almost 20 years ago, and significantly improved patient survival
compared to previous treatments. However, it is now clear that there are at least a few different subtypes of ovarian
cancers that have different response rates to the carboplatin and paclitaxel combination. While high grade serous
carcinoma, the most prevalent histologic type of ovarian cancer, has approximately 80% response rate to standard
chemotherapy, other subtypes show limited to no response: low grade serous carcinoma has a response rate as low as
30%, mucinous and clear cells carcinomas 15%, small cells and Müllerian mixed carcinomas almost no response. These
uncommon malignancies account for less than 20% of ovarian epithelial cancers, among which small cell carcinomas and
Müllerian mixed carcinomas are extremely infrequent. Interestingly, these rare histotypes have morphologically similar,
almost identical, counterparts in cancers arising in different organs, such as small cell carcinomas in the lungs or clear cell
carcinomas in the colon, thus suggesting that they are biologically related diseases despite affecting different organs. While
the research on biomolecular profiling of high-grade serous ovarian cancer has progressed in recent years, very little has
been done towards characterization of more rare subtypes. The purpose of this project is to define the molecular profile
of rare ovarian malignancies. Thus, we will analyze all available cases of these diseases treated at our Institution within the
past 10 years. They will be examined for gene expression and miRNA expression profiles by microarray technology. We will
also compare their profiles to those of identical histotypes affecting other organs, in particular for the most uncommon
histotypes.
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PROGRAM HIGHLIGHTS
Rare ovarian carcinoma histotypes are overshadowed by the most prevalent high grade serous ovarian carcinoma. In fact, they
account for the majority of standard therapy failures. To date, no effective treatment is available for these diseases. Because these cancer subtypes are characterized by limited to no response to chemotherapy and poor prognosis, this study addresses a compelling area
of research. The lack of understanding of their biology constitutes an additional impediment toward the definition of a specific therapy.
Our study will shed light on the biomolecular profiles of these diseases. Indeed, it has been shown that gene expression profiles are
predictive of response to chemotherapy, particularly to platinum based compounds. The comparison between their profile and those
from similar malignant histotypes in other organs will help in identifying effective treatments, as identical cell types may exhibit similar
responses to specific chemotherapies regardless of the organ of origin. Any advances in this field, even the simple identification of a
more effective chemotherapy among those available, will greatly impact not only survival of patients with specific subtypes, but potentially the overall prognosis of ovarian cancer
PROGRAM MEMBERSHIP
Raspagliesi Francesco: MD, Principal Investigator of this project. He is
the Director of the Gynecologic Oncology Unit. He has internationally
recognized leadership in treatment of gynecologic malignancies and
application of innovative approaches. He will coordinate the project and
oversee the execution of each step of the research.
Mezzanzanica Delia: Biologist, Staff Member Head of Molecular
Therapies Unit with long-term experience in biochemistry, cellular
and molecular biology and translational researches applied to ovarian
cancer. She is the Multicenter Italian Trials in Ovarian Cancer (MITO)
translational representative at the international level (GCIG, ENGOT).
She will contribute in the coordination of laboratory activities related to
the project.
Agoni Lorenzo: MD, PhD, Gynecologic Oncologist with extensive
laboratory experience, particularly in cellular and molecular oncology
and translational research. He will be involved in molecular and clinical
data integration analysis from bioinformatic and statistical perspectives.
Canevari S., Raspagliesi F., Lorusso D.: Bevacizumab treatment and
quality of life in advanced ovarian cancer. Future Oncol 2013; 9(7):
951-954
Raspagliesi F., Ditto A., Martinelli F., Haeusler E., Lorusso D.: Advanced
ovarian cancer: omental bursa, lesser omentum, celiac, portal and
triad nodes spread as cause of inaccurate evaluation of residual
tumor. Gynecol Oncol 2013; 129(1): 92-96
Ferrandina G., Salutari V., Vincenzi B., Marinaccio M., Naglieri E., Loizzi
V., Carpano S., Amadio G., Tonini G., Scambia G., Lorusso D.: Trabectedin
as single agent in the salvage treatment of heavily treated ovarian
cancer patients: a retrospective, multicenter study. Gynecol Oncol
2013; 130(3): 505-510
KEYWORDS
Ovarian cancer, rare disease, gene expression, chemotherapy.
Lorusso D., Cirillo F., Mancini M., Spatti G.B., Grijuela B., Ditto A.,
Raspagliesi F.: The different impact of BRCA mutations on the survival
of epithelial ovarian cancer patients: a retrospective single-center
experience. Oncology 2013; 85(2): 122-127
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.Ugo Pastorino.
EARLY DIAGNOSIS OF LUNG CARCINOMA
AND EFFICACY OF PLASMA miRNAS
AS FIRST-LINE TESTS
Three decades of research have shown that radiological screening of heavy smokers can detect resectable early lung
cancers with higher frequency, although the benefits on mortality are still debated. The preliminary results of the first
two randomized spiral-CT screening trials appear conflicting, with one study showing no benefit and the other a limited
mortality reduction (-7%). In the next 3-4 years, ongoing randomized trials in Europe will provide conclusive data on the
efficacy of CT-screening for lung cancer. Nonetheless, no major impact on mortality is to be expected.
A possible explanation of these findings is that not all aggressive lung tumors arise from identifiable slow-growing
precursors, thus suggesting a possible paradigm shift in our understanding of the natural history of lung cancer. In this
respect, the identification of biologic and molecular features of indolent and aggressive disease could be useful to define
clinical predictors of high-risk lesions and select suitable cohorts of patients who might benefit from current treatments as
well as to identify genetic signatures that might represent novel therapeutic targets.
We recently reported that miRNA expression profiles in tumors and in normal lung tissue are indicative of aggressive
lung cancer development, and that specific miRNA signatures can be identified in plasma samples of patients up to two
years before spiral-CT detection of disease. They are also able to identify the occurrence of early metastatic, but spiral-CT
undetectable, lung tumors or small spiral-CT detected lesions with aggressive potential.
Our study is divided in different phases: i) analysis of 1000 plasma samples of disease-free smokers already collected in our
biological repository during the last two years; ii) enrollment of 4000 smoking volunteers, collection of their blood samples,
and enrolment in a program of active surveillance on the basis of their miRNA risk profile; iii) assessment of miRNA
expression profile using a custom-made microfluidic card containing the 24 miRNAs previously identified in diagnostic
signatures; iv) bioinformatic analyses of miRNA ratios in the cohort to determine which individuals are have or will develop
lung cancer, and in particular the aggressive form of the disease; v) assessment of the best diagnostic and treatment
algorithm for subjects with suspicious miRNA profiles; vi) functional validation of miRNAs as novel therapeutic targets
using novel cellular genetically engineered models of transformation and tumor graft models. The study started recruiting
volunteers on January 2013. By the end of 2013, 1016 subjects have been recruited.
Overall, the results of this large prospective study will permit establishing the potential of our plasma microRNA assay as
a first-line screening test for lung cancer detection in routine clinical practice for high-risk population screening with a low
cost, non-toxic, and non-invasive procedure.
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PROGRAM HIGHLIGHTS
For early diagnosis, it is necessary to find non-invasive cancer biomarkers to monitor molecular differences in tumors, which may assist
in the selection of the best possible treatment for individual cancer patients. The cancer biomarkers so far identified in clinical use,
such as carcinoembryonic antigen (CEA) for colon cancer, alpha-fetoprotein (AFP) associated with HCC and prostate specific antigen
(PSA) in prostate cancer, have limitations with respect to their use for screening owing to low sensitivity and specificity in early stages
and inability to distinguish aggressive from indolent tumors. Other common cancers, such as lung cancer, lack established biomarkers
with demonstrated clinical utility in a screening setting. Thus, there is a need for biomarkers with the required sensitivity and specificity for the detection of lung cancer .
Most serum and plasma biomarker studies in lung cancer have so far involved analyses of quite small number of samples, most in retrospective series, and there is a need to prospectively analyze circulating biomarkers in the context of prospective clinical trials. The
challenge for the next decade will be to bring biomarkers to the clinic in ways that are efficient and practical. This proposal represents
an effort to design and implement a validation study with clear pragmatic outcomes that can be expeditiously translated to clinical use.
The prospective spiral-CT screening trials conducted so far did not include biomarkers analyses in their diagnostic algorithm. The innovative aspect of the present proposal is to apply profiling of circulating miRNA in plasma to a large prospective group of heavy smokers
of a screening trial. Our study will enroll a large number of smoker volunteers who will undergo baseline chest CT examination, blood
collection and plasma miRNA profiling. For the first time, the assessment of the best diagnostic and treatment algorithm will be based
on plasma miRNA profile. We will apply a 3 tier classifier based on the accuracy (sensitivity and specificity) observed in an extended
validation of our previously published findings. These results suggest that miRNA signatures are robust enough to make potentially
impactful clinical decisions in the proposed prospective clinical trial.
We believe that plasma miRNA profiling could represent an innovative tool to obtain early diagnosis and have an impact on mortality.
Considering the failures of previous several attempts at achieving early diagnosis and any substantial reduction in mortality of lung
cancer patients, it may represent a useful tool to screen smokers. Our study will help to address these issues.
This project represents a unique attempt to integrate biomarkers in a clinical application such as screening and treatment of lung
cancer and exemplifies an effort to bring basic discoveries to the clinic involving collaboration across disciplines.
PROGRAM MEMBERSHIP
Ugo Pastorino, Principal Investigator, MD, Head of Thoracic Surgery
Unit. Coordination of clinical and experimental team and evaluation
of results. Design, clinical management and evaluation of diagnostic
algorithm for tumors detected on the basis of biomarker profiles.
Assessment of sensitivity, specificity, and clinical value of miRNA
signatures, impact on cure rates and mortality, frequency of false
negative and false positive results, and clinical implications.
Gabriella Sozzi, BiolScD, Head of Tumor Genomics Unit. Coordination
of research team and evaluation of results. Direct participation in
the development and analyses of biomarkers in plasma, thanks to her
expertise in biomarkers. Interaction with lung clinicians and statisticians
to coordinate biological sampling, planning statistical analyses, and
critically discussing the results.
Alfonso Marchianò, Radiologist, Director of Radiodiagnostics
Department. Responsible for the radiological protocol.
Giuseppina Calareso, Mario Silva, Radiologists. CT scan evaluations.
Interaction with surgical and experimental team to discuss the results.
Mattia Boeri, PhD, Biol ScD. Analyses of miRNA signatures in plasma
samples, functional validation of miRNAs as novel therapeutic targets.
Bioinformatic analyses of miRNA profiling in plasma, coordination of the
miRNA functional studies in vitro and in vivo.
Massimo Moro, BiolScD. Tumor graft harvesting from primary tumors,
serial maintenance of tumor grafts in vivo, involvement in biological
and functional studies and for testing combinations of new therapeutic
agents.
Paola Suatoni, BiolScD. Collection of blood samples from the enrolled
volunteers, separation of plasma samples, harvesting and storage of
plasma aliquots. Maintenance of the database. Extraction of RNAs from
plasma samples and performing multiplex-RT-PCR reactions.
Carla Verri, BiolScD. Collaboration in miRNA expression analyses, using
microfluidic cards and q-real time PCR.
Davide Conte, Lab tech. Collaboration in the banking of the biological
specimen and mRNA extractions, RT-PCR and pre-amplification phases
of the miRNA assay, analyses of plasma.
Carlo La Vecchia, Epidemiologist. Design of clinical and experimental
database. Statistical analyses of experimental and clinical data.
Assessment of sensitivity, specificity and clinical value of blood tests.
Effect of miRNA analysis on lung cancer survival, and mortality of
screened population.
Carlotta Galeone, Statistician. Contribution of database design and
quality control. Statistical analysis of experimental and clinical data.
Claudio Jacomelli, Informatics Consultant. Executive Data management.
Annamaria Calanca and Carolina Ninni, Secretary of the Project,
enrollment of volunteers and manage of visits, data entry.
Elena Bertocchi, Scientific Secretariat. Project coordination and data
management.
Pastorino U., Sverzellati N.: Lung cancer: CT screening for lung cancerdo we have an answer? Nat Rev Clin Oncol 2013; 10(12): 672-673
Pastorino U.: Current status of lung cancer screening. Thorac Surg Clin
2013; 23(2): 129-140
Silva M., Sverzellati N., Manna C., Negrini G., Marchianò A., Zompatori
M., Rossi C., Pastorino U.: Long-term surveillance of ground-glass
nodules: evidence from the MILD trial. J Thorac Oncol. 2012; 7(10):
1541-1546
BIOMILD - Prot INT 11/21
MILD – Prot INT 05/53
Italian Association for Cancer Research IG UP11991
Italian Ministry of Health – Finalized Research Program
KEYWORDS
Lung cancer, screening, clinical trials, microRNA, biomarkers
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PEDIATRIC
CANCER
COORDINATOR: Maura Massimino
Studies of childhood tumors aimed at improving prognosis and reducing adverse treatment
effects; studies focused on the prevention, early diagnosis and management of long-term
cancer- and treatment-induced effects; when cure is no longer possible, focus on support
for patients and family to ensure they are not abandoned but supported (through control
of physical and psychological symptoms) and accompanied along the terminal phase of the
disease.
AIMS: Integrating longer survival and improved quality of life. For the most important
childhood tumors (neuroblastoma, Wilms’ tumor, Ewing’s sarcoma), studies will seek
to identify new therapeutic targets and thereby new approaches to biological drugs,
as well as assessing iatrogenic sequelae with respect to thyroid, cardiac, pulmonary
and gonadal function in long-term cancer survivors.
PROJECTS
• Tumors of the central nervous system (Maura Massimino)
• Adolescents with cancer in Italy: from local projects to a National coordinated program (Andrea Ferrari)
• Genetic and biomolecular characterization of Wilms’ tumor and detection
of predictive markers of poor prognosis (Daniela Perotti)
• Introduction of new drugs in the treatment of pediatric cancer (Michela Casanova)
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research activity
.Maura Massimino.
TUMORS OF THE CENTRAL NERVOUS SYSTEM
CNS neoplasms are the leading cause of cancer death in children. The incidence is 2.4 cases per 100,000 per year, with
approximately 450 new cases in Italy. While high-grade malignant astrocytomas (WHO grade III and IV, WHO) are prevalent
in adult histologies, in pediatric patients low-grade gliomas and embryonic tumors (PNET and medulloblastoma) outweigh
other histotypes, which represent, respectively, 50% and 20% of brain tumors under the age of 15 years. The signs and
symptoms by which a tumor of the CNS occurs should not be underestimated either by the physician, parents or teachers in
order to allow a prompt diagnosis and suitable therapy. In fact, at present, more than half of children who are diagnosed with a
brain tumor have a chance for cure and become an adult, but the price of healing is often high in terms of sequelae in terms of
neuro-cognitive deficits and endocrine, metabolic and somatic growth. Aspects of prevention, rehabilitation and correction of
these deficits are thus an integral part of the treatment plan for these children.
For some histologies or presentations of disease (i.e. in the first case: the atypical rhabdoid tumor and, in the second case, the
intrinsic neoplasms of pons-DIPG) or relapse of the disease, however, the chances of recovery are still an open challenge and
treatment with new drugs or combinations of drugs with biological and molecular represent the focus of future therapies.
The aims of our activity include to launch new therapeutic clinical protocols for diseases where a treatment standard already
exists (medulloblastoma and ependymoma in the European context), experimental strategies in disease with poor prognosis
(DIPG, glioblastoma), evaluation of surrogate biochemical markers to understand disease nature and history in those tumors
where biopsy is not common or probably not definitely descriptive of tumor heterogeneity as in DIPG, and evaluation of longterm effects in cured patients through novels bio-engineering tools.
PROGRAM HIGHLIGHTS
Medulloblastoma (MBL) with no residual post-surgery, without metastasis and without biological risk factors (anaplastic / large cell, amplification of myc). The academic protocol for standard risk MBL medulloblastoma for which our center is the national coordinator within the SIOP
(International Society of Pediatric Oncology) has already passed the stage of approval AIFA and the Ethics Committee of the INT. Once awarded
the contract by the University of Hamburg, we will provide activation in other centers.
MBL at relapse. The phase 3 randomized protocol with the inhibitor of the pathway sonic hedgehog - LDE225 was opened. The results of steps 1
and 2 have already been presented in international conference venues.
Metastatic MBL. Ongoing debate at the European level in relation to the establishment of the protocol. The basis on which this Protocol is built,
however, are the results with the strategy published by us in the Journal of Clinical Oncology in 2009.
Ependymoma. Similar stage as for the protocol of medulloblastoma. It obtained the approval of the AIFA and procedures should start at the
ethics committees. Our center is also the national coordinator for this protocol.
Malignant gliomas. Our center, coordinator for Italy of the Protocol, which includes the randomization of temozolomide and radiotherapy versus
radiotherapy, temozolomide + bevacizumab. Eight patients have been enrolled so far and ours is the center with the largest recruitment compared with 81 activated centers around the world including Canada and Australia. A futility report should be made available shortly.)
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PROGRAM MEMBERSHIP
Veronica Biassoni, Clinical researcher, responsible for Italy of the DIPG
network
Elisabetta Schiavello, Clinical researcher
Lorenza Gandola, Senior pediatric radiotherapist
Emilia Pecori, Junior pediatric radiotherapist
Emanuele Pignoli, Senior physicist
Fulvia Gariboldi, Rehabilitation physician
Alfonso Marchiano, Senior radiologist and coordinator of pediatric
diagnostics
Modena P., Buttarelli F.R., Miceli R., Piccinin E., Baldi C., Antonelli
M., Morra I., Lauriola L., Di Rocco C., Garrè M.L., Sardi I., Genitori L.,
Maestro R., Gandola L., Facchinetti F., Collini P., Sozzi G., Giangaspero F.,
Massimino M.: Predictors of outcome in an AIEOP series of childhood
ependymomas: a multifactorial analysis. Neuro Oncol 2012; 14(11):
1346-1356
Sardi I., la Marca G., Cardellicchio S., Giunti L., Malvagia S., Genitori
L., Massimino M., de Martino M., Giovannini M.G.: Pharmacological
modulation of blood-brain barrier increases permeability of
doxorubicin into the rat brain. Am J Cancer Res 2013; 3(4): 424-432
Randomized trial for pediatric malignant glioma (Herby)
Ependymoma 2nd AIEOP trial
Massimino M., Antonelli M., Gandola L., Miceli R., Pollo B., Biassoni
V., Schiavello E., Buttarelli F.R., Spreafico F., Collini P., Giangaspero F.:
Histological variants of medulloblastoma are the most powerful
clinical prognostic indicators. Pediatr Blood Cancer 2013; 60(2):
210-216
Nimotuzumab, vinorelbine and radiotherapy for DIPG,
Massimino M., Casanova M., Polastri D., Biassoni V., Modena P., Pecori
E., Schiavello E., De Pava M.V., Indini A., Rampini P., Bauer D., Catania S.,
Podda M., Gandola L.: Relapse in medulloblastoma: what can be done
after abandoning high-dose chemotherapy? A mono-institutional
experience. Childs Nerv Syst 2013 Apr 18
Massimino M., Gandola L., Biassoni V., Spreafico F., Schiavello E., Poggi
G., Pecori E., Vajna De Pava M., Modena P., Antonelli M., Giangaspero
F.: Evolving of therapeutic strategies for CNS-PNET. Pediatr Blood
Cancer 2013; 60(12): 2031-2035
Tensor imaging evaluation of focally irradiated children
AIRC grant 2012-2014
Lombardy Region Grant 2011-2013 for Diffuse Tensor imaging
evaluation (co-responsible, PI Geraldina Poggi in IRCCS Eugenio
Medea, Bosisio Parini)
Grants by patient charities: Associazione Bianca Garavaglia, Fondo di
Gio
KEYWORDS
Childhood brain tumors, prognosis improvement, marker surrogate,
late-effects decrease
Figure: Images from: Pediatr Blood Cancer, 2013. Histological Variants of Medulloblastoma Are the Most Powerful Clinical Prognostic Indicators.
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research activity
.Andrea Ferrari.
ADOLESCENTS WITH CANCER IN ITALY:
FROM LOCAL PROJECTS TO A NATIONAL
COORDINATED PROGRAM
Adolescents with cancer are a unique group, with special characteristics. Patients in this age group seem to inhabit a “no
man’s land”, belonging neither to the pediatric nor to the adult worlds of oncology. Their optimal management (e.g. coping
with their complex psychological and social needs, providing age-appropriate facilities, and their inclusion in clinical trials)
remains a challenge that requires broad-based processes. In particular, a lack of improvement in survival rates compared
to other age groups has been reported, and survival rates of adolescents are poorer than those of children with the same
disease, partially due to differences in biology but also to treatment delivered (limited access to optimal cancer services and
low accrual to clinical trials).
The Youth Project of the Pediatric Oncology Unit at the INT in Milan was launched in 2011, as a dedicated program within
the pediatric oncology unit (with no any upper age limit for admitting patients with pediatric cancers to the pediatric unit)
focusing on clinical aspects (e.g. inclusion in clinical trials, psycho-social support, fertility preserving facilities), but also with
the view of creating dedicated multifunctional spaces and special events.
Thereafter, the Youth Project group leaded the Committee on Adolescents of the Associazione Italiana Ematologia
Oncologia Pediatrica (AIEOP), which successively evolved from a pediatric oncology-based Committee to a comprehensive
national broad task force dedicated to adolescents and also to young adults, involving various stakeholders and in
particular the adult oncology scientific societies: a new society has been created, called SIAMO (Società Italiana
Adolescenti con Malattie Onco-ematologiche - Italian Society for Adolescents with Onco-hematological Diseases), which
should be the official structure to achieve the support from the National Health Service and other organizations.
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PROGRAM HIGHLIGHTS
Youth Project of the Pediatric Oncology Unit at the INT in Milan (www.ilprogettogiovani.it)
•A new model of specific culture, with the challenge to deal not only with disease, but with the life of patients, and their normality,
creativity, and strength
•Developed within the pediatric oncology unit, as an offshoot of our existing activities, without requiring major changes to organization or new professional staff
•Double objective: 1) to improve and standardize clinical aspects (e.g. inclusion in clinical trials, psycho-social support, school and job
support, fertility preserving facilities, access to care after cancer therapy), 2) to make the hospital a special place for our teenagers,
by creating dedicated multifunctional spaces (including a 30 m2 gym) and special activities, events, and courses (e.g. arts, photography, music, new technologies), involving various professionals working with the patients: in particular, B.LIVE, the stylist collection
and the fashion parade (2012 project), the song Clouds of Oxygen (2013 project), sport (hospital & outdoor activities, e.g. sailing).
•A project on public information using new technologies easily accessible for teenagers (e.g. YouTube) has been developed with the
aim to reduce the delay in diagnosis often observed in adolescents and young adults (www.infoadolescentietumori.it)
SIAMO - Società Italiana Adolescenti con Malattie Onco-ematologiche (www.progettosiamo.it)
•A comprehensive national program dedicated to adolescents (and young adults) with cancer. For the first time, the pediatric cooperative group Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) and the Federation of Parent Associations for pediatric onco-hematology (Federazione Italiana Associazioni Genitori Oncoematologia Pediatrica - FIAGOP) joins the adult cooperative
groups Associazione Italiana di Oncologia Medica (AIOM) and Società Italiana di Ematologia (SIE)
•SIAMO moves from a pediatric oncology-based committee on adolescents to a forward-thinking national broad-based task-force
dedicated to adolescents and young adults, and wants to represent the official structure to achieve the support from national
health service organizations and governments.
•SIAMO involves not only physicians (from both the pediatric and the adult medical oncology world), but also various stakeholders
such as nurse groups, psychologists, social workers, advocacy organizations, and survivor groups.
•SIAMO wants to definitely face up to the strong necessity to bridge the gap in the quality of professional care for adolescents with
cancer. This is the major challenge, and requires broad-based schemes able to involve the public and its awareness, healthcare
providers, cooperative groups running clinical trials, university, and also the national government.
•SIAMO wants to cooperate with the other international specific groups, starting from the European Network for Teenagers and
Young Adults with Cancer (ENTYAC).
PROGRAM MEMBERSHIP
Andrea Ferrari, Responsible of the Youth Project and coordinator of
Italian society SIAMO
Maura Massimino, Director of the Pediatric Oncology Unit
Carlo Alfredo Clerici, Psychologist
Laura Veneroni, Psychologist dedicated to adolescents
Monica Terenziani, Responsible for the Fertility Program
Filippo Spreafico, Responsible for the Sport Project
Ferrari A., Bleyer A.: Participation of adolescents with cancer in clinical
trials. Cancer Treatement Review 2007; 33(7): 603-608
Ferrari A., Clerici C.A., Casanova M., et al.: The Youth Project at the
Istituto Nazionale Tumori in Milan. Tumori 2012; 98(4): 399-407
Ferrari A., Dama E., Pession A., et al.: Adolescents with cancer in Italy:
entry into the national cooperative pediatric oncology group AIEOP
trials. Eur J Cancer 2009; 45(3): 328-334
112
Ferrari A., Thomas D.M., Franklin A., et al.: Starting an AYA program:
some success stories and some obstacles to overcome. J Clin Oncol
2010; 28: 4850-4857
Ferrari A.: The challenge of access to care for adolescents with cancer
in Italy: national and local pediatric oncology programs. International
Perspectives on AYAO, Part 2. Journal of Adolescent and Young Adult
Oncology 2013; 2(3): 112-117
Financial support is provided by the Associazione Bianca Garavaglia
and the Near/Magica Cleme Foundation.
KEYWORDS
Adolescents, young adults, access to care, national program.
research activity
.Daniela Perotti....
.Filippo Spreafico.
GENETIC AND BIOMOLECULAR CHARACTERIZATION
OF WILMS TUMOR AND DETECTION OF
PREDICTIVE MARKERS OF POOR PROGNOSIS
Wilms tumor (WT) is a pediatric renal malignancy characterized by a high degree of histological and genetic heterogeneity.
While most WTs are sporadic, familial cases have also been described. In addition, approximately 5% of WTs are associated
with syndromic conditions.
At present, the genetic factors responsible for WT predisposition and development have been elucidated only in part. One
of the difficulties in the study of WT is represented by the substantial lack of reliable models of the genesis of this disease.
However, a strategy allowing the propagation of primary WTs in vivo has recently been developed (Shakked et al. EMBO
Mol Med 2012, 4:1-20) that warrants more comprehensive investigations on WT-derived cells.
Overall, WTs display good prognosis and, thanks to a multimodal clinical approach, the 5-year overall survival rate
approaches 90%. However, a survival rate <50% is expected in patients who relapse. In addition, a significant proportion
of long-term survivors suffer from severe late therapy-related complications. At present, validated risk factors in use for
therapeutic stratification are tumor stage and diffuse anaplasia. Studies aimed at identifying genetic factors predictive
of adverse prognosis have revealed that loss of heterozygosity (LOH) at chromosomes 1p and 16q occur more frequent
in WTs of relapsing cases, although the relative low incidence of 1p/16q losses renders their predictive value relatively
low. Gain of chromosome 1q has also been reported as an adverse prognostic factor by several groups, but this finding
needs prospective validation. Global gene expression analyses of WTs reported to date have failed to identify a molecular
signature related to prognosis.
Specific aims of this research program are:
1. Identify genes involved in hereditary susceptibility to WT by massive parallel DNA sequencing.
2. Identify and validate genetic signatures predictive of poor prognosis by genome wide approaches, including single
nucleotide polymorphisms (SNPs), gene expression, and miRNA profiling.
3. Verify the accuracy of selected genetic markers in predicting the clinical outcome of WT patients.
4.Obtain WT-derived cell cultures as models recapitulating the disease. Prospective studies and investigations addressing
the molecular pathways leading to relapsing disease will be performed by engrafting fresh minced WTs into mice and,
following serial passages, by recovering single cell suspensions maintaining both in vivo tumor expansion and in vitro
differentiating capabilities.
5.To study functional aspects, relevant to WT, of genes and non-coding RNA misexpressed in tumor specimens. Moreover, as WTs
are of embryonic origin, cancer and kidney-derived cell lines will be exploited as read-out models for the study of genes/miRNAs
depletion or induction to assess their role on cell morphology and transcriptional regulation of early developmental genes.
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PROGRAM HIGHLIGHTS
1.Genome-wide gene expression analysis comparing favorable histology WTs from relapsing and non-relapsing patients has been
performed in collaboration with the Functional Genomics service. Approximately 700 differentially expressed genes and 20 miRNAs were identified as significantly associated with relapse. Strikingly, mRNA levels of genes expressed in the early stages of kidney
development and in the blastemal component of WT tissues were found to be reduced in specimens from relapsing compared to
non-relapsing patients. Moreover, the embryonic stem cell (ESC)-like signature, characterizing cancer-initiating cells, appeared
to be frequently lost in relapsing WTs. Conversely, in these tumors an increase in the level of transcripts of genes associated with
more differentiating steps of kidney organogenesis was observed. The set of genes whose expression was found to be predictive of
poor prognosis included SPP1, MAOA, MUC1, CLDN1, and MYC. Further investigations on additional WT samples are necessary
to verify the prognostic significance of markers emerging from these studies, and to help stratifying WT patients for risk of relapse
thus allowing tailored therapeutic regimens.
2.A total of 125 unilateral favorable histology WTs registered between 2003 and 2008 in the Italian cooperative clinical protocol
were examined at microsatellite markers mapping to chromosomes 1p, 7p, 11q, 16q, and 22q. In line with previous findings, loss
of heterozygosity (LOH) at 1p was significantly associated with a worse disease-free survival (probability 0.67 for patients with
and 0.92 for those without 1p LOH, p = 0.0009), as confirmed by multivariate analysis adjusting for tumor stage and patient age at
diagnosis. There was no difference in disease-free survival probability among children with LOH in the other chromosomal regions
tested. The worse outlook for children older than 2 years at diagnosis did not seem to be influenced by the LOH patterns considered (Spreafico et al., J Urol. 2013;189:260-266).
3.A family with two cases of WT, the mother and her son, was investigated molecularly. A previously unreported frameshift mutation
of the WT1 gene, c.983delC (p.P328QfsX53) causing the loss of the C-terminal of the protein, was detected in both affected family
members. This WT pedigree adds to the few already reported in which a role of WT1 mutations has been established (Melchionda
et al., Pediatr Blood Cancer. 2013;60:1388-9).
4.A pediatric renal tumor tissue bank has been established with approximately 500 cases from multiple centers throughout Italy to
date, with matched clinical and histological data, to support biological studies.
PROGRAM MEMBERSHIP
Daniela Perotti
Research staff scientist - ‘Molecular bases of genetic risk and genetic
testing’ Research Unit, Department of Preventive and Predictive Medicine.
Molecular biologist, involved in the molecular characterization of WT, coresponsible for biological studies of the National Clinical Protocol on WT.
Filippo Spreafico
Staff clinician – Pediatric Oncology Unit, Department of Hematology
and Pediatric Onco-Hematology.
Chair of the National Clinical Protocol on pediatric renal tumors.
Antonio Fiorino
Associated researcher - ‘Molecular bases of genetic risk and genetic
testing’ Research Unit, Department of Preventive and Predictive Medicine.
Cellular and molecular biologist, involved in functional studies on WT.
Paola Collini
Staff clinician - Anatomic Pathology Unit, Department of Pathology and
Laboratory Medicine.
Pathologist reviewing histological diagnoses within the National Clinical
Protocol on WT.
Paolo Radice
Head of ‘Molecular bases of genetic risk and genetic testing’ Research
Unit, Department of Preventive and Predictive Medicine.
Expert in cancer genetics.
Spreafico F., Gamba B., Mariani L., Collini P., D’Angelo P., Pession
A., Di Cataldo A., Indolfi P., Nantron M., Terenziani M., Morosi C.,
Radice P., Perotti D.; AIEOP Wilms Tumor Working Group: Loss of
heterozygosity analysis at different chromosome regions in Wilms
114
tumor confirms 1p allelic loss as a marker of worse prognosis: a study
from the Italian Association of Pediatric Hematology and Oncology. J
Urol 2013; 189(1): 260-266
Melchionda F., Spreafico F., Ciceri S., Lima M., Collini P., Pession A.,
Massimino M., Radice P., Perotti D.: A novel WT1 mutation in familial
Wilms tumor. Pediatr Blood Cancer 2013; 60(8): 1388-1389
Calvello M., Tabano S., Colapietro P., Maitz S., Pansa A., Augello C.,
Lalatta F., Gentilin B., Spreafico F., Calzari L., Perotti D., Larizza L., Russo
S., Selicorni A., Sirchia S.M., Miozzo M.: Quantitative DNA methylation
analysis improves epigenotype-phenotype correlations in BeckwithWiedemann syndrome. Epigenetics 2013; 8(10): 1053-1060
Perotti D., Hohenstein P., Bongarzone I., Maschietto M., Weeks M.,
Radice P., Pritchard-Jones K.: Is Wilms tumor a candidate neoplasia for
treatment with WNT/β-catenin pathway modulators? A report from
the renal tumors biology-driven drug development workshop. Mol
Cancer Ther 2013; 12(12): 2619-2627
Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) 2003
WT Diagnostic and Therapeutic Protocol (AIEOP-TW-2003)
Associazione Bianca Garavaglia
Project title: Bio-molecular characterization of Wilms tumor
Principal investigators: Filippo Spreafico, Paolo Radice
Duration: Jan 2012 – Dec 2014
KEYWORDS
Wilms tumor, genetic markers, prognostic factors, functional studies
research activity
.Michela Casanova.
NEW DRUGS IN PEDIATRIC ONCOLOGY
Despite major progress in the past 40 years, 20% of children with cancer die from their disease, and 40% of survivors have
late adverse effects. Cancer remains the most common fatal disease of childhood. The improvements in cure rates seems
to have slowed down during the past decade, probably because we have reached the level where it is difficult to further
improve outcomes with currently available treatment. Innovative, safe, and effective medicines are urgently needed.
More than 100 drugs are approved by for the treatment of malignancies, and among these about 30 are currently used in
pediatric oncology and only 15 have been labeled for use in children. Possible reasons for the disparity between adult and
pediatric drug approvals include the relative rarity of childhood malignancies, the histopathologic and biologic differences
between many adult and pediatric tumors, and the limited number of pediatric patients eligible for pharmaceutical trials.
Although regulatory initiatives in the past 15 years in the USA and Europe have been introduced, new drug development
for children with cancer remains insufficient. Many pharmaceutical companies consider the adult population as their key
market, and the development of a drug for pediatric use only or primarily is done to comply with regulatory obligations.
Most children with cancer are still largely denied access to innovative drugs in Europe.
In 2003, a European academic Network (42 academic institutions in 9 European countries) was created to properly
address pediatric drug development; ITCC (Innovative Therapies for Children with Cancer) consortium was established
through institutional resources, developing partnerships, collaboration, and clinical and biological research projects. This
shows the clear commitment of all partners to work together, to combine expertise and strength, and to create a critical
mass that is well integrated in the European pediatric oncology research area.
Within this European Network (ITCC Consortium), our Institution is the most active center in Italy and recognized
internationally.
The main objective of the project is to increase preclinical and early clinical evaluation of new drugs in children and
adolescents with cancer, with the final aim to increase the number of patients being cured and improve the quality of cure.
Pediatric-specific needs include:
•Increased knowledge on the pharmacology in pediatric patients (especially in the very young) in order to improve
dosing, tolerance and efficacy
• Age-appropriate formulations
• Evaluation of long-term sequelae in survivors following the use of new drugs.
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PROGRAM HIGHLIGHTS
Thanks to the collaboration with ITCC, the number of clinical trials with innovative drugs was significantly implemented and several
phase I – first in children - studies have been opened recently.
In most of the ongoing studies, our Institution plays a pivotal role; it is the only Italian center selected for participation, and in others it
acts as coordinating center.
As an example, in 2011 we started the phase I- first in children - of LDE225, an oral, potent and selective inhibitor of Smo, a key
positive regulator of Hedgehog signaling ; it was a dose-escalation study to characterize the safety, tolerability, pharmacokinetics, and
pharmacodynamics of the drug in children with recurrent or refractory medulloblastoma, or other tumors potentially dependent on
Hedgehog (Hh) signaling pathway. At that time, our institution was the only Italian center open for accrual. The drug went subsequently entered in phase 2 at is now in phase 3 in patients with recurrent/ refractory medulloblastoma. In the phase 3 study, only patients
with activated Hh-pathway are included, who are identified on the basis of a 5-gene signature defined during the phase 1/2 study. Our
institution is the coordinating center for Italy, which is currently the country with the highest enrollment. The results of the phase 1/2
studies, already presented in several meetings, will be published soon.
Also in the ongoing phase I – first in children – trail on LDK378, a selective inhibitor of ALK, our Institution is the only open center in
Italy. Thanks to the positive interaction with the manufacturer, we also received the compound for preclinical evaluation. In vitro and
in vivo experiments have been performed and are ongoing.
PROGRAM MEMBERSHIP
Michela Casanova, Responsible New Drug Project and member of the
Clinical Trial Committee of ITCC
Maura Massimino, Director of the SC Pediatria Oncologica
Elena Barzanò, Trial Coordinator
Carla Moscheo, Clinical Researcher
Carlo Morosi, Senior Radiologist
Paola Collini, Senior Pathologist
Patrizia Piotti, Senior Cardiologist
Gabriella Saibene, Senior Pharmacist
Valentina Sinno, Clinical Trial Office
Di Giannatale A., Dias-Gastellier N., Devos A., Mc Hugh K., Boubaker A.,
Courbon F., Verschuur A., Ducassoul S., Malekzadeh K., Casanova M.,
Amoroso L., Chastagner P., Zwaan C.M., Munzer C., Aerts I.,
Landman-Parker J., Riccardi R., Le Deley MC., Geoerger B.,
Rubie H.: Phase II study of temozolomide in combination with
topotecan in relapsed or refractory neuroblastoma: A European
Innovative Therapies for Children with Cancer-SIOP-European
Neuroblastoma study. Eur J Cancer 2014; 50(1): 170-177
Zsiros J., Brugieres L., Brock P., Roebuck D., Maibach R.,
Zimmermann A., Childs M., Pariente D., Laithier V., Otte J.B.,
Branchereau S., Aronson D., Rangaswami A., Ronghe M.,
Casanova M., Sullivan M., Morland B., Czauderna P., Perilongo G.;
International Childhood Liver Tumours Strategy Group (SIOPEL):
Dose-dense cisplatin-based chemotherapy and surgery for children
with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm,
feasibility study. Lancet Oncol 2013; 14: 834-842
Semeraro M., Branchereau S., Maibach R., Zsiros J., Casanova M., Brock
P., Domerg C., Aronson D.C., Zimmermann A., Laithier V.,
Childs M., Roebuck D., Perilongo G., Czauderna P., Brugieres L.:
Relapses in hepatoblastoma patients: Clinical characteristics and
outcome-experience of the International Childhood Liver Tumour
Strategy Group (SIOPEL). Eur J Cancer 2013; 49: 915-922
Zsíros J., Brugières L., Brock P., Roebuck D., Maibach R., Child M.,
Morland B., Casanova M., Pariente D., Paris C., de Camargo B.,
Ronghe M., Zimmermann A., Plaschkes J., Czauderna P.,
Perilongo G.: Efficacy of irinotecan single drug treatment in children
with refractory or recurrent hepatoblastoma - A phase II trial of the
childhood liver tumour strategy group (SIOPEL). Eur J Cancer 2012;
48: 3456-3464
Phase II open-label, randomized, multi-center comparative study of
bevacizumab-based therapy in pediatric patients with newly diagnosed
supratentorial high-grade glioma (Herby)
Open-label, multi-center, randomized phase II study evaluating the
addition of bevacizumab to chemotherapy for childhood and adolescent
patients presenting with metastatic rhabdomyosarcoma and nonrhabdomyosarcoma soft tissue sarcoma (the Bernie study)
International randomized phase II trial of the combination of vincristine
and irinotecan with or without temozolomide (VI or VIT) in children and
adults with refractory or relapsed rhabdomyosarcoma
An open-label, multicenter, single-arm, phase I dose- escalation with
efficacy tail extension study of RO5185426 in pediatric patients with
surgically incurable and unresectable stage IIIc or stage IV melanoma
harboring BRAFv600 mutations
A phase I/II study of sunitinib in young patients with advanced
gastrointestinal stromal tumor (GIST)
A phase III, multi-center, open-label, randomized, controlled study of
the efficacy and safety of oral LDE225 versus temozolomide in patients
with HH-pathway activated relapsed medulloblastoma
A phase I, open-label, dose escalation study of LDK378 in pediatric
patients with malignancies that have a genetic alteration in anaplastic
lymphoma kinase (ALK)
A phase I/II, multicenter, open-label, dose-finding study to assess the
safety, tolerability, and preliminary efficacy of weekly nab®-paclitaxel in
pediatric patients with recurrent or refractory solid tumors
Relapse in synovial sarcoma: What can be done for poor outcomes?
Clinical Practice 2013; 10: 389-391
A phase III, randomized, double-blind, active comparator-controlled
clinical trial, conducted under in-house blinding conditions, to
examine the efficacy and safety of aprepitant for the prevention of
chemotherapy-induced nausea and vomiting (CINV) in pediatric
patients.
Massimino M., Casanova M., Polastri D., Biassoni V., Modena P.,
Pecori E., Schiavello E., De Pava M.V., Indini A., Rampini P., Bauer D.,
Catania S., Podda M., Gandola L.: Relapse in medulloblastoma:
What can be done after abandoning high-dose chemotherapy?
A mono-institutional experience. Childs Nerv System 2013; 29:
1107-1112
A phase I/II combined dose ranging and randomized, open-label
comparative study of the efficacy and safety of plerixafor in addition
to standard regimens for mobilization of hematopoietic stem cells
into peripheral blood, and subsequent collection by apheresis, versus
standard mobilization regimens alone in pediatric patients, aged 2 to
<18 years, with solid tumors eligible for autologous transplants
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research activity
Grant from the ROL (Rete Oncologica Lombarda) for the clinical
management of the academic trial - International randomized phase II
trial of the combination of vincristine and irinotecan with or without
temozolomide (VI or VIT) in children and adults with refractory or
relapsed rhabdomyosarcoma – as national sponsor and coordinating
the activities of Italian centers
Grants by patient Charities (Associazione Bianca Garavaglia)
KEYWORDS
New drugs, Phase I studies, Early phase II studies
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PATHWAYS OF RESEARCH/
INTERVENTION AND
ASSESSMENT OF QUALITY
OF LIFE IN PATIENTS
WITH CANCER
COORDINATOR: Martin Langer
Therapeutic and scientific activities have traditionally characterized medical oncology, but
concrete operational and human support for cancer patients is equally important at a time
when the humanization of cancer treatment is among the main goals of the our Institute (as
exemplified by the new hospice facility). Innovation in studies related to palliative care and
rehabilitation is therefore fundamental. Palliative care has received increasing emphasis in
recent years as a means to improve the treatment and quality of life of cancer patients. To
further this goal, evidence from basic knowledge will have to find a place in clinical practice.
With regard to oncological rehabilitation, information on the specific needs of patients with
debilitating treatment sequelae is still incomplete.
AIMS: Assessment of the delivery of analgesic therapy, symptom control and
supportive care (infusion of blood products, parenteral nutrition, etc.). Design
of questionnaires for comprehensive assessment of symptom and quality of life.
Detection of markers potentially associated with the response to compassionate
clinical treatment.
PROJECTS
• Assessment and management of symptoms and quality of life in cancer patients receiving
palliative care (Augusto T. Caraceni)
• Research and training for the physical, emotional, social and spiritual support of patients
on active cancer treatment and their caregivers (Carla Ripamonti)
• Development of algorithms for nutritional therapy in diseases at high risk
of malnutrition (Cecilia Gavazzi)
118
research activity
.Augusto T. Caraceni.
ASSESSMENT AND MANAGEMENT OF
SYMPTOMS AND QUALITY OF LIFE IN CANCER
PATIENTS RECEIVING PALLIATIVE CARE
The project was developed with the main clinical focus on improving clinical guidelines for pain, standardizing the
assessment classification and treatment of cancer pain, understanding genetic and clinical determinants of opioid analgesia,
and evaluating the impact of interventions on symptoms, quality of life, and quality of care at the end of life. These goals
were developed in research performed in close collaboration with the European Palliative Care Research Network
[Norwegian University of Science and Technology (NTNU)], the Mario Negri Institute, and a multicenter European project
(EUROIMPACT).
The European Association for Palliative Care (EAPC) recommendations on the use of opioid analgesics in cancer pain
were coordinated by our group on behalf of EAPC, and were published in the Lancet Oncology in 2012.The update of the
guidelines is ongoing in collaboration with several international groups, and will be continued during 2014 aiming at a new
release by the end of 2015. In this new version, the guidelines will broaden their scope to include recommendations on pain
assessment and classification, as well as pharmacological and non-pharmacological treatment strategies.
Consistent with the content of these guidelines, different research lines were developed with the aim of improving and
standardizing the definition of clinical aspects of cancer pain such as breakthrough pain and neuropathic pain, also using
empirical data analysis. A Delphi consensus study has been carried out with the aim of adapting the IASP criteria for
neuropathic pain assessment to the cancer pain patients. One PhD student based at our center and NTNU is presently
dedicated to this part of the project. Another ongoing project is aimed at developing a software for diagnosis and treatment
of cancer pain and other symptoms through an iPad device (EIR).
Ongoing analgesic clinical trials include: a randomized, double-blind comparison between sublingual transmucosal fentanyl
administration and subcutaneous morphine for the acute treatment of breakthrough pain, single center study, and
participation in the CERP randomized open-label, multicenter trial (Mario Negri Institute, Milan) on comparison of four
opioids for control of cancer pain.
Other national and international collaborative participations include: a) participation in a randomized, multicenter cluster
trial on the impact of the Liverpool Care Pathway on overall cancer care, funded by the Italian Ministry of Health; b) clinical
trials on other symptoms control; c) epidemiological research on the definition of a palliative care population and end-of-life
care (in supervising the EU FP7 project EUROIMPACT).
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PROGRAM HIGHLIGHTS
The project is the result of close collaboration between the European Palliative Care Research Centre (PRC) and the Palliative Care,
Pain Therapy, and Rehabilitation Unit. The primary aim of this international collaboration is to extend knowledge and gain new insight
in prevalence, assessment, and treatment efficacy of the most frequent cancer-related symptoms, using clinical and basic research
methods, and to further develop and consolidate a long-lasting international collaborative in palliative care cancer research. The
collaboration will facilitate well defined companion studies and related projects, including the development of cancer pain guidelines
and a computer based system to aid cancer pain assessment and treatment. In particular, the most recent achievements include the
following:
a) A study on the use of measurement tools for evaluation of cancer pain outcomes, emphasizing the use of 0 to 10 Likert scales and
identify specific clinically significant endpoints, using data from a longitudinal prospective observational clinical trial on the use of
opioids on 1461 patients. The study confirmed that pain ≤4 of 10 is a significant clinical endpoint.
b)The importance of standardized definitions for neuropathic and breakthrough pain and their inclusion in guidelines is paramount,
as demonstrated by our group in several international case series by applying specific tools such Pain Detect and addressing the
concordance of clinicians in applying these clinical diagnoses. The clinical definition of neuropathic pain in cancer and its relationship with the International Association for the Study of Pain criteria was elaborated in an international panel of expert in preparation of a formal evaluation using the Delphi consensus method.
c)The recent emphasis on breakthrough cancer pain, which paralleled the development of a number of fentanyl transmucosal
preparations for acute pain relief, is reflected by a variable use of this concept in international guidelines, as summarized in a recent
review coordinated by our center.
d)In a European survey on 1000 patients with breakthrough cancer pain, 44% reported incident pain, and 41.5% spontaneous pain,
but only 19% were treated with recently developed fentanyl transmucosal preparations.
e)Using the biobank from the European Pharmacogenetic Opioid Study, 759 patients who received chronic morphine for cancer pain
were studied, demonstrating that common polymorphisms in the UGT1A8 and UGT1A1 genes, regulating the expression of the
UDP-glucuronosyltransferase enzymes, together with clinical factors, contribute to the variability in morphine metabolic ratios and
therefore in the production of the metabolytes morphine -3G and morphine-6G in advanced cancer patients.
PROGRAM MEMBERSHIP
Augusto Caraceni, Coordinator of the project
The European Palliative Care Cancer Symptom study (EPCCS).
Sponsored by the European Palliative Care Research Center
Cinzia Brunelli, Statistician and PhD Student
Alessandra Pigni, Research fellow
Ernesto Zecca, Clinical research fellow
Cinzia Martini, Clinical research fellow
Corli O., Montanari M., Greco M.T., Brunelli C., Kaasa S., Caraceni A.,
Apolone G.: How to evaluate the effect of pain treatments in cancer
patients: results from a longitudinal outcomes and endpoint Italian
cohort study. Eur J Pain 2013; 17(6): 858-866
Caraceni A., Davies A., Poulain P., Cortés-Funes H., Panchal S.J., Fanelli
G.: Guidelines for the management of breakthrough pain in patients
with cancer. J Natl Compr Canc Netw 2013; 11 Suppl 1: S29-36
Davies A., Buchanan A., Zeppetella G., Porta-Sales J., Likar R., Weismayr
W., Slama O., Korhonen T., Filbet M., Poulain P., Mystakidou K.,
Ardavanis A., O’Brien T., Wilkinson P., Caraceni A., Zucco F., Zuurmond
W., Andersen S., Damkier A., Vejlgaard T., Nauck F., Radbruch L., Sjolund
K.F., Stenberg M.: Breakthrough cancer pain: an observational study
of 1000 European oncology patients. J Pain Symptom Manage 2013;
46(5): 619-628
Fladvad T., Klepstad P., Langaas M., Dale O., Kaasa S., Caraceni A.,
Skorpen F.: Variability in UDP-glucuronosyltransferase genes
and morphine metabolism: observations from a cross-sectional
multicenter study in advanced cancer patients with pain.
Pharmacogenet Genomics 2013; 23(3): 117-126
120
New update of EAPC guidelines, widening the contents from on the
use of opioid analgesics in cancer pain to cancer pain management.
Sponsored by the European Palliative Care Research Center and the
European Association for Palliative Care Research Network
CERP Study: Open, randomized clinical study to compare the analgesic
efficacy of oxycodone, fentanyl, and buprenorphine to morphine, in
patients with moderate to severe cancer-related pain, starting from
initiation of treatment with the 3rd step of the analgesic scale of the
WHO.
KEYWORDS
Palliative care, pain, opioids, guidelines, genetics, end-of-life care
research activity
.Carla Ripamonti.
RESEARCH AND TRAINING FOR THE PHYSICAL,
EMOTIONAL, SOCIAL, AND SPIRITUAL
SUPPORT OF PATIENTS ON ACTIVE CANCER
TREATMENT AND THEIR CAREGIVERS
The Departmental Supportive Care in Cancer Unit has clinical, educational, and research objectives aimed at detection,
treatment, and study of prevention and treatment of side effects or toxicity resulting from cancer therapy as well as in the
cure of emotional, social, and spiritual patient needs through global care of patients starting from diagnosis, and during
cure and follow-up. The primary purpose is to support the work of each specialist and to implement supportive medical
therapy for the patient during the entire period of cancer treatment to ensure physical well being and improve adherence
to treatment protocols in terms of dose-intensity and dosing intervals. Moreover, the Unit provides real-time answers to
oncological emergencies by treating patients suffering from iatrogenic toxicity. An additional objective is to give support
to family, survivors, and personnel involved in daily care. The treatments carried out are compliant with the guidelines of
the WHO, MASCC, ESMO, and AIOM. The well-being of patients is the core of the decision-making process in different
settings of care in oncology. While the use of validated assessment tools to measure and treat physical symptoms related to
cancer and/or oncological treatments is well known, few data are available regarding spiritual and emotional needs, hope,
search of meaning, and dignity of the patient during anticancer therapies. Such poor knowledge and consequent undertreatment may worsen compliance to anticancer therapies and outcomes.
We believe that it is important to consider, assess, and treat the existential well-being starting from 1. Diagnosis and
staging of the disease, and during all the other moments of “physical and existential crisis” occurring throughout the
disease such as: 2. Waiting for surgical/oncological intervention; 3. The impact of chemotherapy and/or radiation for either
physical symptoms or the meaning of these oncological therapies for patients and their family (change body images, social
situations and working life, fear of death, etc.); 4. Waiting for results of re-staging of disease after treatments; 5. Sense of
abandonment after completing oncological therapies; 6. Diagnosis of recurrence or metastasis; 7. Difficulties of survivors
and families to integrate the experience of the past illness in the actual personal life. Literature data show a positive
correlation between physical and existential well-being in oncological settings. Moreover, patients require the attention of
their oncologist considering their emotional and existential needs, also because the decision-making process of the patient
is influenced by their attitudes towards life. Therefore, good communication on these aspects between patients and their
oncologists is mandatory.
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PROGRAM HIGHLIGHTS
In 2013, Research of the Unit has been oriented to study: 1. Different aspects of cancer-treatment or supportive treatment-related
symptoms and complications in patients with solid or hematological malignancies during cure or follow-up (pain, mucositis, nausea,
vomiting, diarrhea); 2. Assessment of anxiety and depression in routine clinical practice using a simple tool in comparison with a validated screening tool; 3. The different physical, emotional, and existential needs of patients with solid cancer vs. those with hematological malignancies.
All aspects considered represent an innovation in the research. To our knowledge, no comprehensive project has been conducted to
date with the intent to recognize all aspects of well-being of patients during cure or follow-up in a Supportive Care Program.
This is the first step that will be followed by appropriate training of oncologists, which will allow them to achieve integrated, global
care of patients.
1.a) Prospective study on the role of preventive dental measures, after dental screening examination in reducing the incidence of
osteonecrosis of the jaw in oncological patients with bone metastasis and/or osteoporosis receiving BPs and RANKL inhibitors such
as denosumab.
b) Prospective study to collect information on the incidence and intensity of nausea and vomiting during the first three inter-cycle
phases (days 14-16) in CT-naïve cancer patients treated with moderate or high emetogenic chemotherapy, and to define the most
distressing symptoms between nausea and vomiting as reported by patients, with the goal to optimize personalized therapy.
c) Revision of literature on targeted therapy-induced diarrhea.
d) Randomized clinical trials to compare morphine mouthwashes vs. placebo in the treatment of painful mucositis in head & neck
cancer patients.
e) Translation in Italian of The WHO Treatment Guidelines on Persisting Pain in Children with Medical Ilnesses.
f) Co-writing of the research protocol and collaboration in data elaboration of a randomized clinical trial on the role of a two-step
vs. three-step protocol in 250 cancer patients with pain.
g) After the validation in Italian language of the Patient Dignity Inventory (Ripamonti CI, et al. Patient Dignity Inventory (PDI) questionnaire: the validation study in Italian patients with solid and hematological cancers undergoing active oncological treatments.
Tumori 2012), coauthor of a research project on Patient Dignity with countries in southern Europe.
2.Prospective study to assess the performance of the Edmonton Symptom Assessment System (ESAS) item on anxiety and depression when detecting Hospital Anxiety Depression Scale (HADS) “cases” in non-advanced patients with solid or hematological
malignancies during cure or follow-up.
3.Prospective study to assess physical, spiritual, communication, and social needs, as well as hope, in 300 patients with solid cancer
compared to patients with hematological malignancies undergoing oncological therapies cared for at the Supportive Care Unit.
PROGRAM MEMBERSHIP
Maria Adelaide Pessi, MD and Gloria Barone specialized in oncology, are
active in research and clinical activities.
External Collaborations
Azienda Ospedaliera Universitaria, University of Modena and Reggio
Emilia, Italy;
Department of Clinical Pharmacology and Epidemiology, Consorzio
Mario Negri Sud, Santa Maria Imbaro (Chieti);
Amadori D., Mercatali L., Nanni O., Aglietta M., Alessi B., Gianni L.,
Ibrahim T., Farina G., Gaion F., Bertoldo F., Santini D., Rondena R.,
Bogani R., Ripamonti C., Ibrahim T.: What can we learn from the ZOOM
trial? Lancet Oncology 2013; 14: e388-e390
Ramondetta L.M., Sun C., Surbone A., Olver I., Ripamonti C., Konishi
T., Baider L., Johnson J.: Surprising results regarding MASCC
members’ beliefs about spiritual care. Support Care Cancer 2013; 21:
2991-2998
Psychology Unit, Center for Oncological Rehabilitation-CERION of
Florence;
Ripamonti C.I., Sichetti D.A., Fanizza C., Romero M.; ECAD_O Working
Group: Is pain reporting to health care professionals age-related? A
cross sectional multicenter study in a hospital setting. Expert Opin.
Pharmacother 2013; 14(15): 2011-2017
Clinical Epidemiology Unit, ISPO-Institute for the Study and Prevention
of Cancer, Florence;
World Health Organization for cancer pain relief (WHO);
AIFA
Sc Pediatria of Fondazione IRCCS, Istituto Nazionale dei Tumori, Milano
KEYWORDS
supportive care, assessment and treatment of symptoms and
complications, bone health, well-being,
Santini D., Lanzetta G., Dell’Aquila E., Vincenti B., Venditti O., Russano
M., Papapietro N., Denaro V., Tonini G., Ripamonti C.: ‘Old’ and ‘new’
drugs for the treatment of cancer pain. Expert Opin Pharmacother
2013; 14(4): 425-433
Amadori D., Aglietta M., Alessi B., Gianni L., Ibrahim T., Farina G.,
Gaion F., Bertoldo F., Santini D., Rondena R., Bogani R., Ripamonti C.:
Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for
prolonged treatment of patients with bone metastases from breast
cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority
trial. Lancet Oncology 2013; 14: 663-670
122
research activity
.Cecilia Gavazzi.
DEVELOPMENT OF ALGORITHMS FOR
NUTRITIONAL THERAPY IN DISEASES
AT HIGH RISK OF MALNUTRITION
Malnutrition is well known to be a negative prognostic factor in the prognosis of cancer patients, as it reduces tolerance to
oncological treatment, increases morbidity and mortality, and deteriorates the quality of life; nutrition intervention should
be considered throughout all phases of oncologic treatment, from diagnosis, surgery, chemotherapy, and radiotherapy.
However, nutrition therapy should be tailored for different cancer types and different oncological treatments. The main
goal of the project is the development and implementation of an algorithm for correct nutritional therapy in cancer
patients at a high risk of malnutrition starting with head and neck cancer, where we have previously shown that combined
treatments have significant impact of weight loss of patients.
PROGRAM HIGHLIGHTS
International guidelines for nutritional support in cancer patients do not address specific cancer types or oncological treatments.
Therefore, this project will aim to provide a specific algorithm for nutritional support in head and neck, upper GI, pancreatic, colorectal,
and ovarian cancers.
The implementation of the algorithm should distinguish its applicability and efficacy.
PROGRAM MEMBERSHIP
Cecilia Gavazzi, MD, Supervisor and coordinator
Michela Fiscella, MD, Review of literature, development and
implementation of algorithm
Jessica Lops, Evaluation of nutritional risk and nutritional counseling
Palazzi M., Tomatis S., Orlandi E., Guzzo M., Sangalli C., Potepan P.,
Fantini S., Bergamini C., Gavazzi C., Licitra L., Scaramellini G., Cantù
G., Olmi P.: Effects of treatment intensification on acute local
toxicity during radiotherapy for head and neck cancer: Prospective
observational study validating CTCAE, Version 3.0, Scoring System.
Int J Radiat Oncol Biol Phys 2008; 70: 330-337
Gavazzi C., Colatruglio S., Sironi A., Mazzaferro V., Miceli R.: Importance
of early nutritional screening in patients with gastric cancer. Br J Nutr
2011;106: 1773-1778
Bozzetti F., Mariani L., Lo Vullo S., The SCRINIO Working Group,
Amerio M.L., Biffi R., Caccialanza R., Capuano G., Correja I., Cozzaglio
L., Di Leo A., Di Cosmo L., Finocchiaro C., Gavazzi C., Giannoni A.,
Magnanini P., Mantovani G., Pellegrini M., Rovera G.M., Rovera L., Sandri
G., Tinivella M., Vigevani E., Arcovio C., Licitra L.: The nutritional risk in
oncology: a study of 1,453 cancer outpatients. Support Care Cancer
2012; 20: 1919-1928
Mariani L., Lo Vullo S., Bozzetti F., Gavazzi C., Arcovio C., Licitra L., on behalf
of the SCRINIO Working Group: Weight loss in cancer patients: a plea for
a better awareness of the issue. Support Care Cancer 2012; 20: 301-309
KEYWORDS
Malnutrition, nutritional support, artificial nutrition
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publications
PUBLICATIONS
N°
Authors
Title
Journal
IF
1
Abbas S., Linseisen J., Rohrmann S., Chang-Claude
J., Peeters P.H., Engel P., Brustad M., Lund E., Skeie
G., Olsen A., Tjønneland A., Overvad K., BoutronRuault M.-C., Clavel-Chapelon F., Fagherazzi
G., Kaaks R., Boeing H., Buijsse B., Adarakis G.,
Ouranos V., Trichopoulou A., Masala G., Krogh V.,
Mattiello A., Tumino R., Sacerdote C., Buckland
G., Suárez M.V.A., Sánchez M.-J., Chirlaque M.-D.,
Barricarte A., Amiano P., Manjer J., Wirfält E.,
Lenner P., Sund M., Bueno-De-Mesquita H.B., Van
Duijnhoven F.J.B., Khaw K.-T., et al.
Dietary intake of vitamin D and calcium Nutr Cancer 2013;
and breast cancer risk in the European 65: 178-187
prospective investigation into cancer
and nutrition.
2
Adamo M.S., Alessi D., Aletta P., Amodio R.,
Andreone S., Angelin T., Anghinoni E., Annulli M.L.,
Antonini S., Artioli M.E., Autelitano M., Balducci
C., Balottari P., Baracco M., Battisti W., Bella F.,
Bellatalla C., Belluardo C., Benatti P., Benedetto
G., Benfatto L., Bernazza E., Bianconi F., Biavati
P., Bidoli E., Birri S., Bizzoco S., Bonelli L., Bonini
A., Borciani E., Bovo E., Bozzani F., Bozzeda A.,
Braghiroli B., Brucculeri M.A., Brunori V., Bucalo
G., Bucchi L., Bugliarello E., et al.
Italian cancer figures, report 2013:
Multiple tumours.
Epidemiol Prev 2013; [IF 0.919]
37: 1-152
3
Agnoli C., Grioni S., Sieri S., Palli D., Masala G.,
Sacerdote C., Vineis P., Tumino R., Giurdanella
M.C., Pala M.V., Berrino F., Mattiello A., Panico S.,
Krogh V.
Italian mediterranean index and risk of
colorectal cancer in the Italian section
of the EPIC cohort.
Int J Cancer 2013;
132: 1404-1411
[IF 6.198]
4
Agresti R., Trecate G., Ferraris C., Valeri B.,
Maugeri I., Pellitteri C., Martelli G., Migliavacca S.,
Carcangiu M.L., Bohm S., Maffioli L., Vergnaghi D.,
Panizza P.
Ex vivo MRI evaluation of breast
tumors: A novel tool for verifying
resection of nonpalpable only MRI
detected lesions.
Breast J 2013; 19:
659-663
[IF 1.831]
5
Agudo A., Bonet C., Sala N., Muñoz X., Aranda N.,
Fonseca-Nunes A., Clavel-Chapelon F., BoutronRuault M.C., Vineis P., Panico S., Palli D., Tumino
R., Grioni S., Ramón Quirós J., Molina E., Navarro
C., Barricarte A., Chamosa S., Allen N.E., Khaw
K.-T., Bas Bueno-de-Mesquita H., Siersema
P.D., Numans M.E., Trichopoulou A., Lagiou P.,
Trichopoulos D., Kaaks R., Canzian F., Boeing H.,
Meidtner K., Johansson M., Sund M., Manjer J.,
Overvad K., Tjonneland A., Lund E., Weiderpass E.,
Jenab M., Fedirko V., et al.
Carcinogenesis
[IF 5.635]
Hemochromatosis (HFE) gene
2013; 34: 1244-1250
mutations and risk of gastric cancer in
the european prospective investigation
into cancer and nutrition (EPIC) study.
6
Aktolun C., Castellani M.R., Bombardieri E.
Diagnostic and therapeutic use of
MIBG in pheochromocytoma and
paraganglioma.
Q J Nucl Med Mol
Imaging 2013; 57:
109-111
[IF 1.918]
7
Aktolun C., Castellani M.R.
Theranostic role of MIBG in
neuroblastoma.
Q J Nucl Med Mol
Imaging 2013; 57:
3-5
[IF 1.918]
8
Alaggio R., Turrini R., Boldrin D., Merlo A., Gambini
C., Ferrari A., Dall’igna P., Coffin C.M., Martines A.,
Bonaldi L., De Salvo G.L., Zanovello P., Rosato A.
Survivin expression and prognostic
significance in pediatric malignant
peripheral nerve sheath tumors
(MPNST).
PLoS ONE 2013; 8:
e80456
[IF 3.73]
[IF 2.695]
125
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N°
Authors
Title
Journal
IF
9
Aleksandrova K., Pischon T., Buijsse B., May A.M.,
Peeters P.H., Bueno-De-Mesquita H.B., Jenab M.,
Fedirko V., Dahm C.C., Siersema P.D., Freisling H.,
Ferrari P., Overvad K., Tjønneland A., Trichopoulou
A., Lagiou P., Naska A., Pala M.V., Mattiello A.,
Ohlsson B., Jirström K., Key T.J., Khaw K.-T., Riboli
E., Boeing H.
Adult weight change and risk of
colorectal cancer in the European
Prospective Investigation into Cancer
and Nutrition.
Eur J Cancer 2013;
49: 3526-3536
[IF 5.061]
10
Al-Jumaily U., Ayyad O., Masarweh M., Ghandour
K., Almousa A., Al-Hussaini M., Ferrari A., Sultan I.
Improved care of rhabdomyosarcoma
in Jordan using less intensive therapy.
Pediatr Blood Cancer [IF 2.353]
2013; 60: 53-58
11
Allemani C., Minicozzi P., Berrino F., Bastiaannet
E., Gavin A., Galceran J., Ameijide A., Siesling S.,
Mangone L., Ardanaz E., Hédelin G., Mateos A.,
Micheli A., Sant M.
Predictions of survival up to 10 years
after diagnosis for European women
with breast cancer in 2000-2002.
Int J Cancer 2013;
132: 2404-2412
[IF 6.198]
12
Allemani C., Rachet B., Weir H.K., Richardson L.C.,
Lepage C., Faivre J., Gatta G., Capocaccia R., Sant
M., Baili P., Lombardo C., Aareleid T., Ardanaz E.,
Bielska-Lasota M., Bolick S., Cress R., Elferink M.,
Fulton J.P., Galceran J., Gózdz S., Hakulinen T.,
Primic-Žakelj M., Rachtan J., Diba C.S., Sánchez
M.-J., Schymura M.J., Shen T., Tagliabue G., Tumino
R., Vercelli M., Wolf H.J., Wu X.-C., Coleman M.P.
Colorectal cancer survival in the USA
and Europe: A CONCORD highresolution study.
BMJ Open 2013; 3:
e003055
[IF 1.583]
13
Breast cancer survival in the US and
Allemani C., Sant M., Weir H.K., Richardson L.C.,
Europe: A CONCORD high-resolution
Baili P., Storm H., Siesling S., Torrella-Ramos A.,
study.
Voogd A.C., Aareleid T., Ardanaz E., Berrino F.,
Bielska-Lasota M., Bolick S., Cirilli C., Colonna
M., Contiero P., Cress R., Crocetti E., Fulton J.P.,
Grosclaude P., Hakulinen T., Izarzugaza M.I.,
Malmström P., Peignaux K., Primic-Žakelj M.,
Rachtan J., Safaei Diba C., Sánchez M.-J., Schymura
M.J., Shen T., Traina A., Tryggvadottir L., Tumino R.,
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Berger M., Fagioli F., Abate M., Riccardi R., Prete
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Bossi P., Perrone F., Miceli R., Cantù G., Mariani
L., Orlandi E., Fallai C., Locati L., Cortelazzi B.,
Quattrone P., Potepan P., Licitra L., Pilotti S.
Tp53 status as guide for the
management of ethmoid sinus
intestinal-type adenocarcinoma.
Oral Oncol 2013; 49:
413-419
[IF 2.695]
67
Bouvier A.-M., Minicozzi P., Grosclaude P., Bouvier
V., Faivre J., Sant M.
Patterns of adjuvant chemotherapy for
stage II and III colon cancer in France
and Italy.
Dig Liver Dis 2013;
45: 687-691
[IF 3.162]
68
Bozzi F., Conca E., Laurini E., Posocco P., Lo Sardo
A., Jocollè G., Sanfilippo G.R., Gronchi A., Perrone
F., Tamborini E., Pelosi G., Pierotti M.A., Maestro
R., Pricl S., Pilotti S.
In vitro and in silico studies of MDM2/
MDMX isoforms predict Nutlin-3A
sensitivity in well/de-differentiated
liposarcomas.
Lab Invest 2013; 93:
1232-1240
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[IF 4.319]
[IF 3.302]
131
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N°
Authors
Title
Journal
IF
69
Brand J.S., Van Der Schouw Y.T., Onland-Moret
N.C., Sharp S.J., Ong K.K., Khaw K.-T., Ardanaz E.,
Amiano P., Boeing H., Chirlaque M.-D., ClavelChapelon F., Crowe F.L., De Lauzon-Guillain
B., Duell E.J., Fagherazzi G., Franks P.W., Grioni
S., Groop L.C., Kaaks R., Key T.J., Nilsson P.M.,
Overvad K., Palli D., Panico S., Quirós J.R.,
Rolandsson O., Sacerdote C., Sánchez M.-J.,
Slimani N., Teucher B., Tjonneland A., Tumino R.,
Van Der A D.L., Feskens E.J.M., Langenberg C.,
Forouhi N.G., Riboli E., Wareham N.J.
Age at menopause, reproductive life
span, and type 2 diabetes risk: Results
from the EPIC-InterAct study.
Diabetes Care 2013;
36: 1012-1019
[IF 7.735]
70
Bringhen S., Mateos M.V., Zweegman S., Larocca
A., Falcone A.P., Oriol A., Rossi D., Cavalli M.,
Wijermans P., Ria R., Offidani M., Lahuerta J.J.,
Liberati A.M., Mina R., Callea V., Schaafsma
M., Cerrato C., Marasca R., Franceschini L.,
Evangelista A., Teruel A.-I., van der Holt B.,
Montefusco V., Ciccone G., Boccadoro M., Miguel
J.S., Sonneveld P., Palumbo A.
Age and organ damage correlate with
poor survival in myeloma patients:
Meta-analysis of 1435 individual
patient data from 4 randomized trials.
Haematologica 2013; [IF 5.935]
98: 980-987
71
Broggini M., Garassino M.C., Damia G.
Evaluation of safety and efficacy
of tivantinib in the treatment of
inoperable or recurrent non-small-cell
lung cancer.
Cancer Manag Res
2013; 5: 15-20
72
Bruix J., Tak W.-Y., Gasbarrini A., Santoro A.,
Colombo M., Lim H.-Y., Mazzaferro V., Wiest R.,
Reig M., Wagner A., Bolondi L.
Regorafenib as second-line therapy
for intermediate or advanced
hepatocellular carcinoma: Multicentre,
open-label, phase II safety study.
Eur J Cancer 2013;
49: 3412-3419
73
Bruzzone P., Giannarelli D., Adam R., Mazzaferro
V., Pascher A., Settmacher U., Schmeding M., Otto
G., Mirza D., Boudjema K., Meyer D., Donkier V.,
Konigsrainer A., Muhlbacher F., Berlakovich G.,
Yedibela S., Candinas D., Chiche L., Colledan M.,
Friman N.G., Hidalgo E., Krawczyk M., Dor J.M.,
Rossi G., Oliverius M., Belghiti J., Aleh R., Popescu
I., Rentsch M., Pirenne J., Foss A., Pardo F., De
Carlis L., Navarro F., Schnitzbauer A.A., Stippel
D.L., Rolls K., Davidson B.R., Kalicinski P., et al.
A preliminary European Liver and
Intestine Transplant AssociationEuropean Liver Transplant Registry
study on informed recipient consent
and extended criteria liver donation.
Transplant Proc
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2013; 45: 2613-2615
74
Buck C., Börnhorst C., Pohlabeln H., Huybrechts I.,
Pala M.V., Reisch L., Pigeot I.
Clustering of unhealthy food around
German schools and its influence on
dietary behavior in school children: A
pilot study.
Int J Behav Nutr Phys [IF 3.577]
Act 2013; 10: 65
75
Buckland G., Travier N., Cottet V., González C.A.,
Luján-Barroso L., Agudo A., Trichopoulou A.,
Lagiou P., Trichopoulos D., Peeters P.H., May A.,
Bueno-De-Mesquita H.B., Bvan Duijnhoven F.J.,
Key T.J., Allen N., Khaw K.T., Wareham N., Romieu
I., McCormack V., Boutron-Ruault M., ClavelChapelon F., Panico S., Agnoli C., Palli D., Tumino
R., Vineis P., Amiano P., Barricarte A., Rodríguez L.,
Sanchez M.J., Chirlaque M.D., Kaaks R., Teucher
B., Boeing H., Bergmann M.M., Overvad K., Dahm
C.C., Tjønneland A., Olsen A., et al.
Adherence to the mediterranean
diet and risk of breast cancer in the
into cancer and nutrition cohort study.
Int J Cancer 2013;
132: 2918-2927
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76
Budroni M., Sechi O., Cossu A., Palmieri G., Tanda
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Estimates of cancer burden in Sardinia.
Tumori 2013; 99:
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Title
Journal
IF
77
Bul M., Zhu X., Valdagni R., Pickles T., Kakehi Y.,
Rannikko A., Bjartell A., Van Der Schoot D.K.,
Cornel E.B., Conti G.N., Boevé E.R., Staerman F.,
Vis-Maters J.J., Vergunst H., Jaspars J.J., Strölin
P., Van Muilekom E., Schröder F.H., Bangma C.H.,
Roobol M.J.
Active surveillance for low-risk
prostate cancer worldwide: The PRIAS
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Eur Urol 2013; 63:
597-603
[IF
10.476]
78
Burocchi A., Colombo M.P., Piconese S.
Convergences and divergences of
thymus-and peripherally derived
regulatory T cells in cancer.
Front Immunol 2013;
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79
Busse A., Rapion J., Fusi A., Suciu S.,
Nonnenmacher A., Santinami M., Kruit W.H.J.,
Testori A., Punt C.J.A., Dalgleish A.G., Spatz A.,
Eggermont A.M.M., Keilholz U.
Analysis of surrogate gene expression
markers in peripheral blood of
melanoma patients to predict
treatment outcome of adjuvant
pegylated interferon alpha 2b (EORTC
18991 side study).
Cancer Immunol
Immunother 2013;
62: 1223-1233
[IF 3.637]
80
Malignant pheochromocytoma and
Buzzoni R., Pusceddu S., Damato A., Meroni E.,
Aktolun C., Milione M., Mazzaferro V., De Braud F., paraganglioma: Future considerations
Spreafico C., Maccauro M., Zaffaroni N., Castellani for therapy.
M.R.
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Imaging 2013; 57:
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81
Caccia D., Dugo M., Callari M., Bongarzone I.
Bioinformatics tools for secretome
analysis.
Biochim Biophys
Acta - Proteins and
proteomics 2013;
1834: 2442-2453
[IF 3.733]
82
Calafiore L., Amoroso L., Della Casa Alberighi O.,
Luksch R., Zanazzo G., Castellano A., Podda M.,
Dominici C., Haupt R., Corrias M.V., Garaventa A.
Two-stage phase II study of imatinib
mesylate in subjects with refractory or
relapsing neuroblastoma.
Ann Oncol 2013; 24:
1406-1413
[IF 7.384]
83
Callari M., Tiberio P., De Cecco L., Cavadini E.,
Dugo M., Ghimenti C., Daidone M.G., Canevari S.,
Appierto V.
Feasibility of circulating miRNA
microarray analysis from archival
plasma samples.
Anal Biochem 2013;
437: 123-125
[IF 2.582]
84
Calvello M., Tabano S., Colapietro P., Maitz
S., Pansa A., Augello C., Lalatta F., Gentilin B.,
Spreafico F., Calzari L., Perotti D., Larizza L., Russo
S., Selicorni A., Sirchia S.M., Miozzo M.
Quantitative DNA methylation
analysis improves epigenotypephenotype correlations in BeckwithWiedemann syndrome.
Epigenetics 2013; 8:
1053-1060
[IF 4.92]
85
Camisaschi C., Filipazzi P., Tazzari M., Casati C.,
Beretta V., Pilla L., Patuzzo R., Maurichi A., Cova
A., Maio M., Chiarion-Sileni V., Tragni G., Santinami
M., Vergani B., Villa A., Berti E., Umansky L.,
Beckhove P., Umansky V., Parmiani G., Rivoltini L.,
Castelli C.
Effects of cyclophosphamide and IL-2
on regulatory CD4+ T cell frequency
and function in melanoma patients
vaccinated with HLA-class i peptides:
Impact on the antigen-specific T cell
response.
Cancer Immunol
Immunother 2013;
62: 897-908
[IF 3.637]
86
Campagnoli C., Abbà C., Ambroggio S., Brucato T.,
Pasanisi P.
Gynecol Endocrinol
Life-style and metformin for the
prevention of endometrial pathology in 2013; 29: 119-124
postmenopausal women.
87
Clin Breast Cancer
Metformin decreases circulating
Campagnoli C., Berrino F., Venturelli E., Abbà C.,
2013; 13: 433-438
Biglia N., Brucato T., Cogliati P., Danese S., Donadio androgen and estrogen levels in
nondiabetic women with breast cancer.
M., Zito G., Pasanisi P.
[IF 2.422]
88
Campagnoli C., Pasanisi P., Castellano I., Abbà C.,
Brucato T., Berrino F.
Postmenopausal breast cancer,
androgens, and aromatase inhibitors.
Breast Cancer Res
Treat 2013; 139:
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89
Campiglio M., Bufalino R., Sasso M., Ferri E.,
Casalini P., Adamo V., Fabi A., Aiello R., Riccardi F.,
Valle E., Scotti V., Tabaro G., Giuffrida D., Tarenzi
E., Bologna A., Mustacchi G., Bianchi F., Balsari A.,
Ménard S., Tagliabue E.
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133
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N°
Authors
Title
Journal
IF
90
Canevari S., Raspagliesi F., Lorusso D.
Bevacizumab treatment and quality of
life in advanced ovarian cancer.
Future Oncol 2013;
9: 951-954
[IF 3.202]
91
Capello D., Gloghini A., Baldanzi G., Martini M.,
Deambrogi C., Lucioni M., Piranda D., Famà R.,
Graziani A., Spina M., Tirelli U., Paulli M., Larocca
L.M., Gaidano G., Carbone A., Sinigaglia F.
Alterations of negative regulators
of cytokine signalling in
immunodeficiency-related nonHodgkin lymphoma.
Hematol Oncol 2013; [IF 2.036]
31: 22-28
92
Caprioli M., Romano M., Romano A., Rubolini D.,
Motta R., Folini M., Saino N.
Nestling telomere length does not
predict longevity, but covaries with
adult body size in wild barn swallows.
Biol Lett 2013; 9:
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[IF 3.348]
93
Caraceni A., Davies A., Poulain P., Cortés-Funes H.,
Panchal S.J., Fanelli G.
Guidelines for the management of
breakthrough pain in patients with
cancer.
J Natl Compr Canc
Netw 2013; 11:
S29-S36
[IF 5.112]
94
Caraceni A.
Drug-associated delirium in cancer
patients.
EJC Suppl 2013; 11:
233-240
95
Caraceni A.T., Brunelli C., Rocco P., Minghetti P.
Trends in opioid analgesics sales to
community pharmacies and hospitals
in Italy (2000-2010).
Minerva Anestesiol
2013; 79: 906-914
[IF 2.818]
96
Carbone A., Gloghini A.
Nodular lymphocyte predominant
Hodgkin lymphoma may show a
nodular pattern in which tumour cells
do not invade the surrounding spaces.
Br J Haematol 2013;
163: 537-538
[IF 4.942]
97
Relationships between lymphomas
linked to hepatitis C virus infection and
their microenvironment.
World J
Gastroenterol 2013;
19: 7874-7879
[IF 2.547]
98
Activated DDR1 increases RS cell
survival.
Blood 2013; 122:
4152-4154
[IF 9.06]
99
The microenvironment of AIDS-related Blood 2013; 122:
diffuse large B-cell lymphoma provides 459-460
insight into the pathophysiology
and indicates possible therapeutic
strategies.
[IF 9.06]
100
Carbone A., Pennati M., Parrino B., Lopergolo
A., Barraja P., Montalbano A., Spanò V., Sbarra S.,
Doldi V., De Cesare M., Cirrincione G., Diana P.,
Zaffaroni N.
Novel 1H-pyrrolo[2,3-b]pyridine
derivative nortopsentin analogues:
Synthesis and antitumor activity in
peritoneal mesothelioma experimental
models.
J Med Chem 2013;
56: 7060-7072
[IF 5.614]
101
Carbone A., Spina M., Gloghini A., Ponzoni M.,
Doglioni C., Tirelli U.
Nodular lymphocyte predominant
Hodgkin lymphoma with non-invasive
or early invasive growth pattern
suggests an early step of the disease
with a highly favorable outcome.
Am J Hematol 2013;
88: 161-162
[IF 4.003]
102
Carbone A., Volpi C.C., Caccia D., Gualeni A.V., Cilia Extracavitary KSHV-positive solid
A.M., Bongarzone I., Gloghini A.
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effusion lymphoma. (Letter).
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Carbotti G., Barisione G., Orengo A.M., Brizzolara
A., Airoldi I., Bagnoli M., Pinciroli P., Mezzanzanica
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The IL-18 antagonist IL-18-binding
protein is produced in the human
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Am J Surg Pathol
[IF 4.868]
2013; 37: 1459-1461
Clin Cancer Res
[IF 7.837]
2013; 19: 4611-4620
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Authors
Title
Journal
IF
104
Carbotti G., Orengo A.M., Mezzanzanica D.,
Bagnoli M., Brizzolara A., Emionite L., Puppo A.,
Centurioni M.G., Bruzzone M., Marroni P., Rossello
A., Canevari S., Ferrini S., Fabbi M.
Activated leukocyte cell adhesion
molecule soluble form: A potential
biomarker of epithelial ovarian cancer
is increased in type II tumors.
Int J Cancer 2013;
132: 2597-2605
[IF 6.198]
105
Carlessi L., Fusar Poli E., De Filippis L., Delia D.
ATM-deficient human neural stem cells DNA Repair (Amst)
2013; 12: 605-611
as an in vitro model system to study
neurodegeneration.
[IF 4.274]
106
Carlessi L., Fusar Poli E., Delia D.
Brain and induced pluripotent stem
cell-derived neural stem cells as an in
vitro model of neurodegeneration in
ataxia-telangiectasia.
Exp Biol Med 2013;
238: 301-307
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107
Carlo-Stella C., Locatelli S.L., Giacomini A., Cleris
L., Saba E., Righi M., Guidetti A., Gianni A.M.
Sorafenib Inhibits Lymphoma
Xenografts by Targeting MAPK/ERK
and AKT Pathways in Tumor and
Vascular Cells.
PLoS ONE 2013; 8:
[IF 3.73]
108
Carlson J., Licitra L., Locati L., Raben D., Persson F.,
Stenman G.
Salivary gland cancer: an update on
present and emerging therapies.
Am Soc Clin Oncol
Educ Book 2013; 33:
257-263
109
Carrara M., Cavatorta C., Borroni M., Tenconi
C., Cerrotta A., Fallai C., Gambarini G., Vedda A.,
Pignoli E.
Characterization of a Ce3+ doped
SiO2 optical dosimeter for dose
measurements in HDR brachytherapy.
Radiat Meas 2013;
56: 312-315
[IF 0.861]
110
Casali P.G.
Improving methodology to go beyond
histology in rare cancers. (Comment).
Lancet Oncol 2013;
14: 276-277
[IF
25.117]
111
Cassinelli G., Lanzi C., Tortoreto M., Cominetti D.,
Petrangolini G., Favini E., Zaffaroni N., Pisano C.,
Penco S., Vlodavsky I., Zunino F.
Antitumor efficacy of the heparanase
inhibitor SST0001 alone and in
combination with antiangiogenic
agents in the treatment of human
pediatric sarcoma models.
Biochem Pharmacol
[IF 4.576]
2013; 85: 1424-1432
112
Cassinelli G., Zuco V., Gatti L., Lanzi C., Zaffaroni
N., Colombo D., Perego P.
Targeting the akt kinase to modulate
survival, invasiveness and drug
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Curr Med Chem
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2013; 20: 1923-1945
113
Castellani M.R., Aktolun C., Buzzoni R., Seregni E.,
Chiesa C., Maccauro M., Aliberti G.L., Vellani C.,
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Iodine-131 metaiodobenzylguanidine
(I-31 MIBG) diagnosis and therapy
of pheochromocytoma and
paraganglioma: Current problems,
critical issues and presentation of a
sample case.
Q J Nucl Med Mol
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Castelli C., Tazzari M., Negri T., Vergani B., Rivoltini Structured myeloid cells and antiL., Stacchiotti S., Pilotti S.
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J Transl Med 2013;
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Cava C., Zoppis I., Gariboldi M., Castiglioni I.,
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Copy-number alterations for tumor
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Lecture Notes in
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104-109
116
Celio L., Aapro M.
Research on chemotherapy-induced
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J Clin Oncol 2013;
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Celio L., Agustoni F., Ricchini F., Dotti K., Niger M.,
Braud F.D.
Palonosetron plus dexamethasone
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Pooled data from two Phase III trials.
Future Oncol 2013;
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Authors
Title
Journal
IF
118
Celio L., Bonizzoni E., Bajetta E., Sebastiani S.,
Perrone T., Aapro M.S.
Palonosetron plus single-dose
dexamethasone for the prevention
of nausea and vomiting in
women receiving anthracycline/
cyclophosphamide-containing
chemotherapy: Meta-analysis of
individual patient data examining the
effect of age on outcome in two phase
III trials.
Support Care Cancer
2013; 21: 565-573
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119
Celio L., Ricchini F., De Braud F.
Safety, efficacy, and patient
acceptability of single-dose
fosaprepitant regimen for the
prevention of chemotherapy-induced
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Patient Prefer
Adherence 2013; 7:
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120
Censi F., Tosto F., Floridia G., Marra M., Salvatore
M., Baffico A.M., Grasso M., Melis M.A., Pelo E.,
Radice P., Ravani A., Rosatelli C., Resta N., Russo S.,
Seia M., Varesco L., Falbo V., Taruscio D.
The Italian national external quality
assessment program in molecular
genetic testing: Results of the VII
round (2010-2011).
Biomed Res Int 2013;
2013:
121
Ceresoli G.L., Zucali P.A., Mencoboni M., Botta M.,
Grossi F., Cortinovis D., Zilembo N., Ripa C., Tiseo
M., Favaretto A.G., Soto-Parra H., De Vincenzo F.,
Bruzzone A., Lorenzi E., Gianoncelli L., Ercoli B.,
Giordano L., Santoro A.
Phase II study of pemetrexed and
carboplatin plus bevacizumab as
first-line therapy in malignant pleural
mesothelioma.
Br J Cancer 2013;
109: 552-558
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122
Cesaro S., Tintori V., Nesi F., Schiavello E.,
Calore E., Dallorso S., Migliavacca M., Capolsini
I., Desantis R., Caselli D., Fagioli F., Luksch R.,
Panizzolo I., Tridello G., Prete A.
A prospective study on the efficacy of
mobilization of autologous peripheral
stem cells in pediatric oncohematology
patients.
Transfusion 2013;
53: 1501-1509
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123
Chiesa C., Castellani R., Mira M., Lorenzoni A., Flux Dosimetry in 131I-MIBG therapy:
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Moving toward personalized medicine.
Q J Nucl Med Mol
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124
Christodoulou M.S., Sacchetti A., Ronchetti
V., Caufin S., Silvani A., Lesma G., Fontana
G., Minicone F., Riva B., Ventura M., LahtelaKakkonen M., Jarho E., Zuco V., Zunino F.,
Martinet N., Dapiaggi F., Pieraccini S., Sironi M.,
Dalla Via L., Gia O.M., Passarella D.
Quinazolinecarboline alkaloid
evodiamine as scaffold for targeting
topoisomerase i and sirtuins.
Bioorg Med Chem
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2013; 21: 6920-6928
125
Ciampi R., Mian C., Fugazzola L., Cosci B., Romei
C., Barollo S., Cirello V., Bottici V., Marconcini G.,
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Materazzi G., Pinchera A., Elisei R.
Evidence of a low prevalence of ras
mutations in a large medullary thyroid
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Thyroid 2013; 23:
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126
Ciceri S., Cattaneo E., Fossati C., Radice P.,
Selicorni A., Perotti D.
First Evidence of Vertical Paternal
Transmission of Osteopatia Striata
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Am J Med Genet
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127
Cincinelli R., Musso L., Dallavalle S., Artali R.,
Tinelli S., Colangelo D., Zunino F., De Cesare M.,
Beretta G.L., Zaffaroni N.
Design, modeling, synthesis and
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Eur J Med Chem
2013; 63: 387-400
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128
Cleary J., Ddungu H., Distelhorst S.R., Ripamonti
C., Rodin G.M., Bushnaq M.A., Clegg-Lamptey J.N.,
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Supportive and palliative care for
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Breast 2013; 22:
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129
Clendenen T.V., Arslan A.A., Lokshin A.E., Liu M.,
Lundin E., Koenig K.L., Berrino F., Hallmans G.,
Idahl A., Krogh V., Lukanova A., Marrangoni A.,
Muti P., Nolen B.M., Ohlson N., Shore R.E., Sieri S.,
Zeleniuch-Jacquotte A.
Circulating prolactin levels and risk of
epithelial ovarian cancer.
Cancer Causes
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130
Clerici C.A., Giacon B., Veneroni L., Ferrari A.,
Luksch R., Meazza C., Polastri D., Simonetti F.,
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[Psycho-organic diseases in children
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Minerva Pediatr
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131
Colombini A., Perego S., Ardoino I., Marasco E.,
Lombardi G., Fiorilli A., Biganzoli E., Tettamanti G.,
Ferraretto A.
Evaluation of a possible direct effect
by casein phosphopeptides on
paracellular and vitamin D controlled
transcellular calcium transport
mechanisms in intestinal human HT-29
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Food Funct 2013; 4:
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132
Colombo C., Miceli R., Lazar A.J., Perrone F.,
Pollock R.E., Le Cesne A., Hartgrink H.H., CletonJansen A.-M., Domont J., Bovée J.V.M.G., Bonvalot
S., Lev D., Gronchi A.
CTNNB1 45F mutation is a molecular
prognosticator of increased
postoperative primary desmoid
tumor recurrence: An independent,
multicenter validation study.
Cancer 2013; 119:
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133
Colombo M., de Vecchi G., Caleca L., Foglia C.,
Ripamonti C.B., Ficarazzi F., Barile M., Varesco L.,
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PLoS ONE 2013; 8:
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Adolescents suffering from cancer:
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Lipscomb J., Yabroff K.R., Hornbrook M.C., Gigli A., Comparing cancer care, outcomes, and
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Liu M., Lu W., Krogh V., Hallmans G., Clendenen
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Biostatistics 2013;
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Locatelli S.L., Giacomini A., Guidetti A., Cleris L.,
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Longoni P., Milanesi M., Di Nicola M., Devizzi L.,
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Lopci E., Zanoni L., Fanti S., Ambrosini V.,
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Gallium-68 DOTANOC imaging in
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Mariani G., Ricchini F., Sica L., Bianchi G.V.
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Martinez J.O., Parodi A., Liu X., Kolonin M.G.,
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Masala G., Assedi M., Bendinelli B., Ermini I.,
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Massimino M., Casanova M., Polastri D., Biassoni
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Maynadié M., De Angelis R., Marcos-Gragera R.,
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Mazzaferro V., Sposito C., Bhoori S., Romito R.,
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Melchionda F., Spreafico F., Ciceri S., Lima M.,
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Meyer K.B., O'Reilly M., Michailidou K., Carlebur S.,
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349
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Association of low-penetrance alleles
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Papadia F., Basso V., Patuzzo R., Maurichi A., Di
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Isolated limb perfusion with the tumor- J Surg Oncol 2013;
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The ubiquitin proteasome system as
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Ripamonti C.B., Sichetti D.A., Fanizza C., Romero M.
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Height, age at menarche and risk
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Molina-Montes E., Chirlaque M.-D., Ardanaz E.,
Amiano P., Bueno-de-Mesquita H.B., van Gils C.H.,
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Roayaie S., Obeidat K., Sposito C., Mariani L.,
Bhoori S., Pellegrinelli A., Labow D., Llovet J.M.,
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425
Rohrmann S., Linseisen J., Allen N., BuenoDe-Mesquita H.B., Johnsen N.F., Tjønneland
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Trichopoulos D., Palli D., Krogh V., Tumino R.,
Ricceri F., Argüelles Suárez M.V., Agudo A.,
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Larrañaga N., Boshuizen H., Van Kranen H.J.,
Stattin P., Johansson M., Bjartell A., Ulmert D.,
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Rohrmann S., Overvad K., Bueno-de-Mesquita
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Nailler L., Boutron-Ruault M.-C., Clavel-Chapelon
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Bergmann M.M., Boeing H., Li K., Kaaks R., Khaw
K.-T., Wareham N.J., Crowe F.L., Key T.J., Naska
A., Trichopoulou A., Trichopoulos D., Leenders
M., Peeters P.H.M., Engeset D., Parr C.L., Skeie G.,
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BMC Medicine 2013;
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428
Rosato V., Bertuccio P., Bosetti C., Negri E.,
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Nutritional factors, physical activity,
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Breast 2013; 22:
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429
Rossi G., Pelosi G., Barbareschi M., Graziano P.,
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Subtyping non-small cell lung cancer:
Relevant issues and operative
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Int J Surg Pathol
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430
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Proanthocyanidins and other
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431
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Estimates of cancer burden in Italy.
Tumori 2013; 99:
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432
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434
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The use of polytetrafluoroethylene
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Sabbatini R., Ortega C., Procopio G., Masini C.,
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Metastatic renal cell carcinoma: How
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Saberi Hosnijeh F., Romieu I., Gallo V., Riboli E.,
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Trichopoulou A., Lagiou P., Katsoulis M., Panico
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J.M., Ardanaz E., Sánchez M.-J., Johansen D.,
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Cancer Causes
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Investigation into Cancer and Nutrition
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440
Sagrini E., Ardoino I., Marano G., Gianstefani A.,
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Development and validation of a
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prediction of clinically significant liver
fibrosis in chronic hepatitis C virus
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441
Salem R., Mazzaferro V., Sangro B.
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Yttrium 90 radioembolization for the
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Sandoval J., Mendez-Gonzalez J., Nadal E., Chen
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The intriguing patterns of tumor
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Expert Rev
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444
Sanfilippo G.R., Dei Tos A.P., Casali P.G.
Myxoid liposarcoma and the
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Curr Opin Oncol
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445
Santini D., Lanzetta G., Dell'Aquila E., Vincenzi B.,
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Tonini G., Ripamonti C.
Old' and 'new' drugs for the treatment
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Expert Opin
Pharmacother 2013;
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Santini D., Procopio G., Porta C., Ibrahim T., Barni
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Natural history of malignant bone
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447
Sardi I., la Marca G., Cardellicchio S., Giunti L.,
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Pharmacological modulation of bloodbrain barrier increases permeability of
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Am J Cancer Res
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Satta A., Mezzanzanica D., Turatti F., Canevari S.,
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Saunders D.P., Epstein J.B., Elad S., Allemano J.,
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Systematic review of antimicrobials,
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Scavullo C., Servida F., Lecis D., Onida F., Drago C.,
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Single-agent Smac-mimetic
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456
Schernhammer E.S., Sperati F., Razavi P., Agnoli
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Schlesinger S., Aleksandrova K., Pischon T.,
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Boeing H., Trichopoulou A., Pantzalis M., Kritikou
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Scott R.A., Langenberg C., Sharp S.J., Franks P.W.,
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Deloukas P., Fagherazzi G., Gonzalez C., Griffin
S.J., Groop L.C., Halkjaer J., Huerta J.M., Kaaks
R., Khaw K.T., Krogh V., Nilsson P.M., Norat T.,
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The link between family history and
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Diabetologia 2013;
56: 60-69
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Segev Y., Iqbal J., Lubinski J., Gronwald J., Lynch
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Singer C.F., Karlan B., Ping S., Narod S.A., Ginsburg
O., Robidoux A., Maehle L., Sweet K., Gilchrist D.,
Olopade O., Ainsworth P., Eisen A., Couch F., Isaacs
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The incidence of endometrial
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Gynecol Oncol 2013;
130: 127-131
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461
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Relapses in hepatoblastoma patients:
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Sfondrini L., Sommariva M., Tortoreto M., Meini
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Bonecchi R., Zaffaroni N., Colombo M.P., Tagliabue
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Shang S., Liu M., Zeleniuch-Jacquotte A.,
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Alsinet C., Cornella H., Klotzle B., Fan J.-B.,
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Integrative molecular analysis of
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Gastroenterology
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468
Sia D., Tovar V., Moeini A., Llovet J.M.
Intrahepatic cholangiocarcinoma:
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469
Sieri S., Brighenti F., Agnoli C., Grioni S., Masala G.,
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Dietary Glycemic Load and Glycemic
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PLoS ONE 2013; 8:
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Nutr Metab
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Siesling S., Kwast A., Gavin A., Baili P., Otter R.
Availability of stage at diagnosis,
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Silvestrini R., Martelli G., Miceli R., Agresti R.,
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Sluijs I., Beulens J.W.J., Van Der Schouw Y.T., Van
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Dietary glycemic index, glycemic load,
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Cisplatin and fluorouracil with or
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recurrent or metastatic squamouscell carcinoma of the head and neck
(SPECTRUM): An open-label phase 3
randomised trial.
Lancet Oncol 2013;
14: 697-710
[IF
25.117]
174
[IF 3.162]
publications
N°
Authors
Title
Journal
IF
531
Verpelli C., Carlessi L., Bechi G., Poli E.F., Orellana
D., Heise C., Franceschetti S., Mantegazza R.,
Mantegazza M., Delia D., Sala C.
Comparative neuronal differentiation
of self-renewing neural progenitor cell
lines obtained from human induced
pluripotent stem cells.
Front Cell Neurosci
2013; 7: 175
[IF 4.469]
532
Verzoni E., De Braud F., Fabiani F., Grassi P., Testa
I., Procopio G.
Patient approach in advanced/
metastatic renal cell carcinoma:
Focus on the elderly population and
treatment-related toxicity.
Future Oncol 2013;
9: 1599-1607
[IF 3.202]
533
Verzoni E., Garanzini E., Procopio G.
Complete responses in advanced renal
cell carcinoma: Utopia or real chance?.
Clin Exp Nephrol
2013; 17: 151-152
[IF 1.246]
534
Villa R., Cerroni B., Viganò L., Margheritelli S.,
Abolafio G., Oddo L., Paradossi G., Zaffaroni N.
Targeted doxorubicin delivery
by chitosan-galactosylated
modified polymer microbubbles to
hepatocarcinoma cells.
Colloids Surf B
Biointerfaces 2013;
110: 434-442
[IF 3.554]
535
Vinceti M., Crespi C.M., Malagoli C., Del Giovane
C., Krogh V.
Friend or foe? The current
epidemiologic evidence on selenium
and human cancer risk.
J Environ Sci Health
C Environ Carcinog
Ecotoxicol Rev 2013;
31: 305-341
[IF 3.565]
536
Vinceti M., Malagoli C., Iacuzio L., Crespi C.M.,
Sieri S., Krogh V., Marmiroli S., Pellacani G.,
Venturelli E.
Serum fatty acids and risk of cutaneous Dermatol Res Pract
2013; 2013:
melanoma: A population-based casecontrol study.
537
Virzi S., Iusco D., Baratti D., Bonomi S., Grassi A.,
Kusamura S., Deraco M.
Pilot study of adjuvant hyperthermic
intraperitoneal chemotherapy in
patients with colorectal cancer at high
risk for the development of peritoneal
metastases.
Tumori 2013; 99:
589-595
538
Waks Z., Goldbraich E., Farkash A., Torresani M.,
Bertulli R., Restifo N., Locatelli P., Casali P., Carmeli
B.
Analyzing the "CareGap": assessing
gaps in adherence to clinical guidelines
in adult soft tissue sarcoma.
Stud Health Technol
Inform 2013; 186:
46-50
539
Walker L.C., Whiley P.J., Houdayer C., Hansen
T.V.O., Vega A., Santamarina M., Blanco A., Fachal
L., Southey M.C., Lafferty A., Colombo M., De
Vecchi G., Radice P., Spurdle A.B.
Evaluation of a 5-Tier scheme
proposed for classification of sequence
variants using bioinformatic and
splicing assay data: Inter-reviewer
variability and promotion of minimum
reporting guidelines.
Hum Mutat 2013;
34: 1424-1431
540
Zaffaroni N.
Preface: MicroRNAs as novel cancer
biomarkers and therapeutic targets.
Crit Rev Oncog
2013; 18:
541
Zamora-Ros R., Fedirko V., Trichopoulou A.,
González C.A., Bamia C., Trepo E., Nöthlings
U., Duarte-Salles T., Serafini M., Bredsdorff L.,
Overvad K., Tjønneland A., Halkjær J., Fagherazzi
G., Perquier F., Boutron-Ruault M.-C., Katzke
V., Lukanova A., Floegel A., Boeing H., Lagiou P.,
Trichopoulos D., Saieva C., Agnoli C., Mattiello
A., Tumino R., Sacerdote C., Bueno-De-Mesquita
H.B., Peeters P.H.M., Weiderpass E., Engeset
D., Skeie G., Argüelles M.V., Molina-Montes E.,
Dorronsoro M., Tormo M.J., Ardanaz E., Ericson U.,
Sonestedt E., et al.
Dietary flavonoid, lignan and
antioxidant capacity and risk of
hepatocellular carcinoma in the
into cancer and nutrition study.
Int J Cancer 2013;
133: 2429-2443
[IF 0.922]
[IF 5.213]
[IF 6.198]
175
back to contents
N°
Authors
Title
542
Zamora-Ros R., Ferrari P., González C.A.,
Tjønneland A., Olsen A., Bredsdorff L., Overvad
K., Touillaud M., Perquier F., Fagherazzi G.,
Lukanova A., Tikk K., Aleksandrova K., Boeing H.,
Trichopoulou A., Trichopoulos D., Dilis V., Masala G.,
Sieri S., Mattiello A., Tumino R., Ricceri F., BuenoDe-Mesquita H.B., Peeters P.H.M., Weiderpass
E., Skeie G., Engeset D., Menéndez V., Travier N.,
Molina-Montes E., Amiano P., Chirlaque M.-D.,
Barricarte A., Wallström P., Sonestedt E., Sund M.,
Landberg R., Khaw K.-T., Wareham N.J., et al.
Breast Cancer Res
Dietary flavonoid and lignan intake
Treat 2013; 139:
and breast cancer risk according to
163-176
menopause and hormone receptor
status in the European Prospective
(EPIC) Study.
543
Zamora-Ros R., Forouhi N.G., Sharp S.J., González
C.A., Buijsse B., Guevara M., van der Schouw
Y.T., Amiano P., Boeing H., Bredsdorff L., ClavelChapelon F., Fagherazzi G., Feskens E.J., Franks
P.W., Grioni S., Katzke V., Key T.J., Khaw K.T., Kühn
T., Masala G., Mattiello A., Molina-Montes E.
The association between dietary
flavonoid and lignan intakes and
incident type 2 diabetes in European
populations: the EPIC-InterAct study.
Diabetes Care 2013;
36: 3961-3970
[IF 7.735]
544
Zamora-Ros R., Knaze V., Luján-Barroso L., Romieu
I., Scalbert A., Slimani N., Hjartåker A., Engeset D.,
Skeie G., Overvad K., Bredsdorff L., Tjonneland
A., Halkjær J., Key T.J., Khaw K.-T., Mulligan A.A.,
Winkvist A., Johansson I., Bas Bueno-De-Mesquita
H., Peeters P.H.M., Wallström P., Ericson U.,
Pala V., De Magistris M.S., Polidoro S., Tumino
R., Trichopoulou A., Dilis V., Katsoulis M., María
Huerta J., Martínez V., Sánchez M.-J., Ardanaz
E., Amiano P., Teucher B., Grote V., Bendinelli B.,
Boeing H., Förster J., Pala V., et al.
Differences in dietary intakes, food
sources and determinants of total
flavonoids between Mediterranean
and non-Mediterranean countries
participating in the European
Br J Nutr 2013; 109:
1498-1507
[IF 3.302]
545
Zamora-Ros R., Knaze V., Romieu I., Scalbert
A., Slimani N., Clavel-Chapelon F., Touillaud M.,
Perquier F., Skeie G., Engeset D., Weiderpass E.,
Johansson I., Landberg R., Bueno-De-Mesquita
H.B., Sieri S., Masala G., Peeters P.H.M., Grote
V., Huerta J.M., Barricarte A., Amiano P., Crowe
F.L., Molina-Montes E., Khaw K.-T., Argüelles
M.V., Tjønneland A., Halkjær J., De Magistris
M.S., Ricceri F., Tumino R., Wirfält E., Ericson U.,
Overvad K., Trichopoulou A., Dilis V., Vidalis P.,
Boeing H., Förster J., Riboli E., et al.
Impact of thearubigins on the
67: 779-782
estimation of total dietary flavonoids
in the European Prospective
(EPIC) study.
[IF 2.756]
546
Zamora-Ros R., Rothwell J.A., Scalbert A., Knaze
V., Romieu I., Slimani N., Fagherazzi G., Perquier
F., Touillaud M., Molina-Montes E., Huerta J.M.,
Barricarte A., Amiano P., Menéndez V., Tumino R.,
de Magistris M.S., Palli D., Ricceri F., Sieri S., Crowe
F.L., Khaw K.T., Wareham N.J.
Dietary intakes and food sources
of phenolic acids in the European
Br J Nutr 2013; 110:
1500-1511
[IF 3.302]
547
Zanaboni F., Grijuela B., Giudici S., Cormio G.,
Babilonti L., Ghezzi F., Giorda G., Scambia G.,
Franchi M., Lorusso M., Ditto A., Lorusso D.,
Raspagliesi F.
Weekly topotecan and cisplatin
(TOPOCIS) as neo-adjuvant
chemotherapy for locally-advanced
squamous cervical carcinoma: Results
of a phase II multicentric study.
Eur J Cancer 2013;
49: 1065-1072
[IF 5.061]
548
Zanoni I., Spreafico R., Bodio C., DiGioia M.,
Cigni C., Broggi A., Gorletta T., Caccia M., Chirico
G., Sironi L., Collini M., Colombo M.P., Garbi N.,
Granucci F.
IL-15 cis Presentation Is Required
for Optimal NK Cell Activation
in Lipopolysaccharide-Mediated
Inflammatory Conditions.
Cell Rep 2013; 4:
1235-1249
176
Journal
IF
[IF 4.469]
publications
N°
Authors
Title
Journal
IF
549
Zinzani P.L., Viviani S., Anastasia A., Vitolo
U., Luminari S., Zaja F., Corradini P., Spina M.,
Brusamolino E., Gianni A.M., Santoro A., Botto B.,
Derenzini E., Pellegrini C., Argnani L.
Brentuximab vedotin in relapsed/
refractory Hodgkin's lymphoma: The
Italian experience and results of its use
in daily clinical practice outside clinical
trials.
98: 1232-1236
550
Zompatori M., Mascalchi M., Ciccarese F.,
Sverzellati N., Pastorino U.
Screening for lung cancer using lowdose spiral CT: 10 years later, state of
the art.
Radiol Med 2013;
118: 51-61
551
Zsiros J., Brugieres L., Brock P., Roebuck D.,
Maibach R., Zimmermann A., Childs M., Pariente
D., Laithier V., Otte J.-B., Branchereau S., Aronson
D., Rangaswami A., Ronghe M., Casanova M.,
Sullivan M., Morland B., Czauderna P., Perilongo G.
Lancet Oncol 2013;
Dose-dense cisplatin-based
chemotherapy and surgery for children 14: 834-842
with high-risk hepatoblastoma
(SIOPEL-4): A prospective, single-arm,
feasibility study.
[IF 1.461]
[IF
25.117]
177
back to contents
ongoing supported projects
179
180
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ongoing supported projects
181
182
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back to contents
ongoing clinical studies
ONGOING CLINICAL STUDIES
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
BREAST CARCINOMA
32/03
Prognostic significance of blood concentrations of
F. Berrino
testosterone and insulin in women with early breast
cancer
2003
Observational 2467
Closed
accrual
06/04
Immunization of patients with locally advanced/
A. M. Gianni
metastatic breast and ovarian cancer with
autologous monocyte-derived dendritic cells loaded
with apoptotic/necrotic autologous tumor cells
exposed to heat shock
2004
Pilot
4
Closed
accrual
68/05
A phase II, single arm, multicentre study to evaluate
the efficacy and safety of the combination of
Omnitarg and Herceptin in patients with HER2
positive metastatic breast cancer
G. V. Bianchi
2006
II
7
Closed
accrual
39/06
A randomized, open-label, 2-arm, multicentre,
A. Moliterni
phase III study to evaluate the efficacy and safety
of bevacizumab in combination with Trastuzumab/
docetaxel compared with Trastuzumab/Docetaxel
alone as first line treatment for patients with HER2
positive locally recurrent or metastatic breast cancer.
2006
III
14
Closed
accrual
37/07
Randomized trial of diet, physical activity and breast F. Berrino
cancer recurrences: the DIANA-5 study
2007
-
1.667
Closed
accrual
47/07
A randomized multicentric international phase
II study of Herceptin® and docetaxel versus
docetaxel in association with OmnitargTM and
Herceptin® versus OmnitargTM and Herceptin®
in the treatment of locally advanced HER-2 positive
breast cancer, inflammatory or early breast cancer
G. Bianchi
2007
II
28
Closed
accrual
18/08
Phase II study. Safety of the scheme of adjuvant
or primary sequential chemotherapy in operable
breast cancer at high risk (AT x 3 - CMF x 3)
A. Moliterni
2008
II
352
Closed
accrual
76/08
Tevere project: primary prevention of breast cancer F. Berrino
by diet, physical activity or Metformin assumption
2009
III
350
100
16/09
A randomized, multicenter, phase III open-label
G. Bianchi
study of the efficacy and safety of trastuzumabMCC-DM1 vs capecitabine+lapatinib in patients
with HER2-positive locally advanced or metastatic
breast cancer who have received prior trastuzumabbased therapy
2009
III
6
Closed
accrual
33/09
A phase Ib, open label, dose escalation study of the
safety and pharmacology of P13-kinase inhibitor
GDC-0941 in combination with paclitaxel and
bevacizumab in patients with locally recurrent or
metastatic breast cancer
2009
Ib
22
5
S. Cresta
185
back to contents
Study
Code
Title
Coordinator
Activated
63/09
A randomized phase III, double-blind, placebocontrolled multicenter trial of daily everolimus in
combination with trastuzumab and vinorelbine, in
pretreated women with HER2/neu over-expressing
locally advanced or metastatic breast cancer
G. Bianchi
15/11
Phase
Total
patients
Patients
enrolled
in 2013
2010
III
8
Closed
accrual
The SERISCAFFOLD Use in reconstruction postM. Nava
market study for tissue support and repair in directto-implant breast reconstruction surgery
2011
Observational 4
Closed
accrual
43/07
A multinational double-blind, randomized phase
IIb cooperative group study evaluating the efficacy
and safety of sorafenib compared to placebo when
administered in combination with chemotherapy
and/or endocrine therapy in patients with locally
recurrent or metastatic Breast cancer
G. Mariani
2007
IIb
26
Closed
accrual
101/11
Effect of oral red clover on the symptoms of
menopausal syndrome induced by adjuvant
hormonal treatment in women with a diagnosis of
breast cancer
C. Ferraris
2012
IV
77
53
102/11
A randomized, two-arm, open label, multicenter
G. V. Bianchi
phase II trial assessing the efficacy and safety of
pertuzimab given in combination with trastuzumab
plus in aromatase inhibitor in first line patients with
HER 2-positive and hormone receptor-positive
advanced (metastastic and locally advanced) breast
cancer
2011
II
2
1
29/12
A phase III prospective, two-cohort nonrandomized, multi-centre, miltinational, open
label study to assess the safety of asisted-and
self-admnistered subcutaneous trastuzumab as
adjuvant therapy in patients with operable HER-2positive early breast cancer
2013
III
5
5
51/12
Identification of genes associated with toxicity from L. Lozza
radiation in breast cancer patients
2012
Observational 87
56
64/12
An open-label, multi-center, expanded access
study for postmenopausal women with estrogen
receptor positive locally advanced or metastatic
breast cancer who have progressed following prior
endocrine therapy, investigating the treatment
of everolimus (RAD001) in combination with
exemestane
G. Mariani
2012
III
32
69/12
NY-ESO1, MAGE-A3, PRAME and WT1 expression
in different groups of breast carcinoma
A. Tessari
2012
Observational 84
5
81/12
A randomized, blinded, single center study to
assess the incidence of surgical site infections
in breast cancer surgery after preoperative skin
preparation with chlorhexidine 2% in alcohol 70%
(CHLORAPREP ®) versus 10% povidone-iodine
M. Langer
2013
IV
757
757
92/12
A randomized trial comparing sentinel lymph node R. Agresti
biopsy vs no axillary surgical staging in patients with
small breast cancer and a negative preoperative
axillary assessment.
2013
-
35
35
186
G. Mariani
Closed
28/01/13
34
Study
Code
Title
Coordinator
Activated
109/12
SHARE - Cyberknife Partial Breast Irradiation for
Early Stage Breast Cancer. A phase I prospective
study
L. Lozza
111/12
Metabolic disorders and breast cancer
116/12
Phase
Total
patients
Patients
enrolled
in 2013
2013
I
15
15
R. Agresti
2012
Observational 1442
1284
Assessment of the performance of tomosynthesis
as diagnostic tool in adjunct to mammography in
women with dense breasts evaluated also with
breast ultrasound
C. Ferranti
2013
Observational 205
205
125/12
A multicenter, single arm study of trastuzumab
emtansine (T-DM1) in HER2 positive locally
advanced or metastatic breast cancer patients who
have received prior anti-HER2 and chemotherapybased treatment
G. V. Bianchi
2013
III
5
5
127/12
Impact of acellular dermal matrix in reduction of
surgical complexity of breast reconstructions with
implants
M. Nava
2013
IV
15
15
146/12
Pre-operative evaluation of distress thermometer in
breast cancer patients
R. Agresti
2013
Observational 1.000
1.000
148/12
Screening of women at high family-genetic risk of
P. Panizza
breast cancer with only MRI: prospective randomized
study with cost-effectiveness analysis (ISS-HIBCRIT3
– ISS High Breast Cancer Risk Italian Study n. 3)
2013
-
38
38
01/13
A phase II, open label, single arm trial of neoadjuvant S. Di Cosimo
therapy in patients with triple negative breast cancer
evaluating the efficacy of eribulin mesylate following
anthracycline and taxane and correlative science
studies attempting to identify predictors of response
2013
II
1
1
02/13
Circulating miRNAs as biomarkers predictive of
breast cancer relapse
M. G.
Daidone
2013
Observational 41
41
24/13
A multicenter, open-label, dose escalation, Phase
S. Cresta
I study of LJM716 administered intravenously in
combination with trastuzumab in patients with HER2
overexpressing metastatic breast cancer or gastric
cancer
2013
I
4
4
26/13
Neoadjuvant chemotherapy with nab-paclitaxel in
women with HER2-negative high-risk breast cancer
ETNA (Evaluating Treatment with naoadjuvant
Abraxane)
A. Moliterni
2013
III
1
1
39/13
Hepatic trans-arterial chemoembolization (TACE) in
metastatic breast cancer
S. Cresta
2013
49/13
Postmastectomy radiotherapy in reconstructed
L. Lozza
breast: evaluation of dose distribution in partially and
completed inflated tissue expanders
55/13
A randomized, multicenter, open-label phase
III study to evaluate the efficacy and safety of
trastuzumab emtansine versus trastuzumab as
adjuvant therapy for patients with HER2-positive
primary breast cancer who have residual tumor
present pathologically in the breast or axillary
lymph nodes following preoperative therapy
G. V. Bianchi
Closed
04/12/13
Observational 15
15
2013
-
5
5
2013
III
1
1
187
back to contents
Study
Code
Title
Coordinator
Activated
Closed
Phase
59/13
Expression of NY-ESO-1, PD1-L, miRNA profile in
triple negative metastatic breast cancer
S. Cresta
2013
28/06/13
Observational 32
32
60/13
Study of regional lymph node metastases in
breast cancer and comparison in terms of
predictive diagnostics between Positron Emission
Tomography with FluoroDeoxyGlucose (FDG-PET)
and sentinel lymph node biopsy identified with
lymphoscintigraphy and radio-guided surgery
R. Agresti
2013
15/09/13
Observational 145
145
66/13
Risk for breast cancer related lymphoedema after
selected axillary lymph node dissection in patients
with node positive breast cancer
M. Gennaro
2013
01/11/13
Observational 60
60
67/13
Risk for local relapses after breast conserving
surgery in patients with ductal carcinoma in situ of
the breast
M. Gennaro
2013
Observational 250
Closed
accrual
89/13
Analysis of MRI semeiotic patterns in hereditary
breast carcinoma
G. Trecate
2013
Observational 150
150
Randomized controlled trial of diet and physical
activity in carriers of BRCA mutation
P. Pasanisi
2013
-
20
106/13
01/09/13
Total
patients
20
Patients
enrolled
in 2013
111/13
Assessment of breast cancer progression risk based E. Tagliabue
on extracellular matrix characteristics
2013
Observational 200
200
115/13
Pilot study for the identification of miRNA
predictive of chemotherapy response with
gemcitabine in metastatic breast cancer
S. Cresta
2013
Observational 39
39
127/13
Long term results from INT-HER study:
retrospective evaluation of adjuvant trastuzumab
in unselected HER2 positive breast cancer patients.
Single institution experience
F. De Braud
2013
Observational 296
296
131/13
Role of extracellular matrix in breast cancer
response to chemotherapy
E. Tagliabue
2013
Observational 100
Closed
accrual
133/13
Analysis of MRI semeiotic patterns in invasive breast
carcinoma not combined with contrast uptake
G. Trecate
2013
Observational 16
16
165/13
Observational study to assess the impact of
hormonal treatment with aromatase inhibitors on
the psychological dimension of patients with breast
cancer
C. Borreani
2013
Observational 1
1
67/09
Multicenter, randomized, open label study evaluating A. Moliterni
a poly(AFP-ribosio) polymerase-1(PARP-1) inibitor,
SAR240550 (BSI-201), administered twice weekly or
weekly, in combination with gemcitabine/carboplatin,
in patients with Triple Negative breast Cancer
(mTNBC)
2010
18/03/13
II
8
Closed
accrual
05/10
A randomized, open label, phase II study to evaluate G. Mariani
the safety, tolerability and efficacy of trastuzumab
in combination with vinorelbine in patients with
metastatic HER-2 positive breast cancer who have
cardiovascular diseases
2010
31/01/13
II
1
1
188
31/12/13
15/12/13
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
35/10
Evaluation of [18F]FLT-PET/CT in early monitoring E.
of response to primary medical therapy in patients
Bombardieri
with breast cancer and as in vivo indicator of cellular
proliferation
2010
30/04/13
-
15
Closed
accrual
46/10
A multicenter, multinational phase II study
to assess the clinical safety and feasibility of
T-DM1 sequantially with anthracycline based
chemotherapy, as adjuvant or neoadjuvant therapy
for patients with early stage HER2-positive breast
cancer
2011
12/06/13
II
1
Closed
accrual
43/11
Dual ERbB1/ErbB2 Inhibitor lapatinib and or the
A. Moliterni
anti-diabetic biguanide metformin as treatment in
metastatic breast cancer ER+HER2- to modulate
the response after progression to first line hormonal
therapy
2011
04/12/13
II
10
3
86/11
An open label randomized phase 1b/2 study of PF04691502 in combination with letrozole compared
with letrozole alone in patients with estrogen
receptor positive, HER2 negative early breast
cancer
2011
15/07/13
I-II
3
Closed
accrual
93/11
An open-label, multicenter extension study of
G. V. Bianchi
trastuzumab- MCC-DM1 (T-DM1) administered
as a single agent or in combination with other anticancer therapies in patients previously treated with
the equivalent T-DM1 regimen in a Genentech and /
or F. Hoffmann-La Roche Ltd. - sponsored - T-DM1
study
2011
21/10/13
II
1
Closed
accrual
87/12
Adipose tissue derived mesenchymal stem cells:
immunophenotypic and functional characterization
M. Nava
2012
01/10/13
Observational 60
Closed
accrual
89/12
Recent trends in axillary and sentinel lymph node
dissection practices among breast cancer patients–
an international comparison
M. Sant
2012
30/06/13
Observational 1421
658
G. Bianchi
S. Cresta
GASTROINTESTINAL CANCERS
28/04
Open label randomized, multicenter phase III
study of adjuvant chemotherapy in radically
resected adenocarcinoma of the stomach or
gastroesophageal junction: comparison of
sequential treatment (CPT11 + 5-FU/LV TXT +
CDDP versus a 5-FU/LV regimen)
M. Di
Bartolomeo
2005
21/01/13
III
71
Closed
accrual
54/06
Phase III, randomised, double-blind, stratified,
comparative, placebo controlled, parallel group,
multicentre study to assess the effect of deep
subcutaneous injections of lanreotide autogel
120 mg administered every 28 days on tumour
progression free survival in patients with non
functioning entero-pancreatic endocrine tumour.
R. Buzzoni
2006
19/09/13
III
1
Closed
accrual
25/07
A study of the genetic polymorphisms of patients
with gastrointestinal stromal tumors (GIST) and of
their predictive value of clinical activity of tyrosin
kinase inhibitors
P. Casali
2007
30/01/13
Observational 36
Closed
accrual
189
back to contents
Study
Code
Title
Coordinator
Activated
Closed
Phase
32/07
The Global Observational registry colllecting
Longitudinal Data on Advanced GIST patients
(GOLD reGISTry)
P. Casali
2007
25/02/13
Observational 54
Closed
accrual
69/07
A double-blind, randomised, multicenter, phase
III study of bevacizumab in combination with
capecitabine and cisplatin versus placebo in
combination with capecitabine and cisplatin, as firstline therapy in patients with advanced gastric cancer
M. Di
Bartolomeo
2007
22/01/13
III
9
Closed
accrual
17/04
A phase II, open label study of PTK787/ZK222584 in P. Casali
the treatment of metastatic Gastrointestinal Stromal
Tumors (GISTs) resistant to imatinib mesylate
2005
II
22
Closed
accrual
75/06
A prospective randomized, open-label trial
comparing Sirolimus-containing versus mTOR
-inhibitor-free immunosuppression in patients
undergoing liver transplantation for hepatocellular
carcinoma.
V.
Mazzaferro
2006
II
39
Closed
accrual
09/07
LIVER MATCH. An Italian multicentric study to
evaluate the impact of donor-recipient matching
in the outcome of liver transplantation at short,
medium and long term
E. Regalia
2007
-
54
Closed
accrual
08/08
Accrual of patients with colorectal cancer and of
healthy sisters/brothers for studies on genetic risk
factors
T. Dragani
2008
-
1258
106
52/07
A randomized trial investigating the role of
FOLFOX-4 regimen duration (3 versus 6 months)
and bevacizumab as adjuvant therapy for patients
with stage II/III colon cancer
M. Di
Bartolomeo
2007
III
131
Closed
accrual
27/08
Perioperative treatment with COI-E (capecetabine,
oxaliplatin, irinotecan and cetuximab) of liver
metastasis of colorectal carcinoma potentially
resectable although at high risk of recurrences
R. Buzzoni
2008
II
34
6
38/08
A phase III randomized, double-blind, placebocontrolled study of sorafenib as adjuvant treatment
for hepatocellular carcinoma after surgical
resection or local ablation (STORM)
V.
Mazzaferro
2008
III
46
Closed
accrual
01/09
Open label extension study of lanreotide autogel
120 mg in patients with non functioning enteropancreatic endocrine tumour
R. Buzzoni
2009
III
1
Closed
accrual
21/09
A randomized, open-label, multicenter phase III
study to evaluate the efficacy and safety of nilotinib
versus imatinib in adult patients with unresectable
or metastatic gastrointestinal stromal tumors
P. Casali
2009
III
1
Closed
accrual
12/09
Capecetabine in combination with oxaliplatin,
irinotecan and bevacizumab (COI-B regime) as first.
line therapy for metastatic colorectal cancer: a
phase II ITMO study
M. Di
Bartolomeo
2009
26/06/13
II
33
Closed
accrual
24/09
A randomized, double-blind, multicenter phase III
study of brivanib plus best supportive care (BSC)
versus placebo plus BSC in subjects with advanced
hepatocellular carcinoma (HCC) who have failed or
are intolerant to sorafenib
V.
Mazzaferro
2009
17/05/13
III
6
Closed
accrual
190
15/10/13
Total
patients
Patients
enrolled
in 2013
Study
Code
Title
Coordinator
Activated
79/09
Observational study of plasma levels of Imatinib in
patients with gastrointestinal stromal tumor
P. Casali
2010
Observational 80
7
80/09
Controlled extension of conventional criteria for
liver tranplantation in hepatocellular carcinoma
(HCC): a prospective validation study
V.
Mazzaferro
2009
II
32
7
21/10
A phase II, open label study to evaluate the activity
and safety of Everolimus in association to Imatinib
in PDGFRA-D842V unresectable or metastatic
gastrointestinal stromal tumours (GISTs) as first line
treatment
P. Casali
2010
II
5
2
80/10
A randomized, double-blind, placebo-controlled
P. Casali
phase III of regorafenib plus best supportive care
versus placebo plus best supportive care for subjects
with metastatic and/or unresectable gastrointestinal
stromal tumors (GIST) whose disease has progressed
despite prior treatment with at least imatinib and
sunitinib
2011
III
10
Closed
accrual
14/11
ITACA-S- 2 (Intergroup trial in adjuvant
R. Buzzoni
chemotherapy for adenocarcinoma of the stomach)
comparison of the efficacy of a peri-operative versus
a post-operative chemotherapy treatment in patients
with operable gastriic cancer and assessment of the
benefit op a post-operative chemo-radiotherapy
2011
III
1
Closed
accrual
30/11
Phase 2 placebo-controlled double-blind trial of
dasatinib added to gemcitabinae for subjects with
locally-advanced pancreatic cancer
R. Buzzoni
2011
II
5
Closed
accrual
75/11
DOVIGIST: Phase II trial to evaluate the efficacy
and safety of Dovitinib (TKI258) in patients with
gastrointestinal stromal tumors refractory and/or
intolerant to imatinib
P. Casali
2011
II
3
Closed
accrual
85/11
Phase I dose escalation study of S. 78454 (HDACi)
in combination with FOLFOX in patients with locally
advanced or metastatic digestive cancer
F. de Braud
2011
I
8
2
94/11
Evaluation of diagnostic accuracy of diffusionweighted magnetic resonance (DW-MRI) and
perfusion magnetic resonance (DCE-MRI) in the
dilation of mesorectal lymph nodes in colorectal
cancer
D.
Scaramuzza
2011
Observational 32
0
A randomized, open-label, multicenter phase IIIb
M. Di
study comparing two trastuzumab dosing regimens, Bartolomeo
each in combination with cisplatin/capecitabine
chemotherapy, as first-line therapy in patients
with HER 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma who have not
received prior treatment for metastatic disease
2011
III
7
1
Efficacy of tandem treatment with [90Y-DOTA,
E. Seregni
Tyr(3)] Octreotate and [177LuDOTA, Tyr(3)]
Octreotate in patients with neuroendocrine
tumour overexpressing somatostatin receptors and
refractory to conventional therapy
2012
II
52
28
100/11
06/12
Closed
Phase
Total
patients
Patients
enrolled
in 2013
191
back to contents
Study
Code
Title
Coordinator
Activated
15/12
Pseudomixoma peritonei: prognostic analysis of
micro-RNA and other factors using tissue
M. Deraco
2012
Observational 24
11
16/12
Multicenter Italian study on the CEUS assessment
R. Lanocita
of Response of colorectal cancer metastasis Treated
with Avastin
2012
IV
2
0
22/12
A randomized, double-blind, multicenter, Phase III
study of everolimus (RAD001) plus best supportive
care versus placebo plus best supportive care in the
treatment of patients with advanced NET of GI or
lung origin - RADIANT-4
R. Buzzoni
2012
III
23
Closed
accrual
31/12
Peritoneal Mesothelioma: Optimize Outcomes
by the Integration of new Prognostic Factors and
Potential Therapeutic Targets in a Individualized
Treatment based on Molecular Characterization
and Chemosensitivity Profile on Primary Cultures
M. Deraco
2012
II
16
12
42/12
A multi-center, open-label study to assess
F. de Braud
pharmacokinetics of TKI258 in adult cancer
patients with normal and impaired hepatic function
2012
I
8
2
60/12
"A Randomized, Open-label, Two-Arm Phase II Trial
Comparing the Efficacy of Sequential Ipilimumab
versus Best Supportive Care Following First-line
Chemotherapy in Subjects with Unresectable
Locally Advanced/Metastatic Gastric or GastroEsophageal Junction Cancer”
Maria Di
Bartolomeo
2012
II
16
8
73/12
Identification of circulating tumor cells in blood
of patients with advanced colorectal cancer and
assessment of their modifications during treatment
with cetuximab or panitumumab, alone or
associated with chemotherapy
F. de Braud
2012
Observational 52
25
74/12
A Multicenter, Single arm, Open Label Clinical Trial
to Evaluate the Safety and Health-Related Quality
of Life of Aflibercept in Patients with Metastatic
Colorectal Cancer (mCRC) Previously Treated with
an Oxaliplatin-Containing Regimen
Maria Di
Bartolomeo
2012
III
15
Closed
Accrual
97/12
A randomized, phase III, multicenter, doubleblid, placebo-controlled study evaluating the
efficacy and safety of onartuzumab (MetMab) in
combination with metastatic HER2 negative, METPositive Gastriesophageal cancer
Maria Di
Bartolomeo
2012
III
18
17
99/12
An open-label phase IIIb study of regorafenib in
patients with metastatic colorectal cancer (CRC)
who have progressed after standard therapy
M. Di
Bartolomeo
2013
III
15
Closed
accrual
A multicenter, two stage, phase II study, evaluating
the efficacy of oral BEZ235 plus best supportive
care (BSC) versus placebo plus BSC in the
treatment of patients with advanced pancreatic
neuroendocrine tumors (pNET) after failure of
mTOR inhibitor therapy
R. Buzzoni
2013
II
6
Closed
accrual
102/12
192
Closed
Phase
Total
patients
Patients
enrolled
in 2013
Study
Code
107/12
Title
Coordinator
Activated
Randomized, couble-blind, phase 3 study of TAS102 plus best supportive care (BSC) versus placebo
plus BSC in patients with metastatic colorectal
cancer refractory to standard chemotherapies
M. Di
Bartolomeo
Closed
Phase
Total
patients
Patients
enrolled
in 2013
2013
III
9
Closed
accrual
117/12
Identification of circulating biomarkers of resistance F. de Braud
to antiangiogenic treatment in patients with
advanced colorectal cancer and assessment of their
modification during therapy with antiangiogenic
drugs (bevacizumab, aflibercept and regorafenib)
2012
Observational 56
55
139/12
A phase II, multicenter, open-label, randomized
study evaluating the efficacy and safety of Folfiri +
MEHD7945A versus Folfiri + Cetuximab in second
line in patients with KRAS Wild type metastatic
colorectal cancer
M. Di
Bartolomeo
2013
II
Closed
accrual
149/12
The EGF rs4444903 AG polymorphism in
relationship to detection rate and tumour size at
diagnosis in patients undergoing surveillance for
HCC and to HCC doubling time
V.
Mazzaferro
2013
03/13
Identification of Genetic Circulating Biomarkers for
the Early Diagnosis of Colorectal Cancer
07/13
Observational 58
58
M. A. Pierotti 2013
Observational 115
115
A Phase III, Randomized, Double-Blind Study
of Tivantinib (ARQ 197) in Subjects with MET
Diagnostic-High Inoperable Hepatocellular
Carcinoma (HCC) Treated with One Prior Systemic
Therapy
V.
Mazzaferro
2013
III
9
9
35/13
Prospective randomized phase II trial comparing
mandatory second-look surgery with hyperthermic
intraperitoneal chemotherapy (HIPEC) and
cytoreductive surgery, vs. standard postoperative
follow-up in patients at high risk of developing
colorectal cancer peritoneal metastases
D. Baratti
2013
-
3
3
36/13
Identification of Genetic Circulating Biomarkers
for monitoring and early detection of recurrence in
surgically treated colorectal Cancer patients.
M. Gariboldi
2013
Observational 65
65
50/13
Perioperative treatment with COI-B (Capecitabine,
Oxaliplatin, Irinotecan and Bevacizumab) of high
risk or borderline resectable colorectal cancer liver
metastases
F. De Braud
2013
II
7
7
79/13
A multicenter, stratified, open, randomized,
E. Seregni
comparator-controlled, parallelgroup phase III
study comparing treatment with 177Lu-DOTA0Tyr3-Octreotate to Octreotide LAR in patients with
inoperable, progressive, somatostatin receptor
positive midgut carcinoid tumours
2013
III
1
1
87/13
Retrospective-prospective observational study
on the natural history of brain metastases from
colorectal cancer
F. De Braud
2013
Observational 39
39
IL-6-related inflammation signatures as a predictive
marker of recurrence in liver cancer patients
V.
Mazzaferro
2013
Observational 30
30
110/13
01/07/13
4
193
back to contents
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
126/13
Prospective observational study on the impact
of genetic polymorphisms on the occurrence of
chemotherapy-induced toxicity in gastrointestinal
epithelial neoplasms
F. De Braud
2013
Observational 9
9
137/13
A Single-Arm, Open Label Study of Aflibercept as
Maintenance Therapy Following Induction with
Aflibercept in Combination with XELOX, as FirstLine Treatment for Metastatic Colorectal Cancer
Patient
M. Di
Bartolomeo
2013
I-II
2
2
141/13
"A prospective, single-arm, multicenter,
uncontrolled, open-label Phase II trial of refametinib
(BAY 86-9766) in patients with RAS mutant
Hepatocellular Carcinoma
141/13
A prospective, single-arm, multicenter, uncontrolled, V.
open-label Phase II trial of refametinib (BAY 86Mazzaferro
9766) in patients with RAS mutant Hepatocellular
Carcinoma (HCC)
2013
II
8
8
159/13
DNA-seq analysis for prediction of outcome to first
line irinotecan versus oxaliplatin-based regimens
in advanced colorectal cancer patients enrolled in a
randomized phase II, prospective study
M. Gariboldi
2013
Observational 43
43
61/09
An uncontrolled open label multicenter phase
II safety study of BAY73-4506 in patients with
hepatocellular carcinoma (HCC)
V.
Mazzaferro
2010
09/07/13
II
2
Closed
accrual
64/10
The role of natural fluorescence of plasma in
colorectal cancer patients
E. Leo
2010
30/04/13
-
200
Closed
accrual
14/12
Post-traumatic growth and psycho-social
adaptation in patients submitted to liver transplant
C. Borreani
2012
12/11/13
Observational 233
10
44/09
A randomized, double-blind, placebo-controlled,
F. Raspagliesi 2009
phase 3 study to assess the efficacy and safety of
weekly farletuzumab (MORAb-003) in combination
with carboplatin and taxane in subjects with
platinum-sensitive ovarian cancer in first relapsed
10/01/13
III
3
Closed
accrual
46/07
Prostate cancer research international: active
surveillance (PRIAS)
R. Valdagni
2007
-
327
50
54/07
Identification of Men with a genetic predisposition
to Prostate Cancer: Target Screening in BRCA1/2
mutation carriers and controls - the IMPACTstudy
N. Nicolai
2008
-
16
5
10/09
Carboplatin and Paclitaxel administered every three F. Raspagliesi 2009
weeks vs Carboplatin and Paclitaxel administered
weekly to patients with ovary carcinoma:
multicentric randomized study
III
39
Closed
accrual
65/09
LION - Lymphadenectomy in ovarian neoplasm. An
open randomized prospective multicenter trial. A
project of the AGO Study Group
-
32
Closed
accrual
GENITAL APPARATUS
194
F. Raspagliesi 2010
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
68/09
A multi-centre, open-label, randomised, two arm
F. Raspagliesi 2010
phase III trial of bevacizumab plus chemotherapy
versus chemotherapy alone in patients with
platinum-resistant, epithelial ovarian, fallopian tube
or primary peritoneal cancer
III
3
Closed
accrual
71/09
A phase III study to evaluate the efficacy and
safety of pazopanib monotherapy versus placebo
in women who have not progressed after first line
chemotherapy for epithelial ovarian, fallopian tube,
or primary peritoneal cancer
F. Raspagliesi 2010
III
2
Closed
accrual
22/10
An open label, phase II study of vaccination with
surviving peptides emulsified in Montanide ISA
51VG after IMP 321TM injection in prostate
carcinoma patients with biochemical failure
L. Rivoltini
2010
II
26
Closed
accrual
38/10
Tandem transplantation of autologous
hematopoietic progenitors in relapsed/refractory
patients with metastatic germinal tumors
R. Salvioni
2010
II
44
15
50/10
Multicentric observational study DUE-01: urinary
S. Villa
and erectile dysfunction after radical external beam
therapy in localized prostate cancer
2010
Observational 148
47
03/11
A phase III, randomized, double-blind trial of weekly F. Raspagliesi 2011
paclitaxel plus AMG386 or placebo in women with
recurrent partially platinum sensitive or resistant
epithelial ovarian, primary peritoneal or fallopian
tube cancers
III
Closed
accrual
11/11
Breathing analysis by electronic nose for detection
of ovarian cancer in general population and in
population at risk
F. Raspagliesi 2011
Observational 159
29
61/11
Randomized multicentric study comparing the
efficacy of additional cytoreductive surgery vs
exclusive chemotherapy in patients with platinumsensitive recurrent ovarian cancer
F. Raspagliesi 2011
IV
7
5
63/11
NGR018: randomized phase II study of NGR-hTNF
plus pegylated liposomial doxorubicin (PLD) versus
PLD in platinum-resistant ovarian cancer
F. Raspagliesi 2011
II
33
Closed
accrual
87/11
A Randomized phase III study comparing stabdard
first-line docetaxel prednisone to docetaxel
prednisone in combination with custirsen (CGX011) in men with metastatic castrate resistant
prostate cancer
G. Procopio
2011
III
5
Closed
accrual
95/11
Active surveillance “SA INT” in prostate cancer
patients with low progression risk
R. Valdagni
2011
Observational 40
20
105/11
A randomized controlled study on the effectiveness
of first-line chemotherapy (carboplatin and
paclitaxel) versus chemo-immunotherapy
(carboplatin-paclitaxel-oregovomab) in patients
with advanced epithelial ovarian, adnexal or
peritoneal carcinoma
F. Raspagliesi 2011
II
11
0
106/11
A randomized phase II study of carboplatin and
paclitaxel +/- cetuximab, in advanced and/or
recurrent cervical cancer
F. Raspagliesi 2011
II
13
3
12
195
back to contents
Study
Code
Title
Coordinator
Activated
107/11
Phase III International Multicenter Randomized
Study Testing the Effect on Survival of Prolonging
Platinum-free Interval in Patients With Ovarian
Cancer Recurring Between 6 and 12 Months After
Previous Platinum Based Chemotherapy
F. Raspagliesi 2013
108/11
Randomized multicentric phase II study with weekly D. Lorusso
pazopanib plus taxolo versus weekly taxolo alone in
platinum-resistant or refractory ovarian carcinoma
2011
67/10
A prospective evaluation of plasma levels of
R. Valdagni
inflammatory markers in radiotherapy treatment of
prostate cancer and relationship with acute and late
rectal toxicity
2010
02/12
A phase III randomized, double-blind, placebocontrolled, multi-center study of AMG 386 with
paclitaxel and carboplatin as first-line treatment of
subjects with FIGO stage III-IV epithelial ovarian,
primary peritoneal or fallopian tube cancers
18/12
Closed
Phase
Total
patients
Patients
enrolled
in 2013
III
8
8
II
16
10
Observational 25
Closed
accrual
III
11
3
A randomized phase II trial of carboplatin-paclitaxel F. Raspagliesi 2012
compared to carbplatin-paclitaxel-bevacizumab in
advanced (stage III-IV) or recurrent endometrial
cancer
II
21
16
19/12
A phase II randomized Open label study of MM-121 F. Raspagliesi 2012
in combination with paclitaxel versus paclitaxel
alone in patients with platinum resistant/refractory
advanced ovarian cancer
II
11
5
20/12
F. Raspagliesi 2012
Phase II study of trabectedi (Yondelis) in BRCA1 e
BRCA2 mutation carrier and BRCA ness phemotype
advanced ovarian cancer patients
II
18
9
32/12
A phase II, open-lebal, singlie-arm, non randomized,
multicenter study to evaluate the efficacy of oral
TK258 as second-line therapy in patients with
either FGFR2 mutated or wild-type advanced and/
or metastatic endometrial cancer
F. Raspagliesi 2012
II
10
5
33/12
Study of circulanting biological factors in
gynecological cancer (ovary, uterine cervix,
endometrium)
F. Raspagliesi 2012
Observational 29
1
50/12
Does Palliative Chemotherapy Improve Symptoms
in Women with Recurrent Ovarian Cancer?
Measuring subjective improvement as well as
objective response to estimate the benefit of
palliative chemotherapy in women with platinum
resistant or refractory ovarian cancer
F. Raspagliesi 2013
Observational 27
27
68/12
Rare tumors in gynecologic oncology: retrospective
and prospective collection data on diagnosis and
treatment of rare gynecologic neoplasia
D. Lorusso
2012
Observational 281
100
70/12
Evaluation of the geriatric care needs and pathways R. Valdagni
after initial treatment in elderly patients with
urogenital cancer (prostate, kidney, bladder and
penis)
2012
Observational 78
70
196
F. Raspagliesi 2012
03/10/13
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
110/12
Phase II study of the Pan-HER inhibitor Dacomitinib A. Necchi
(PF-00299804) for patients with locally advanced
or metastatic squamous cell carcinoma of the penis
2013
II
1
1
123/12
Phase II study of single-agent Pazopanib (Votrient®) A. Necchi
for patients with relapsed or refractory germ-cell
tumors (GCT)
2013
II
13
13
124/12
Radium-223 Chloride (Alpharadin) in Castrationresistant (Hormone-Refractory) Prostate Cancer
Patients with Bone Metastasis
G. Procopio
2013
III
7
Closed
accrual
126/12
A multicenter study in patients with stage III-IV
epithelial ovarian cancer treated with carboplatin/
paclitaxel with bevacizumab: clinical and biological
prognostic factors
D. Lorusso
2013
IV
52
52
12/13
NGR018: Randomized phase II study of NGR-hTNF
plus an anthracycline versus an anthracycline alone
in platinum-resistant ovarian cancer
F. Raspagliesi 2013
II
12
Closed
accrual
25/13
A Phase 3, Randomized, Double-Blind Trial of
Pegylated Liposomal Doxorubicin (PLD) Plus AMG
386 or Placebo in Women With Recurrent Partially
Platinum Sensitive or Resistant Epithelial Ovarian,
Primary Peritoneal, or Fallopian Tube Cancer
F. Raspagliesi 2013
III
14
Closed
accrual
30/13
A. Necchi
Brentuximab vedotin (SGN-35) as salvage therapy
for males with advanced and platinum-resistant
germ-cell tumors. An open label, single group, phase
2 trial
2013
II
2
2
33/13
External radiotherapy for intermediate or high risk
prostate cancer: Irradiation of the pelvis and boost
to the prostate in two 9 Gy fractions
S. Villa
2013
-
3
3
82/13
A Double-blind, Placebo-controlled, Randomized,
Phase 2 Study to Evaluate the Efficacy and Safety
of Maintenance Therapy With PankoMab-GEX™
After Chemotherapy in Patients With Recurrent
Epithelial Ovarian Carcinoma
F. Raspagliesi 2013
II
3
3
101/13
Pertuzumab in Platinum-resistant low HER3
mRNA epithelial ovarian cancer (Pertuzumab nel
carcinoma ovarico epiteliale a bassa espressione di
mRNA di HER3, resistente al platino)
D. Lorusso
2013
III
5
5
17/11
An open-label study of abiraterone acetate in
subjects with metastatic castration-resistant
prostate cancer who have progressed after taxanebased chemotherapy
G. Procopio
2011
13/12/13
III
37
Closed
accrual
22/11
Multicentre, single-arm, open label, clinical trial
G. Procopio
intended to provide early access to cabazitaxel
in patients with metastatic hormone refractory
prostate cancer previously treated with a docetaxelcontaining regimen and to document safety of
cabzitaxel in these patients
2011
04/07/13
III
6
Closed
accrual
197
back to contents
Study
Code
96/11
111/11
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
Evaluation of a software allowing fusion of prostate
magnetic resonance and transrectal ultrasound
images
C. Fallai
2011
31/12/13
Observational 16
8
Registry of treatment patterns in patients with
metastatic castration-resistant prostate cancer
(mCRPC) with progression during or after
docetaxel-based regimen
G. Procopio
2011
18/03/13
Observational 43
17
HEAD & NECK AND THYROID TUMORS
04/09
Phase II, multicenter, open-labe, single arm trial to
evaluate the safety and efficacy of oral E7080 in
medullary and iodine-131 refractory, unresectable
differentiated thyroid cancers, stratified by
histology
L. Licitra
2009
II
11
Closed
accrual
05/09
An internationall, randomized, double-blinded,
phase 3 efficacy study of XL184 versus placebo in
subjects with unresectable, locally advanced, or
metastatic medullary thyroid cancer
L. Licitra
2009
III
9
Closed
accrual
29/10
Sorafenib in recurrent and/or metastatic salivary
gland carcinomas
L. Locati
2010
II
37
Closed
accrual
40/10
Phase II study of preoperative TPF chemotherapy
in locally advanced resectable oral cavity squamous
cell cancer in order to improve the rate of
pathological complete response
L. Licitra
2010
II
9
2
65/10
A double-blind, randomized phase III study
L. Licitra
evalutating the efficacy and safety of Sorafenib
compared to placebo in locally advanced/metastatic
RAI-refractory differentiated thyroid cancer
2011
III
5
Closed
accrual
07/11
A randomized, international, open-label. Multicentre, phase III study to assess the effect of a
patient outreach program on the percentage of
time patients with locally advanced or metastatic
medullary thyroid cancer experience grade 2 or
higher adverse events during the first 12 months of
treatment with vandetannib
L. Licitra
2011
III
8
Closed
accrual
35/11
Cetuximab and Cisplatin with or without Paclitaxel
in recurrent/metastatic head and neck cancer
L. Licitra
2012
II
13
8
44/11
Randomized, double-blind, multicenter twostage adaptive phase 3 study of intravenous
adnìministration of REOLYSIN (Reovirus type
3 dearing) in combination with paclitaxel and
carboplatin versus the chemotherapy alone in
patients with metastatic or recurrent squamous
cell carcinoma of the head and neck who have
progressed on or after prior platinum-based
chemotherapy
L. Licitra
2011
III
9
Closed
accrual
198
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
45/11
A single arm, open-label, phase II, multicentre study, L. Licitra
to assess the safety of vismodegib (GDC-0449) in
patients with locally advanced or metastatic basal
cell carcinoma
2011
II
34
8
57/11
A randomised, double-blind, placebo-controlled,
L. Licitra
of afatinib (BIBW 2992) as adjuvant therapy after
chemo-radiotherapy in primary unresected patients
with stage III, IVa, or IVb loco-regionally advanced
head and neck squamous cell carcinoma
2011
III
3
2
68/11
A randomised, open.label, phase III study to
L. Licitra
evaluate the efficacy and safety of oral afatinib
(BIBW 2992) versus intravenous methotrexate in
patients with recurrent and/or metastatic head and
neck squamous cell carcinoma who have progressed
after platinum-based therapy
2011
III
24
18
69/11
A phase 2, multi-center, randomized, double-blind,
placebo-controlled clinical trial to evaluate the
safety and efficacy of ALD518 in the reduction
of oral receiving concomitant chemotherapy and
radiotherapy
L. Licitra
2011
II
17
3
70/11
An open -label, multi-center phase II study of
the BRAF inhibitor RO5185426 in patients with
metastatic or unresectable papillary thyroid cancer
(PTC) positive for the BRAF V600 mutation and
resistant to radioactive iodine
L. Licitra
2011
II
1
Closed
accrual
71/11
A multicentre, randomized, double-blind,
placebo-controlled, phase III trialof E7080 in
131I-Refractory differentiated thyroid cancer
L. Licitra
2011
III
15
Closed
accrual
91/11
Radioiodine therapy of differentiated thyroid
carcinoma with maximized activity based on
individualized dosimetry
E. Seregni
2011
II
8
1
35/12
An international, randomized, double-blind,
two-arm study to evaluate the safety and efficacy
of vandetanib 150 and 300 mg/day in patients
with unresecable locally advanced or metastatic
medullary thyroid carcinoma with progressive or
symptomatic disease
L. Licitra
2012
IV
13
Closed
accrual
36/12
Continuing access ti the tyrosine kinase inhibitor of
vegfr-2, ag-013736 (A406) for patienys previously
receiving ag-013736 in clinical trias
L. Licitra
2012
III
1
Closed
accrual
44/12
TP53 as a biomarker to personalize chemotherapy
for patients with head and neck cancer
P. Bossi
2012
Observational 8
0
76/12
Neoadjuvant afatinib based treatment strategies
L. Licitra
followed by surgery in squamous cell carcinoma of
the head and neck: an EORTC NOCI-HNCG window
study
2012
II
7
8
199
back to contents
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
29/13
Multidisciplinary approach for poor prognosis
sinonasal tumors: Phase II study of chemotherapy,
photon and heavy ion radiotherapy integration
for more effective and less toxic treatment in
inoperable patients.
L. Licitra
2013
II
4
4
37/13
Retrospective study on first line treatments in
patients with recurrent and/or metastatic head
and neck squamous cell carcinomas: dose intensity,
toxicity, combinations used
P. Bossi
2013
04/12/13
Observational 70
70
38/13
Cross-sectional study for the evaluation of
P. Bossi
dysphagia and aspiration caused by IMRT +
chemotherapy in oropharyngeal tumors oropharynx
2013
01/10/13
Observational 110
110
69/13
INduction chemoThERapy followed by CEtuximab
Plus definiTive radiOtheRapy versus radiation plus
cisplatin
L. Licitra
2013
III
1
88/13
Linguistic validation of quality of life questionnaire
MDASI-HN
P. Bossi
2013
92/13
"A Randomised, Double-Blind, Placebo-Controlled,
Multi-Centre Phase III Study to Assess the Efficacy
and Safety of Vandetanib (CAPRELSA™) 300 mg
in Patients with Papillary or Poorly Differentiated
Thyroid Cancer That Is Either Locally Advanced or
Metastatic Who Are Refractory or Unsuitable for
Radioiodine (RAI) Therapy”
L. Licitra
112/13
Development of an EORTC questionnaire for
the assessment of quality of life in thyroid cancer
patients (EORTC QLQ-THY) Phase I / II
L. Locati
2013
Observational 18
121/13
"Phase II multicenter randomized, double blind,
L. Licitra
placebo controlled study assessing the efficacy of
buparlisib (BKM120) plus paclitaxel vs. placebo
plus paclitaxel in patients with platinum pre-treated
recurrent or metastatic head and neck squamous
cell carcinoma”
2013
II
1
1
15/11/13
Observational 56
56
2013
III
3
3
Closed
accrual
HEMATOLOGIC MALIGNANCIES
34/05
Multicentric randomized phase III study that
A. M. Gianni,
compares high-dose chemotherapy with rituximab P. Corradini
and autotransplantation of circulating hemopoietic
precursors with CHOP with rituximab administered
every 14 days as first-line therapy for patients at
high risk with large B-cell non-Hodgkin’s lymphoma
2005
31/07/13
III
40
Closed
accrual
44/06
Intensive chemo-immunotherapy as first-line in
adult patients with peripheral T-cell Lymphoma
P. Corradini
2006
31/01/13
II
15
Closed
accrual
59/09
Phase I/II of desamethasone, ofatumumab and
bendamustine (TREANDA) (DOT) as first-line
treatment of mantle-cell lymphoma (MCL) in the
elderly
A. M. Gianni
2009
27/08/13
I-II
13
Closed
accrual
200
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
32/04
Prospective observational study in the adult with
Burkitt’s lymphoma of a polychemotherapy scheme
in use in pediatrics
A. M. Gianni,
M. Di Nicola
2004
Observational 21
3
02/05
A multicenter, open label study of oral melphalan,
P. Corradini
and CC-5013 (Revlimid) (MPR) as induction therapy
in elderly newly diagnosed multiple mieloma
patients
2005
I-II
4
Closed
accrual
12/06
A phase II, multicenter study of bortezomib,
pegylated liposomal doxorubicin, dexamethasone
(PAD) as induction and melphalan 100 mg/m2
(MEL 100) as transplant, in elderly newly diagnosed
multiple myeloma patients
P. Corradini
2006
II
12
Closed
accrual
13/06
A phase III, multicenter, randomized open label
study of velcade, melphalan, prednisone and
thalidomide (V-MPT) versus velcade, melphalan,
prednisone (V-MP) in elderly untreated multiple
myeloma patients
P. Corradini
2006
III
9
Closed
accrual
14/06
A phase 3, prospective, randomized clinical study
with velcade-thalidomide-dexamethasone versus
thalidomide-dexamethasone for previously
untreated patients with symptomatic multiple
myeloma who are candidates to receive double
autologous transplantation
P. Corradini
2006
III
13
Closed
accrual
28/06
Zevalin at myeloablative doses in aggressive
lymphomas of elderly patients
P. Corradini
2006
III
4
Closed
accrual
50/06
A phase II, multicenter study of meplphalan 100
mg/m2 (MEL 100) as transplant, Revlimid and
Prednisone (RP) as consolidation and Revlimid
alone as maintenance in elderly newly diagnosed
multiple myeloma patients.
P. Corradini
2006
II
12
Closed
accrual
67/06
A phase II, multi-center, randomized, open label
P. Corradini
study of Velcade, Doxorubicin and Dexamethasone
(PAD) vs Thalidomide and Dexamethasone (TD) in
advanced and refractory multiple myeloma patients.
2007
II
3
Closed
accrual
38/07
A multicentric randomized trial in adult patients
P. Corradini
with acute myelogenous leukemia (AML) to
compare: 1) a standard-dose versus high-dose
remission induction regimen, and 2) an autologous
blood stem cell transplantation versus an
autologous blood cell-supported multicycle highdose chemotherapy program,, within a risk-oriented
postremission strategy reserving allogeneic stem
cell transplantation for high-risk cases
2007
III
11
Closed
accrual
48/07
Reduced intensity conditioning with high-dose
rituximan followed by allogeneic transplantation of
hematopoietic cells for the treatment of relapsed/
refractory B-cell non Hodgkin's lymphomas
P. Corradini
2007
II
20
4
55/07
Treatment with imatinib mesylate (Glivec) of severe P. Corradini
chronic scleroderma-like GVHD, refractory to
conventional immunosuppressive therapy
2008
II
8
Closed
accrual
201
back to contents
Study
Code
Title
Coordinator
Activated
63/07
Lombardy registry of HCV positive lymphomas
P. Corradini
2008
Observational 7
Closed
accrual
02/08
A phase 3, multicentre, randomized, controlled
A.M. Gianni,
study to determine the efficacy and safety of
P. Corradini
lenalidomide, melphalan and prednisone (MPR)
versus melphalan (200 mg/m2) followed by stem
cell transplant in newly diagnosed multiple myeloma
subjects
2008
III
16
Closed
accrual
34/08
Randomized study comparing intravenous busulfan
(i.v. BU;Bulsivex) plus fludarabine (BUFLU) versus
intravenous busulfanplus Cyclophosphamide
(BUCY2) as conditioning regimes prior to
allogenic hematopoietic stem cell transplantation
(ALLOHSCT) in patients (aged >=40 and <=55
years) with acute myeloid leukemia (AML) in
complete remission (CR)
P. Corradini
2008
III
4
Closed
accrual
49/08
Multicentre clinical study with early treatment
intensification in patients with high-risk Hodgkin
lymphoma, identified as FDG-PET scan positive
after two conventional BVD courses
A. M. Gianni,
P. Corradini
2008
II
49
14
09/09
Phase III study comparing rituximab-supplemented A. M. Gianni,
ABVD (R-ABVD) with ABVD followed by involved- P. Corradini
field radiotherapy (ABVD-RT) in limited-stage (stage
I-IIA with no areas of bulk) Hodgkin's lymphoma
2009
III
12
2
13/09
Safety and efficacy of lenalidomide as main
therapy in patients with newly diagnosed multiple
myeloma following a tandem autologous-allogeneic
transplant
P. Corradini
2009
II
1
0
39/09
A phase 3 intergroup multicentre, randomized,
controlled 3 arm parallel group study to determine
the efficacy and safety of lenalidomide in
combination with dexamethasone (Rd9 versus
melphalan, prednisone and lenalidomide (MPR)
versus cyclophosphamide, prednisone and
lenalidomide (CPR) in newly diagnosed multiple
myeloma subjects
P. Corradini
2009
III
16
Closed
accrual
46/09
A phase 3, multicentre, randomized, controlled
study to determine the efficacy amd safety
of ciclophosphamide, lenalidomide and
dexamethasone (CRD) versus melphalan (200
mg/m2) followed by stem cell transplant in newly
diagnosed multiple myeloma subjects
P. Corradini
2009
III
11
Closed
accrual
69/09
A multicenter, randomized, doble-blind, placebo
controlled phase III study of panobinostat in
combination with bortezomib and dexamethasone
in patients with relapsed multiple myeloma
P. Corradini
2010
III
12
Closed
accrual
76/09
Brief induction chemoimmunotherapy with
P. Corradini
rituximab + bendamustine + mitoxantrone followed
by rituximab in elderly patients with advanced stage
previously unrtreated follicular lymphoma
2010
II
4
Closed
accrual
202
Closed
Phase
Total
patients
Patients
enrolled
in 2013
Study
Code
Title
Coordinator
Activated
07/10
Monitoring of human polyomavirus reactivation in
patients with lymphoproliferative disease treated
with chemotherapy, chemotherapy and rituximab,
and rituximab alone
P.Corradini
12/10
A phase I/II, multicenter, open label study of
pomalidomide cyclophosphamide and prednisone
(PCP) in patients with multiple myeloma relapsed
and/or refractory to lenalidomide
13/10
Prospective audit on stem cell mobilization in
malignant lymphoma
Closed
Phase
Total
patients
Patients
enrolled
in 2013
2010
-
8
0
P. Corradini
2010
I-II
11
Closed
accrual
P. Corradini
2010
Observational 8
Closed
accrual
27/10
Randomized phase II trial on primary chemotherapy M. Di Nicola
with high-dose methotrexate and high-dose
cytarabine with or without thiotepa, and with or
without rituximab, followed by brain irradiation vs
high-dose chemotherapy supported by autologous
stem cells transplantation for immunocompetent
patients with newly dignosed primary CNS
lymphoma
2010
II
2
1
31/10
A randomized, double-blind, placebo-controlled
A. M. Gianni
phase 3 study of SGN-35 (brentuximab vedotin) and
best supportive care (BSC) versus placebo and BSC
in the treatment of patients at high risk of residual
Hodgkin lymphoma (HL) following autologous stem
cell transplant (ASCT)
2010
III
7
Closed
accrual
48/10
Intensified program including bendamustine
followed by PBSC mobilization and high dose
therapy and autograft for patients with relapsed
or resistant CD 20+ follicular Non Hodgkin
Lymphoma: a multicenter, pivotal GITIL study
P. Corradini
2010
II
2
0
56/10
A randomized, open label study of Ofatumumab and P. Corradini
Bendamustine combination therapy compared with
Bendamustine monotherapy in indolent B-cell nonHodgkin's lymphoma unresponsive to Rituximab or
a Rituximab-containing regimen during or within six
months of treatment
2013
III
2
2
57/10
A phase III trial comparing bertozomib,
P. Corradini
cyclofosfamide and dexamethasone versus
lenalidomide cyclofosfamide and dexamethasone in
patients with multiple myeloma at first relapse
2010
III
15
6
83/10
A phase III, double-blind, randomized, placebocontrolled, multicenter clinical trial to study the
safety, tolerability, efficacy and immunogenicity of
212 in recipients of autologous hematopoietic cell
transplants
P. Corradini
2010
III
3
0
86/10
Prognosis of patients with relapsed/refractory HL
treated with IGEV induction therapy before HDCT
with AHSCT
P. Corradini
2011
-
1
Closed
accrual
08/11
A multicenter phase II study of subcutaneous
velcade plus oral melphalan and prednisone or plus
oral cyclophosphamide and prednisone or plus
prednisone in newly diagnosed elderly multiple
myeloma patients
P. Corradini
2011
II
3
Closed
accrual
203
back to contents
Study
Code
Title
Coordinator
Activated
Cardiac biomarkers and innovative
echocardiographic parameters as predictors of
cardiotoxicity in B-cell non-Hodgkin/Hodgkin's
lymphoma patients treated with anthracyclines or
high-dose chemotherapy
P. Corradini
2011
Observational 26
23
33/11
A phase III, multicenter, open.label. Randomized
P. Corradini
trial comparing the efficacy of GA 101
(RO50722759) in combination with CHOP
(G-CHOP) versus rituximab and CHOP (R-CHOP) in
previously untreated patients with CD20-positive
diffuse large B-cell lymphoma (DLBCL)
2011
III
14
6
34/11
An open-label, single-arm, phase I study of AEB071 P. Corradini
(a protein kinase C inhibitor) in patients with CD79mutant diffuse large B-cell lymphoma
2011
I
12
2
37/11
A multicenter, open label phase II study of
P. Corradini
carfilzomib, cyclophosphamide and dexamethasone
in newly diagnosed multiple myeloma patients
2011
II
2
Closed
accrual
58/11
A phase 3, Randomized, open label trial of
lenalidomide/dexamethasone with or without
elotuzumab in relapsed or refractory multipl
myeloma
P. Corradini
2011
III
3
Closed
accrual
72/11
An open label non randomized phase 2 study
evaluating SAR3419, an anti-CD19 antobodymaytansine conjugate administred as single agent
by intrevnous infusion to patients with relapsed or
refractory D19+ diffuse large B cell lymphoma
A. M. Gianni
2011
II
3
Closed
accrual
80/11
Prospective, phase I/II, non -randomized, open label, P. Corradini
multicenter study to determine safety and efficacy
of Nilotinib in a population with steroid-refractory/
or steroid-dependent cGVHD
2011
I-II
1
0
89/11
A randomized phase III study to compare
P. Corradini
Bortezomib, melphalan, prednisone (VMP) with
high dose melphalan followed by Bortezomib,
Lenalidomide, Dexamethasone (VRD) consolidation
and Lenalidomide maintenance in patients with
newly diagnosed multiple myeloma
2011
III
21
14
53/12
A open label, phase 2, non randomized, multicentre
trial to assess the feasibility of induction treatment
with 5-Azacitidine (5-AZA) followed by allogeneic
stem cell transplantation (allo-SCT) or continued
5-AZA treatment in patients without a suitable
-sibling or unrelated- stem cell donor with IPSS Int2/High risk myelodysplastic syndromes (MDS)
P. Corradini
2012
II
3
1
66/12
A phase III multicenter, randomized study
P. Corradini
comparing consolidation with 90YTTRIUMLABELED IBRITUMOMAB TIUXETAN (ZEVALIN®)
radioimmunotherapy vs autologous stem cell
transplantation (ASCT) in patients with relapsed
follicular lymphoma (FL) aged 18-65 years
2013
III
2
2
110/11
204
Closed
Phase
Total
patients
Patients
enrolled
in 2013
Study
Code
80/12
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
Bendamustine, lenalidomide and rituximab (R2-B)
P. Corradini
combination as a second-line therapy for first
relapsed-refractory mantle cell lymphomas: a phase
II study
2013
II
1
Closed
accrual
112/12
Observational retrospective/prospective study in
Hodgkin’s Lymphoma and Anaplastic Large Cell
Limphoma patients who received SGN35 according
to compassionate use (named patient program)
P. Corradini
2013
Observational 4
Closed
accrual
113/12
Extracorporeal photopheresis for the treatment of
acute and chronic steroid-resistant Graft Versus
Host Disease (GvHD): a multicenter, retrospective,
observational study
P. Corradini
2013
Observational 9
9
131/12
A randomized open-label multicenter phase II trial
evaluating the safety and activity of DCDT2980S
in combination with Rituximab or DCDS4501A
in combination with Rituximab in patients with
relapsed or refractory B-cell Non-Hodgkin’s
lymphoma
A. M. Gianni
2013
II
Closed
accrual
132/12
Allogeneic hematopoietic stem cell transplantation P. Corradini
for patients with chemorefractory or relapsed
Hodgkin's lymphoma: a retrospective, observational
study
2013
133/12
Chronic Lymphocytic Leukemia (CLL) Registry: a
prospective, observational study within the Rete
Ematologica Lombarda
P. Corradini
138/12
A multicenter, single-arm, open-label study with
pomalidomide in combination with a low dose
of dexamethasone in subjects with refractory or
relapsed and refractory multiple myeloma
144/12
An open-label phase II study of BKM120 in patients
with relapsed and refractory diffuse large B-cell
lymphoma, mantle cell lymphoma and follicular
lymphoma
151/12
06/06/13
Observational 53
53
2013
Observational 12
12
P. Corradini
2013
III
28
28
P. Corradini
2013
II
3
3
Genetics-driven targeted management of lymphoid A. M. Gianni
malignancies. Improving molecular characterization
and diagnosis of hairy cell leukemia and classical
hodgkin lymphoma
2013
Observational 2
Closed
accrual
11/13
Myeloablative Conditioning, followed by
Unmanipulated Haploidentical Bone Marrow
Transplantation and post-transplant high dose
Cyclophosphamide , for Patients with Hematologic
Malignancies: a Phase II study
P. Corradini
2013
II
2
2
31/13
A multicenter, open label, study of weekly
P. Corradini
carfilzomib, cyclophosphamide and dexamethasone
(wCCyd) in newly diagnosed multiple myeloma
(MM) patients
2013
I-II
4
4
41/13
Clinical outcome in patients with myelodysplastic
syndrome receiving allogeneic stem cell transplant
from unrelated donor: impact of donor availability
and transplant procedure timing
2013
Observational 4
4
P. Corradini
01/12/13
2
30/08/13
205
back to contents
Study
Code
Title
Coordinator
Activated
51/13
An observational prospective study on fertility and
gonadal function in young adult female patients
with lymphoma or sarcoma, who choose to
undergo fertility preservation by mature ovocytes
cryopreservation before starting chemotherapy
S. Viviani
2013
52/13
Multicentric retrospective study evaluating
L. Devizzi
the efficacy and the tolerability of four doses of
Rituximab followed by involved field radiotherapy in
non bulky stage I-II follicular Lymphoma (grade 1-2)
2013
57/13
A phase I/II study of Danusertib in Combination
with romidepsin in adult patients with mature
peripheral T-Cell lymphoma (PTCL)
A. M. Gianni
63/13
An open label, single arm, phase II study of nilotinib
300 mg BID in newly diagnosed CPCML patients,
in order to verify disappearance of CD34+/lin-Ph+
cells from bone marrow during treatment
86/13
Closed
Phase
Total
patients
Patients
enrolled
in 2013
Observational 3
3
Observational 19
19
2013
II
1
1
P. Corradini
2013
II
1
1
Identification of possible genetic causes responsible P. Corradini
of a familiar form of Multiple Myeloma
2013
Observational 2
Closed
accrual
100/13
Multi-center, phase II study to assess the safety
and efficacy of haploidentical bone marrow
transplantation using reduced intensity
conditioning (RIC) regimen and post-transplant
cyclophosphamide, in patients with poor prognosis
lymphomas
P. Corradini
2013
II
2
113/13
Role of T memory stem cell in the process of
immune reconstitution following bone marrow
transplantation
P. Corradini
2013
Observational 11
11
149/13
Retrospective observational study on monitoring
of serum levels of TARC and PET results of patients
with Hodgkin's lymphoma undergoing allogenic
hematopoietic stem cell
P. Corradini
2013
22
22
150/13
Treatment with bendamustine in relapsed/
refractory patients with Hodgkin's lymphoma
already treated with brentuximab vedotin. An
observational retrospective multicenter study
S. Viviani
2013
10/11/13
Observational 4
4
97/11
Non invasive prediction of acute Graft-Verus-Host
Disease following allogeneic hematopoietic cell
transplantation by circulating miRNA profiling
P. Corradini
2011
30/06/13
Observational 47
Closed
accrual
27/12
Retrospective assessment of the effficacy of
P. Corradini
bendamustine in patients with relapsed/refractory
Hodgkin's lymphoma after high-dose chemotherapy
or allogenic transplantation:experience of the FIL
center
2012
28/02/13
Observational 7
Closed
accrual
34/12
An open label phase II study on the use of
Panobinostat in combination with bortezomib and
dexamethasone as induction in miltiple myeloma
patients candidate to high-dose therapy
2012
22/03/13
II
Closed
accrual
206
P. Corradini
30/09/13
2
4
Study
Code
45/12
114/12
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
Correlation between the frequencies of myeloid
derived suppressor cells (MDSC) present in
matched unrelated donors (MUD) grafts and
the incidence of aGvHD following allogeneic
hematopoietic cell transplantation
P. Corradini
2012
30/06/13
Observational 40
Closed
accrual
Observational retrospective/prospective study in
Hodgkin’s Lymphoma and Anaplastic Large Cell
Limphoma patients who received SGN35 according
to compassionate use (named patient program)
A. M. Gianni
2012
03/01/13
Observational 16
Closed
accrual
LUNG CANCER
35/07
A phase II study of NGR-hTNF administered as
N. Zilembo
single agent every 3 weeks in patients affected
by advanced or metastatic malignant pleural
mesothelioma previously treated with no more than
one systemic therapeutic regimen
2007
20/05/13
II
4
Closed
accrual
74/09
A randomized, multicenter, open-label phase 3
study of gemcitabine-cisplatin chemotherapy
plus IMC-11F8 versus gemcitabine-cisplatin
chemotherapy alone in the first-line treatment of
patients with squamous stage IIIb or IV non-small
cell lung cancer (NSCLC)
2010
27/11/13
III
6
Closed
accrual
53/05
Spiral CAT, biomarkers and proteomic analysis,
U. Pastorino
associated to a program of primary prevention for
the early diagnosis of lung cancer: randomized study
in subjects at high risk: project MILD
2006
-
4.099
Closed
accrual
18/07
START - stimulating Targeted Antigenic Responses
To NSCLC
M. Platania
2007
III
5
Closed
accrual
27/09
Randomized phase II study of NGR-hTNF in
combination with standard chemotherapy versus
standard chemotherapy alone in previously
untreated patients with advanced non-small cell
lung cancer (NSCLC)
N. Zilembo
2009
II
31
Closed
accrual
66/09
Multicenter phase III randomized study of cisplatin N. Zilembo
and etoposide with or without bevacizumab as firstline treatment in extensive stage (ED) small cell lung
cancer (SCLC)
2013
III
1
1
75/09
A randomized, multicenter, open-label phase 3
study of pemetrexed-cisplatin chemotherapy
plus IMC-11F8 versus pemetrexed-cisplatin
chemotherapy alone in the first-line treatment of
patients with non squamous stage IIIb or IV nonsmall cell lung cancer (NSCLC)
N. Zilembo
2010
III
9
Closed
accrual
10/10
HSRL-02-2007 PROSE: Randomized Proteomic
Stratified Phase III Study of Second Line Erlotinib
versus Chemotherapy in Patients with Inoperable
Non–Small Cell Lung Cancer
N. Zilembo
2010
III
2
Closed
accrual
23/10
Phase III randomized trial of BIBW 2992 plus
weekly paclitaxel versus investigator's choice of
chemotherapy following BIBW 2992 monotherapy
in non-small cell lung cancer patients failing
previuos erlotinib or geftinib treatment
M. Platania
2010
III
5
Closed
accrual
N. Zilembo
207
back to contents
Study
Code
Title
Coordinator
Activated
45/10
An exploratory phase II study of pemetrexed and
ciplatin as preoperative chemotherapy in the
treatmnet of stage IIIAN2 nonsquamous non small
cell lung cancer
U. Pastorino
72/10
The airINTrial: a prospective randomized phase
III trial of the use of different modalities of pleural
aspiration for the management of breath loss after
lung surgical resection
21/11
Phase
Total
patients
Patients
enrolled
in 2013
2011
II
13
1
F. Leo
2011
III
580
30
BioMILD: a prospective study of efficacy of plasma
microRNA as first line test for early dignosis of lung
cancer
U. Pastorino
2013
Observational 1.004
1.004
52/11
An open label two-stage study of orally
administered BKM120 in patients with metastatic
non-small cell lung cancer with activated PI3K
pathway
F. De Braud
2012
II
3
1
92/11
Phase III randomized, open-label study of the
F. de Braud
efficacy and safety of crizotinib versus pemetrexed/
cisplatin or pemetrexed/carboplatin in previously
untreated patients with non-squamous carcinoma
of the lung harboring a traslocation or inversion
event involving the anaplastic lymphoma kinase
(alk) gene locus
2011
III
2
Closed
accrual
83/11
Prospective randomized study on efficacy of
autologous adipose tissue with Stem Cells
to prevent air-leaks after laser pulmonary
metastasectomy
2011
II
17
Closed
accrual
21/12
A randomized, open-label. Multicenter, phase 3
M. Platania
study to compare the efficacy and asafety of eribulin
with treatment of physician's choice in subjects with
advanced non-smal celle lung cancer
2012
III
8
Closed
accrual
40/12
A randomized, phase II, multicenter, double-blind,
F. de Braud
placebo-controlled study evaluating the efficacy
and safety of MetMab in combination with
paclitaxel + cisplatin or carboplatin as first -line
treatment for patients with stage IIIb (T4 disease) or
IV squamous non-small cell lung cancer (NSCLC)
2012
II
1
Closed
accrual
41/12
A randomized, phase II, multicenter, double-blind,
placebo-controlled study evaluating the efficacy
and safety of MetMab in combination with either
bevacizumab +platinum + paclitaxel or pemetrexed
+ platinum as first -line treatment for patients with
stage IIIb or IV non-squamous non-small cell lung
cancer (NSCLC)
F. de Braud
2012
II
11
Closed
accrual
48/12
Be-positive: Beyond progression after tki in egfr
positive NSCLC patients
M. Garassino 2012
Observational 4
0
49/12
Maintanance metronomic per os navelbine in
advanced NSCLC patients after previous platinum
based chemotherapy: a mutlicenter randomized
best supportive care controlled phase II study
MANILA
M. Platania
II
5
208
U. Pastorino
2013
Closed
20/12/13
5
Study
Code
Title
Coordinator
63/12
Phase II study of oral PHA-848125AC in patients
with thymic carcinoma previously treated with
chemotherapy
100/12
Phase
Total
patients
Patients
enrolled
in 2013
M. Garassino 2012
II
12
6
An Open-label Randomized Phase III Trial of BMS936558 versus Docetaxel in Previously Treated
Advanced or Metastatic Squamous Cell Non-small
Cell Lung Cancer (NSCLC)
M. Garassino 2013
III
8
Closed
accrual
136/12
A multicenter, open-label, randomized phase
II study to evaluate the efficacy of AUY922 vs
pemetrexed or docetaxel in NSCLC patients with
EGFR mutations who have progressed on prior
EGFR TKI treatment
N. Zilembo
II
2
2
137/12
An Open-Label Randomized Phase III Trial of BMS936558 versus Docetaxel in Previously Treated
Metastatic Non-squamous Non-small cell Lung
Cancer (NSCLC)
M. Garassino 2013
III
11
Closed
accrual
34/13
Phase II study of oral PHA-848125AC in patients
with malignant thymoma previously treated with
multiple lines of chemotherapy
Marina
Garassino
II
2
2
61/13
POST-ALK: observational study of treatment and
outcome after crizotinib in advanced ALK-positive
NSCLC patients
M. Garassino 2013
Observational 7
7
65/13
Post-operative pulmonary complications in major
abdominal surgery. A prospective multicenter
observational study
F. Piccioni
Observational 122
Closed
accrual
99/13
Phase I Study of Single Agent MK-3475 in Patients
with Progressive Locally Advanced or Metastatic
Carcinoma, Melanoma, and Non-Small Cell Lung
Carcinoma
M. Garassino 2013
I
12
12
E-Cigarette and Normal Cigarette Sidestream
Analysis and Comparison Project
R. Boffi
-
3
Closed
accrual
II
2
Closed
accrual
III
37
Closed
accrual
III
21
Closed
accrual
108/13
98/11
A phase II, open lebel, multicenter, randomized
F. de Braud
study to assess the rfficacy and safety of
GSK1120212 compared with docetaxel in 2nd line
subjects with targeted mutations (KRAS, NRAS,
BRAF, MEK1) in locally advanced or metastatic nonsmall cell lung cancer (NSCLC stage IIIBwet-IV)
Activated
Closed
2013
2013
2013
2013
2011
24/09/13
MELANOMA
52/08
A double-blind, randomized, placebo-controlled
phase III study to assess the efficacy of
recMAGE-A3 + AS15 ASCI as adjuvant therapy in
patients with MAGE-A3 positive resected stage III
melanoma
42/09
An open label, multicenter, phase III trial of ABI-007 M. Del
vs dacarbazine in previously untreated patients
Vecchio
with metastatic malignant melanoma
M. Santinami 2009
2009
209
back to contents
Study
Code
Title
Coordinator
Activated
06/10
BRIM 3: a randomized, open-label, controlled,
multicenter, phase III study in previuosly untreated
patients with unresectable stage IIIC or stage IV
melanoma with V600E BRAF mutation receiving
RO5185426 or dacarbazine
M. Del
Vecchio
24/10
The TEAM trial (Tasigna efficacy in advanced
melanoma): A randomized, phase III, open label,
multi-center, two-arm study to compare the
efficacy of Tasigna® versus dacarbazine (DTIC) in
the treatment of patients with metastatic and/or
inoperable melanoma harboring a c-Kit mutation
M. Del
Vecchio
25/10
An open, dose-escalation phase I/II study to
assess the safety, immunogenicity and clinical
activity of rec-PRAME + AS15 Antigen-specific
Cancer Immunotherapeutic as first-line treatment
of patients with PRAME-positive metastatic
melanoma
33/10
Phase
Total
patients
Patients
enrolled
in 2013
2010
III
10
Closed
accrual
2010
III
11
Closed
accrual
M. Santinami 2010
I-II
12
Closed
accrual
An open-label, multicenter, randomized, phase Ib/
II study of E7080 in combination with dacarbazine
versus dacarbazine alone as first line therapy in
patients with stage IV melanoma
M. Del
Vecchio
Ib-II
9
Closed
accrual
34/10
A phase II single arm study of the combination of
Ipilimumab and fotemustine in patients with nonresectable stage III or stage IV melanoma
M. Santinami 2010
II
9
Closed
accrual
62/10
An open phase I study of immunization with the
rec-NY-ESO-1 + AS15 antigen-specific cancer
immunotherapeutic in patients with NY-ESO-1
positive unresectable and progressive metastatic
cutaneous melanoma
M. Santinami 2010
I
26
0
01/11
A phase III randomized, open-label study comparing M. Del
GSK1120212 to chemotherapy in subjects with
Vecchio
advanced or metastatic BRAFV600E/K mutationpositive melanoma
2011
III
5
Closed
accrual
16/11
An open-label, multicenter expanded access
study of RO5185426 in patients with metastatic
melanoma
M. Del
Vecchio
2011
III
78
Closed
accrual
39/11
Identification of circulating microRNAs as potential
indicators of progression in metastatic melanoma
L. Rivoltini
2011
Observational 248
146
40/11
A study of immunomodulatory effect of BRAF and
MEK inhibitors in melanoma patients
L. Rivoltini
2011
Observational 65
23
76/11
An open-label, multicenter, single arm, phase I
dose.escaltion with efficacy tail extension study of
Vemurafenib (RO5185426) in pediatric patients
with surgically incurable and unresctable stage
IIIC or stage IV melanoma harboring BRAFV600
mutations
A.Ferrari
2013
I
1
1
23/12
A Randomized Double-Blind phase III study of
Ipilimumab Administered at 3 mg/kg vs at 10 mg/
kg in subjects with previously treated or untreated
unresectable or metastatic melanoma
M. Del
Vecchio
2012
III
40
Closed
accrual
210
2010
Closed
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
28/12
Tracing the melanoma lineage: cancer stem cells and M. Santinami 2012
genetic noise
Observational 26
Closed
accrual
37/12
Malignant skin lesions in patients with cancer: an
observational prospective study
A. T.
Caraceni
2012
Observational 99
77
38/12
A phase III, randomized, double-blinded study
comparing the combination of the BRAF inhibitor,
dabrafenib and the MEK inhibitor, trametinib to
dabrafenib and placebo as first-line therapy in
subjects with unresectable (Stage IIIC) or metstatic
(STAGE IV) BRAF V600E/K mutation-positive
cutaneous melanoma
F. de Braud
2012
III
20
Closed
accrual
52/12
A phase III, randomised, open-label study comparing M. Del
the combination of the BRAF inhibitor, dabrafenib
Vecchio
and the MEK inhibitor, trametinib to the BRAF
inhibitor vemurafenib in subjects with unresectable
(stage IIIc) or metastatic (stage IV) BRAF V600E/K
mutation positive cutaneous melanoma
2013
III
13
Closed
accrual
58/12
Potentiating clinical and immunological effects of
chemotherapy by neutralizing acidic pH at tumor
site: a phase II randomized study in melanoma
patients
M. Santinami 2012
II
4
1
71/12
A phase II study of intratumoral application of
M. Santinami 2012
L19IL2/L19TNF in melanoma patients in clinical
stage III or stage IV M1a with presence of injectable
cutaneous and/or subcutaneous lesions
II
9
7
103/12
A multicentre, open label, randomized Phase II trial Filippo De
of the MEK inhibitor pimasertib or dacarbazine in
Braud
previously untreated subjects with N-Ras mutated
locally advanced or metastatic malignant cutaneous
melanoma
2012
II
8
7
106/12
An open-label, single-arm, phase II, multicenter
study to evaluate the efficacy of vemurafenib
in metastatic melanoma patients with brain
metastases
M. Del
Vecchio
2013
II
1
Closed
accrual
140/12
A Randomized, Open-Label Phase 3 Trial of BMS936558 versus Investigator's Choice in Advanced
(Unresectable or Metastatic) Melanoma Patients
Progressing Post Anti-CTLA-4 Therapy
M. Del
Vecchio
2013
III
2
Closed
accrual
143/12
COMBI-AD: A phase III randomized double blind
M. Santinami 2013
study of dabrafenib (GSK2118436) in COMBInation
with trametinib (GSK1120212) versus two placebos
in the ADjuvant treatment of high-risk BRAF
V600 mutation-positive melanoma after surgical
resection.
III
13
13
"A Phase 3, Randomized, Double-Blind Study of
BMS-936558 vs Dacarbazine in Subjects with
Previously Untreated Unresectable or Metastatic
Melanoma
III
9
9
42/13
F. De Braud
2013
211
back to contents
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
43/13
A phase III, double-blind, placebo-controlled study
F. De Braud
of vemurafenib versus vemurafenib plus GDC0973 in previously untreated BRAFV600-mutation
positive patients with unresectable locally advanced
or metastatic melanoma
2013
III
11
Closed
accrual
44/13
A randomized, Phase III study of Fotemustine versus M. Del
the Combination of Fotemustine and Ipilimumab
Vecchio
in Patients with Metastatic Melanoma with brain
metastasis
2013
III
3
3
94/13
A Phase 3, Randomized, Double-Blind Study of
M. Del
Nivolumab Monotherapy or Nivolumab Combined Vecchio
with Ipilimumab Versus Ipilimumab Monotherapy in
Subjects with Previously Untreated Unresectable or
Metastatic Melanoma
2013
III
13
13
III
2
Closed
accrual
SARCOMAS
25/08
A multinational, randomized, double-blind
placebo controlled study of AVE8062 (25 mg/
m2) administered every 3 weeks, in patients with
advanced -stage soft tissue sarcoma treated with
cisplatin (75 mg/m2) after failure of antracycline
and ifosfamide chemotherapies
P. Casali
2008
31/03
EUROpean Bone Over 40 Sarcoma Study. A
European treatment protocol for bone-sarcoma in
patients older than 40 years
P. Casali
2003
II-III
13
1
46/03
Ifosfamide at high doses in prolonged continuous
infusion by a portable infusion system in soft-tissue
sarcomas typical of the adult in an advanced phase
in second/further line chemotherapy
R. Bertulli
2004
II
21
Closed
accrual
01/04
Gemcitabine in leiomyosarcoma in an advanced
phase in second or further line of chemotherapy
R. Bertulli
2004
II
15
Closed
accrual
31/05
EpSSG RMS 2005 - A protocol for non metastatic
Rhabdomyosarcoma
A. Ferrari
2005
III
102
8
32/05
EpSSG NRSTS 2005. A protocol for localized nonrhabdomyosarcoma soft tissue sarcomas
A. Ferrari
2005
III
155
12
53/06
Trabectedin (ET743) in metastatic or locally
advanced cell liposarcoma pretreated with
chemotherapy
P. Casali
2006
II
27
Closed
accrual
45/08
A randomized, multicenter, phase III trial of
Trabectedin (yondelis) versus doxorubicin-based
chemotherapy as first-line therapy in patients with
traslocation related sarcomas (TRS)
P. Casali
2008
III
3
Closed
accrual
62/08
Open label, multi-center, phase 2 study denosumab
in subject with giant cell tumor of bone
P. Casali
2008
II
26
1
78/09
A phase II randomized - non comparative - study
onthe activity of trabectedin or gemcitabine +
docetaxel in metastatic or locally relapsed uterine
leiomyosarcoma pretreated with conventional
chemotherapy
P. Casali
2010
II
4
0
212
13/03/13
Study
Code
Title
Coordinator
Activated
30/10
Randomized phase II study evaluating two doses
of NGR-hTNF administered either as single agent
or in combination with doxorubicin in patients with
advanced soft tissue sarcoma (STS)
P. Casali
44/10
Phase II study on imatinib in combination with
RAD001 in advanced chordoma
66/10
Localized high-risk soft tissue sarcomas of the
A. Gronchi
extremities and trunk wall in adults: an integrating
approach comprising standard vs histotype-tailored
neoadjuvant chemotherapy
85/10
Evaluation of the role of immunosuppressive
mechanisms in the prognosis and response to
treatment with targeted therapy drugs in sarcoma
patients
05/11
Closed
Phase
Total
patients
Patients
enrolled
in 2013
2010
II
11
Closed
accrual
S. Stacchiotti 2011
II
30
7
2010
II
36
12
L. Rivoltini
2010
Observational 143
15
Translational study on modulation of gene
transcription induced by Trabectedin in patients
with myxoid/round cell liposarcoma
P. Casali
2011
-
0
06/11
A retrospective study on retroperitoneal sarcomas
A. Gronchi
2011
19/11
A randomized, open label, multicenter, phase 3
study to compare the efficacy and safety of eribulin
with dacarbazine in subjects with soft tissue
sarcoma
P. Casali
28/11
Rabdomiosarcoma of adults. An observational
prospective study
59/11
31/12/13
2
Observational 210
Closed
accrual
2011
III
Closed
accrual
R. Bertulli
2011
Observational 6
0
STARSS: a phase III randomized STudy of
preoperative RAdiotherapy plus Surgery versus
surgery alone for patients with Retroperitoneal
Sarcoma (RPS)
A. Gronchi
2011
III
12
8
73/11
ABCB1/P- glycoprotein expression as factor
for the biologic stratification of the metastatic
osteosarcoma of the extremities: a prospective
study
R. Bertulli
2011
II
16
2
13/12
Tailore Beta-catenin mutational approach in extraabdominal sporadic desmoid tumor patients
A. Gronchi
2013
Observational 11
11
119/12
Y-IMAGE: a non-interventional multicenter,
prospective study to evaluate treatment outcome
assessment methods used in routine clinical
practice on patients with advaced soft tissue
sarcoma treated with trabectedin according to the
Summary of Product Characteristics (SmPC)
P. G. Casali
2013
Observational 7
7
Observational study of whole-trascriptome and
S. Stacchiotti 2013
whole-exome sequencing analysis in tumor samples
of extraskeletal myxoid chondrosarcoma, malignant
myoepithelioma, and dermatofibrosarcoma
protuberans with or without fibrosarcomatous
component
Observational 8
8
54/13
4
213
back to contents
Study
Code
Title
Coordinator
Activated
114/13
Patients with atipical osteosarcoma and/or are not
elegible in other ISG clinical trials
R. Bertulli
2013
168/13
Retrospective study of anthracycline-based
chemotherapy in extraskeletal myxoid
chondrosarcoma
S. Stacchiotti 2013
Closed
Phase
Total
patients
Patients
enrolled
in 2013
Observational 1
1
31/12/13
Observational 11
11
12/09/13
II
7
Closed
accrual
III
6
0
URINARY APPARATUS
41/08
A randomized, open label, multi-center phase II
G. Procopio
study to compare bevacizumab plus RAD001 versus
interferon alfa-A plus bevacizumab for the first-line
treatment of patients with metastatic clear cell
carcinoma of the kidney
2008
53/07
Sunitinib treatment of renal adjuvant cancer
G. Procopio
(S-TRAC): a randomized double-blind phase 3 study
of adjuvant sunitinib vs placebo in subjetcs with high
risk RCC
2007
81/11
Retrospective analysis of sorafenib as the first
or second target therapy administered in mRCC
patients. Three years Italian experience
G. Procopio
2011
51/08
Axitinib (AG 013736) as second line therapy for
metastatic renal cell cancer: AXIS trial
G. Procopio
11/10
14/01/13
Observational 25
Closed
accrual
2008
III
5
Closed
accrual
Phase II study of sunitinib in metastatic renal cancer G. Procopio
with non-clear cell histology
2010
II
11
Closed
accrual
52/10
A phase II study of neoadjuvant Cisplatin and
Gemcitabine plus Sorafenib for patients with
transitional cell carcinoma of the bladder
R. Salvioni
2010
II
26
2
09/11
A randomized, double.blind, placebo-controlled
of pazopanib as adjuvant therapy for subjects
with localized or locally advanced RCC following
nephrectomy
G. Procopio
2011
III
12
Closed
accrual
10/11
Biotech of prostate cancer
N. Zaffaroni
2011
Observational 113
62
32/11
An open-label, randomized, multicenter, phase III
study to compare safety and efficacy of TK1258
versus soafenib in patients with metastatic renal
cell carcinoma after failure of anti-angiogenic
(VEGF-targeted and m-TOR inhibitor) therapies
G. Procopio
2011
III
4
Closed
accrual
09/12
An open label pharmacokinetic and tolerability
study of cabazitaxel in patients with solid tumors
with moderately and severely impaired and with
normal renal function
F. De Braud
2012
I
5
Closed
accrual
46/12
Evaluation of microRNA expression in prostate
cancer for the identification of novel diagnostic and
prognostic markers
D. Zaffaroni
2012
Observational 13
12
47/12
The decision making of patients with prostate
cancer in multidisciplinary visit
R. Valdagni
2013
Observational 97
97
214
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
62/12
A randomized, open label, multicenter phase 2
G. Procopio
study, to evaluate the efficacy of Sorafenib in
patients with advanced Renal Cell Carcinoma (RCC)
after a radical resection of the metastases.
2012
II
12
10
65/12
PRINCIPAL: A Prospective Observational Study
of Real World Treatment Patterns and Treatment
Outcomes in Patients with Advanced or Metastatic
Renal Cell Carcinoma Receiving Pazopanib
G. Procopio
2012
Observational 22
13
90/12
Study for the validation of PROSQOLI (Prostate
Cancer Specific Quality of Life Instrument). A
questionnaire for the assessment of health-related
quality of life in patients with prostate cancer
R. Valdagni
2013
Observational 19
19
94/12
A Phase 3, Randomized, Double-blind, Controlled
Study of Cabozantinib (XL184) vs. Prednisone in
Metastatic Castrationresistant Prostate Cancer
Patients who have Received Prior Docetaxel and
Prior Abiraterone or MDV3100
G. Procopio
2013
III
7
Closed
accrual
A Randomized, Open-Label, Phase 3 Study of BMS- G. Procopio
936558 vs. Everolimus in Subjects with Advanced
or Metastatic Clear-Cell Renal Cell Carcinoma Who
Have Received Prior Anti-Angiogenic Therapy
2013
III
14
Closed
accrual
62/13
Retrospective Observational Study of Sunitinib
administered in schedule 2/1-2/1 (2 week on-1
week off for an overall cycle lenght of 6 weeks)
in patients with metastatic Renal Cell Carcinoma
(mRCC): RAINBOW Study
G. Procopio
2013
98/13
A phase Ib/II study of GDC-0068 or GDC-0980 with G. Procopio
abiraterone acetate versus abiraterone acetate
in patients with castration-resistant prostate
cancer previously treated with docetaxel-based
chemotherapy
162/13
Retrospective analysis of eventual relationship
between previous AWS (Antiandrogen withdrawal
sindrome) and response to Enzalutamide in
Docetaxel refractory metastatic castrate-resistant
prostate cancer (mCRPC) patients
01/12
Phase II study of the fully human monoclonal
antibody against transforming growth factor-beta
(TGFß) receptor ALK1 (PF-03446962) in relapsed
or refractory urothelial cancer (UC) failing first-line
treatment
108/12
31/10/13
31/08/13
Observational 16
16
2013
I-II
1
1
G. Procopio
2013
Observational 9
9
A. Necchi
2012
09/09/13
II
10
14
PEDIATRIC TUMORS
41/01
Protocol for evaluation and therapy of the
diencephalohypophysial alterations in pediatric
patients with cerebral neoplasms
E. Seregni, E.
Bombardieri
2001
31/12/13
Observational 460
15
31/07
Guidelines for the treatment of patients with
localized resectable neuroblastoma and analysis of
prognostic factors
R. Luksch
2007
01/06/13
-
Closed
accrual
16
215
back to contents
Study
Code
Title
Coordinator
Activated
Closed
Phase
47/11
Quality of life and personality factors in patients
recovered from osteosarcoma in evolutive age
towards a deeper understanding of long-term
adaptation
C. Meazza
2011
30/10/13
Observational 43
4
55/11
A phase III, randomized, double-blind, active
comparator-controlled clinical trial, conducted
under in house blinding conditions, to examine the
efficacy and safety of aprepitant for the prevention
of chemotherapy induced nausea and vomiting
(CINV) in pediatric patients
M. Casanova
2011
07/11/13
III
6
Closed
accrual
26/95
Immunotherapy (IL-2 and activated circulating
mononucleate cells) and pre/post-surgical
antineoplastic chemotherapy in the primary
treatment of osteosarcoma
C. Meazza
1995
II
86
2
40/01
Protocol NB-AR-01: First European Cooperative
Study for high-risk neuroblastoma
R. Luksch
2002
III
58
5
12/03
Second protocol for diagnosis and treatment of
ependymoma in a pediatric age
M.
Massimino
2003
Observational 49
1
13/03
Non-controlled clinical study for the treatment of
Ewing’s sarcoma in relapse
R. Luksch
2003
II
2
14/03
Wilms’ tumor: diagnostic-therapeutic protocol
AIEOP 2003
F. Spreafico
2003
Observational 116
10
16/03
Germ cell tumors: diagnostic-therapeutic protocol
AIEOP 2003
M.
Terenziani
2003
III
103
6
17/05
Phase II protocol with combined chemotherapy
and 131I-MIBG in the treatment of patients with
neuroblastoma resistant or in relapse (I-METCH)
R. Luksch
2005
II
1
Closed
accrual
08/07
LCH-III. Treatment protocol of the third
S. Catania
international study for Langerhan's cell histiocytosis
2007
III
56
14
13/08
Open-label, multi -center, randomized, two stage
adaptive design study of the combination of
bevacizumab with standard chemotherapy in minor
patients with metastatic rhabdomyosarcoma, nonrhabdomyosarcoma soft-tissue sarcoma or Ewing
sarcoma/soft tissue primitive neuroectdermal
tumour
M. Casanova
2008
II
10
Closed
accrual
17/08
HL PED 2008 Hodgkin’s lymphoma. A therapeutic
protocol for sequels reduction
M.
Terenziani
2008
II
25
8
22/09
A phase II study on the efficacy of dose
intensification in patients with non-metastatic
Ewing’s sarcoma
P. Casali, R.
Luksch
2009
III
26
15
25/09
Therapeutic protocol with high-dose chemotherapy, P. Casali, R.
radiotherapy, maintenance therapy with low-dose
Luksch
Cyclophosphamide and anti-COX2 in metastatic
Ewing’s sarcoma: ISG/AIEOP study
2009
II
25
15
57/09
Phase II single-arm study of temozolomide in
M. Casanova
combination with topotecan in refractory or relapsing
neuroblastoma and other pediatric solid tumors
2009
II
7
Closed
accrual
216
Total
patients
23
Patients
enrolled
in 2013
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
2
0
53/10
Phase 1/2combined dose ranging and randomised, R. Luksch
open-label, comparative study of efficacy and safety
of plerixafor in addition to standard regimens for
mobilisation of haematopoietic stem cells into
peripheral blood, and subsequent collection by
apheresis, vesus standard mobilisation regimens
alone in pediatric patients, aged 2 to<18 years, with
solid tumours eligible for autologous transplants
2011
I-II
84/10
Evaluation and treatment of bone mass and body
composition alterations in pediatric patients with
oncological disease of central nervous system
2010
Observational 43
38
02/11
A phase I study of LDE225 in pediatric patients with M. Casanova
recurrent or refractory medulloblastoma or other
tumors potentially dependent on the Hedgehogsignaling pathway
2011
I
Closed
accrual
20/11
"Neurocognitive outcome correlated to radiation
dose and diffusion-tensor MRI information (DTI)
in children focally irradiated for primitive pediatric
malignant brain tumours
M.
Massimino
2011
Observational 21
7
46/11
A phase II open-label. Randomized, multi-centre
comparqative study of bevacizumab-based
therapy in paediatric patients with newly dignosed
supratentorial high-grade glioma
M.
Massimino
2011
II
4
48/11
Immunohistochemical and molecular analysis of a
pediatric series of salivary glands cancer from the
Istituto Nazionale dei Tumori, Milan
L. Locati
2011
Observational 16
Closed
accrual
49/11
International randomized phase ii trial of the
combination of vincristine and irinotecan
with or without temozolomide (VI or VIT) in
children and adults with refractory or relapsed
rhabdomyosarcoma
M. Casanova
2011
II
1
07/12
Nimotuzumab and vinorelbina concomitantly to
radiation and as maintenance for newly diagnosed
diffuse pontine glioma in childhood
M.
Massimino
2012
Observational 16
5
43/12
European Low an Intermediate Risk Neuroblastoma R. Luksch
2013
III
4
93/12
PanCareSurFup: PanCare Childhood and Adolescent M.
Cancer Survivor Care and Follow-up Studies
Terenziani
2013
Observational 164
Closed
accrual
145/12
A phase III multi-center, open-label, randomized,
controlled study of the efficacy and safety of oral
LDE225 versus temozolomide in patients with Hhpathway activated relapsed medulloblastoma
2013
III
2
147/12
Assessment of symptoms in children and adolescents S. Macchi
with malignant disease during treatment
2013
Observational 33
33
05/13
Re-induction protocol for patients with high-risk
neuroblastoma at first relapse
R. Luksch
2013
II
1
1
14/13
Intergroup trial for children or adolescents with
b-cell NHL or B-AL: evaluation of rituximab efficacy
and safety in high risk patients
F. Spreafico
2013
II
2
2
E. Seregni
M. Casanova
8
8
2
4
2
217
back to contents
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
1
1
16/13
A phase I/II dose schedule finding study of
R. Luksch
CH14.18/CHO continuous infusione combined with
subcutaneous aldesleukin (IL-2) in patients with
primary refractory or relapsed neuroblastoma. A
SIOPEN Study
2013
I-II
68/13
The school activity during cancer treatment
in developmental age: a survey about limits
and resources through the administration of a
questionnaire to parents
2013
Observational 33
33
80/13
A Phase I, open-label, dose escalation study of
M. Casanova
LDK378 in pediatric patients with malignancies that
have a genetic alteration in anaplastic lymphoma
kinase (ALK)
2013
I
5
90/13
Study of equivalence eco abdomen CT abdomen in
pediatric patients with Hodgkin's lymphoma
M.
Terenziani
2013
The point of view of adolescents with cancer
A. Ferrari
2013
147/13
G. Casiraghi
31/12/13
5
Observational 10
10
Observational 24
24
Observational 108
10
PALLIATIVE CARE
23/11
A no-profit observational, prospective study
C. Ripamonti
describing the presence and intensity of nausea,
vomiting (N/V), of related symptoms and of
subjective feeling of malaise in patients with the
following neoplasms: head and neck , lung (NSCLC/
SCLC) and pleural, urothelial, male genital apparatus
(germinal neoplasm, penile spinocellular carcinoma)
treated first with chemotherapy including drugs with
high/moderate vomiting risk and in inter cycle phase
2011
36/10
An open-label randomized controlled clinical trial
to compare the analgesic efficacy of therapeutic
strategies with Oxycodone, Fentanyl and
Buprenorphine versus Morphine in patients with
cancer-related pain of moderate-severe intensity,
since the start of third-step treatment of the WHO
analgesic scale
A. Caraceni
2011
IV
23
4
Sublingual Fentanyl versus subcutaneous morphine
for the management of severe cancer pain episodes
in patients on opioid treatment: a double-blind
randomized non-inferiority trial
A. Caraceni
2013
IV
5
5
123/13
27/09/13
MISCELLANEA
77/06
Phase II study oh PHA-739358 administered by
a 24-Hour IV infusion every 14 days in advanced/
metastatic breast, ovarian, colorectal, pancreatic,
small cell lung and non-small cell lung cancer
L. Celio
2007
26/09/13
II
10
Closed
accrual
03/07
A randomized, double-blind, placebo-controlled,
multicenter phase III study in patients with
advanced carcinoid tumor receiving Sandostatina
LAR and RAD001 10 mg/die or Sandostatin LAR
and placebo
R. Buzzoni
2007
04/06/13
III
8
Closed
accrual
218
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
19/08
An open-label, non-randomized, dose esclation,
G. Capri
safety and pharmacokinetics phase I study
of AVE8062 in combination with cisplatin
administered on day 1 followed by docetaxel on day
2, every 3 weeks, in patients with advanced solid
tumors
2008
23/05/13
I
19
Closed
accrual
42/10
An open-label, non-randomized dose escalation,
safety and pharmacokinetics phase I studyof
ombrabulin (AVE8062) in combination with
bevacizumab administered by intravenous infusion
every 3 weeks in patients with advanced solid
tumors
G. Capri
2010
08/01/13
I
4
Closed
accrual
67/11
Role of genetic profile in the evaluation of the
smoker and personalization of anti-smoking
therapies
R. Boffi
2011
31/12/13
-
330
140
82/11
Feasibility study of autologous adipose tissue Stem- U. Pastorino
Cells transplantation in 10 chest-wall resections
with prosthetic replacements
2011
17/05/13
I
10
1
66/05
Registry of congenital malformations in Lombardy
G. Tagliabue
2006
Observational 19431
2366
40/07
Dose-finding study of Caelix and RAD001 in
patients with advanced solid tumors
S. Cresta
2007
I
23
Closed
accrual
12/08
An open-label, safety, pharmacockinetics and
pharmacodynamic dose escalation phase Ib study
of pazopanib in combination with epirubicin or
doxorubicin in subjects with advanced solid tumors
G. Capri
2008
Ib
54
Closed
accrual
32/09
Epidemiologic studies on environmental risk factors A. Decarli
and their interactions with genetic factors of
bladder cancer and sarcomas
2009
Observational 680
353
35/09
Efficay of thermal treatment for respiratory airways U. Pastorino
in heavy smokers
2009
-
468
Closed
accrual
47/09
A phase I, open label, multicenter, study to assess
the safety, tolerability and pharmacology of AZ
D2281 in combination with liposomal doxorubicin
(Caelyx) in patients with advanced solid tumors
2009
I
8
Closed
accrual
54/09
Phase Ib study of CC-5013 and paclitaxel in patients G. Capri
with advanced solid tumors
2009
I
11
Closed
accrual
16/10
The role of spiritual and religiuos behaviours and
C. Ripamonti
beliefs as search of meaning, in the coping with
cancer. Pivotal study on factibility and on the impact
of a religiuos intervention
2010
Observational 25
4
32/10
Dose-escalation, PK and safety study with single
agent CetuGEX in patients with locally advanced
and/or metastatic cancer
S. Cresta
2010
I
6
Closed
accrual
54/10
Phase II study of nilotinib efficacy in pigmented
villo-nodular synovitis/tenosynovial giant cell
tumour (PVNS/TGCT)
P. G. Casali
2011
II
5
Closed
accrual
S. Cresta
219
back to contents
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2013
30
1
55/10
Evaluation of the response according to dimensional C. Morosi
and tissue criteria using contrast-enhanced
amplifier ultrasonography in patients with soft
tissue sarcomas or gastrointestinal stromal
tumors (GIST) after molecular target therapies
- CONTICANET
2010
-
27/11
Role of chemotherapy in trastuzumab cytotoxic
activity
E. Tagliabue
2011
Observational 11
Closed
accrual
41/11
Prospective, phase II randomized to compare
busulfan-fludarabine reduced-intensity
conditioning (RIC) with thiotepa-fludarabine
RIC regimen prior to allogeneic transplantation
of hematopoietic cells for the treatment of
myelofifrosis
P. Corradini
2011
II
1
0
42/11
SUTNET Trial: biological and clinical phase II study
of sunitinib in patients with unresectable and/or
metastatic pheochromocytomas/paragangliomas
R. Buzzoni
2011
II
16
7
56/11
A phase I dose-escalation study of PHA-739358
administered in combination with docetaxel or
gemcitabine or bevacizumab or carboplatin in adult
patients with advanced solid tumors, including
Hodgkin's and non-Hodgkin's lymphoma
A. Guidetti
2011
I
11
1
84/11
Interventional study, non-pharmacological,
multicenter, randomized, controlled, open-label,
aimed at preventing Alzheimer's disease with
nutrition
V. Krogh
2012
I-II
13
Closed
accrual
104/11
An open label, multicenter, expanded access study
P. Corradini
of INC424 for patients with primary myelofibrosis
(PMF) or post polycythemia myelofibrosis (PPV MF)
or post-essential thrombocythemia myelofibrosis
(PET-MF)
2011
III
4
2
112/11
Toremifene in desmoid tumor: prospective clinical
C.Colombo
trial and identification of potential molecular targets
2011
II
12
8
08/12
Hypercoagulation screening as an innovative tool
for risk assessment, early diagnosis and prognosis
in cancer
2012
Observational 229
151
12/12
A non-interventional retrospective correlation
P. Casali
of tumor mutation status to clinical benefit from
the SU011248, A6181036 treatment protocol
titled: a treatment protocol for patients with
gastrointestinal stromal tumor who are ineligible for
participation in other SU011248 protocols and are
refractory to or intolerant of imatinib mesylate
2012
Observational 11
Closed
accrual
25/12
Identification and validation of microRNAs as
novel biomarkers and therapeutic targets in diffuse
malignant peritoneal mesothelioma
N. Zaffaroni
2012
Observational 62
7
39/12
A phase I dose escalation study of NMS-1191372
in adult patients with advanced/metastatic solid
tumors
F. de Braud
2012
I
13
220
F. de Braud
23/07/13
16
Study
Code
Title
Coordinator
Activated
Closed
59/12
Identification of Polymorphisms Predicting
Bevacizumab-Related Side Effects: SToPtrial
M. Di
Bartolomeo
2012
Observational 63
23
61/12
A Phase 1b, multi-center, open label, dose escalation F. de Braud
study of oral LDE225 in combination with BKM120
in patients with advanced solid tumors
2012
I
3
1
75/12
A Phase 1a/1b, Multi-Center, Open-Label, Dose
F. De Braud
Finding Study to Assess the Safety, Tolerability,
Pharmacokinetics and Preliminary Efficacy of the
Pleiotropic Pathway Modifier CC-122 Administered
Orally to Subjects with Advanced Solid Tumors,
Non-Hodgkin’s Lymphoma or Multiple Myeloma
2013
I
6
6
82/12
A multicenter, multinational, randomized study
A.
of standard vs patients adapted protocols in
Marchianò
MultiDetector Computed Tomography (MDCT) of
the chest, abdomen, liver or aorta (Tailored CT study)
2013
03/07/13
-
62
62
86/12
The experience of pain in cancer patients: features
and possible solutions. A national research
(Epidemiological Study of Pain in Oncology
- ESOPO)
R. Buzzoni
2012
15/05/13
Observational 163
3
91/12
Database of patients with bone metastases from
germ cell cancer - An international database of the
G3 consortium
A. Necchi
2012
07/03/13
Observational 48
6
104/12
Incidence of thromboembolic events during
chemotherapy in metastatic/advanced cancer
patients
R. Buzzoni
2012
Observational 9
3
105/12
The Lombardy Rare Donor Programme
F. Arienti
2012
Observational 34
22
122/12
Phase 1b study of the tumor-targeting human
L19TNFalfa monocloonal antibody-cytokine fusion
protein in combination with doxorubicin in patients
with advanced solid tumours
F. De Braud
2013
I
8
134/12
Informative Note Project on Informed Consent:
understandability and usefulness of informed
consent in clinical interventional trials
C. Borreani
2013
Observational 20
20
135/12
Expectations, experiences and preferences of
patients and physicians involved in the informed
consent process for Phase 2 and Phase 3 clinical
trials: construction of a model
C. Borreani
2013
Observational 10
10
150/12
Epidural catheter related early complications.
The experience of the Fondazione IRCCS Istituto
Nazionale dei Tumori.
F. Piccioni
2013
Observational 1696
1696
15/04/13
Phase
Total
patients
8
Patients
enrolled
in 2013
06/13
Cross-tumoral phase 2 clinical trial exploring
P. G. Casali
crizotinib (PF-02341066) in patients with advanced
tumors induced by causal alterations of ALK and/or
MET ("CREATE")
2013
II
8
8
10/13
A Phase I open-label dose escalation study with
expansion to assess the safety and tolerability
of INC280 in patients with c-MET dependent
advanced solid tumors
2013
I
3
3
F. De Braud
221
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Study
Code
Title
Coordinator
Activated
21/13
Variation of respiratory function and chest wall
mechanics after resection and rib-like costal
reconstruction
F. Piccioni
2013
22/13
Airway management in thoracic surgery
F. Piccioni
2013
32/13
Multicenter, randomized, double-blind, placebo
controlled, study to evaluate the activity of a
ginger (Zingiber officinale) food supplement in
the management of nausea in patients receiving
highly emetogenic treatments and standard antiemetogenic therapy
P. Bossi
46/13
An open-label, multi-center everolimus roll-over
protocol for patients who have completed a
previous Novartis sponsored everolimus study
and are judged by the investigator to benefit from
continued everolimus treatment
56/13
Closed
22/10/13
Phase
Total
patients
Patients
enrolled
in 2013
-
9
9
Observational 201
201
2013
-
33
33
R. Buzzoni
2013
IV
2
Closed
accrual
Italian Oncologic Pain multiSetting - Multicentric
Survey (IOPS-MS)
A. T.
Caraceni
2013
Observational 30
30
76/13
An open label phase I dose finding study of BI
860585 administered orally in a continuous dosing
schedule as single agent and in combination with
exemestane or with paclitaxel in patients with
various advanced and/or metastatic solid tumours
F. De Braud
2013
I
3
3
77/13
Dose escalation, safety, pharmacokinetic
F. De Braud
and pharmacodynamic, first in man study, of
SAR125844 single agent administered as slow
intravenous infusion in adult patients with advanced
malignant solid tumors
2013
I
18
18
107/13
PreveDi (Prevention Disease) - Prevention of
chronic degenerative diseases
A. Villarini
2013
-
150
150
109/13
Oncology nutritionDay in Hospitals worldwide
C. Gavazzi
2013
Observational 139
139
129/13
Evaluation of outpatients's needs with solid or
haematological tumors at the S.S.D. "Supportive
Care Unit"
C. Ripamonti
2013
Observational 200
200
130/13
Tumor molecular markers able to predict benefit
from trastuzumab treatment
E. Tagliabue
2013
Observational 70
70
132/13
Analysis of the expression levels of biomarkers in
the blood of healthy donors
M. G.
Daidone
2013
Observational 90
90
143/13
Innovative approaches in the treatment of giant
congenital nevi melanocytes
A.
Colombetti
2013
-
10
160/13
Evaluation of the effect and tolerability of
pneumatic pressure therapy in the treatment
of lymphedema of the upper and lower limbs,
secondary to cancer surgery
A. T.
Caraceni
2013
Observational 112
222
09/12/13
10
Closed
accrual
back to contents
Editor
Marco A. Pierotti
Coordinator
Aurora Costa
Editorial management and Graphic Design
Rosaria Parentela
Collaborators
Daniela Majerna, Cecilia Melani
Copy editing and Translation
Patrick Moore
Photographer
Massimo Brega
Contribution to Graphics realization
Andrea Spinazzola
Studio Luvié
Fondazione IRCCS Istituto Nazionale dei Tumori
Via G. Venezian, 1 - 20133 Milan - Italy
Scientific Directorate
Tel. +39 02 2390 2300
Fax +39 02 2390 3141
direzionescientifica@istitutotumori.mi.it
http://www.istitutotumori.mi.it
Printed in June 2014 by M4, Milan
This report is printed on premium certified stock from well managed sustainable forests.
Cover: Fedrigoni Ispira Purezza 360 g/sm.
Internal pages: Fedrigoni Xper white 140 g/sm.
Copyright © 2014 Fondazione IRCCS Istituto Nazionale dei Tumori.
No part of this communication may be cited, reproduced, stored in a retrieval system,
or transmitted by electronic or other means without prior written permission
of the Scientific Director and the appropriate investigator.
224

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