scientific report 2015 - Istituto Nazionale dei Tumori

Transcription

SCIENTIFIC
REPORT
2015
2
SCIENTIFIC REPORT 2015
CONTENTS
INTRODUCING INT
FROM THE PRESIDENT
4
FROM THE SCIENTIFIC DIRECTOR
5
THE ESSENTIAL ABOUT INT IN 2015
7
FACTS AND FIGURES
8
INTERNATIONAL NETWORK
10
INT IN THE WEB
12
AWARDS AND RECOGNITIONS
13
SCIENTIFIC DIRECTORATE
14
RESEARCH POLICY PLAN
18
HIGHLIGHTS20
RESEARCH AND MULTIDISCIPLINARY ACTIVITIES
ANTIBODY-BASED REAGENTS FOR DIAGNOSTIC AND THERAPEUTIC USE: DEVELOPMENT, PRECLINICAL, AND CLINICAL
VALIDATION
23
BIOSPECIMEN REPOSITORY - BIOBANK
25
CLINICAL CANCER REGISTRY
27
DIET AND PREVENTION
31
EARLY DIAGNOSIS
34
HEAD AND NECK CANCER: A MULTIDISCIPLINARY APPROACH
37
HEMATOLOGICAL MALIGNANCIES, BONE MARROW TRANSPLANT AND NEXT GENERATION SEQUENCING IN HEMATOLOGY
39
HEREDITARY CANCER AND MEDICAL GENETICS
41
IMMUNITY 43
MELANOMA MULTIDISCIPLINARY PROGRAM
48
METASTATIC DISEASE: THE SURGICAL MANAGEMENT
53
MICROENVIRONMENT AND INFLAMMATION
58
NEW DRUGS AND PERSONALIZED MEDICINE
60
ORGAN REPLACEMENT & RECONSTRUCTION: LIVER TRANSPLANTATION
63
PATIENT-DERIVED XENOGRAFTS
66
PEDIATRIC TUMORS
68
PROSTATE CANCER PROGRAM
72
THORACIC ONCOLOGY: MULTIDISCIPLINARY RESEARCH
77
THYROID PATHOLOGIES AND CANCER: A MULTIDISCIPLINARY APPROACH
78
DEPARTMENTS AND UNITS
SURGERY81
MEDICAL ONCOLOGY
103
HEMATOLOGY AND PEDIATRIC ONCO-HEMATOLOGY 115
ANESTHESIA, INTENSIVE CARE, PAIN THERAPY, AND PALLIATIVE CARE 127
DIAGNOSTIC IMAGING AND RADIOTHERAPY 135
PATHOLOGY AND LABORATORY MEDICINE
147
EXPERIMENTAL ONCOLOGY AND MOLECULAR MEDICINE 154
PREVENTIVE AND PREDICTIVE MEDICINE
179
EDUCATION AND TRAINING
198
PUBLICATIONS202
ONGOING PROJECTS SUPPORTED BY CHARITIES, INTERNATIONAL AND NATIONAL ORGANIZATIONS
244
ETHICS COMMITTEE
252
ONGOING CLINICAL STUDIES
254
3
FROM THE PRESIDENT
ENZO LUCCHINI
S
ince January 1, 2016 I have been President of the Fondazione IRCCS – Istituto
Nazionale Tumori, the historical oncology center envisioned by Luigi
Mangiagalli and inaugurated on April 12, 1928, by Vittorio Emanuele III. The
Istituto Nazionale dei Tumori in Milan was the first center in Italy to organically
address the "dark evil", a term which Carlo Emilio Gadda called cancer in his novel
"The pain cognition" of 1941. Today the Institute has grown to the point that it has
become a reference of great international prestige for the research and treatment
of cancer, an "horizon of hope" for so many patients who come not only from all
Italian regions, but also from abroad.
The Institute I chair represents a human, cultural, scientific and technological
heritage for both the Lombardy Region, for Italy, and also abroad. INT is an
international cancer center certified by the Organization of European Cancer
Institutes (OECI) as a "Comprehensive Cancer Center". The Institute site is a composite
hospital structure where research activity is closely connected to the clinical
dimension of care. In Luigi Mangiagalli’s time, the “dark evil” would lethally affect
about 25 thousand people because of lack of good treatment and care, including
untold suffering. Today in Italy there are about 365 thousand new cases diagnosed
each year. Thanks also to the contribution of our Institute, cancer deaths in recent
decades have decreased by 18% among men and 10% among women. These results
were achieved thanks to prevention and research activity and thanks to the new
therapeutic options which have become available for the most common cancers as
well as for the most rare, investigated here and treated with excellence.
Thus, the INT stands for its patients as an "horizon of hope": through its multifold
excellence and a continuous collegial effort towards innovative frontiers of research,
immediately translating the latest evidence in the fields of prevention, diagnosis and
treatment into practice.
The underlying feature to this is INT’s signature: attention and care to the person
affected by the disease, not to the disease alone.
4
FROM THE SCIENTIFIC DIRECTORS
UGO PASTORINO (until August 2015)
GIOVANNI APOLONE (from September 2015)
T
he Scientific Report for 2014 accurately reflected, both in form and content,
the changes introduced by Dr Ugo Pastorino, head of the Thoracic Surgery
Department, who in 2014 took on the interim position of Scientific Director.
Drawing on his experience as an internationally renowned clinician with vast
expertise in large-scale clinical trials, Dr Pastorino designed a two-year strategic
plan that was agreed upon by all department directors. This 2015 Scientific Report
outlines the first results of the implementation of a strategy aimed at promoting
innovative areas of research with a strong focus on the constant improvement
of clinical outcomes. In particular, this report details the progress made towards
the objectives identified in the field of translational research; for example, the
validation of a personalized approach to cancer treatment; the inclusion of more
patients in clinical trials conducted to evaluate not only new drugs but also earlydetection, screening and active surveillance programs; the use of genetic and
epigenetic profiling to identify poor-prognosis cases; the development of innovative
and minimally invasive medical and surgical treatments; and the development of
programs aimed at primary prevention.
In September 2015, Dr Giovanni Apolone was appointed by the Minister of Health
to be the new Scientific Director of the Institute. On the basis of his experience as
a researcher and health system manager, and building upon the work of previous
directors, he has planned a new research program that was agreed upon by the
Scientific Institutional Committee and will be put in place from 2016 onwards. It will
include the production of a three-year research plan agenda, the re-organization
of research departments with the establishment of a new research infrastructure,
the creation of a dedicated research fund and budget, and the implementation of an
annual competitive, externally peer-reviewed, institutional call to support research
projects aligned with the research objectives of the Foundation.
An independent assessment conducted by the Ministry of Health to evaluate the
performance of the 49 Italian IRCCSs in 2015 ranked INT at the first place among
Italian Comprehensive Cancer Centers, against a set of 14 indicators of excellence in
scientific research, healthcare and networking.
In 2015, INT upheld the highest standards of healthcare with over 18,000 inpatients
treated and, even more strikingly, 1,200,000 patients seen at INT every year: a figure
that prompts some reflection. On average, every day 8000 people – patients and
their families - walk into our Institute, 25 percent coming from outside our region.
What they are looking for and what they find here is quality healthcare in primary
prevention, early diagnosis and treatment, as well as the opportunity to participate in
trials of innovative health technologies.
5
As part of the mission of any IRCCS, research at INT covers all the most significant
areas of cancer research, with structures and scientific programs ranging from
basic to clinical and healthcare research. The graphs and figures presented in the
first part of this report give an overview of these activities; we would like to stress
that these could only be achieved thanks to the strong focus of our Institute on
translational research, where research activities and healthcare are connected
through multidisciplinary programs designed and coordinated by teams with diverse
clinical and scientific backgrounds. All researchers collaborate within the framework
of a strategic program based on the history and the very nature of INT. Themes and
strategies revolving around INT’s identity as a public institution are therefore favored,
with special emphasis on innovation and the advancement of knowledge, but without
forgetting the clinical and healthcare needs of patients and the population that are
not always met in other, for-profit institutes and organizations.
Finally, the scientific output in 2015 has enjoyed an upward trend according to all
standards conventionally used to classify research activity: 590 clinical trials were
conducted, 376 of which classifiable as studies on new drugs or health technologies.
Over 25,000 patients had the opportunity to participate in research protocols
that, besides offering them the best possible treatment, also gave them access to
innovative drugs and devices. In 2015, we published more scientific papers (667
with 3878 IF) than in 2014, thereby upholding the positive trend of recent years. All
departments at the Institute contributed to the research activity, as made clear by
the affiliations of the authors and the attribution of 60% of the total IF to the clinical
departments, 20% to the experimental department, and the remaining 20% to the
epidemiology department. It is also worth noting that our researchers were either
first or corresponding authors in almost half of the publications by INT-affiliated
scientists.
6
THE ESSENTIAL
ABOUT INT
IN 2015
SCIENTIFIC ACTIVITY
667
PUBLICATIONS
RESEARCH
IMPACT FACTOR
3878.03
PUBLICATIONS
AS FIRST/LAST
AUTHOR
45.7%
590
CLINICAL
STUDIES
OBSERVATIONAL
STUDIES
214
EXPERIMENTAL
STUDIES
376
PATIENTS
INCLUDED IN
CLINICAL STUDIES
PATIENTS ENROLLED IN
OBSERVATIONAL STUDIES
23,086
PATIENTS ENROLLED IN
EXPERIMENTAL STUDIES
2,759
CLINICAL DATA
EDUCATION
188
EVENTS
25,845
PARTICIPANTS
4,004
482
BEDS
FORMATIVE HOURS
36,216
TOTAL INPATIENTS
18,522
OF WHICH
DAY HOSPITAL
4,606
CONSULTATIONS
FORMATIVE CREDITS
1,203,672
30,451
PATENT PORTFOLIO*
RESEARCH FUNDING
16
PATENTS
€
24,343,394.88
TOTAL EUROS
MINISTRY OF HEALTH
7 PATENTS
CO-OWNER OF 9 PATENTS
OWNER OF
€ 7,546,313.34
FUNDING AGENCIES
€ 13,443,081.54
CLINICAL TRIALS
€ 3,354,000.00
7
FACTS
& FIGURES
RESEARCH
FUNDING
IMPACT FACTOR
AND PUBLISHED PAPERS
Published
Papers
8
Impact
Factor
2015
667
3878.03
2014
638
3513.49
2013
550
2761.98
2012
518
2519.29
2011
450
2353.98
2010
426
2274.62
Ministry
of Health
Funding
Agencies
Clinical
Trials
2015
€ 7.546.313,34
€ 13.443.081,54
€ 3.354.000,00
2014
€ 7.638.385,53
€ 11.526.824,80
€ 4.149.409,14
2013
€ 8.052.592,96
€ 13.548.844,54
€ 3.039.755,47
2012
€ 9.165.658,00
€ 14.789.237,67
€ 3.004.978,64
(N. PTS / YEARS)
OBSERVATIONAL STUDIES
ONGOING IN 2015
(N. PTS / YEARS)
EXPERIMENTAL STUDIES
ONGOING IN 2015
CLINICAL STUDIES
Clinical studies ongoing
2015
590
2014
534
2013
468
2012
356
Experimental studies ongoing in 2015
RANDOMIZED
NO RANDOMIZED
Profit
No Profit
124 (33%)
85 (23%)
71 (19%)
96 (26%)
No Randomized studies
Randomized studies
Profit
No Profit
Profit
No Profit
2015
359
517
400
1.483
2014
401
478
305
1.768
2013
251
327
373
1.324
2012
130
220
349
585
Sponsor
Profit
Sponsor
No Profit
2015
196
22.890
2014
298
13.301
2013
50
9.544
2012
9
2.902
9
INTERNATIONAL
NETWORK
INTERNATIONAL
RESEARCH NETWORK
INTERNATIONAL
CANCER ORGANIZATIONS
BCAC
CIMBA
CONTICANET
EAPC
EBMT
Breast Cancer
Association
Consortium
Consortium
of Investigators
of Modifiers
of BRCA1/2
European
sarcoma
database and
tumour bank
European
Association for
Palliative Care
European
Society for Blood
and Marrow
Transplantation
CRYO-ONCO NETWORK
Includes oncologists,
hematologists, pediatricians,
surgeons, andrologists
and gynecologists, who
are all experts in assisted
reproductive medicine
ITCC
The Innovative
Therapies for
Children with
Cancer Consortium
ENETS
European
Neuroendocrine
Tumor Society
ECCO
EHA
European
Network
of Cancer
Registries
European CanCer
Organisation
European
Hematology
Association
ENIGMA
Evidence-based
Network for the
Interpretation of
Germline Mutant Alleles
NICSO
PANCARE
Network Italiano
Cure di Supporto
in Oncologia
Pan European
Network for Care
of Survivors after
Childhood and
Adolescent Cancer
PCR
European
Palliative Care
Research Centre
WORLD SARCOMA NETWORK
Cooperative group gathering the
main reference centres for sarcomas
around the World dedicated to the
development and the support of
innovative and collaborative clinical
trials and to the drug development
in sarcomas
10
ENCR
EHNS
European
Head and
Neck Society
EORTC
European Organisation
for Research and
Treatment of Cancer
ESMO
European Society for
Medical Oncology
EUROPADONNA
EUROPAUOMO
The European Breast
Cancer Coalition
The European
Prostate Cancer
Coalition
OECI
Organization
of European
Cancer
Institutes
UICC
Union for
International Cancer
Control
WIN
Worldwide Innovative
Networking in
Personalized Cancer
Medicine
EUROPEAN
RESEARCH PROGRAMS
BENCH-CAN
BIO RARE K-RAS
CANCON
Benchmarking comprehensive
cancer care that provides
interdisciplinary treatment
for patients, and yield
examples of best practice in
comprehensive cancer care
Mutations and DNA
repair function in
NSCLC
European guide on
quality improvement
in comprehensive
cancer control
EPIC-CVD
DietINT
EPIC
A randomized phase II study
for tertiary prevention of
squamocellular cancer of
head and neck (SCCHN)
with a dietary intervention
European
Prospective
Investigation
into Cancer and
Nutrition
EUROCAN PLATFORM
A European Platform
for Translational Cancer
Research
EUROCARE
EUROSARC
European Cancer
Registry based Study
on Survival and Care
of Cancer Patients
European Clinical
trials in Rare
Sarcomas within
an integrated
translational trial
network
Expo-r-Net
European Expert
Paediatric
Oncology
Reference
Network for
Diagnostics and
Treatment
I.FAMILY
Investigating the
determinants
of food choice,
lifestyle and
health in
European children,
adolescents and
their parents
Individualised CVD risk
assessment:tailoring
targeted and costeffective approaches
to Europe’s diverse
populations
IACT
Immunostimolatory
Agonist Antibodies for
Cancer Therapy
MEMEME
Randomized controlled trial
of metformin and dietary
restriction to prevent agerelated morbid events in people
with metabolic syndrome
IMMUNOCAN
Toward enhancing
activities of European
institutions in the
FDUSCC-IM cancer
research joint institute
in China
RARECARENet
Information network
on rare cancers
REQUITE
JARC
Joint Action on Rare
Cancers
Validating predictive
models and
biomarkers of
radiotherapy toxicity
to reduce side-effects
and improve quality
of life in cancer
survivors
TackSHS
Tackling secondhand
tobacco smoke and
e-cigarette emissions:
exposure assessment, novel
interventions, impact on
lung diseases and economic
burden in diverse European
populations
11
INT IN THE WEB
Institutional website
www.istitutotumori.mi.it
Art in the Ward Project
www.arteinreparto.com
Early Detection and Risk Assessment Project
www.ederaproject.it
Health Educational website
www.lascuoladellasalute.it
Italian Epidemiological Database on Cancer
www.tumori.net
Italian Society for Adolescents with Onco-Hematological Diseases
www.progettosiamo.it
Lombardy Oncology Network
www.progettorol.it
Multicentric Italian Lung Detection - Clinical Trial
www.biomild.org
Pediatric Oncology - Youth Project
www.ilprogettogiovani.it
SIURO - PRIAS - ITA (Prostate Cancer Research International: Active Surveillance)
www.siuro.it
“When Art meets Medicine” Project
www.artemedicina.com
Tumori Journal website
www.tumorijournal.com
Voluntary Associations
ADSINT - Associazione Donatori di Sangue Istituto Tumori di Milano www.adsint.mi.it
AIG - Associazione Italiana GIST Onlus www.gistonline.it
AILAR - Associazione Italiana Laringectomizzati Onlus www.ailar.it
ALSI - Associazione Lombarda Stomizzati Incontinenti www.alsilombardia.it
Amici per la pelle www.amicixlapelle.it
Associazione Bianca Garavaglia – Onlus www.abianca.org
Associazione Marta Nurizzo www.martalive.org
Associazione PaliNUro www.associazionepalinuro.com
Attive come prima – Onlus www.attive.org
Casa Amica Onlus www.casamica.it
F.A.V.O. - Federazione italiana delle associazioni di Volontariato in Oncologia www.favo.it/associazioni-federate
Fondazione Theodora – onlus www.theodora.it
Lega Italiana per la Lotta contro i Tumori – LILT www.legatumori.it
Officine Buone www.officinebuone.it
Onlus PROMETEO - IRCCS, Istituto Nazionale dei Tumori www.onlusprometeo.org
Salute Donna – Onlus www.salutedonnaweb.it
12
AWARDS
AND
RECOGNITIONS
The Joint Commission International
Network Italia awarded the
Fondazione IRCCS INT with the “Premio
Miglioramento della Qualità” (ranked
third best).
The Commettee Ospedaledonna
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 female patients.
Dr Giulia Bertolini
won the “Marzia Galli Kienle Award”
of the Associazione SOS - Solidarietà
in Oncologia San Marco Zingonia –
Onlus (Second Edition) for best papers
published by young researchers in
oncology in 2015.
Dr Dario Callegaro
was given the “Premio Lorini 2015” of
the Fondazione Andrea e Libi Lorini, for
the article “Development and external
validation of two nomograms to predict
overall survival and distant metastases
after surgical resection of localised soft
tissue sarcomas of the extremities: a
retrospective analysis” (published in The
Lancet Oncology 2016).
Dr Chiara Camisaschi
was awarded with the "2015 SITC
International Scholar Prize” in
recognition of her early career
achievements through scientific
excellence and exemplary work in
the field of cancer immunotherapy.
November 7, 2015, National Harbor, MD
Dr Martina Di Modica
received the “Piero Trivella Award” for
the best poster (“Role of exosomeassociated miR-939 in breast cancer
metastatic process”) during the EACRAACR-SIC Special Conference 2015.
Dr Luca Forte
was bestowed the “Premio Fondazione
Grazioli 2015” for best graduate student
thesis in the field of mathematical sciences.
Dr Orazio Fortunato
won an “AACR-SIC Scholar-in-Training
Award” to attend the AACR Annual
Meeting 2016.
Dr Giulia Grazia
was given a Honorable Mention in
the “Marzia Galli Kienle Award” of
the Associazione SOS - Solidarietà in
Oncologia San Marco Zingonia – Onlus
(Second Edition) for best papers published
by young researchers in oncology in 2015.
Dr Marilena Iorio
won an “AACR-SIC Scholar-in-training
Award” to attend the AACR Annual
Meeting 2016.
Dr Lisa Licitra
was conferred the 2015 “Hubertus
Wald Award” of University Cancer
Center Hamburg “in recognition of her
outstanding achievements in the field of
cancer research and cancer therapy”.
Dr Andrea Necchi
was the recipient of the “Conquer Cancer
Foundation of ASCO (American Society of
Clinical Oncology) Merit Award” 2015.
The “Giovani Ricercatori 2015” Award of the Fondazione IRCCS INT was conferred
upon the following young researchers:
Dr Mattia Boeri and Dr Alice Rigoni (ex-aequo) for translational research;
Dr Maria Chiara Anania for basic research;
Dr Alberto Mussetti for clinical research.
13
SCIENTIFIC
DIRECTORATE
Medical Statistics,
Biometry, and
Bioinformatics
Clinical Epidemiology
and Trial Organization
Staff
Units
SCIENTIFIC DIRECTOR
Experimental Oncology and Molecular Medicine
Department
14
Preventive and Predictive Medicine
Department
Tumor Genomics
Immunobiology
of Human Tumors
Epidemiology
and Prevention
Genetic Epidemiology
and
Pharmacogenomics
Biomarkers
Molecular
Mechanisms of Cell
Cycle Control
Analytical
Epidemiology
and Health Impact
Hereditary Digestive
Tract Tumors
Molecular
Immunology
Immunotherapy
of Human Tumors
Molecular Bases
of Genetic Risk
and Genetic Testing
Medical Genetics
Molecular
Pharmacology
Molecular
Therapies
Evaluative
Epidemiology
Molecular
Targeting
Cancer Registry
Molecular
Mechanisms
Environmental
Epidemiology
The Scientific Directorate coordinates research and education
activities, planning scientific policy and evaluating research
projects and clinical trial proposals through the internal
review board (Committee of the Scientific Directorate). It keeps
institutional relationships with key health authorities at regional
and national level, it supports researchers seeking public
and private funding through the Grant Office (GO), it provides
access to information resources through the Biomedical
Library services, it sustains scientific communication and, in
collaboration with the institutional press office, it promotes
dissemination of information about health and science to the
larger public.
SCIENTIFIC DIRECTORATE UNITS
MEDICAL STATISTICS, BIOMETRY AND BIOINFORMATICS (MSBB)
Director: Adriano Decarli, PhD
This Unit 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 an
agreement with the University of Milan.
Biostatistics for Oriented Basic Research and Quality Control
Paolo Verderio, Biol Sci D, PhD; Sara Pizzamiglio, MSc; Chiara Maura Ciniselli, MSc;
Stefano Bottelli, MSc; Mara Lecchi, MSc; Maddalena Plebani, PhD
The group provides methodological support at different stages of translational
research in oncology, starting from the genesis of laboratory data to their
interpretation in a clinical view through the identification, implementation of new
methodological and statistical procedures and the development of innovative
approaches of analysis. Specifically, the activity of the team are focused on:
a) s
tudies for setting up and validation of biological assays for biomarkers
identification;
b) quality control studies for tumor biomarkers and in vitro-diagnostic tools;
c) s
tudies for the evaluation of inherited diseases in oncology;
d) studies of preclinical pharmacology;
e) studies for testing new molecular detection strategies based on innovative
technologies.
Currently, the main research areas of the group are related to the design and analysis
of studies aimed at identifying and developing oncology biomarkers of potential
clinical relevance.
Biostatistics for Bioinformatics and Translational Research
Elia M. Biganzoli, PhD; Giuseppe Marano, 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 highthroughput 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.
Networking
Pancreatic Cancer Case-Control Consortium (PANC4) an International Network
including more than 10,000 PC cases and 15,000 controls.
15
Keywords
Statistical analysis, Quality control schemes, Next Generation Sequencing
Selected Publications (2013-2015)
C. La Vecchia, A. Decarli, M. Serafini, M. Parpinel,R. Bellocco, C. Galeone, C. Bosetti, A. Zucchetto, J, Polesel, P. Lagiou , E.
Negri and M. Rossi. Dietary total antioxidant capacity and colorectal cancer: A large case–control study in Italy. Int. J.
cancer, 133: 1447-1451, 2013
M. Cristofolini , S.· Boi, D. Cattoni, M.C. Sicher , A. Decarli, R. Micciolo. A 10-Year Follow-Up Study of Subjects Recruited
in a Health Campaign for the Early Diagnosis of Cutaneous Melanoma: Suggestions for the Screening Timetable.
Dermatology 231:345-352 , 2015
Palassini E, Ferrari S, Verderio P, De Paoli A, Martin Broto J, Quagliuolo V, Comandone A, Sangalli C, Palmerini E, LopezPousa A, De Sanctis R, Bottelli S, Libertini M, Picci P, Casali PG, Gronchi A. Feasibility of Preoperative Chemotherapy
With or Without Radiation Therapy in Localized Soft Tissue Sarcomas of Limbs and Superficial Trunk in the Italian
Sarcoma Group/Grupo Español de Investigación en Sarcomas Randomized Clinical Trial: Three Versus Five Cycles of
Full-Dose Epirubicin Plus Ifosfamide. J Clin Oncol. 2015 Nov 1;33(31):3628-34. doi: 10.1200/JCO.2015.62.9394. Epub 2015
Sep 8.
Malentacchi F, Pazzagli M, Simi L, Orlando C, Wyrich R, Günther K, Verderio P, Pizzamiglio S, Ciniselli CM, Zhang H,
Korenková V, Rainen L, Bar T, Kubista M, and Gelmini S. SPIDIA-RNA: Second External Quality Assessment for the preanalytical phase of blood samples used for RNA based analyses. PLoS One. 2014;10; 9:e112293
Verderio P, Bottelli S, Ciniselli CM, Pierotti MA, Gariboldi M, Pizzamiglio S. NqA: an R-based algorithm for the
normalization and analysis of microRNA qPCR data. Anal Biochem. 2014. 461C:7-9
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.
The above activity benefits from the experience and staff expertise in biostatistics,
informatics and biomedicine. By taking into account the developments of statistical
methodology in many areas of current interest (like early study design, event history
analysis, quality of life and pharmacoeconomic evaluation tools), the Unit strives to
put into practice the most updated methodologies suitable for design and analysis of
diagnostic, therapeutic, chemoprevention and prognostic trials.
Part of this activity translates into the contributions to congresses or in the
publication of methodological articles.
Selected Publications (2013-2015)
E. Landoni, R. Miceli, M. Callari, P. Tiberio, V. Appierto, V. Angeloni, L mariani, and M. G. Daidone. Proposal of supervised
data analysis strategy of plasma mirnas from hybridisation array data with an application to assess hemolysisrelated deregulation . BMC bioinformatics 16: 2015
Maurichi A., Miceli R., Camerini T., Mariani L., Patuzzo R., Ruggeri R., Gallino G., Tolomio E., Tragni G., Valeri B., Anichini
A., Mortarini R., Moglia D., Pellacani G., Bassoli S., Longo C., Quaglino P., Pimpinelli N., Borgognoni L., Bergamaschi D.,
Harwood C., Zoras O., Santinami M.: Prediction of survival in patients with thin melanoma: Results from a multiinstitution study. J Clin Oncol 2014; 32: 2479-2485
Gronchi, A., Miceli, R., Shurell, E., Eilber, F. C., Eilber, F. R., Anaya, D. A., Kattan, M. W., Honoré, C., Lev, D. C., Colombo,
C., Bonvalot, S., Mariani, L., and Pollock, R. E. Outcome Prediction in Primary Resected Retroperitoneal Soft Tissue
Sarcoma: Histology-Specific Overall Survival and Disease-Free Survival Nomograms Built on Major Sarcoma Center
Data Sets. Journal of Clinical Oncology 31(13), 1649-1655. 2013.
16
SPECIAL PROJECTS/ACTIVITIES
CLINICAL TRIALS CENTER
Coordinators: Valentina Sinno, Biol Sci D; Luigi Mariani, MD PhD
The operative Clinical Trial Center (CTC) was 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
one “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.
The CTC works through validated and updated SOP and electronic CRF customized
for each 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.
Since its inception, the CTC managed 387 clinical studies; 171 of which investigatordriven; in 2015, 97 clinical studies were activated, 47 of which non-profit.
TUMORI JOURNAL
TJ
Tumorijournal.com
Tumori
Journal
Editor in Chief: Ugo Pastorino
ISSN: 0300-8916 - e-ISSN: 2038-2529
Frequency: 6 issues per year
Impact Factor: 1.071
In 2014 the journal was completely renewed, establishing a new editorial board,
creating a new graphic design, restoring the publisher, and replacing the old title in
Tumori Journal (TJ).
• International reviewers panel: 63% from Europe, 27% from
USA/Canada, 10% from ROW
• Altmetrics data availaible for all articles
• Wide visibility in international libraries/data aggregators/document delivery
services
• Indexed in all major databases
• Section Editors median age = 42
• Section Editors H-Index = 18.5
Bonadonna Lecture Series
The Bonadonna Lecture Series is a novel initiative that will accompany you through
the rest of 2016 and beyond.
This lecture series is a due recognition of the enormous contribution that Gianni
Bonadonna gave to the field of clinical oncology, pioneering the adoption of
innovative approaches in the management of cancer patients. Most importantly,
these reviews will help all of us to put into a broader context some of the critical
issues facing medical and surgical oncology today.
New affililiations
European School of Oncology (ESO); Italian Association of Medical Oncology (AIOM),
Organization of European Cancer Institute (OECI).
17
RESEARCH
POLICY PLAN
2013-2015
approved by the
ITALIAN MINISTRY OF HEALTH
LINE 1
PREVENTIVE AND
PREDICTIVE MEDICINE
LINE 2
STUDY OF THE MOLECULAR
BASIS OF CANCER
DEVELOPMENT AND
PROGRESSION AND THE
ROLE OF TUMOR-HOST
INTERACTIONS
LINE 3
INNOVATIVE PROBLEMORIENTED APPROACHES TO
DIAGNOSIS AND TREATMENT
Description
Description
Description
Research activity focuses on epidemiology
and prevention through prospective
epidemiological studies, case-control
studies and survival studies. Our Institute
coordinates National and International
multicenter studies including European
projects on rare tumors as well as
interventional prevention projects. Our
research on families with high genetic
risk included a series of interventions
developed towards people with a genetic
predisposition to cancer and is carried
out with the clinical and molecular
characterization of the involved genes.
Aims
Organization and implementation of
interventional prevention projects, and
management of the related biobanks.
Creation of information networks based on
data of population-based cancer registries.
Determining the causes of survival
differences present between populations
of the same or of different countries;
production of health indicators; promotion
of information on health and healthy
lifestyles; knowledge distribution of cancer
epidemiology.
With regard to the familial-hereditary
cancer: identification of individuals with
increased genetic risk and of predisposing
gene(s); coordination of correct
surveillance programs and feasible options
for prevention; planning an adequate
treatment in case of disease development.
18
Study of the molecular mechanisms (and
their alterations) responsible for the
origin, growth and progression of solid
tumors and development of treatment
approaches selectively targeting these
mechanisms; Identification of tumor
mechanisms of interaction with the
surrounding microenvironment (stroma,
immune system cells, extracellular
matrix) during cancer progression, 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, as
well as predictive markers of 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. Detection and assessment of
molecular targets against which to develop
innovative treatments and clinical tests.
Development of new drug combinations for
advanced experimental systems.
Study of tumor-microenvironment
interaction and identification of the
molecular and genetic characteristics
that can be translated into biomarkers
for cancer diagnosis 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) prognostic characterization
of rare tumors (“big killers” that constitute
yet an unsolved problem both from
a diagnostic and therapeutic point of
view); b) knowledge of the mechanisms
responsible for the different degrees of
radiotherapy toxicity in different tumor
types; iii) anticancer vaccines, genetic and
biological therapies in certain tumors for
the clinical testing of new substances.
Aims
Selection of biomarkers for early
diagnosis, cancer risk assessment and
treatment response; development of
radiopharmaceuticals for biological
characterization and use in imaging and
treatment.
LINE 4
MULTIDISCIPLINARY
DISEASE-ORIENTED
APPROACH
LINE 5
PEDIATRIC CANCER
LINE 6
PATHWAYS OF RESEARCH/
INTERVENTION AND
ASSESSMENT OF QUALITY
OF LIFE IN PATIENTS WITH
CANCER
Description
Description
Description
Interdisciplinary studies by organ disease
including lung carcinoma, hepatocellular
carcinoma, soft tissue sarcomas, tumors
of the adult lymphohematopoietic
system, and eventually other tumor
types. Enhance/intensify the relationship
between preclinical and clinical
research starting with novel molecular
characterization techniques intended for
new treatment approaches and a wider
use of targeted molecular therapies.
Translational project development in
the context of every single disease with
operational support for the design and
conduct of non-profit institutional clinical
studies.
Aims
Promoting the development of a
multidisciplinary disease-oriented
approach across different types of
cancer. Focal areas of study will be
chemoprevention and treatment of
preinvasive disease; early diagnosis;
molecular typing and staging; conservative
and minimally invasive treatment;
targeted, biologically based therapies.
Additional areas will include assessing
the potential of individual patient tailored
therapies (personalized medicine) using
both conventional cytotoxic drugs and new
molecular compounds to minimize toxicity.
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 patient and
family support to ensure they are not
abandoned but fully supported (control of
physical and psychological symptoms) and
accompanied along the terminal phase of
the disease.
Aims
Integrating longer survival and improving
quality of life. For the most important
childhood tumors (neuroblastoma, Wilms’
tumor, Ewing’s sarcoma), studies will seek
to identify new therapeutic targets, thus
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.
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 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 treatment and quality
of life of cancer patients. With regard to
oncological rehabilitation, information on
the specific patient needs with debilitating
treatment sequelae is still incomplete.
Aims
Assessment of analgesic therapy delivery,
symptom control and supportive care
(infusion of blood products, parenteral
nutrition, etc.), comprehensive symptom
and quality of life assessment, detection
of markers potentially associated with
the response to compassionate clinical
treatment.
19
HIGHLIGHTS
1
Nuvole di Ossigeno, is the title of a song
originally written by our adolescent patients
which has the dignity of a scientific paper
in Journal of Clinical Oncology (J Clin Oncol 33:218,
2015). Patients’ stories and their song are the center of
interest of this prestigious journal. The song, born inside
the unit, is like a hymn devoted to the “Youth Project”
and the desire for normality. Patients tell us how
dreadful is to substitute classmates with sick siblings
and blood exams with school performances. They
want to recall to everyone that “the best feeling of all is
knowing you have a future and that it’s in your hands”
2
Atmospheric fine particulate matter and breast
cancer mortality
A population-based cohort study on female
breast cancer patients has been conducted. Results show
how risk of breast cancer death increased from 72% to
82% as exposure to fine particulate matter increased.
3
2-JULIET: An innovative trial employing
chimeric antigen receptor (CAR) T cells that
have been shown in early clinical trials
to be particularly effective in treating lymphoma. In
CAR T cell therapy, T cells from a patient are removed
and then genetically modified to express a protein
receptor that recognizes the CD19 antigen found on
lymphoma cells. For the first time in Italy, patients
with Diffuse Large B-cell Non-Hodgkin’s Lymphoma
(DLBCL) relapsed or refractory to first-line therapy,
and those who are not candidates for autologous
transplant, will have access to this highly effective
anti-tumor cell therapy.
4
Several antibody-based reagents have been
engineered reaching patent deposition and
clinical application: EU patent application
for bispecific anti-TRAILR\Anti-CD3, able to redirect
T-cell lymphocyte on a wide panel of tumors, for cancer
immunotherapy use.
Preclinical evaluation completion of scFv D2B, directed
against prostate specific membrane antigen, to be tested
for prostate cancer imaging in a human pilot study.
First in human study of the new therapeutic antibody
MOv18 IgE anti alpha-FR, in patients with advanced solid
tumors: collaborative phase I clinical trial NCT02546921.
20
5
Microenvironment-Modulated Metastatic CD133+/
CXCR4+/EpCAM− Lung Cancer–Initiating Cells
Sustain Tumor Dissemination and Correlate with
Poor Prognosis.
The published results highlight the CXCR4 signaling axis as
a target for disrupting the development of chemotherapyresistant cancer-initiating cells in the metastatic niche,
suggesting an effective therapeutic strategy to improve
the clinical management of lung cancer patients.
6
Gene expression analysis in desmoid tumors
grouped on the basis of b-catenin mutation status
Desmoid tumors (DTs) are rare mesenchymal
infiltrative lesions with lack of metastatic potential but high
frequency of mutations (T41A and S45F) in the CTNNB1
gene encoding b-catenin. These mutations are associated
with higher risk of local recurrence. To explore the DT
clinical association with its gene expression an analysis
on 33 formalin-fixed DTs specimens was performed. This
analysis,complemented by Molecular Dynamics simulations,
investigated the mutations and non mutated protein
differences in terms of thermodynamic stability and b-actin
affinity.
7
We develop treatments using new molecular
compounds, and investigate new therapeutic
strategies, with particular attention to the
immune system, for solid tumors. This is carried out by a
Unit fully dedicated to new drug development (phase I and
Ib studies) and promotion of translational research projects,
as well as conducting both non sponsored and sponsored
phase II/III trials. The Unit is strictly connected to a wellequipped preclinical laboratory focused on translational
medicine to test novel therapeutic approaches.
8
After several decades of non therapeutic
progression in the field of urothelial carcinoma
(UC), the introduction of immune checkpoint
inhibitors to use in clinical trials is now revitalizing
the therapeutic options for UC. In 2015 the Urology Unit
opened a number of significant phase II and III trials of
immunotherapy in the field of advanced UC, the results of
which will be published in 2016 and will likely reinvigorate
a new therapeutic paradigm.
9
Targeting of a master regulator of
melanoma differentiation to
counteract resistance to therapy
Loss of expression of the transcription
factor MITF is associated with melanoma
dedifferentiation and with development of
resistance to immunotherapy and to target
therapy. We identified NFATc2 as a negative
regulator of MITF. NFATc2 targeting, by silencing
or pharmacological inhibition, restored MITF
expression and rescued tumor recognition by
cytotoxic T lymphocytes. Reversal of melanoma
resistance to BRAF- and MEK- inhibitors by
targeting of NFATc2 is currently investigated.
10
Personalized treatment in gynecological
cancers
Medical treatments based on tumors’
molecular characteristics (protocols with PARP
inhibitors in HRD+ patients alone or in combination with
antiangiogenic treatments, immunotherapy in advanced
ovarian and cervical cancer, MEK inhibitors in low grade
serous tumors, Temozolamide in MGMT hyperventilated
mucinous and clear cell tumors, Trastuzumab in Her2+
mucinous ovarian cancer). Surgery based on patients’
clinical characteristics (conservative treatments in
early stage cervical and endometrial cancer, sentinel
lymph nodes procedures rother than invasive
lymphadenectomy in endometrial cancer).
11
In 2015, the accrual of 38 peritoneal
mesothelioma patients has been
completed for the prospective trial
“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”.
The study wanted to assess a personalized
approach of postoperative systemic therapies based
on tumor molecular profile and chemosensitivity
tests performed on cell cultures derived from
mesothelioma specimens.
12
Guidelines for the management of
localized retroperitoneal sarcoma
In 2015, after 2 years of INT coordinated
work, the first consensus about the approach to primary
retroperitoneal sarcoma (RPS) has been published.
Several European and North American Institutions
collaborated for a new RPS specific nomogram able to
predict the risk of individual patient. This nomogram is
integrated in the new AJCC Sarcoma staging system.
With this collaboration the primary approach to RPS
was made uniform across the Atlantic, by implementing
as standard the primary extended resection and
including an upfront multidisciplinary evaluation before
any surgical procedure.
13
The promise of liquid biopsy in cancer:
moving toward precision medicine
Recent advances have made it possible
to isolate from bodily fluids circulating tumor cells,
exosomes, nucleic acids — including microRNAs - and
proteins that are investigated as novel biomarkers
for early detection, risk assessment and monitoring
treatment response. Indeed, assessment of tumor
characteristics by ‘liquid biopsy’ represents a promising
opportunity. These biomarkers may be useful to:
investigate new genetic changes occurring in tumors
bearing targeted therapies; improve treatment selection,
thus moving toward more personalized treatments.
14
Determine the relevance of tumor/
microenvironment cross-talk in breast
carcinoma progression, response to
therapy and early diagnosis
According to our recent results the cross-talk between
transformed cells and microenvironment is a key force
in conditioning breast carcinoma evolution in patients.
We recently found that extracellular matrix proteins
and microRNA released upon the interaction between
an incipient breast carcinoma clone and the adjacent
microenvironment could be an amplified marker of breast
neoplastic transformation detectable in peripheral blood.
15
Main focus is the development and
refinement of surgical techniques able to
simplify surgical procedures and improve
peri-operative outcomes. For liver tumors treatment,
expanded application of laparoscopic technique improved
the outcomes, resulting in shorter hospital stayand lower
complications rates. A new technique called “chemical
pancreatectomy with neoprene”, employed for resections
of the pancreatic head, is under clinical evaluation. It
seems to dramatically reduce postoperative pancreatic
fistula, the most fearful complication in this kind of
surgery, particularly in high risk patients.
21
RESEARCH AND
MULTI
DISCIPLINARY
ACTIVITIES
DEVELOPMENT,
PRECLINICAL,
AND CLINICAL
VALIDATION OF
ANTIBODY-BASED
REAGENTS FOR
ANTIBODY-BASED REAGENTS FOR DIAGNOSTIC
AND THERAPEUTIC USE: DEVELOPMENT,
PRECLINICAL, AND CLINICAL VALIDATION
PROGRAM MEMBERSHIP
M. FIGINI (COORDINATOR)
E. TAGLIABUE
Antigen-specific monoclonal antibodies (MAbs) with direct
pharmacological effects as naked antibodies, conjugated
with chemotherapy/toxic agents, or able to stimulate
immunological responses, are promising therapeutic
agents for various cancers, either as frontline treatment or
in maintenance of remission.
The main purpose of this area of research is the preparation, characterization, and
optimization of antibody-based reagents, using antibody engineering, to better
respond to clinical needs. All research projects presented herein are the result of
collaboration between biotechnologists, biologists, chemists, and clinicians. For the
design of a good antibody-based reagent and for optimization of its clinical use, it
is important to know the mechanism by which the antibody exerts its activity, the
biology of the target, and the characteristics of the targeted disease.
The results obtained in 2015 are summarized below.
Antibody-based reagent directed to α Folate Receptor (αFR)
Completely human Fab
fragments against αFR were
generated using antibody
phage display libraries
The αFR has the characteristics of a tumour-associated antigen with limited normal
tissue distribution and altered expression after chemotherapy, thus making it a
potential target even in previously treated relapsing tumours. On the other hand,
it is over-expressed in many tumours, such as epithelial ovarian cancer (EOC),
mesothelioma, lung cancer, head and neck and in a significant subgroup of ER/
PR-negative and triple-negative breast cancers, indicating that a reagent directed
against this target may have a great spectrum of applicability. To exploit the
specificity of this receptor we are developing different approaches:
Completely human Fab fragments against αFR were generated in our laboratory
using antibody phage display libraries obtained from EOC patients. One of
the selected human fragments was considered as a suitable agent for radioimmunotherapy in EOC and is under evaluation in collaboration with Advanced
Accelerator Applications (AAA), Ivrea Italy.
The success achieved with spherical magnetic iron oxide nanoparticles (20 nm
in diameter) conjugated with one of our human anti-FR antibody fragment for
preclinical in vivo studies in mice bearing tumours (Quarta et al Nanoscale 2016) has
encouraged us to continue with this approach. We intend to use these nanoparticles
to bring on EOC drugs or microRNAs which, when correctly expressed, sensitizes EOC
cell lines to platinum treatment (the study is funded by a CARIPLO grant).
The possibility to use antibodies for lymphocyte retargeting is a very promising
application, which can be exploited using chimeric antigen receptors (CARs) by T-cell
engineering or by using bispecific antibodies (BsAbs). Both approaches are under
evaluation using our anti FR antibodies.
A fully human CAR with
potent activity against cancer
cells with reduced risk
for off-tumor toxicity
In collaboration with the University of Pennsylvania, we recently obtained a fully
human CAR with potent activity against cancer cells but reduced risk for off-tumor
toxicity using the human scFv anti αFR (Song et al., Oncotarget 2015 and Schutsky
et al., Oncotarget 2015). Moreover in INT we developed a bispecific antibody antiFR/anti-CD3. The characterization of these reagents and the potentiality of these
approaches are under evaluation.
We are evaluating the possibility to use our antibody-based reagents also on other
cancer such as lung, cervix and triple negative breast cancer where the Folate
Receptor is expressed.
23
Bispecific Antibodies anti-TRAILR2/anti-CD3
BsAb with a potent
cytotoxic effect in many
different cancers
In an AIRC 5x1000 research framework, with prof. AM Gianni as PI, dr. Figini is a
group leader project with the aim to build a BsAb directed against TRAIL R2 with
one arm and against CD3 with the other. Among more than 50 different formats
to produce BsAb, we chose the single chain format were two scFv, anti TRAILRII and anti CD3, have been joined by a linker. This format can be purified to near
homogeneity and being a small molecule of only 55 KDa, induces the formation of
an immunological synapse between T cells and tumour cells that results in T-cell
activation and proliferation as well as potent T-cell mediated anti-tumour activity.
The BsAb demonstrates a potent cytotoxic effect in many different types of cancer
including EOC, melanoma, prostate, liver and breast carcinoma. A preliminary in vivo
experiment demonstrates that the BsAb was able to slow down the tumour growth,
indicating that the BsAb is able to circulate in vivo and to reach the tumour. The
project is still ongoing to find the more suitable animal model and to better evaluate
the mechanism of activation of lymphocyte and the mechanism by which the BsAb
provokes the death of cancer cells.
Antibody-based reagent directed against prostate specific
membrane antigen (PSMA)
PSMA is an antigen specifically expressed on prostate cancer (PC). Moreover, several
studies have shown that anti-PSMA antibodies bind to the vasculature associated
with many solid malignant tumors, suggesting a possible wider use of these
reagents. Starting from the property of our anti-PSMA mouse MAb D2B, we converted
it into a single chain Fv (scFv) format (PCT /IB2009/005326). This scFv was used for
the construction of a second generation of CAR that is able to exert relevant cytotoxic
activity by engagement with PSMA+ prostate tumor cells (Zuccolotto et al. PloSOne
2014).
Moreover, the therapeutic potential of a recombinant immunotoxin composed of this
scFv and the de-immunized PE toxin is under evaluation in collaboration with Dr.
Fracasso (University of Verona).
In clinical practice, the role of imaging in PC diagnosis and treatment is three-fold:
tumor localization, staging of disease, and detection of recurrence. The development
of a suitable reagent is therefore an actual need.
Despite its monovalent binding mode, scFvD2B retained a good strength of binding,
this characteristic enabled us to use it radiolabeled (Frigerio et al. Immunol. Lett.
2015) with different tracers for in vivo imaging. In three animal models we showed its
ability to target only PSMA-expressing cancer cells.
Design and implementation of a phase I clinical study to assess safety, tolerability
and dosimetry of 123I-scFvD2B GMP administered i.v. and followed by scintigraphy is
ready to be submitted to the Ministry of Health.
Production of monoclonal antibodies against maspin
From microarray supervised analysis on a dataset of chemotherapy-treated breast
carcinoma patients, maspin, a member of the serpin protease inhibitor family,
has been the foremost variable identified in non-responsive versus responsive
tumors. Accordingly, in a series of human BCs, we detected high maspin expression
in tumors that progressed under doxorubicin (DXR)-based chemotherapy. Our
analysis of the role of maspin in response to chemotherapy in human BC cell lines
transfected to overexpress maspin and injected into mice showed that maspin
overexpression led to DXR resistance through the maspin-induced collagenenriched microenvironment. Therefore, using recombinant GST-maspin protein as an
immunogen, we derived 10 monoclonal antibodies that are specific for recombinant
maspin by ELISA assay and one (MPI1) able to neutralize maspin activity. Treatment
of mice, injected with maspin-overexpressing cells, with this antibody decreased
collagen content and, as a consequence, overcame maspin-induced DXR resistance
decreasing tumor volume upon DRX treatment. These findings suggest the promise
of this antibody in combination with a standard chemotherapeutic agent, such as
DXR, as a novel therapeutic strategy to overcome drug resistance induced by the
tumor microenvironment and to consistently achieve objective responses in breast
carcinomas that progress after traditional therapy (Triulzi T. et al. Int J Cancer 2014).
24
BIOSPECIMEN REPOSITORY - BIOBANK
PROGRAM MEMBERSHIP
Since 2002, the INT Biobank (INT-BioB) has been
dedicated to the collection and distribution of neoplastic,
preneoplastic, and normal tissues from human subjects
for research projects.
BIOSPECIMEN
REPOSITORY
BIOBANK
G. PELOSI AND M.G DAIDONE
All patients/subjects sign an
informed consent document
to donate leftover tissue/
biological specimens to the
INT-BioB for future studies
INT-BioB was certified to
implement and maintain a
Quality Management System
fulfilling ISO 9001:2008
standards
More recently, starting from 2012, collection and processing of blood samples
have been implemented for selected tumor types. This resource is a project of INT
Scientific Directorate, with day-to-day staff supervision provided by personnel
from the Departments of Diagnostic Pathology and Laboratory Medicine, and of
Experimental Oncology and Molecular Medicine. Activities are overseen by an
interdepartmental advisory committee, which evaluates and approves research
projects depending on the availability of tissue specimens. Adopting TUBAFROST
procedures, although slightly modified to comply with local conditions, the INTBioB stores frozen samples (primary and metastatic lesions, with corresponding
normal tissues) and blood samples (whole blood, plasma, serum, red cells and buffy
coats) 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 INT-BioB for future studies. It is a one-time general consent with a two-step
decision process that allows patients to control the use of their samples and foster
important research. Guidelines have been proposed to define responsibilities for
INT-BioB management, policies, and procedures to protect patient confidentiality and
privacy, and establish priorities for specimen distribution. INT-BioB was certified to
implement and maintain a Quality Management System fulfilling the requirements of
ISO 9001:2008 standards, and become a member of the Biobanking and BioMolecular
resources Research Infrastracture (BBMRI) (www.bbmri.it). Its personnel
collaborates with experts from 18 European national nodes within the Biobanking
and BioMolecular Resources Infrastracture- European Research Infrastructure
Consortium (BBMRI-ERIC) network on the CEN (Comité Europeen de Normalisation)
Technical Specifications for pre-examination processes, with special reference
to snap frozen or formalin-fixed paraffin-embedded (FFPE) tissues, whole blood
(including procedures to isolate cellular RNA, genomic DNA and circulating cell-free
DNA from plasma) at intra-Biobank and inter-Biobank level. Further activities regard
the development of standardised process descriptions and Standard Operating
Procedures (SOPs)and contribute results to a self-assessment tool for Biobanks,
with an ambitious perspective regarding the improvement of the produced Quality of
the sample to foster scientific excellence, and safeguard interoperability. In fact, the
BBMRI-ERIC community aims to provide support and guidance to jointly establish,
improve and/or implement an appropriate Quality Management System for biobanks
of human derived materials, on a pan-European basis.
INT investigators collaborated within the European Platform for Translational Cancer
Research (http://eurocanplatform.eu) in creating an European infrastructure for
translational cancer research including a biobanking initiative (EurocanPlatform
Biobanking, EPB). EPB took advantage from the experience of existing biobanks and
was addressed to identify and remove barriers in order to stimulate cooperation
and sharing of human samples and associated data (Riegman PHJ et al., Science
Translational Medicine 2015). This initiative involved biobanking experts from eight
European countries representing more than 10 well-established biorepositories that
house human samples from hospitals, clinical trials, and the general population.
Examples of successful cooperation regarding sample sharing in the EPB consortium
have been analyzed, and different models that enable successful sample collection
were identified, including benefits of sharing, coauthorship and intellectual property,
reimbursement of maintenance costs, interbiobank harmonization, SOPs, quality
management and support in study design even with stakeholder involvement
and access definition rules (including external requests from researchers of
25
other Institutions) following a publicly available regulatory document with a clear
description of the request evaluation procedure, and upon respecting ethical, legal,
and social issues.
During 2015, the strong collaboration has continued among the Analytical
Epidemiology and Health Impact, the Information Communication Technology
(ICT) and Breast Surgery Units and INT-BioB to integrate the institutional breast
cancer clinical registry with the different repositories (e.g., bio-banks and blood
exam database). Such an initiative represents an asset in a comprehensive cancer
centre since it can be used for an assessment of bio-bank specimens with specific
characteristics, and thus is instrumental for translational studies.
26
CLINICAL CANCER
REGISTRIES
CLINICAL CANCER REGISTRIES
PROGRAM MEMBERSHIP
M. SANT (COORDINATOR)
Clinical registries are available in many oncological
Institutes and are mainly aimed to facilitate clinical and
translational research, although they can also be useful for
patient management and follow-up.
The utility of cancer registration encompasses several research fields, e.g. estimate
of number of cases needed for clinical studies; monitoring clinical procedures and
adhesion to guidelines; clinical validation of potentially prognostic biomarkers;
comparative studies between clinical and population sets of patients; studies on
cancer prognosis and survivorship.
Disease-specific INTbased registries would
provide a set of pre-defined
anagraphic and clinicalbiological variables
A large amount of information is produced at INT in daily clinical activity, yet
researchers or clinicians do not have straightforward access to it and the data format
is not always suitable for statistical analyses. Tumor morphology, for instance, is
not always coded according to international classifications such as the International
Classification of Disease for Oncology (ICDO). For this reason, it is often necessary
to inspect many clinical notes to identify patients with specific characteristics who
are eligible for a given study, with a considerable utilization of personnel time and
resources. Furthermore, the scattered availability of data in non-homogeneous
formats leads to the creation of many ad-hoc datasets, with duplication of efforts
and limited comparability of results.
Disease-specific INT-based registries would allow researchers and clinicians to
identify and access specific cases of their interest, providing a set of pre-defined
anagraphic and clinical-biological variables (i.e., disease-specific “core information”)
to which further information for specific studies can be added. The linkage between
clinical registry and institutional bio-repositories facilitates clinical translational
research, observational studies, and generation of novel study hypotheses.
The Breast Cancer Clinical Registry (B-CCR) at INT in place since 1st October 2011,
systematically collects clinical, pathological, and biomolecular data of all cases
operated at the INT Breast Surgery Unit. On 30th April 2016, B-CCR contained the
data of about 5000 patients, 65% of whom had a primary breast cancer (Table 1).
Registration of follow-up information is planned for the next year. The registry is
updated weekly with clinical data of patients undergoing surgery the previous week,
and with bio-molecular data extracted from pathological reports by ad hoc text
mining algorithms. Information on chemotherapy performed at INT is extracted
automatically, from the INT electronic patient record (EPR) .
The B-CCR is accessible through a web-based interface which guarantees direct
control on data during input and allows performing systematic control of the quality
of data, e.g. on completeness and internal consistency of variables.
The B-CCR is accessible
through a web-based
interface which guarantees
direct control on data
allowing a systematic
control of the quality of data
The B-CCR is connected with the INT blood bank, which contains samples donated by
breast cancer patients at their first hospital admission; the registry is also linked to
the INT blood exam database.
Thanks to the collaboration between clinicians, epidemiologists, experimental
research units and pathologists, two observational studies, using the data made
available by the B-CCR, were published:
Agresti R et al., Breast Cancer Res Treat 2016: the results of this study suggest
dysmetabolisms play a role in the biological determinism of breast cancer subtypes.
In premenopausal patients overweight and chronic inflammation raised the odds
of being diagnosed with triple-negative tumor, while after menopause metabolic
syndrome was associated with hormone-positive breast cancer subtypes.
Gondos A et al., Acta Oncol. 2016: the study examined time trends in axilla
management among patients with early breast cancer in European clinical settings
using data from both population-based and comprehensive cancer centers registries
showing persisting differences in axillary management throughout the recent decade.
27
The B-CCR methodology and its aims were published in Baili P et al., Tumori Journal
2015.
Further studies are in course on the outcome of women with locally advanced breast
cancer treated at INT and on the relation between breast cancer ki67, tumor size and
axillary nodes status.
Table1. Distribution of clinical-pathological characteristics of patients diagnosed
with primary breast cancer and included in the INT Breast Cancer Registry from
October 1st 2011 to April 30th 2016
n
TABLE LEGEND
WHO. ICDO-3
UICC. TNM
c
Subtype according to Goldhirsch et al. Ann
Oncol. 2011; 22:1736–1747
ER+: >1%; PR+: >1%; HER2+: 3+, 2+ & Fish amplified;
Ki-67+: >14%
Luminal A HER2-: ER+ or PR+, HER2-, Ki-67Luminal B HER2-: ER+ or PR+, HER2-, Ki-67+
Luminal HER2-: ER+ or PR+ HER2-, Ki-67 not known
Luminal HER2+: ER+ or PR+, HER2+, any Ki-67
HER2+ (not luminal): ER-, PR-, HER2+, any Ki-67
Triple Negative: ER-, PR-,HER2-, any Ki-67
a
b
28
Gender
Females
3135
Males
33
Age at diagnosis
<50
1048
>=50
2120
Laterality
Sx
1620
Dx
1548
Morphologya
Ductal invasive
1900
Lobular Invasive
288
Mixed type Invasive
356
Other invasive
266
Insitu
258
Grading
I
238
II
1591
III
1192
Not known
147
Pre-surgical adjuvant treatment
Present
346
Not present
2822
pT stage in women without pre-surgical
adjuvant treatmentb
pTis
266
pT1mic
85
pT1a
115
pT1b
537
pT1c
1084
pT2
595
pT3
41
pT4b
19
pTx
80
pN stage in cases without pre-surgical adjuvant treatmentb
pN0
1727
pN0 (i+)
66
pN1
458
pN1mic
110
pN2
151
pN3
126
pNx
184
Breast cancer Subtypec
Luminal A HER2703
1441
Luminal B HER2354
Luminal HER2+
Luminal (HER2 not known)
74
167
HER2+ (non luminal+)
Triple negative
226
Not known (in situ)
95
Not known (invasive)
108
%
99.0%
1.0%
33.0%
67.0%
51.1%
48.9%
60.0%
9.1%
11.2%
8.4%
11.3%
7.5%
50.2%
37.6%
4.6%
10.9%
89.1%
9.4%
3.0%
4.1%
19.0%
38.4%
21.1%
1.5%
0.7%
2.8%
61.2%
2.3%
16.2%
3.9%
5.4%
4.5%
6.5%
22.2%
45.5%
11.2%
2.3%
5.3%
7.1%
3.0%
3.4%
Other INT Clinical Registries (ICRs)
Based on the consolidated experience of the B-CCR, we are examining the extension
of registration to further neoplasms.
In accordance with specialised clinicians, cancers of the lung, colorectum and
pancreas have been identified as suitable for registration, and the relevant clinical
information to be registered is under study. Other neoplasms will be considered,
according to interest and suggestions from clinicians.
For each neoplasm considered:
• the clinical and administrative databases available at INT are exploited to the
maximum extent to recuperate the information to be included in the registry
• ICR will be implemented using open source software
• a web-based interface allows the interested INT specialists to access the CRs data
(under specific rules)
• ICR can be connected with other INT data repositories
• ICR should be compatible with population-based data in order to ease a future link.
Presently the basic information necessary to construct the clinical registry at
INT is extracted from the following INT databases which are centralized by the
Communications Technology Unit (ICT) and periodically delivered to the ICR team.
Database of the Pathology Department (AP), containing all histological examinations
carried out at INT. Diagnoses are mostly reported in a narrative form (international
classification codes, useful for statistical analyses on the data, are not complete)
thus text mining algorithms for coding are necessary.
Hospital admission records (SDO) containing all main therapeutic and diagnostic
procedures carried out during hospitalization.
EPR containing information on diagnosis exams, follow-up visits, chemotherapy,
radiotherapy, etc performed at INT outside hospitalization.
Other databases to be analyzed are pharmaceutical records (File F), containing
information on drugs administered to patients and the OECI form collecting coded
data from the hospital discharge letter (i.e. on previous tumors, type of treatment,
disease phase, etc.).
The scheme of connections
is designed to define the
Structured Query Language
(SQL) linking algorithms
Text mining algorithms of AP records have been developed for automated coding of
the disease type (i.e. primary cancer, metastases of other cancers in the examined
site, other cancers), broad morphology grouping. To date, this procedure is being
applied and tested to pathological reports of lung cancer and pancreatic cancer;
subsequently it will be applied to colorectal cancer.
As pilot studies, for lung cancer we examined AP records of about 9700 patients from
January 1st 2003 to November 20th 2015 identifying about 4500 lung cancer cases.
While for pancreatic cancer we examined AP and SDO records of about 870 patients
from 1st January 2013 to 15th April 2016 identifying about 300 pancreatic cancer
cases.
For each neoplasm, the scheme of connections between the above databases is
designed to define the Structured Query Language (SQL) linking algorithms. The data
flow and connection can be briefly described as follows: the list of INT cases should
be provided by the INT Units or by ICT through the SDO files. ICT periodically provides
also the files deriving from the above databases. The key for linking all these input
databases is the clinical record number, assigned to each patient when they first
accesses the INT.
The disease phase (i.e. diagnosis, recurrences, etc.) is established combining AP
text mining algorithms and manual collection from clinical records. The integration
of automated data collection with manual collection of clinical data through
examination of the patient’s clinical records or EPR is envisaged for each neoplasm
suitable for registration. Dedicated personnel at the Analytic Epidemiology and
Health Impact Unit (AEHI) is in charge of this task, prior to agreement with Directors
of the relevant Units.
Data collection and storage procedures that proved to be effective for the B-CCR are
adopted also for the registration of the other neoplasms, with adequate changes
when necessary.
29
Regulation for data access and ethical issues
A Steering Committee (SC) will be established, including the Directors of the Units
providing data to the registry, or their representatives, the clinical registry scientific
and technical director, and representatives of AEHI Unit analysts who will carry our
main statistical analyses.
Two Study protocols envisaging the use of B-CCR data have been approved by the INT
Ethical Committee. Protocols for other neoplasms are in preparation.
The SC composition, its tasks and main study regulations are under definition, as well
as regulations for data access or release.
Personnel involved at AEHI unit
Milena Sant: project leader, initial conception and clinical definition of the registries
Paolo Baili: coordination, design organisation of the registries and management of
data collection
Ilaria Cavallo, Francesco Funaro: SQL and Web interface implementation
Hade Amash, Alberto Turco: data collection
Elisabetta Meneghini, Francesca Di Salvo, Pamela Minicozzi: data analyses
We thank Giuseppe Rosito, Michele Torresani and Marco Giunco at ICT for their
support in providing INT databases.
30
DIET AND PREVENTION
PROGRAM MEMBERSHIP
V. KROGH (COORDINATOR),
DIET AND
PREVENTION
P. PASANISI, A. VILLARINI
The Diet and Prevention research program is structured
in two main investigative approaches: 1. prospective
cohort studies, to define individual risks related to diet;
2. intervention studies, to test strategies for prevention
of incidence and recurrence of cancer and other chronicdegenerative diseases.
The EPIC project represents
an ideal natural laboratory
thanks to the very
heterogeneous dietary
habits
The European Prospective Investigation into Cancer and Nutrition (EPIC) study
was designed to investigate the relationships between diet, lifestyle, genetic, and
environmental factors and the incidence of cancer and other chronic diseases in 23
centers across 10 European Countries: Denmark, France, Germany, Greece, Italy, The
Netherlands, Norway, Spain, Sweden, and the United Kingdom. Data were collected
from more than 520,000 healthy volunteers on diet, physical activity, reproductive
history, lifetime consumption of alcohol and tobacco, previous and current illnesses,
and current medication. Blood samples were also collected, processed, and stored
in liquid nitrogen at –196°C. 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. The EPIC project represents an ideal
natural laboratory thanks to the very heterogeneous dietary habits still to be found
in different European populations. At the same time, the incidence of several major
cancer sites varies substantially across countries and even more across regions.
Another crucial element of statistical power, which was central in the design of EPIC,
is the study size.
The main results on diet and cancer risk published in 2015 were:
• colorectal cancer: dietary antioxidant capacity reduces the risk of colon cancer but
increases the risk of rectal cancer; adherence to the WCRF/AICR recommendations
prior to diagnosis improves survival after diagnosis;
• ovarian cancer: the long-term use of HRT increases survival in women with this
cancer; the number of pregnancies and the use of oral contraceptives are protective
for the different subtypes of this cancer;
• breast cancer: lignans improve survival among postmenopausal women but reduces
it among premenopausal women; metabolic syndrome increases the risk among
postmenopausal women; a diet rich in beta-carotene, riboflavin, thiamin, vit. C and
B6, fibre, Fe, Ca, K, Mg, P and folate reduces overall, ER+ and PR+ breast cancer risk;
caffeinated coffee reduces the risk among postmenopausal women;
•e
ndometrial cancer: coffee reduces the risk;
•d
ifferentiated thyroid carcinoma: moderate alcohol intake reduces papillary and
follicular carcinoma risk; elevated energy and polyunsaturated fat intake increases
the risk;
•h
ead and neck cancer: elevated homocysteine levels increase squamous cell
carcinoma risk;
•e
sophageal adenocarcinoma: abdominal obesity increases the risk, general obesity
decreases the risk;
•g
astric cancer: elevated serum iron and ferritin reduce the risk; abdominal obesity
increases the risk;
•h
epatocellular carcinoma: monounsaturated fat decreases the risk; coffee and tea
decrease the risk; vegetables, but not fruit, decrease the risk;
•p
ancreatic cancer: elevated plasma beta-carotene, zeaxanthin and alfa-tocopherol
decrease the risk;
• r enal cancer: moderate alcohol intake decreases the risk.
31
Our results suggest
protective effects of
thiamine, folate, riboflavin,
and vitamin B6 against
breast cancer
The ORDET study is one of the first prospective European studies on the role of
hORmones and Diet in the Etiology of breast Tumor. A total of 10,786 healthy women,
aged 35–69 years, residents in Varese province, Northern Italy, were recruited in
1987−1992. At recruitment, several sources of hormone variability were controlled for
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 those affected by liver diseases
were not eligible for the study. Information on lifestyle characteristics, menstrual
and reproductive history, dietary habits, and anthropometric measurements have
been collected at baseline. Moreover, blood samples were collected after 12 hours of
fasting. All 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.
In 2015, a manuscript on micronutrients involved in one-carbon metabolism and risk
of breast cancer subtypes has been published. The results support protective effects
of thiamine, folate, riboflavin, and vitamin B6 against breast cancer in general; while
folate may also protect against ER+PR+ and HER2- disease; and thiamine against ERPR-, and HER2+ disease.
The ORDET study is participating the “Pooling Project of Prospective Studies of Diet
and Cancer”, an international collaboration that involves 28 European and North
American cohort studies, with more than 2,000,000 volunteers, coordinated by
Harvard University. A manuscript published in 2015 found that alcohol consumption
was positively associated with risk of both ER+ and ER- breast cancer, even among
women with high folate intake, whilst folate intake was not associated with breast
cancer risk.
The COS study is a randomized controlled trial of diet and physical activity in BRCA
mutation carriers. The aim of the study is to test whether moderate caloric and
protein restriction (including avoidance of milk protein) together with physical
activity, decrease IGF-I, insulin, and insulin resistance in women with a genetic
susceptibility to breast cancer. The study is recruiting a cohort of 300 BRCA mutation
carriers and 224 women have been already randomized. This trial is now expanding
thanks to AIRC funding to randomize 600 mutated women. This large cohort of
women with BRCA mutations will allow to test potential modulators of penetrance
and prognosis.
The TEVERE (Diana-4) study is a blinded randomized controlled trial of diet and
metformin for primary prevention of breast cancer. The study is recruiting healthy
women aged 45−74 years, with waist circumference >85 cm, and at least one feature
of metabolic syndrome. The aim of the study is to test the effect of metformin, an
antidiabetic drug, on breast cancer occurrence. The study hypothesis is that study
participants treated with metformin (1700 mg/day) will have a lower incidence of
breast cancer in comparison with women given placebo on breast cancer prevention
during 5-year follow-up. Participants also receive dietary recommendation to reduce
the risk of metabolic syndrome and insulin resistance. At the moment, we have
recruited 542 women and 380 are under treatment.
The MeMeMe study is a
randomized controlled trial
of diet and metformin for
primary prevention of agerelated chronic diseases
The MeMeMe study is a randomized controlled trial of diet and metformin for
primary prevention of age-related chronic diseases (ArCD). The plan is to carry out a
randomized controlled trial on 2,000 healthy men and women, 55-74 years of age, at
high risk of ArCD because of metabolic syndrome. The aim of the study is to evaluate
the effect of comprehensive life-style intervention (including moderate physical
activity and Mediterranean/macrobiotic diet with moderate caloric restriction), and
treatment with metformin for prevention of ArCD. The recruitment is in progress and
about 400 persons are already under treatment.
The DIANA-5 study is a multicenter randomized controlled trial of the effectiveness
of a diet based on Mediterranean and macrobiotic principles, associated with
moderate and daily physical activity, in reducing additional breast cancer events in
women with early stage invasive breast cancer at high risk of recurrence because of
metabolic or endocrine milieu. The intervention is expected to reduce serum insulin,
sex hormones, serum IGF-I, and metabolic syndrome (defined by the presence of at
least three among abdominal obesity, hypertension, low plasma HDL-cholesterol,
high plasma glucose, and high triglycerides), which were associated with breast
prognosis in previous studies.
32
The study enrolled 2,356 women diagnosed with invasive breast cancer within
the previous 5 years who had not developed distant metastasis, local recurrence
or second primary breast cancer. All participants were asked to change their diet
according to the WCRF/AICR (2007) guidelines for prevention of cancer and were
allocated to one of three different groups. Women with no metabolic/endocrine traits
of high recurrence risk (ER- tumor, metabolic syndrome, high serum testosterone or
insulin level) were allocated to an observational group (n=681). Women with one or
more of the above high risk traits were randomly assigned to a control group (n=833),
which received only WCRF/AICR recommendations, and an active intervention group
(n=842) requested to participate in kitchen courses and physical exercise sessions.
Compliance assessments in control and intervention groups include repeated
24-hour food frequency and physical activity diaries, anthropometric measures,
impedance evaluation of body fat distribution, one week registration of energy
expenditure integrating the measure of movement, and several other physiological
signals collected with a SenseWear Armband, plasma glucose, cholesterol,
triglycerides, insulin, SHBG, and sex hormones. At baseline and after 12 months, blood
samples are collected and stored in a dedicated biological bank. The collection of
additional blood samples is planned at 36 and 60 months.
33
EARLY DIAGNOSIS
PROGRAM MEMBERSHIP
G. SOZZI (COORDINATOR),
M. BOERI, M.G. DAIDONE, M. GARIBOLDI, E. LEO,
U. PASTORINO, E. TAGLIABUE
Understanding the biological changes in early tumor and stroma could have a
profound impact on how cancer is detected, prevented, and treated, and might
provide blood and tissue-based biomarkers that are able to identify progressing
lesions. Such a novel perspective might improve early cancer detection and allows
identification of aggressive tumors, thereby overcoming the well-known limitations
of current screening and diagnostic approaches that, apart from causing anxiety,
exposure to potentially harmful amounts of radiation or surgical procedures
and additional expenses to the healthcare system, are also unable to predict the
biological aggressiveness of the detected lesion. Goal of our translational studies
is the implementation of highly sensitive molecular tests that could be used within
screening programs to improve both early detection and clinical management of
different cancer types. Institutional efforts are ongoing for three major cancer types
(colorectal, lung, and breast) which represent the most significant malignancies in
terms of clinical and economic burden.
EARLY
DIAGNOSIS
Goal of our translational
studies is the
implementation of highly
sensitive molecular tests
to improve both early
detection and clinical
management
Detection of cancer at an early stage offers the genuine
potential to reduce mortality with new chances of cure.
Discovery and validation of biomarkers is central to this
goal.
LUNG CANCER (G. Sozzi and U. Pastorino)
Lung cancer still remains a highly aggressive disease, accounting for almost
30% of cancer deaths worldwide. Lung tumors are typically asymptomatic in the
early stages, they are often diagnosed at a late stage, at a metastatic phase, and
thus failing in successful treatment. Considering that 5-year survival for stage Ia
patients is over 70%, it appears clear that advances in early detection are crucial to
enable timely curative surgery. The implementation of molecular markers for risk
stratification appears a priority, and microRNAs (miRNAs) constitute an extremely
promising new class of blood-based biomarkers for cancer detection and prognosis.
Highlights
We recently reported the results of a large retrospective validation of a plasmatic
miRNA signature classifier (MSC) as Low-Dose CT (LDCT) complementary tool in 1,000
cases and control subjects enrolled in the MILD trial. The diagnostic performance of
MSC for lung cancer detection was 87% for sensitivity and 81% for specificity. For all
subjects, MSC had a negative predictive value of 99% and 99.86% for detection and
death-by-disease, respectively. LDCT had a sensitivity of 79% and a specificity of
81% with a false positive rate of 19.4%. Combination of both MSC and LDCT resulted
in a 5-fold reduction of LDCT false positive rate to 3.7%. MSC risk groups were
significantly associated with survival (χ2=49.53, p<0.0001) (G Sozzi et al. JCO 2014).
The MSC test was also employed to monitor disease status during follow-up in
longitudinal plasma samples obtained from patients before and after surgical
resection of primary lung tumors. For this purpose, changes of MSC risk profiles at
follow-up were assessed for 31 patients of the MILD cohort with longitudinal plasma
samples (n=100) collected after curative surgery, The MSC risk level decreased after
curative surgery in 76% of disease free individuals (median time 20 months), while
for 3 relapsing patients MSC remained or returned positive at the time of detection of
second primary tumor or metastatic progression (S Sestini et al. Oncotarget 2015).
Future outlook
In collaboration with the Thoracic Surgery and Radiology Units, the bioMILD trial
(www.biomild.org) is ongoing in INT. The bioMILD is a truly innovative study testing
the efficacy of a combined molecular and imaging approach, where blood miRNAs
(MSC) and LDCT are both applied at baseline screening, and their results establish
the intensity and modality of subsequent investigations. The BioMILD trial aims to
34
define the individual risks of cancer among a cohort of heavy smokers, modulate the
screening program on this basis, and reduce the number of unnecessary diagnostic
investigations and useless surgery for benign disease. As of January 2016, we
enrolled 4,119 volunteers and performed 6,204 miRNA tests and 5,493 low dose CT
evaluations according to a proprietary BioMILD decisional algorithm.
BREAST CANCER (E. Tagliabue and M.G. Daidone)
The identification of reliable
circulating biomarkers may
also represent a paradigm
shift for personalized
treatments
Regular screening tests (mammographic screening and breast ultrasound scan)
reduce the chance of death from breast cancer (BC). However, to demonstrate that
abnormal areas are malignant, biopsy is still required in many women. The procedures
for a biopsy are invasive for the patient and expensive for the healthcare system, and
this may present a problem, especially for high-risk younger women who need early
breast cancer screening. Therefore, a simpler, valid alternative is highly desirable. The
solution may reside in the monitoring of circulating molecular markers in blood. The
identification of reliable circulating biomarkers that could track tumor behavior, and
anticipate diagnosis of unfavorable events in potentially curable disease such as early
BC, may also represent a paradigm shift for personalized treatments.
Highlights
• Starting from the hypothesis that biological changes in early tumor and stroma
could have an impact on tumor detection, we investigated whether the interaction
between BC and its microenvironment allows the release of extracellular matrix
(ECM) proteins in blood. The selection of ECM genes significantly up-modulated in
tumor versus normal breast tissue followed by searching for molecules encoded
by relevant genes, showed up-modulation of COL11A1, COMP and COL10A1 genes
in breast carcinoma-conditioned normal fibroblasts reflected in consequent
improvement of production and release of correspondent proteins. These molecules
were detected in plasma from patients and the combination of circulating COL11A1,
COMP and COL10A1 showed discriminative ability between patients with malignant
and benign breast disease. The increased levels in COL11A1, COMP and COL10A1 were
independent of clinico-pathological characteristics (e.g., size, node status, grade, ER,
PgR, and HER2 expression), supporting the notion that the host microenvironmental
response to BC represents a blood biomarker of transformed cells independent of
their different molecular characteristics.
• The presence of small peptides in plasma is likely due to proteases located in
the tumor microenvironment. We investigated the presence of these peptides in
plasma of BC patients and healthy subjects using high-throughput profiling by
liquid chromatography-mass spectrometry (LC-MS). Two MS signals corresponding
to small peptides able to distinguish BC patients from healthy donors were
identified in a training set of plasma from BC and healthy subjects and validated in
2 independent plasma cohorts also including women with benign breast disease. To
improve the specific detection of malignant disease, an 8 signal-based MS signature
discriminating malignant vs benign disease was also identified.
We investigated whether the
interaction between BC and its
microenvironment allows the
release of extracellular matrix
proteins in blood
• To investigate circulating miRNAs as possible sensors of tumor occurrence, plasma
samples from a training and a testing plasma cohort were profiled using the
OpenArray Technology. By looking at the training set, a list of miRNAs associated
with disease status (BC or benign breast disease) was identified by univariate
analysis and ranked according to its significance. Starting from these miRNAs,
19 signatures with a highly significant performance in discriminating BC patients
from healthy donors and women with benign breast disease were identified in the
training and confirmed in the testing set.
• Paracrine-mediated, microenvironment–cancer cell interactions were studied by
treating breast cancer cell lines (BCCLs) representative of HER2+, luminal and basal
subtype, with conditioned media obtained from normal and cancer-associated
fibroblasts. The obtained signatures were challenged as prognostic biomarkers in
clinical tumors by in silico analysis on published gene expression profiles (GEPs)
of breast cancer samples by correlating their GEPs and classifying the tumors as
microenvironment-positive (µENV+) if directly correlated with the signature. In
univariable analysis, patients with luminal µENV+ tumors were characterized by
2.5-fold higher risk of developing distant metastases (HR= 2.546; 95% Cl: 1.751-3.701,
P=9.84E-07). Such findings held true even in a multivariate analysis including size,
age and genomic grade index (HR=2.098; CI: 1.214-3.624; P=0.00791). Functional
studies investigating on luminal BCCLs biological endpoints such as proliferation,
migration/invasion supported the validity of in vitro model.
35
Future outlook
We will investigate the clinical utility of the produced BC biomarker classifiers by
validating them in a prospective clinical study planned to collect plasma from women
with an imaging suggestive of breast malignant tumor addressed to biopsy for
diagnostic assessment in our Institute. The predictive capability of the signatures
above identified will be assessed in terms of AUC and the performance of the
corresponding classifiers will be quantified with respect to the true status according
to histopathological assessment of biopsy.
COLORECTAL CANCER (M. Gariboldi)
Colorectal cancer (CRC) is the second most common tumor in women and third in
men. If CRC is diagnosed at early stages, when the tumor is still localized in the
colon, the survival rate is high. At this step of progression, removal of polyps or
adenomas can even avoid the development of cancer. CRC screenings on healthy
individuals, through tests for the detection of occult blood in stool (FIT) followed by
colonoscopy in case of positivity, has increased the early detection of the disease and
reduced deaths by 20−30%. However, the test currently used for screening has suboptimal sensitivity and specificity, especially for precancerous lesions. A promising
technology in this field is the identification of blood circulating miRNAs linked to the
presence of tumor in patients with precancerous lesions/CRC.
Highlights
We have designed a study for
the identification of miRNAs
in plasma of individuals at
high risk for CRC to extend
their use to subjects who are
under close colonoscopic
surveillance
We have used qRT-PCR to analyze the expression levels of 381 miRNAs in plasma
from subjects undergoing colonoscopy screening at INT after a positive FIT test, and
identified 13 miRNAs that show significantly different expression in subjects with
precancerous lesions/CRC compared to subjects without lesions. To validate the
results, we have designed a custom card including the 13 miRNAs and 4 reference
miRNAs identified, together with miR-378 (Zanutto S et al, Br J Cancer 2014). The card
has been assayed on 137 FIT+ samples, leading to the identification of three lesion
specific (low-grade or high-grade adenomas or cancers) signatures. To generalize
our results, we have designed a clinical study to enroll FIT+ subjects that undergo
colonoscopy at 8 Hospitals participating to the Milan CRC screening program, in
addition to INT. Plasma from the 1400 FIT+ subjects that agreed to participate to the
study will be analysed on the new custom card we have designed that includes the
miRNAs from the three lesion-specific signatures. Cards have been already assayed
on a set of 700 subjects ad-hoc randomized according to type of lesion and Hospital
and statistical analysis is ongoing (Verderio P. et al., Int J Biol. Markers 2015; Verderio
P. et al., BJC 2016).
Future outlook
• The results of the first set of cards will be of help for the final confirmation of the
performances of our signature on the remaining subjects of the external validation
cohort. The output of this task could allow an estimation of the performance of
the miRNAs-based test after a positive FIT-test. A qPCR assay based on the digital
PCR technology will be used to technically validate the signatures confirmed on the
external validation cohort and set up an easy-to-use kit for their evaluation that
could be transferred in the clinical setting.
• In parallel, we have designed a study for the identification of miRNAs in plasma of
individuals at high risk for CRC, such as those with familial CRC, to extend their use
to subjects who are under close colonoscopic surveillance and who would greatly
benefit from a non-invasive test. A total of 270 subjects selected from the HeredoFamiliar CRC Registry of INT (either with Familial Adenomatous Polyposis or Lynch
Syndrome) have already been enrolled.
36
THE MULTIDISCIPL
APPROACH FOR H
AND NECK CANCE
HEAD AND NECK CANCER: A
MULTIDISCIPLINARY APPROACH
PROGRAM MEMBERSHIP
C. FALLAI, M. GUZZO, L. LICITRA
PARTICIPATING UNITS
RADIOTHERAPY 2
MEDICAL ONCOLOGY HEAD AND NECK
OTOLARYNGOLOGY/HEAD AND NECK SURGERY
SUPPORTIVE CARE
PALLIATIVE, PAIN AND REHABILITATION THERAPY
Multidisciplinarity is the basis of a modern therapeutic
approach in Oncology; the simultaneous interaction of
various medical specialties is essential in order to provide
the most appropriate care to cancer patients and is
emerging as the best strategy to allow a comprehensive
evaluation of cancer patients.
In the last few years, several studies showed the positive impact of this overall
evaluation on many diseases, thus ensuring even better treatment outcomes and
improving patients’ satisfaction.
In Head and Neck Cancer, this approach is even more important given the many
therapeutic options that modern oncology can offer in a very heterogenous cancer
patient population. This complex scenario strongly suggests a full and prolonged
interaction of many disciplines.
Objectives
• To offer the most appropriate evidence based care to Head and Neck Cancer patients
• To optimize the management of Head and Neck Cancer patients
• To contribute to scientific production
• To perform educational activities
• To contribute to the definition of Regional, Italian and European guidelines of Head
and Neck Cancer management
Activities
The Head and Neck Cancer Unit of Fondazione IRCCS Istituto Nazionale dei Tumori
performs its multidisciplinary (MDT) activities through biweekly first visits and
follow-up outpatient clinics. During these visits, one surgeon, one radiotherapist and
one medical oncologist see the patient together.
The Head and Neck
Cancer Unit performs its
multidisciplinary activities
through biweekly first visits
and follow-up outpatient
clinics
In 2015, 329 (320 in 2014) multidisciplinary first visits and 1053 (962 in 2014)
multidisciplinary follow up visits were performed. Once a week a multidisciplinary
clinical case discussion takes place. Every week a dedicated radiologist joins the
meeting. From time to time other INT professional figures (nutritionist, cardiologist,
pneumologist, dentist, supportive and palliative Unit, psychologist, social worker,
nurse etc) are needed and they are asked to participate to the case discussions. The
simultaneous work of all these different figures is needed to optimize and tailor
the best evidence-based treatment, to manage the less typical clinical cases and to
assess all specific clinical needs.
The optimization of Head and Neck Cancer management depends on their
cooperation within the complex care process. Every patient gets a leading doctor that
coordinates all the activities during the diagnostic and therapeutic phase.
In December 2015, in the Head and Neck Cancer Unit, the “Tutor” connecting figure,
as a (not a doctor) was introduced (funded by AIOM GRANT) linking all members
of MDT activities and help them during the entire diagnostic/therapeutic patients’
course. Until the end of November 2016, this activity will be monitored and objectively
measured. This project aims to define if the Tutor’s activity may better manage the
multidisciplinary Head and Neck Cancer group.
Due to the relative rarity of the disease, research can only be performed in
collaboration with other Centers. In this regard, the connection with national (e.g.
CNAO) and international Centers resulted in the activation of many clinical studies.
37
The Head and Neck Medical Oncology Unit has been involved in 47 trials in these
following fields:
• Curative treatment (6 trials)
•R
ecurrent/metastatic disease (9 trials)
• Thyroid cancer (12 trials)
•N
on melanoma skin cancer (2 trials)
•S
alivary glands cancer (4 trials)
•Q
uality of life and supportive care (12 trials)
•B
iological studies (2 trials)
A total of 454 patients were enrolled in clinical trials during 2015.
Four on-site international courses were held in 2015.
An International Conference, Seminar on Nasopharyngeal Cancer, was organized.
In 2015, the scientific production of Head and Neck Cancer Unit resulted in 34 (29 in
2014) papers published with a total impact factor index of 177.749 (171.345 in 2014).
Relevant output
The Head and Neck multidisciplinary team’s activity optimizes the complex
management of Head and Neck Cancer patients. The very experienced professionals
involved allow for efficient planning and decisions.
To date, the multidisciplinary work resulted in a high number of patients treated and
in a very high number of patients enrolled in clinical studies. This is rather unique
due to the relative rare tumor and to the complexity of the disease. However, INT
investments are at present substantial in terms of dedicated physicians (6 surgeons,
7 medical oncologists, 2 radiation oncologists) and dedicated administrative workers
(5).
The Head and Neck Cancer Unit contributes to establish the scientific knowledge in
this evolving field.
Keywords
Multidisciplinary approach, head and neck cancer, Tutor, research
38
HEMATOLOGICAL
MALIGNANCIES, B
MARROW TRANSP
AND NEXT GENER
SEQUENCING IN
HEMATOLOGY
HEMATOLOGICAL MALIGNANCIES, BONE
MARROW TRANSPLANT AND NEXT
GENERATION SEQUENCING IN HEMATOLOGY
PROGRAM MEMBERSHIP
P. CORRADINI (COORDINATOR)
The Hematologic Malignancies Program encompasses
research regarding leukemia, lymphoma and multiple
myeloma, incorporating a substantial commitment
to redefining diagnostic and therapeutic approaches,
including stem cell transplantation, for blood cancers
using cutting-edge technologies such as next generation
sequencing.
We are committed to the development of novel treatment strategies informed
by laboratory-based science. We focus on several areas of laboratory research
including tumor cell biology, the identification of genetic pathways and genetic
lesions involved in hematological malignant diseases. These studies allow us to
identify and validate novel targets and compounds and translate them rapidly into
clinical trials.
The main unmet clinical need
is to develop methods able
to discriminate patients with
primary refractory disease or
at high risk of early relapse
We are now actively working in the field of liquid biopsy. As pre-clinical and clinical
research are rapidly evolving and producing novel treatment combinations which
are active but very expensive, the main unmet clinical need is to develop methods
able to discriminate patients with primary refractory disease or at high risk of
early relapse, in order to personalize treatments to improve survival. The optimal
strategy for the early monitoring of inadequate disease response is not yet available.
Response definition is the area of imaging diagnostics, however false positive results
are not uncommon and novel methods for a rapid, non-invasive identification of
tumor presence at various time points during disease history are urgently needed.
The analysis of circulating tumor cells (CTCs) and/or cell-free circulating tumor
DNA (ctDNA) are cost-effective, blood-based tests that might be incorporated in
the surveillance reducing conventional imaging and improving the monitoring of
disease recurrence. Moreover, the detailed analysis of ctDNA with Next Generation
Sequencing (NGS) as a surrogate of the entire tumor genome, allows the complete
characterization of genetic alterations, providing information on the presence of
different clonotypes during the course of disease, possibly highlighting different
chemosensitivity patterns. The aims of our studies are: i) to prospectively validate
novel NGS approaches to target the genomic lesions using ctDNA; ii) to identify poor
prognosis patients through the quantification of plasma specific gene lesions during
treatment and follow-up; iii) to establish whether this approach can be used for longterm monitoring with less radiation exposure due to follow-up imaging; iv) to monitor
the presence or emergence of different clonal populations over time, as an indirect
sign of non chemosensitive clones.
Program members made significant contributions to understanding the molecular
biology of leukemia, lymphoma and myeloma in the areas of gene expression and
disease specific abnormalities (Bolli et al). Program members have also participated
in studies to translate such observations into novel therapeutic approaches to
hematological malignancies and novel approaches for stem cell transplantation.
Active collaboration between clinical and laboratory investigators resulted
in the evidence that JAK inhibition represents a new and potentially clinically
relevant approach to GVHD prevention (Carniti et al) and highlighted the cellular
mechanisms responsible for T-cell reconstitution following haploidentical stem cell
transplantation and post-transplant cyclophosphamide (pt-Cy)( (Roberto et al.).
Patient blood sample banks are established for acute leukemia, chronic lymphocitic
leukemia, lymphomas and myeloma. Program members continued with active
participation in national cooperative groups and a new research collaboration
agreement between the our Division and the Sanger Institute in Cambridge, UK, was
signed and will allow us to study the genes and genetic pathways involved in the
development of chemoresistance in blood cancers, with a particular emphasis on
Peripheral T cell Lymphoma. The ultimate goal of this agreement is to help build up a
NGS expertise in our Institute.
39
Selected publications
1. Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano
A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca
F, Hajek R, Spencer A, Boccadoro M, Palumbo A.Chemotherapy plus lenalidomide versus autologous transplantation,
followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a
randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. doi: 10.1016/S1470-2045(15)00389-7.
Epub 2015 Nov 17.
2. R
ambaldi A, Grassi A, Masciulli A, Boschini C, Micò MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi
R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E,
Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scimè R, Mordini N,
Oldani E, Marfisi RM, Bacigalupo A, Bosi A. Busulfan plus cyclophosphamide versus busulfan plus fludarabine
as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid
leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1525-36. doi:
10.1016/S1470-2045(15)00200-4. Epub 2015 Sep 2
3. Palumbo A, Gay F, Cavallo F, Di Raimondo F, Larocca A, Hardan I, Nagler A, Petrucci MT, Hajek R, Pezzatti S, Delforge
M, Patriarca F, Donato F, Cerrato C, Nozzoli C, Yu Z, Boccadifuoco L, Caravita T, Benevolo G, Guglielmelli T, Vincelli D,
Jacques C, Dimopoulos MA, Ciccone G, Musto P, Corradini P, Cavo M, Boccadoro M. Continuous Therapy Versus Fixed
Duration of Therapy in Patients With Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2015 Oct 20;33(30):3459-66.
doi: 10.1200/JCO.2014.60.2466. Epub 2015 Aug 17.
4. Carniti C, Gimondi S, Vendramin A, Recordati C, Confalonieri D, Bermema A, Corradini P, Mariotti J. Pharmacologic
Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects. Clin
Cancer Res. 2015 May 14. pii: clincanres.2758.2014. [Epub ahead of print] PubMed PMID: 25977345.
40
HEREDITARY
CANCER AND
MEDICAL GENETIC
HEREDITARY CANCER
AND MEDICAL GENETICS
PROGRAM MEMBERSHIP
S. MANOUKIAN, P. RADICE, M. VITELLARO,
S. SIGNORONI
Cancer is a disease generally caused by both genetic and
environmental factors. Occasionally, certain types of
cancer seem to recur in some families.
In some cases, this is because family members have certain risk factors in common
such as smoking, but in others the cancer is caused by an abnormal gene that is being
passed along family members from generation to generation. This is often referred
to as inherited cancer. What is inherited is the abnormal gene that can lead to cancer,
not the cancer itself. Only about 5% to 10% of all cancers result directly from gene
defects (called mutations) present in families.
HEREDITARY BREAST AND OVARIAN CANCER SYNDROME (HBOC)
Paolo Radice, Siranoush Manoukian
The project is carried out in collaboration among Molecular Bases of Genetic Risk
and Genetic Testing Unit, Medical Genetics Unit of the Department of Preventive
and Predictive Medicine, and the Unit of Anatomic Pathology 1 of the Department of
Diagnostic Pathology and Laboratory Medicine. The project takes advantage on the
collaboration with National and International research groups, including consortia
and scientific societies.
We intend to verify the
occurrence of additional
pathogenic founder mutations
in population enriched in
genetic isolates.
Furthermore, we seek to
investigate breast cancer
patients who survived from
pediatric malignancies
While we will pursue the description of the complex landscape of the molecular basis
of breast cancer susceptibility and of the associated risks, we plan to exploit recently
developed technological approaches, including Next Generation Sequencing. This
will be applied to the examination of selected gene panels or of the entire exome or
genome. More specifically, we intend to verify the occurrence of additional pathogenic
founder mutations in population enriched in genetic isolates. Furthermore, we seek to
investigate breast cancer patients who survived from pediatric malignancies. These
will be screened for constitutional pathogenic mutations in a panel of seven breast
cancer predisposing genes. The analysis will include, in addition to coding exons,
all non-coding regions spanning the genes of interest. In fact, little information is
available on the role on cancer predisposition of variants in such regions. Identified
variants will be prioritized through bioinformatics analyses and their pathogenicity
assessed by functional assay. The occurrence of specific correlations between
the detected mutations and the characteristics of the patients will be verified, in
particular as concerned the age of breast cancer onset and type of treatments for
childhood cancer. The main outcomes expected from this project are an increase
of the current knowledge on the contribution of breast cancer predisposing genes
to pediatric cancer onset and the development of genetic tests to identify specific
subgroups of cancer prone individuals. Since compelling evidences indicate that a
subset of cancer predisposing alleles have a preferential geographic distribution, we
will foster the constitution of a nation-wide network of cancer genetic laboratories
with the aim of promoting the development of collaborative project specifically
addressed to the Italian population and of facilitating the connections with the above
mentioned international consortia.
The diagnostic activity is integrated with several research programs, taking
advantage from the continuous recruitment through genetic counseling of selected
individuals and families with evidence of genetic predisposition to cancer. In
particular, the consolidated and long lasting clinical activity of the Medical Genetics
Unit has allowed the assembling of the largest Italian collection of HBOC patients
and relatives, including at present about 9,350 individuals belonging to about 4,360
different HBOC families collected. When available, all relevant data have been
recorded in the Medical Genetics HBOC database. Actually, more than 760 BRCA1/
BRCA2 mutated families have been collected, including 1,448 gene carriers (165
men and 1,283 women). Moreover data on 155 families with variants of unknown
significance and 1,991 high risk families tested negative for BRCA1/BRCA2 mutation,
are available. Tumor specimens and blood samples are routinely collected from all
patients treated at INT. Taking advantage of the high number of families maintaining
41
a long lasting contact with the Unit, all new clinical, familial, pathological and
molecular data of the individuals belonging to HBOC families are constantly updated.
Major relevant studies are:
•G
enetic characterization of HBOC (penetrance, survival, disease features and
presentation, tumor features, as well as genetic and environmental risk factor
modifiers)
•L
ong-term efficacy, clinical and psychological impact of surveillance, risk reducing
measures and treatment in HBOC individuals
•B
iological and clinical significance of BRCA gene mutations with unknown
significance genomic and transcriptomic analyses for the identification of modifier
risk factors and new genes involved in genetic predisposition to HBOC
•E
ffective strategies for identification and referral to risk evaluation of women at
increased genetic risk for breast and ovarian cancer.
HEREDITARY DIGESTIVE TRACT TUMORS
Marco Vitellaro, Stefano Signoroni
We are devoted to the
counseling, molecular testing,
and clinical management
of individuals with genetic
predisposition to the major
hereditary syndromes of
gastrointestinal cancer
Several genetic factors associated with hereditary susceptibility to cancer have been
identified. Genetic test is routinely applied in clinical practice to search for germline
cancer predisposing alleles. This allows clinicians to identify, within cancer-prone
families, at-risk individuals. Once the gene carriers are identified, it is possible to offer
them the appropriate surveillance programs and/or other measures of risk reduction,
such as chemoprevention or prophylactic surgery. Conversely, family members not
found to be mutation carriers may be advised to follow the same recommendations
of the general population. We are devoted to counseling, molecular testing, and
clinical management of individuals with genetic predisposition to the major
hereditary syndromes of gastrointestinal cancer. These include Lynch Syndrome
(or Hereditary Non-Polyposis Colorectal Cancer -HNPCC-), Familial Adenomatous
Polyposis (FAP) and its variants Attenuated-FAP or MAP, Peutz Jeghers Syndrome,
Juvenile Polyposis and Hereditary Gastric Cancer. Individuals with evidence of
hereditary susceptibility to cancer are counseled and informed about personal and
relatives risk. Depending of the fulfillment of defined clinical 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, specific clinical phenotypes, and tumor characteristics.
The screened genes at present include: MLH1, MSH2, MSH6, and PMS2, cumulatively
referred to as DNA mismatch repair (MMR) genes (Lynch Syndrome); APC and
MUTYH (FAP and attenuated FAP); STK11 (Peutz-Jeghers Syndrome), PTEN (Cowden
Syndrome), CDH1 (Hereditary Gastric Cancer) and p53 (Li Fraumeni Syndrome). During
2015, about 500 individuals were counseled and screened for germline mutations
in cancer predisposing genes. A multidisciplinary meeting is run weekly to better
address patients to a comprehensive surveillance program. This activity is integrated
by several research programs.
Beyond the hereditary genes already identified, there is an amount of CRC cases
that presenting familial aggregation for the disease without a known germline
genetic cause. Moreover, CRC can be also considered a complex disease in which the
combinations of genomic variants with rare-to-common prevalence and high-to-low
penetrance could play a role in the etiology of the disease. In the recent years, new
sequencing technologies including whole-exome sequencing have provided further
insights into familial CRC, revealing new candidate susceptibility genes for CRC
predisposition.
The identification of predisposing variants for CRC could have substantial
implications for disease risk assessment, management, and surveillance in family
members with a strong CRC family history, without a detectable germline mutation
in the known predisposition genes. Moreover, it could represent an important tool
to improve the efficiency and the efficacy of treatment and surveillance protocols of
selected patients/individuals, reducing costs and improving compliance and quality
of life. At present a discovery phase of whole exome sequencing is in progress on
selected patients with the support of the Functional Genomics and Bioinformatics Department of Experimental Oncology and Molecular Medicine.
42
IMMUNITY
PARTICIPATING/PROGRAM MEMBERSHIP
A. ANICHINI (COORDINATOR)
M.G. DAIDONE, M.P. COLOMBO, L. RIVOLTINI,
S. PUPA, G. SOZZI, F. DE BRAUD, M. DEL VECCHIO,
M. GARASSINO, G. PROCOPIO, M. DI BARTOLOMEO,
M. DI NICOLA, A. NECCHI, V. MAZZAFERRO,
M. SANTINAMI, U. PASTORINO, P. CORRADINI,
M. MILIONE.
PARTICIPATING DEPARTMENTS AND UNITS.
•DEPT. OF EXPERIMENTAL ONCOLOGY AND
MOLECULAR MEDICINE.
-BIOMARKERS UNIT.
- MOLECULAR IMMUNOLOGY UNIT.
- IMMUNOTHERAPY OF HUMAN TUMORS UNIT.
- IMMUNOBIOLOGY OF HUMAN TUMORS UNIT.
- TUMOR GENOMICS UNIT.
- MOLECULAR TARGETING UNIT.
IMMUNITY
• DEPT. OF MEDICAL ONCOLOGY.
- MEDICAL ONCOLOGY UNIT 1.
- THORACIC ONCOLOGY UNIT.
- IMMUNOTHERAPY AND ANTICANCER
INNOVATIVE THERAPEUTICS.
- GASTROINTESTINAL ONCOLOGY UNIT.
- GENITOURINARY ONCOLOGY UNIT.
• DEPT. OF SURGERY.
- HEPATO-GASTRO-PANCREATIC SURGERY
UNIT.
- MELANOMA AND SARCOMA SURGERY UNIT.
- THORACIC SURGERY UNIT.
- UROLOGIC SURGERY UNIT.
• DEPT. OF PATHOLOGY.
- ANATOMIC PATHOLOGY UNIT 1.
• DEPT. OF HEMATOLOGY AND PEDIATRIC
ONCOHEMATOLOGY.
- HEMATOLOGY UNIT.
Improving clinical efficacy of cancer immunotherapy
in solid tumors by tackling mechanisms of resistance,
exploiting novel combinatorial approaches and identifying
predictive biomarkers.
Over the past 6 years, results of several Phase I to III clinical trials of cancer
immunotherapy targeting immune checkpoints (initially CTLA-4 and, subsequently,
the PD-1/PD-L1 axis) have fostered the dawn of a new era in the treatment of several
advanced cancers including melanoma, non-small cell lung cancer (NSCLC), urothelial
cancer, renal cancer, head and neck squamous cell carcinoma, triple-negative breast
cancer, gastric cancer, colorectal cancer, Merkel cell carcinomas and Hodgkin’s
lymphomas.
The initial evidence for a high rate of durable objective responses and subsequently,
the significant improvement in progression-free and/or overall survival in several
of these tumors, achieved by immune checkpoint blockade, when compared to
previously available conventional treatments, have firmly established the principle
that it is possible to effectively treat advanced cancers by promoting/rescuing the
anti-tumor functions of the patients’ immune system. In spite of these remarkable
advances achieved by the immunological treatment of metastatic tumors, still only a
fraction of patients achieve long lasting clinical benefit from immunotherapy.
Promoting a better understanding of the immune circuits which explain patients’
response to immunotherapy, deciphering mechanisms of innate and acquired
resistance to immune checkpoint blockade, defining at pre-clinical and clinical levels
the potentially effective combinatorial approaches to counteract tumor-dependent
immune suppression, identifying biomarkers able to predict responsiveness or
resistance to immunotherapy, are some of the main goals of the integrated preclinical and clinical research activity that is carried out at our Institute.
The “Immunity program” at INT stems from the remarkable experience developed
in the Units of the Clinical Departments in all aspects of immune-related treatment
of an increasing range of human cancers, fostered by the ever increasing number of
clinical trials of immune intervention being carried out at our Institute. The Immunity
program also builds upon the unique, long standing and broad research experience
developed in different Units in the Department of Experimental Oncology and
Molecular Medicine, in basic, pre-clinical and translational tumor immunology.
This expertise is the key element that allows our Institute to develop an integrated
project able to address relevant aspects of tumor immunology starting from the role
of genes, signatures and signaling pathways in immune cells and neoplastic cells,
to the mechanisms regulating the host-tumor interaction in experimental models
and human neoplastic tissues, to reach the definition of new molecular and cellular
targets for immune intervention.
The Immunity program at INT reflects and describes these efforts towards few
shared, key goals: improving the fraction of responding patients, broadening the
types of tumors that can be treated by immunotherapy, providing evidence for
enhanced efficacy compared to conventional approaches, extending the usage of
immunotherapy to adjuvant, neoadjuvant and first line settings, and ultimately,
fostering a significant improvement in patients’ survival.
43
The pre-clinical and clinical research activity in tumor
immunology and immunotherapy in 2015
The study identified a 6-gene
T-cell related metagene
directly associated with
prognosis and benefit from
adjuvant/neoadjuvant
chemotherapy in triplenegative breast cancer
Myeloid cell type, the mast
cells, has been found capable
of double activities promoting
the healing of inflammationassociated wound, whereas
acquiring a pro-tumorigenic
profile when adjacent to
transformed epithelial cells
A cellular blood score
quantifying the level
of systemic myeloid
dysfunctions associated
with a poor prognosis and
poor response to therapy in
metastatic melanoma
44
• M.G. Daidone and collaborators (Biomarkers Unit) investigated the prognostic
and predictive value of specific gene set in breast cancer. The association with
outcome of robust gene cluster–based metagenes linked to immune response was
challenged on more than 3,500 publicly available gene-expression profiles from
breast cancer patients untreated or subjected to systemic adjuvant or neoadjuvant
treatments and belonging to the different molecular subtypes. The study, carried
out in collaboration with the Medical Oncology Department of San Raffaele Hospital,
identified a 6-gene T-cell related metagene directly associated with prognosis and
benefit from adjuvant/neoadjuvant chemotherapy in triple-negative breast cancer,
since patients with highly expressing tumors showed a high rate of achieving a pCR
and higher distant metastasis-free survival at 5 years compared to those presenting
with low expressing tumors (85% vs 44%). The immune metagene identified one
third of patients with a dismal prognosis, resulting from both a higher baseline risk
of recurrences and lack of benefit from standard therapy. These patients deserve a
priority enrolment in trials testing investigational compounds.
•M
.P. Colombo and collaborators (Molecular Immunology Unit) reported new
discovery in the myeloid field, particularly: unveiled a role for Mef2c in regulation of
SOCS2 during emergency hematopoiesis also characterizing unfavorable subset of
acute myeloid and lymphoblastic leukemia (Cancer Res. 2015). In collaboration with
A. Sica (University of Novara) they identified subsets of Myeloid Derived Suppressor
Cells (MDSCs) and TAMs based on the expression of retinoic-acid-related orphan
receptor (RORC1/RORγ) in human and mouse tumor bearers. Ablation of RORC1 in
the hematopoietic compartment prevented cancer-driven myelopoiesis (Cancer Cell.
2015). Another myeloid cell type, the mast cells, has been found capable of double
activities promoting the healing of inflammation-associated wound, whereas
acquiring a pro-tumorigenic profile when adjacent to transformed epithelial
cells. (Cancer Res. 2015). The study of costimulatory molecule OX40 continued
in characterizing its role on the fitness of regulatory T cells in ovarian cancer
and testing new humanized monoclonal antibodies for targeting OX40 activity
(Collaboration with Martin Glennie, Southampton).
•L
. Rivoltini and collaborators (Immunotherapy of Human Tumors Unit) elucidated
the pathways leading to the accumulation of regulatory immunosuppressive cells in
patients with cancers, with the goal of identifying prognostic/predictive biomarkers
and novel targets for cancer therapeutics. Main ongoing projects involved: 1. myeloid
suppressive cell compartment. Within the concept of “immune liquid biopsy”, they
developed a cellular blood score (Myeloid Index Score, MIS) quantifying the level
of systemic myeloid dysfunctions that associate with a progressively deteriorating
prognosis and poor response to therapy in patients with metastatic melanoma
(with ongoing studies in HCC and lung cancer). If confirmed in prospective setting
and in additional cancer histologies, MIS could soon become a tool for assessing
general immune state conditions at single patient’s level. The use of an in vitro
model of MDSC generation based on the conversion of monocytes by melanoma
exosomes, provided information about the mechanisms responsible for cancermediated myeloid conditioning, that involves selective miRNAs. The MDSC-related
miRNA panel, overexpressed in circulating myeloid cells and in melanoma lesions,
is under validation as potential myeloid immune suppressive plasma biomarker,
and therapeutic target in murine setting. Several of these miRNAs are also involved
in the induction of resistance to BRAFi in melanoma cells, through a process that
promotes tumor insensitivity to apoptosis and the concomitant accrual of myeloid
immunosuppressive cells at tumor site (Vergani E. et al., Oncotarget 2015). Through
the use of MDSC in vitro model, vATPAse was been identified as a key molecule
and the inhibiting drug esomeprazole as a potential tool to contrast MDSC in vivo
generation. A phase II clinical trial (Adesom2) investigating the immunomodulating
properties of esomeprazole is presently ongoing in early melanoma patients,
unraveling a pivotal role of this drug in reducing cancer-related immunosuppression
in the lack of significant toxicity. The myeloid compartment of hepatocellular
carcinoma (HCC) is being studied for prognostic and therapeutic purposes, focusing
on the role of hypoxia and related biochemical alterations in the accrual of MDSC
and the maintenance of cancer stem cell phenotype. A gene-expression profile of
large case collection of HCC specimens (and related liver) allowed to identify a pH/
myeloid/stemness Index Score which appears to predict time to recurrence after
radical surgery and is presently under validation in conjunction with the Mount Sinai
Hospital, NY. The expression of pH regulatory molecules (CA9, CA12), together with
the antitumor activity of selective inhibitors, has been investigated in HCC lesions
and lines.
2. Sentinel node as source of prognostic biomarkers and novel immune checkpoint
for melanoma therapy. The evaluation of sentinel and draining lymph nodes (LN)
provides pivotal information about the outcome of tumor immunity. Through geneexpression profiling, CD30 had been previously found to be upregulated in sentinel
node of melanoma patients undergoing disease progression. CD30 defines a subset
of anergic and immunosuppressive lymphocytes, and possibly represents a novel
immune checkpoint involved in tumor immune evasion. The evidence that CD30
inhibition results in reduced melanoma growth in mice is in line with this hypothesis
and supports further studies on the potential prognostic and therapeutic role of this
marker. Immunological monitoring of patients receiving anti-CD30 Ab (therapeutic
strategy for CD30+ lymphoma) is currently ongoing. Melanoma-invaded LN are
also enriched in a specific subset of plasmacytoid dendritic cells (pDCs) expressing
LAG-3 and exerting immunosuppressive activity and myeloid cell recruitment.
pDCs are thus a crucial component of the tumor microenvironment that should be
counteracted to restore effective immunity. The immune checkpoint molecule LAG-3
when expressed on plasmacytoid dendritic cells (pDCs) or in T regulatory cells
(Tregs), exerts strong immunosuppressive functions in melanoma invaded lymph
nodes. A strong association was demonstrated between the expression of LAG-3 on
Tregs and a set of genes encoding for B/T signaling molecules and we showed that
these Treg subsets blocked the final differentiation of antibody secreting B cells
in melanoma invaded lymph nodes. These subset of Tregs with follicular features/
functions are detectable in the PBMCs of melanoma patients and mediate a new
mechanism of tumor escape involving B cell control. The above mentioned studies
are being conducted in collaboration with internal and external groups, including:
Melanoma Unit (M. Santinami), Liver Unit (V. Mazzaferro), Medical Oncology
Department (F. De Braud and M. Del Vecchio), Hemato-Oncology Department (P.
Corradini), DKFZ Heidelberg (Victor Umansky) and Mount Sinai Hospital, NY (Josef
Llovet).
The early effector T cells
(EECs) retain ability to
recognize autologous tumor
cells, providing the rationale
for immune checkpoint
blockade therapy even in early
stage NSCLC
• A. Anichini and colleagues (Human Tumors Immunobiology Unit) have investigated
the mechanisms that contribute to the development of the earliest phase of
adaptive immunity in primary NSCLC, in collaboration with U. Pastorino (Thoracic
Surgery Unit) and with G. Sozzi (Tumor Genomics Unit). Efficacy of immune
checkpoint blockade in advanced NSCLC depends on functional rescue of a preexisting anti-tumor adaptive response. Therefore, analysis of primary NSCLC tissues
should reveal the presence of recently activated tumor-reactive T cells retaining
functional competence. Accordingly, a subset of PD-1+ CD8+ FOXP3+ T cells was
found at tumor site. By extensive phenotypic and functional analysis, this subset
was characterized as representing the first stage of functional differentiation
after priming, the so called “early effector T cells” (EECs). These lymphocytes
were activated but not exhausted, in spite of co-expression of multiple inhibitory
receptors. The EECs retain ability to recognize autologous tumor cells, providing the
rationale for immune checkpoint blockade therapy even in early stage NSCLC.
In collaboration with M. Garassino (Thoracic Oncology Unit) an extensive flowcytometry-based assessment of all main circulating immune subsets in peripheral
blood of NSCLC patients treated with antibodies targeting the PD-1/PD-L1 pathway
is under way. The main goal is to define a predictive algorithm to explain response
or resistance to immunotherapy by taking into consideration levels and dynamics of
both activated T cells and of main immunosuppressive subsets.
In collaboration with M. del Vecchio (Medical Oncology Unit 1), M. Di Nicola (Clinical
Immunotherapy and Innovative Therapies Unit), and with M. Milione (Unit of
Anatomic Pathology 1), analysis of pre-therapy neoplastic lesions from independent
panels of metastatic melanoma patients treated with anti-CTLA-4 or anti-PD-1
antibodies has begun. Preliminary results indicate immune escape mechanisms
and expression of immunoregulatory molecules in lesions from non responding
patients.
In collaboration with M. Milione (Unit of Anatomic Pathology 1), the immune
contexture and expression of main immunoregulatory markers in the tumor and
stroma of primary and metastatic neuroendocrine tumors and carcinomas localized
in gastroenteropancreatic district was investigated. Goals included the definition of
new prognostic biomarkers, refinement of the current classification based only on
grading and providing support for developing immune checkpoint blockade therapy
in these pathologies. Preliminary results indicate that a subset of patients with
neuroendocrine carcinoma (NEC G3) have an “inflamed tumor microenvironment”
characterized by infiltrating T cells and high stromal expression of relevant
immunoregulatory markers”.
45
In collaboration with A. Necchi (Medical Oncology Unit 1), immunomodulatory
activity of Brentuximab-Vedotin was investigated in CD30-expressing germ cell
tumors after chemotherapy failure. In the first 7 treated patients, this therapy
showeds remarkable immune modulatory activity by modulation of absolute counts
and phenotype of most subsets in peripheral blood, including B, activated T cells,
monocytes and dendritic cells. The relationship of immune modulation with the
clinical outcome is currently being investigated.
•M
. Di Nicola (Immunotherapy and Anticancer Innovative Therapeutics) and
Collaborators (S. Pupa, Molecular Targeting Unit, DOSMM; Claudio Tripodo,
University of Palermo) have clarified the role of heat shock protein (HSP)H1/105
in B-cell non-Hodgkin lymphomas (NHL). HSPH1 physically interacts with both
c-Myc and Bcl-6, two key lymphoma oncoproteins, promoting their stabilization
and oncogenicity. This study confirms the candidacy of HSPH1 as a valuable
therapeutic target of aggressive B-NHLs (Blood. 2015). The anti-tumor response
can be also modulated by the tumor microenvironment perturbation. In aggressive
lymphoma models, poorly responsive to conventional agents, it was demonstrated
that the destructuration of tumor stroma by a heparanase inhibitor potentiate
the complement-mediated tumor cell killing induced by the anti-CD20 rituximab,
making this combination a novel promising therapeutic approach for the treatment
of aggressive lymphomas. In collaboration with M.P. Colombo (Molecular
Immunology Unit), the role of co-stimulatory molecules as complementary
mechanisms of immune regulation is being addressed. We have identifeid a
negative prognostic impact of OX40 expression on ovarian cancer-infiltrating Tregs
indicating that OX40 may constitute a rational target to counteract effector Treg
functions. Experiments to test new humanized monoclonal antibodies for targeting
OX40 activity (Collaboration with Martin Glennie, Southampton) are in progress.
•M
. Di Bartolomeo and collaborators (Gastrointestinal Oncology Unit) have been
involved in different aspects of immunotherapy in gastrointestinal cancer. The
group was one of the top recruiter in the enrollment of patients in different
international study protocols such as the maintenance trial with Ipilimumab in
gastric or gastro-esophageal cancer. A phase III study of Pembrolizumab (MK-3475)
in second line gastric or gastroesophageal junction adenocarcinoma patients is
currently ongoing. Several studies addressing the potential correlation between
Helicobacter Pylori (HP) infection and the expression of PDL-1 in non-diffusetype gastric cancer were also conducted. It has been found that HP positivity
is significantly associated with PD-L1 expression and that PD-L1 expression
is not associated with ILs, N and T stage. Also, it was highlighted that PD-L1 is
overexpressed in EBV positive patients and in those with microsatellite instability.
This may represent the rationale for future research on immunotherapy in
patients with HP-positive gastric cancer. Regarding colorectal cancer, the group
has been involved in a study of the efficacy of atezolizumab plus chemotherapy
and bevacizumab as maintenance treatment after induction therapy in metastatic
colorectal cancer patients.
46
Outline of active clinical studies of immunotherapy at our
Institute in 2015
Phase II and III trials based
on antibodies directed to
the CTLA-4 and PD-1/PD-L1
axis have steadily increased
throughout 2015
Phase II and III trials based on antibodies directed to the CTLA-4 and PD-1/PD-L1
axis have steadily increased at our Institute throughout 2015, by extending the
types of tumors being treated with immune checkpoint blockade, even in the first
line setting, and by introducing combinatorial studies. Most of these studies are
being carried out in the Units belonging to the Division of Medical Oncology (Director
F. de Braud) or to the Division of Surgery (Director V. Mazzaferro). Most of these
studies are Phase II to III trials of immune checkpoint blockade in melanoma (M. del
Vecchio), SCLC and NSCLC (M. Garassino), renal cell carcinoma (G. Procopio), urothelial
cancer (A. Necchi), and gastric cancer (M. Di Bartolomeo) either following failure
of previous conventional treatment or comparing immune checkpoint blockade
with chemotherapy. In particular, the Thoracic Oncology Unit (M. Garassino) had an
important role in the Checkmate-017 study, which led to the FDA approval of antiPD-1 in squamous cell carcinoma. Recruiting trials of immunotherapy in lung cancer
are mainly Phase II and Phase III studies, including trials testing the association
of anti-PD-1 with a demethylating agent in NSCLC, and several Phase III studies
comparing immunotherapy vs. chemotherapy. In melanoma (M. del Vecchio) several
Phase II and III studies were active in 2015, including treatment with anti-PD-1 after
a previous therapy with anti-CTLA-4, a Phase III, randomized, double-blind study of
adjuvant Immunotherapy with anti-PD-1 vs anti-CTLA-4 after complete resection
of stage IIIb/c or stage IV tumors, and a phase III study of Fotemustine versus the
combination of Fotemustine and anti-CTLA-4 in patients with brain metastasis. F. de
Braud, M. Di Nicola and colleagues (Medical Oncology Unit 1) are involved in basket
phase I/II clinical trials in patients with advanced disease with anti-PD1 alone or in
combination with anti-CTLA4, anti-PDL1 and combination of LDK (an ALK inhibitor)
and anti-PD1. In 2015 the Institute has contributed to the Checkmate 025 trial that
led to the registration of anti-PD-1 for the treatment of clear cell renal carcinoma
(G. Procopio). Translational studies to identify predictive factors of response and
resistance are ongoing at the Genitourinary Oncology Unit. Additional trials in renal
cancer are ongoing on the role of combination immunotherapy (anti-PD-1 and
anti-CTLA-4), or on combinations of anti-PD-L1 with target-specific
inhibitors, on the role of anti-PD-L1 as adjuvant
therapy after nephrectomy and of antiPD-1 in rare RCC histologies including
Bellini ducts and non clear cells cancer.
In urothelial cancers (A. Necchi) four
Phase II or III trials were active in 2015
with antibodies targeting the PD-1/PDL1 axis in patients with locally advanced
or metastatic disease, compared with
chemotherapy or following failure of
previous chemotherapeutic treatment.
47
MELANOMA
MULTIDISCIPLINA
PROGRAM
MELANOMA MULTIDISCIPLINARY
PROGRAM
PROGRAM MEMBERSHIP
M. SANTINAMI, R. PATUZZO, A. MAURICHI,
F. GALLINO, R. RUGGERI, I. MATTAVELLI,
L. RIVOLTINI, M. RODOLFO, C. CASTELLI,
A. ANICHINI, R. MORTARINI, F. DE BRAUD,
M. DEL VECCHIO, L. DI GUARDO, C. CIMMINIELLO
PARTICIPATING UNITS
MELANOMA AND SARCOMA SURGERY (MSSU)
IMMUNOTHERAPY OF HUMAN TUMORS (IHTU)
IMMUNOBIOLOGY OF HUMAN TUMORS (IBHTU)
MEDICAL ONCOLOGY (MOU)
The Melanoma Multidisciplinary Program has been active
since 2013 by the Melanoma and Sarcoma Surgical Unit in
collaboration with specialists of other participating Units,
with special emphasis on a multidisciplinary approach to
diagnosis and translational and clinical research.
The goal is to implement research strategies and promote clinical and experimental
studies to offer patients the best choice of therapy and the opportunity to access
experimental treatments. The core of this multidisciplinary approach has been
organized at a weekly meeting involving surgeons, medical oncologists, experimental
oncologists, clinical study coordinators, data managers, and nurses. During the
meeting, participants discuss several topics including new and ongoing clinical
studies and scientific reports, and also share decisions and paths of care on clinical
cases to plan the best therapeutic options for patients, including enrollment in
experimental protocols. In 2015, more than 40 meetings took place and more than
250 clinical cases were discussed. Through the interaction of the units participating
to the program, several collaborative studies and activities were conducted in 2015,
often involving national and international groups.
Activities
During 2015, the MSSU performed clinical-dermatoscopic examination and follow-up
control on about >15,000 patients; 682 patients were hospitalized and underwent
major surgery after a diagnosis of melanoma; these patients were submitted to 380
wide excision and sentinel node biopsies, 216 lymph-node dissections, 40 surgical
excisions and skin grafts, 8 isolated limb perfusions, 30 electrochemotherapies,
and 19 other various surgeries. 1937 conventional surgeries and 30
electrochemotherapies were performed in day surgery. The MSSU participated
as leader to the Lombardy Oncology Network (Rete Oncologica Lombarda, ROL), a
regional oncology network built in Lombardy to improve prevention and care for
people with a diagnosis of all kinds of cancer. All patients who underwent surgery
in 2015 were included in the ROL. The MSSU improved the perspective computerized
database of all melanoma patients who were treated at this Institution from 2000
to date: the database contains more than 8,000 patients and represents one of the
largest and more complete melanoma databases worldwide. In 2015 The MSSU
was invited by the The American Joint Committee on Cancer (AJCC) to partecipate in
building the new melanoma staging sistem and classification and give a support of
more than 7,000 cases over a total fo 30,000.
The MSSU was one of the referral centers in Europe and gave specific attention
to pediatric melanomas and melanocytic tumors of uncertain malignant potential
(MELTUMP) that typically occur in children and adolescents. About 420 pediatric
patients were submitted to a clinical and dermatoscopic examination at out pediatric
outpatient clinic during 2015 and 12 cases underwent major surgery for histological
diagnosis of cutaneous melanoma or MELTUMP. The MSSU also was one of the
referral centers in Europe for locoregional treatments such as isolated limb perfusion
(ILP) and electrochemotherapy (ECT) in melanoma patients. During 2015, the MOU
performed about 380 first visits of patients with unresectable/metastatic melanoma
and about 3,300 visits for disease control and oral/intravenous therapies with only
few hospitalizations due to adverse side effects of patients under treatment.
The main goals of the MOU clinical trials were: a) to compare combined targeted
therapy (BRAF inhibitor + MEK inhibitor) versus mono-targeted therapy with BRAF
inhibitor as first-line treatment of advanced BRAF mutated melanoma in terms
of progression-free survival and overall survival; b) to compare the new immune
checkpoint inhibitor nivolumab (anti-PD-1 mAb) versus chemotherapy in previously
untreated metastatic melanoma patients and in patients affected by metastatic
melanoma after disease progression following ipilimumab and/or BRAF inhibitor; c)
48
The MOU worked on the
possibility to surpass the limits
related to the specific patterns
of response of BRAF inhibitors
and ipilimumab
to compare the efficacy of the combination of ipilimumab and fotemustine-based
chemotherapy or ipilimumab and nivolumab versus fotemustine alone in terms
of overall survival in patients with metastatic melanoma and brain metastases;
d) to compare, in terms of overall survival, combined immunotherapy (nivolumab
+ ipilimumab) versus single therapy with nivolumab or ipilimumab in previously
untreated patients with metastatic melanoma. The MOU worked on the possibility to
surpass the limits related to the specific patterns of response of BRAF inhibitors and
ipilimumab. The limit of mono-targeted-therapy is represented by the short median
response duration (6-8 months), whereas ipilimumab requires less time to mount an
efficient anti-tumor immune response. Another research topic consists of designing a
new therapeutic algorithm for treatment of brain metastases, in the light of the new
therapeutic tools available.
The combination of a BRAF inhibitor and MEK inhibitor (dabrafenib + trametinib or
vemurafenib + cobimetinib) developed by the MOU has met three main endpoints: a)
Improvement of the global clinical activity (up to more than 60% of response rate);
b) Increase of median duration of response (nearly double); c) Significant reduction
of the incidence of cutaneous squamous cell carcinoma (from more than 20% to
less than 5%). MOU and IBHTU collaborate to identify potential biomarkers that are
predictive of response and resistance to immune checkpoint inhibitors.
Relevant output of the clinical units
The MMSU took part in various clinical trials during 2015 and particularly:
• 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. GSK 2132231A Antigen-Specific Cancer
Immunotherapeutic as adjuvant therapy in patients with resected melanoma.
• A Phase II study of intratumoral application of L19IL2/L19TNF in melanoma patients
in clinical stage III or stage IV M1a with presence of injectable cutaneous and/or
subcutaneous lesions.
• An open, dose-escalation Phase I/II study to assess the safety, immunogenicity and
clinical activity of recPRAME + AS15 Antigen-Specific Cancer Immunotherapeutic as
first-line treatment of patients with PRAME-positive metastatic melanoma.
• An open Phase I Study of immunization with the recNY-ESO-1 + AS15 AntigenSpecific Cancer Immunotherapeutic in patients with NY-ESO-1-positive unresectable
and progressive metastatic cutaneous melanoma.
• A Phase III randomized double blind 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.
The MOU took part in various clinical trials during 2015 and particularly:
• BRF117277: A Phase II, Open-Label, Multicentre Study of Dabrafenib plus Trametinib
in Subjects with BRAF Mutation- Positive Melanoma that has Metastasized to the
Brain.
• CA184-367 An observational study to evaluate the effectiveness and safety of
ipilimumab, administered during the european expamded Access programme in
pretreated patients with advanced (unresectable or metastatic) melanoma.
• CA209-172: A multicentric, singol-arm, open-label, clinical trial with Nivolumab
(BMS-936558) in patients with (unresectable) stage III melanoma or histologically
confirmed stage IV progressing after prior treatment containing a monoclonal antiCTLA-4 antibody.
• A Phase III, Randomized, Double-blind Study of Adjuvant Immunotherapy with
Nivolumab versus Ipilimumab after Complete Resection of Stage IIIb/c or Stage IV
Melanoma in Subjects who are at High Risk for Recurrence (Coordinator Center in
Italy).
• A randomized, Phase III study of Fotemustine versus the Combination of
Fotemustine and Ipilimumab and the combination of Ipilimumab and Nivolumab in
patients with metastatic melanomawith brain metastasis. -The NEMO trial (NRAS
melanoma and MEK inhibitor): A randomized Phase III, open label, multicenter, twoarm study comparing the efficacy of MEK162 versus dacarbazine in patients with
advanced unresectable or metastatic NRAS mutation-positive melanoma patients.
49
Activities of the experimental units
Phenotypic profiling of blood
cells, through an “immune
liquid biopsy” approach
based on multiparametric
cytofluorimetry, while
molecular miRNA signatures
were searched in plasma to
monitor resistance to BRAF/
MEKi and immune checkpoints
Studies on miRNA profiles
in sentinel LN identified a
set of miRNA differentially
expressed in melanomapositive SNB samples from
patients with progressing
disease
The IHTU focused on defining the role of circulating myeloid cells and related
miRNA markers, together with immunosuppressive/exhausted T cell subsets in
creating a systemic status of immune hypo-responsiveness that could facilitate
disease progression and poor response to treatment. Phenotypic profiling of blood
cells, through an “immune liquid biopsy” approach based on multiparametric
cytofluorimetry was applied, while molecular miRNA signatures were searched
in plasma to monitor resistance to BRAF/MEKi and immune checkpoints. Lymph
nodes were interrogated by gene-expression, miRNA profiling, and immune cell
profile. A Myeloid Index Score was identified that clusters metastatic melanoma
patients in groups with progressively deteriorating prognosis and poor response
to therapy (including Ipilimumab and BRAFi). Prospective validation of this score is
presently ongoing. The Adesom2 trial, performed in active collaboration with the
MSSU, showed that myeloid cell-mediated immunosuppression can be counteracted
by esomeprazole in early melanoma patients, with no toxicity and reduced costs.
The IHTU further characterized the CD30 positive immune cells subpopulations
molecules mainly represented by exhausted and anergic lymphocytes in tumor
draining LN and in the systemic circulation of melanoma patients. Preliminary
data from immune monitoring studies suggest a potential prognostic association
of CD30+ populations. Studies on miRNA profiles in sentinel LN identified a set of
miRNA differentially expressed in melanoma-positive SNB samples from patients
with progressing disease. Differential miRNA expression patterns were confirmed
by qRT-PCR analysis in other sentinel node biopsy (SNB) samples. Studies have been
planned to evaluate miRNA as potential markers associated to prognosis in SNB
samples The genetic studies in multiple primary melanomas (MPM) were included in
a national-based analysis of Italian patients concluding that melanoma patients who
developed 2 melanomas, even in situ, should be referred for genetic counseling even
in the absence of family history. The same case collection has been also included an
international consortium on melanoma genetics (Melanostrum, NIH/NCI) for future
collaborative studies. In melanoma-invaded LN we defined two novel subsets of
plasmacytoid dendritic cells (pDCs) and regulatory T cells (Tregs) expressing the
immune checkpoint LAG-3 and exerting strong immunosuppression on antitumor
immunity. LAG-3+ Tregs express a specific gene-expression profile including B/T
signaling molecules and blocked final differentiation of antibody-secreting B cells
in melanoma invaded lymph nodes. These follicular Tregs are also detectable in the
PBMCs of melanoma patients, where they might mediate a new mechanism of tumor
immune escape involving B cell control. By in vitro and ex-vivo analysis of melanoma
specimens we show that two cytokines, namely IL10 and IL6, influence melanoma
aggressiveness by modulating its intrinsic stem cells features. Our results stress
the notion that inflammation and local immune suppression are driving forces in the
dynamic stemness of melanoma.(Tuccitto et al, Stem Cells, 2016).
The activities at IBHTU during 2015 were: a) identification of biomarkers predicting
intrinsic resistance to BRAF inhibitors in BRAF-mutant melanoma, b) preclinical assessment of combinatorial treatments that can overcome intrinsic
BRAF-resistance; c) definition and targeting of a master regulator of melanoma
dedifferentiation and immune escape, d) assessment of the modulation of
responsiveness of endothelial cells to MEK inhibitors upon interaction with
melanoma cells.
Three melanoma subsets
distinguished by differential
expression of receptor
tyrosine kinase genes and of
invasive vs. proliferative gene
programs
50
The first relevant output of the IBHTU, in collaboration with Units in the Division of
Medical Oncology and in the Dept. of Experimental Oncology and Molecular Medicine,
was the definition of a new melanoma classification with translational relevance
for target-specific therapy. Three melanoma subsets distinguished by differential
expression of receptor tyrosine kinase genes and of invasive vs. proliferative
gene programs were identified. Melanomas displaying an intrinsic resistance to
BRAF inhibitors were identified as belonging to the “EGFR+ ERBB3- invasive gene
program” subset (Dugo et al Oncotarget 2015). In a subsequent study, BRAF-resistant
melanomas were found to be also cross-resistant to MEK and PI3K/mTOR inhibitors.
However, by extensive drug interaction analysis, comparing different associations of
inhibitors, we found that combinatorial targeting of MEK1/2 and PI3K/mTOR, but not
of mutant BRAF and PI3KmTOR, led to synergistic anti-tumor effects, both in-vitro
and in pre-clinical in-vivo models, not only in BRAF-resistant melanomas, but even
in the tumors with intrinsic cross-resistance to both MAPK and PI3K/mTOR targeting.
These results provide a proof of concept evidence for a feasible strategy that allows
to: a) identify BRAF-inhibitor resistant patients with BRAF-mutant melanomas before
therapy and b) define a combinatorial strategy targeted to BRAF-resistant tumors
based on inhibitors already used in clinical practice in different solid malignancies.
Through NFATc2-mediated
inhibition of MITF, melanomas
loose expression of several
pigmentation related genes
A further relevant output of the IBHTU, in collaboration with MMSU, was the
identification of the transcription factor (TF) NFATc2 as an intrinsic suppressor of
MITF and as an inducer of melanoma immune escape (Perotti et al, Oncogene, 2015).
It was found that through NFATc2-mediated inhibition of MITF, melanomas loose
expression of several pigmentation related genes (known target genes of MITF). As
a consequence of this process of dedifferentiation, tumors are no longer recognized
by patients’ cytotoxic T cells specific for the immunogenic melanocyte differentiation
antigens (MDA) regulated by MITF. The pathway that regulated the function of
NFATc2 was also elucidated. This TF induces production of TNF-α that, in an autocrine
fashion, stimulates expression in melanoma cells of c-Myc. The latter gene in turn
drives expression of the MITF suppressor Brn-2, leading to dedifferentiation and
immune escape. siRNA-mediated targeting and pharmacological inhibition of NFATc2,
by an active metabolite of a common anti-inflammatory drug, suppressed the whole
NFATc2-dependent dedifferentiation pathway and led to re-expression of MITF
and to rescue of tumor-recognition by MDA-specific T cells. These results provide
pre-clinical evidence for a feasible strategy to counteract the process of melanoma
dedifferentiation.
An additional output of the IBHTU in 2015 was the initial evidence that co-culture of
melanoma cells with endothelial cells can promote the susceptibility of the latter cell
types to the inhibitory effects of MEK inhibitors, as well to the anti-tumor activity of the
association of MEK inhibitors with TRAIL. Gene expression analysis of endothelial cells
co-cultured with human melanoma cells is in progress to identify the main pathways
that explain how endothelial cells can become susceptible to MEK inhibitors, as well as
to identify the subset of melanomas that can promote such effect.
Keywords
Multidisciplinary approach, Melanoma, Immunotherapy, Target therapy
Selected publications
Danielli R, Patuzzo R, Di Giacomo AM, Gallino G, Maurichi A, Di Florio A, Cutaia O, Lazzeri A, Fazio C, Miracco
C, Giovannoni L, Elia G, Neri D, Maio M, Santinami M. Intralesional administration of L19-IL2/L19-TNF in
stage III or stage IVM1a melanoma patients: results of a phase II study. Cancer Immunol Immunother. 2015
Aug;64(8):999-1009. doi: 10.1007/s00262-015-1704-6.
Mozzillo N, Pasquali S, Santinami M, Testori A, Di Marzo M, Crispo A, Patuzzo R, Verrecchia F, Botti G,
Montella M, Rossi CR, Caracò C. Factors predictive of pelvic lymph node involvement and outcomes in
melanoma patients with metastatic sentinel lymph node of the groin: A multicentre study. Eur J Surg Oncol.
2015 Jul;41(7):823-9. doi: 10.1016/j.ejso.2015.02.005.
Fava P, Astrua C, Chiarugi A, Crocetti E, Pimpinelli N, Fargnoli MC, Maurichi A, Rubegni P, Manganoni AM,
Bottoni U, Catricalà C, Cavicchini S, Santinami M, Alaibac M, Annetta A, Borghi A, Calzavara Pinton P,
Capizzi R, Clerico R, Colombo E, Corradin MT, De Simone P, Fantini F, Ferreli C, Filosa G, Girgenti V, Giulioni
E, Guarneri C, Lamberti A, Lisi P, Nardini P, Papini M, Peris K, Pizzichetta MA, Salvini C, Savoia P, Strippoli D,
Tolomio E, Tomassini MA, Vena GA, Zichichi L, Patrizi A, Argenziano G, Simonacci M, Quaglino P. Differences
in clinicopathological features and distribution of risk factors in Italian melanoma patients. Dermatology.
2015;230(3):256-62. doi: 10.1159/000368775.
Di Giacomo AM, Ascierto PA, Queirolo P, Pilla L, Ridolfi R, Santinami M, Testori A, Simeone E, Guidoboni M,
Maurichi A, Orgiano L, Spadola G, Del Vecchio M, Danielli R, Calabrò L, Annesi D, Giannarelli D, Maccalli
C, Fonsatti E, Parmiani G, Maio M. Three-year follow-up of advanced melanoma patients who received
ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study.Ann
Oncol. 2015 Apr;26(4):798-803. doi: 10.1093/annonc/mdu577.
Danielli R, Patuzzo R, Ruffini PA, Maurichi A, Giovannoni L, Elia G, Neri D, Santinami M. Armed antibodies for
cancer treatment: a promising tool in a changing era. Cancer Immunol Immunother. 2015 Jan;64(1):113-21.
doi: 10.1007/s00262-014-1621-0.
Gomez-Lira M, Ferronato S, Orlandi E, Dal Molin A, Malerba G, Frigerio S,Rodolfo M, Romanelli MG.
Association of microRNA 146a polymorphism rs2910164 and the risk of melanoma in an Italian population.
Exp Dermatol. 2015 Oct;24(10):794-5.
Perotti V, Baldassari P, Molla A, Vegetti C, Bersani I, Maurichi A, Santinami M, Anichini A, Mortarini R. NFATc2
is an intrinsic regulator of melanoma dedifferentiation. Oncogene. 2015. doi: 10.1038/onc.2015.355.
Dugo M, Nicolini G, Tragni G, Bersani I, Tomassetti A, Colonna V, Del Vecchio M, De Braud F, Canevari S,
Anichini A, Sensi M. A melanoma subtype with intrinsic resistance to BRAF inhibition identified by receptor
tyrosine kinases gene-driven classification. Oncotarget. 2015; 6:5118-33.
Loria R, Bon G, Perotti V, Gallo E, Bersani I, Baldassari P, Porru M, Leonetti C, Di Carlo S, Visca P, Brizzi MF,
Anichini A, Mortarini R, Falcioni R. Sema6A and Mical1 control cell growth and survival of BRAFV600E human
melanoma cells. Oncotarget. 2015;6:2779-93.
Vergani E, Di Guardo L, Dugo M, Rigoletto S, Tragni G, Ruggeri R, Perrone F, Tamborini E, Gloghini A, Arienti
F, Vergani B, Deho P, De Cecco L, Vallacchi V, Frati P, Shahaj E, Villa A, Santinami M, De Braud F, Rivoltini L,
Rodolfo M. Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100
and miR-125b. Oncotarget. 2015 Dec 14. doi: 10.18632/oncotarget.6599.
Castelli C, Rivoltini L, Rodolfo M, Tazzari M, Belgiovine C, Allavena P. Modulation of the myeloid
compartment of the immune system by angiogenic- and kinase inhibitor-targeted anti-cancer therapies.
Cancer Immunol Immunother. 2015 Jan;64(1):83-9. doi: 10.1007/s00262-014-1576-1. Epub 2014 Jul 4. Review.
PubMed PMID: 24993564.
Rizzo A, Vasco C, Girgenti V, Fugnanesi V, Calatozzolo C, Canazza A, Salmaggi A, Rivoltini L, Morbin M,
Ciusani E. Melanoma cells homing to the brain: an in vitro model. Biomed Res Int. 2015;2015:476069. doi:
10.1155/2015/476069. Epub 2015 Jan 26. PubMed PMID: 25692137; PubMed Central PMCID: PMC4321090.
51
Del Vecchio M, Ascierto PA, Mandalà M, Chiarion Sileni V, Maio M, Di Guardo L, Simeone E , Queirolo P.
Vemurafenib in BRAFV600 mutated metastatic melanoma (MM): a subanalysis of the Italian population of a
global safety study. Future Oncology. 2015; 11:1355
Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A,
Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I,
Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-paclitaxel versus dacarbazine in
chemotherapy-naïvepatients with metastatic melanoma.
Ann Oncol. 2015; 26:2267
52
METASTATIC DISEASE:
THE SURGICAL MANAGEMENT
Liver resection is a worthwhile therapeutic aim and
provides the best opportunity for long-term survival in
the treatment of metastatic colorectal cancer. Likewise
Pulmonary metastasectomy is a treatment of proven
clinical efficacy in carefully selected patients, resulting in
long-term survival and permanent cure.
METASTATIC
DISEASE: THE
SURGICAL
MANAGEMENT
PARTICIPATING MEMBERSHIP
U. PASTORINO (COORDINATOR),
J. COPPA AND R. LUKSCH
The results of International Registry of Lung Metastases (IRLM), established
in this Institute twenty years ago, have defined the long-term survival after
metastasectomy and provided a new classification system combining anatomical
and biological features to assess prognosis in the various primary tumors. Advances
in clinical surgery, diagnostic and interventional radiology and medical oncology
created multidisciplinary specialized teams, able to offer metastatic patients the best
chances of cure.
SURGICAL MANAGEMENT OF LIVER METASTASES
Jorgelina Coppa
A multidisciplinary team
approach favors management
of the disease. The model
includes surgeons,
oncologists, radiologists and
pathologists
Colorectal cancer is the third most common cancer in the Western world and
approximately 25% of these cancers present with liver synchronous disease, while
another 25% will develop liver metastasis (CRCLM) during the course of disease (1).
Liver resection is a worthwhile therapeutic aim and provides the best opportunity
for long-term survival (2). The management of CRLM has changed dramatically
in the past two decades. In the early 1990, liver resection was associated with a
surgical mortality of 5% and was offered to only 10% of patients, leading to a 5-year
survival of 2.5%. Dramatic progress in management of CRLM has taken place, with
complementary and often synergistic results. Improvement in surgical techniques
and the increased effectiveness of new chemotherapies has allowed for a R0 surgery
from 20% to 35% of patients with stage IV CRC. The global result has been a 5-year
survival rate of 35% to 63%, according to severity of disease, and response to
therapy (3). Major advances have been made in the chemotherapeutic management
of advanced CRC. Systemic chemotherapy can reduce tumor size in some cases and
convert the disease from unresectable to resectable. The introduction of agents
targeting the VEGF (bevacizumab) and EGFR (cetuximab) pathways in combination
with cytotoxic therapies have improved outcomes for patients, but it remains unclear
whether the increased efficacy of these regimens in terms of long-term survival can
be extrapolated to improved rates of secondary liver resection.
In our experience, a multidisciplinary team approach favors management of the
disease. The model includes surgeons, oncologists, radiologists and pathologists.
In this way, we are able to choose the best timing and indications for surgery and
chemotherapy. As reported in literature, important patient benefits have been
observed, including greater accuracy of disease staging, fewer treatment and
referral delays, individualized evidence-based practice for greater continuity of care,
enhanced quality of life, and better clinical and survival outcomes.
As part of this work, we present our internal guidelines for management of CRLM
below. (see figure below). On the left side, clear conditions of non-resectable liver
disease (too much liver involvement and <25% remnant liver after resection) lead to
primary chemotherapy; at the right side, clearly resectable situations with patients
at low risk (single nodule <5 cm, CEA <200 mg/ml, metachronous, and N0 at primary
tumor) follow liver surgery as a first option. In the middle of the figure there are
conditions frequently called ‘borderline’ and at high risk of recurrence. We have
focused our studies on these latter situations.
53
Principal current strategies
Chemotherapy and its role in peri-operative setting. Chemotherapy given to
unresectable patients to convert the disease to resectable CRCLM is known as
‘conversion chemotherapy’, with the aim of achieving resectability. Neoadjuvant
chemotherapy is reserved for patients with resectable (at high risk) or/and
potentially resectable disease, prior to surgery. Several trials have demonstrated
improved progression–free-survival after liver resection using peri-operative
chemotherapy, although the real benefit of this on overall survival and the role in liver
injury remain to be addressed (4). In the last 10 years, overall survival of patients with
CRCLM has improved substantially, and reflects the increased number of available
therapies (5-FU, FOLFOX, FOLFIRI regimens). More recently, chemotherapy with
monoclonal antibodies targeting EGFR, (cetuximab, panitumumab) in patients with
RAS wild type, and anti-VEGF (bevacizumab) improve outcomes (2).
In collaboration with the Medical Oncology Department, we have conducted 2 studies
with patients affected by CRCLM that is potentially resectable although at high
risk of recurrence. Patients were treated with triplet chemotherapy (capecitabine,
oxaliplatin, irinotecan) associated with erbitux (COI-E) or becacizumab (COI-B).
In the COI-E trial, a total of 40 patients were recruited and treated for 4 cycles of
therapy followed by surgery and then another 4 cycles. In the COI-B study, we treated
20 patients and to date all cases underwent radical surgery. We are planning to
complete the accrual after 44 patients.
Disappearing (no visible on imaging) liver metastases (DLM). DLM refers to
the complete response or disappearance of a liver metastasis on imaging after
administration of preoperative chemotherapy. This phenomenon occurs in 5−38% of
patients who undergo preoperative systemic therapy (4), and in our experience are
not less than 20% of patients following liver resection after favorable response to
chemotherapy. Undoubtedly, the quality and type of imaging and the parenchymal
liver changes the damage due to chemotherapy (steatosis and steatohepatitis)
in this situation. The management of this situation is challenging because a
complete response on imaging does not necessarily correlate with complete
clinical or pathological response. Results of studies regarding the outcome of DLM
are discrepant and conflicting. Elias et al. (5) reported 62% of patients remained
recurrence-free at 51 months. In contrast, Benoist at al. (6) found macroscopic
residual disease in more than 25% of DLM during surgery.
The extent of surgery needed in cases of DLM remains unclear; there are several
proposed management strategies such as resection of all initial sites of DLM
when possible, surgical removal of residual macroscopic disease while leaving
the disappeared lesions in situ if the resection would be too extensive, resection
followed by additional chemotherapy, continuing systemic chemotherapy alone, etc.
We personally prefer removing of initial sites of disease. However, there is no strong
evidence from randomized trials to support any of these management options,
particularly extensive resections. We recommend use of best judgment and adopting
a risk-benefit approach to establish the extent of surgical treatment.
54
The liver-first approach. This is the reverse of the classic approach and begins with
systemic chemotherapy, directed against the CRCLM, followed by liver resection;
the treatment of rectal cancer is considered in a subsequent step. This approach
is proposed for patients with important synchronous liver involvement and
asymptomatic primary tumor, given the prognostic decisive role of CRCLM in longterm survival. From a theoretical point of view, this approach has an advantage,
underlying the importance of prioritizing treatment of the most problematic
component of the patient’s disease. Data that support this argument are limited.
In some circumstances, we consider this strategy for patients whose prognosis is
related to prominent liver involvement, followed by systemic chemotherapy for the
liver and primary tumor.
To date, no randomized, controlled studies have assessed the benefits of this modern
strategy or its effects on recurrence and long-term survival. An adequately-powered
randomized controlled trial examining the effect of the liver-first approach on
recurrence and long-term survival might be worthwhile, but complexity of the study
design limits this possibility.
Two-stage hepatectomy. This strategy achieves curative resection in a selected group
of patients with multiple bilobar liver metastases in which complete resection would
not have been possible with a single procedure. Sometimes, in case of insufficient
volume of the liver, this approach combines portal vein embolization (PVE) with the
tumor resection of the future remnant liver, followed by major resection when the liver
has achieved sufficient size. We recommend tumor clearance of the non-embolized
hemi-liver before the application of PVE to avoid the risk of stimulating tumor growth.
However, we have seen that about 25% of patients do not proceed to planned
hepatectomy because of disease progression or inadequate hypertrophy. A large series
reported operative morbidity for first and second stage as 14% and 54% respectively,
and 5-year survival for those who complete the two stages of 32% (7).
Portal vein embolization (PVE). Improved knowledge of liver regeneration has
allowed devising new solutions for patients who, after liver resection, would be
left with an insufficient functional liver parenchyma. PVE has clearly contributed to
increasing the number of patients who can undergo major hepatectomy with lower
risk of postoperative liver failure. We perform PVE for conditions that will leave less
than 35−40% of functional parenchyma as a rule in patients who received intense
chemotherapy.
In general, two types of approaches are utilized: in the first, an interventional
radiologist performs percutaneous super-selective PVE using microcatheters and
embolic agents (cyanoacrylate + lipiodol). In the second option, intraoperative
PVE during the first step of liver resection is performed as preparation for major
hepatectomy. It should be emphasized that adding segment IV embolization to a
right PVE may contribute to a better hypertrophy of segments 1, 2,and 3 in case of
extended right hepatectomy.
Ablation associated with liver resection. To increase treatment options for patients
with unresectable disease, local ablation can be performed during hepatectomy for
non-resectable lesions (<2 cm), or in patients at high risk of morbidity mortality.
Many advances in liver
surgery, diagnostic and
interventional radiology as
well as medical oncology
contributed to the creation
of multidisciplinary
specialized teams
The positive impact of ablation on long-term outcomes has been independently
demonstrated by 2 prospective studies. EORTC 40004 compared systemic
chemotherapy vs. chemotherapy + ablation for patients with unresectable disease,
and 3-year disease-free-survival (DFS) was improved in the combined ablation
+chemotherapy arm (10%, p=0.025) with a trend towards improved overall survival
(OS) (median 45.3 months vs. 40.5, p=0.22)(8). Another French study (ARF2003)
treated patients with unresectable, limited liver disease with a combined ablation +
resection strategy; 1 year DFS was 46%, while 5-year OS was 43%, demonstrating
that ablation and resection can lead to good long-term survival (9).
However, there remains a lack of clarity surrounding the role of ablation in the
management of metastatic CRC: to date there is no high-quality data published
for this technique, which limited its application, nevertheless, liver resection is
considered as the gold standard for the treatment of CRCLM.
Surgical management with simultaneous liver and lung metastases. The
management of simultaneously diagnosed liver and lung metastases from CRC is
a matter of debate. A number of studies have suggested potential benefits from
resecting both liver and lung metastases, supported by better outcomes for patients
with lung metastasis compared with metastasis at other extra-hepatic sites,
although contradictory outcomes have been reported.
55
Liver resection for metastases from neuroendocrine tumors (NET)
Liver metastasis occurs in 50−75% of patients affected by NETs, and complete
resection is only possible in 7−15% of cases. Surgical treatments of NET consist in
curative resection, cytoreductive resection, and liver transplantation, and provide
effective symptomatic relief and improved overall survival (10). Complete surgical
resection is possible in a minority of cases, and few prospective studies comparing
different types of treatments have been published. Surgical management is considered
the best approach for resectable hepatic metastasis from NET, because it is the only
approach with intent to cure, even though the incidence of recurrence after surgery
remains high (11). Patients suitable for liver resection include those whose primary
tumor was resected or resectable, grade 1 or 2 (G1-G2), without the presence of other
extrahepatic disease, anticipated liver remnant of at least 30%, and especially intent of
curative surgery. In our experience of 75 patients resected radically, 5- and 10-year OS
are 85% and 73%, respectively. As reported in the literature, despite long-term survival,
recurrence free-survival (5- and-10 year 50% and 24%) is a strategic point to consider
in future studies.
Many advances in liver surgery, diagnostic and interventional radiology as well as
medical oncology contributed to the creation of multidisciplinary specialized teams
who are able to offer patients the best chances of cure. Despite advanced disease at
presentation, current outcomes include cure in more than 20% of cases, and a survival
rate of 30−60%, with a surgical mortality of <1% at a specialized Hepatobiliary Centre.
These outcomes were unimaginable only two decades ago, and represent a remarkable
collective achievement.
References
1. Mentha G, Terraz S, Andres A, et al. Operative Management of Colorectal Liver Metastases. Seminars in Liver Disease
2013;33:2262-72.
2. Kassaahum W. Unresolved issues and controversies surrounding the management of colorectal cancer liver
metastasis. World Journal of Surgical Oncology 2015;13:1-11.
3. Jones R P, Stattner S, Dunne D F, et al. Controversies in the Oncosurgical management of liver limited stage IV
colorectal cancer. Surgical Oncology 2014;23:53-60.
4. Zendel A, Lahat E, Dreznik Y, et al. Vanishing liver metastases- A real challenge for liver surgeons. Hepatobiliary Surg
Nutr 2014;3:295-302.
5. Elias D, Goere D, Boige V. Outcome of posthepatectomy-missing colorectal liver metastases after complete
response to chemotherapy: impact of adjuvanat intra-arterial hepatic oxaliplatin. Ann Surg Oncol. 2007;14:188-94.
6. Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal liver metastases after chemotherapy: does it
mean cure? J Clin Oncol 2006;24:3939-45.
7. Narita M, Oussoultzoglou E, Jaeck D, et al .Two stage Hepatectomy for multiplt bilobar colorectal liver metastases.
BR J Surg 2010;98:1463-75.
8. Rues T, Punt C, Van Coevorden F, et al. Radiofrequency ablation combined with systemic treatment vs systemic
treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup
phase II study (EORTC 40004). Ann Oncol 2012;23:2619-26.
9. Evrard S, Rivoire M, Arnaud P, et al. Unresectable colorectal cancer liver metastases treated by intraoperative
radiofrenquency ablation with or without resection. Br J SUrg 2012,99:558-65.
10. Frilling A, Modlin I, Kidd M, et al. Recommendations for management of patients with neuroendocrine liver
metastases. The lancet oncology. 2014;15: e8-21.
11. Lesurtel M, Nagorney D, Mazzaferro V, et al. When should a liver resection be performed in patients with liver
metastases from neuroendocrine tumors? A systematic review with practice recommendations. 2014. HPB
(Oxford) 17:17-22.
SURGICAL MANAGEMENT OF LUNG METASTASES
Roberto Luksch
In an autopsy series of patients who died from extrathoracic malignancies, 20−50%
had pulmonary metastasis at death, and among these, 10−15% had metastatic
disease limited to the lungs. The presence of lung metastatic disease dramatically
lowers the probability of survival and the majority of patients have non-resectable
locally advanced disease or concurrent metastases to other organs, which excludes
therapeutic metastasectomy. In this situation, chemotherapy and radiotherapy permit
a median survival of 9−12 months, with long-term survival probabilities around 5%.
Lung metastases are the expression of the presence of circulating disease, and
theoretically the surgical resection of metastatic lung nodules seems a paradox.
However, since 1926 when the first lung metastasectomy was described, many case
reports have surprisingly shown that surgical resection of lung metastases could
improve survival in selected patients. In 1947, Alexander and Haight published a
series of lung metastasectomies and were the first to describe aggressive control of
metastatic disease in the chest by carrying successive metastectomies. They proposed
the preliminary selection criteria for lung metastasectomy with curative intent: good
performance status, absence of extra pulmonary metastases, and good control of the
primary tumor. In the following 40 years, Mayo Clinic, Memorial Sloan-Kettering, the
INT and a few other highly-specialized centers worldwide emphasized the curative
56
value of surgery in the treatment of metastatic lung disease in different settings, and
demonstrated the importance of limited resections for salvage iterative surgery.
The role of complete surgery
for lung metastases in
patients with high-grade
osteosarcoma is well
established
In 1990, the INT established the International Registry of Lung Metastases to create a
database and exchange information with major thoracic surgery centers across Europe
and North America. This Registry also served for a homogeneous analysis of results to
identify prognostic criteria and other information on this type of surgery. The Registry
collected data on 5206 lung metastasectomies of various primary tumors, defined
the long-term survival after metastasectomy, and strengthened the idea that lung
metastasectomy is potentially curative, showing that survival after complete resection
(R0) was 36% at 5 years and 26% at 10 years, compared with survival after incomplete
resection (R1) that was 13% at 5 years and 7% at 10 years. The results of multivariate
analysis revealed that complete resectability, disease-free interval, and number of
metastases were independent prognostic factors, thus providing a new classification
system combining anatomical and biological features to assess prognosis in various
primary tumors. Furthermore, the idea born in INT to launch this International Registry
permitted, at that time, to demonstrate the inaccuracy of radiologic staging in a
large proportion of cases, and the importance of intraoperative exploration by an
experienced surgeon to optimize resection of all metastases.
In the years following the publication of the results of the International Registry of Lung
Metastases (1997), prognostic factors were validated with prospective studies. The
“law of 3” (3 cm diameter, 3 year disease-free interval, and 3 as diameter ratio) as a tool
was identified for the planning for adequate indications of lung metastatic resections.
The best outcome was confirmed in the germ cell tumors, but the surgical approach to
pulmonary metastatic disease permitted observing improvement of clinical outcome
even in other histotypes.
The complete surgical
resection of the metastases
is predictive of survival
In particular, the role of complete surgery for lung metastases in patients with highgrade osteosarcoma is well established, and complete surgical resection of the
metastases is predictive of survival. Repeated metastasectomies in patients with
metachronous lung disease can cure some patients. However, it is unclear if surgery is
always indicated regardless of the number of lesions or when an early relapse occurs:
the definition of the role of challenging surgery in this context is one of the ongoing
projects conducted at INT Milan.
At present, some debate remains on the best indications for lung metastasectomy
for each single histotype, especially in a context of a multidisciplinary approach in
highly specialized and dedicated teams. Furthermore, the availability of new tools for
the radiological diagnosis, PET and EBUS, brings new insights and questions. These
considerations, together with the continuous advances in bioinformatics that offer
rapid and precise technological support for sharing of data, led to new prospective
studies, including the creation of a prospective National Registry of Lung Metastases,
with as a leading position of the INT of Milan.
References
1. Pastorino U, et al. The International Registry of Lung Metastases. J Thorac Cardiovasc Surg 1997;113:37-49.
2. Pastorino U, et al. History of the surgical management of pulmonary metastases and development of the
International Registry. Semin Thorac Cardiovasc Surg. 2002;14:18-28.
3. Friedel G, et al. Results of lung metastasectomy from breast cancer: prognostic criteria on the basis of 467 cases of
the International Registry of Lung Metastases. Eur J Cardiothorac Surg. 2002;22:335-44.
4. Mizuno T, et al. Pulmonary metastasectomy for osteogenic and soft tissue sarcoma: who really benefits from
surgical treatment?European Journal of Cardio-Thoracic Surgery 2013;43:795–9.
5. Kim S, et al. Pulmonary resection of metastatic sarcoma: prognostic factors associated with improved outcomes.
Ann Thorac Surg 2011;92:1780–6.
6. Kanzaki R, et al. Outcome of surgical resection for recurrent pulmonary metastasis from colorectal carcinoma. Am J
Surg 2011;202:419-26.
7. Riquet M , et al. Pulmonary resection for metastases of colorectal adenocarcinoma. Ann Thorac Surg 2010;89:375–80.
8. Meimarakis G, et al. Evaluation of a new prognostic score (Munich score) to predict long-term survival after
resection of pulmonary renal cell carcinoma metastases. Am J Surg 2011;202:158–67.
9. Shiono S, et al. Pulmonary metastasectomy for pulmonary metastases of head and neck squamous cell
carcinomas. Ann Thorac Surg 2009;88:856–60.
10. L
etourneau PA, et al. Location of pulmonary metastasis in pediatric osteosarcoma is predictive of outcome. J
Pediatr Surg 2011;46:1333–7.
11. Pastorino U, et al. The contribution of salvage surgery to the management of childhood osteosarcoma.J Clin Oncol.
1991;9:1357-62.
12. Kesler KA, et al. Survival after resection for metastatic testicular nonseminomatous germ cell cancer to the lung or
mediastinum. Ann Thorac Surg 2011;91:1085–93.
13. Besse B, et al. Nonseminomatous germ cell tumors: assessing the need for post-chemotherapy contralateral
pulmonary resection in patients with ipsilateral complete necrosis. J Thorac Cardiovasc Surg 2009;137:448–52.
14. Schuhan C, et al. Survival after pulmonary metastasectomy in patients with malignant melanoma. Thorac
Cardiovasc Surg 2011;59:158–62.
15. Pastorino U, et al. Fluorodeoxyglucose positron emission tomography improves preoperative staging of resectable
lung metastasis. J Thorac Cardiovasc Surg. 2003;126:1906-10.
16. How far can we go with surgery in metastatic osteosarcoma patients?
Meazza C, et al Med Oncol. 2015 Sep;32(9):223.
57
MICROENVIRONM
AND
INFLAMMATION
MICROENVIRONMENT
AND INFLAMMATION
PROGRAM MEMBERSHIP
M.P. COLOMBO (COORDINATOR)
L. ROZ, D. DELIA, M. GARIBOLDI, E. TAGLIABUE,
N. ZAFFARONI, M.G. DAIDONE, L. RIVOLTINI
A core project grouping several Units of INT aims at the
identification of new molecules detectable in blood
circulation that may have diagnostic and prognostic value
at cancer onset or recurrence.
We foresee an approach in which stroma cell components, through the interaction
with nascent or recurrent tumor, can generate early markers detectable in blood.
Stroma cell components coevolve with tumors to form a functional unit which
misinterpretating wound-like signals favors tumor remodeling and progression.
Stroma cell components
recruited at the tumor site
from bone marrow and
the signals of such crosscomunication may represent
potential biomarkers
Many stroma cell components are recruited at the tumor site from bone marrow
and the signals of such cross-comunication may represent potential biomarkers.
Thus, detection of circulating miRNAs predictive of incipient lung cancer earlier than
spiral CT, or linked to existing precancerous lesions in subjects with increased risk of
colorectal cancer, indicate that the approach is realistic. Therefore, since 2013, the
group of Mario Colombo together with that of Claudio Tripodo (University of Palermo)
has investigated the morphologic, phenotypic, and molecular variations occurring in
primary and secondary lymphoid organs in relation to transforming mammary glands
of transgenic mice selectively expressing an oncogene in the breast. Differentially
expressed genes in such organs and circulating miRNAs have been identified
and some of the latter were also found in the context of human carcinomas. This
correlation will be tested retrospectively in cohorts of patients with known diagnoses
and validated in a prospective study. Investigation of cross-communication between
distinct environments (tumor and bone marrow) performed in mice is not possible in
humans. Consequently, several groups have tried to dissect the tumor environment
to identify the relevant cellular and extracellular players, while other groups
have combined tumor cells and fibroblasts to identify molecules governing their
communication.
Maria Grazia Daidone and collaborators have found that, in vitro, cancer-associated
fibroblasts (CAFs) can promote an autocrine loop sustained by IL-6 and IL-8 in
luminal and HER-2 positive cancer cells, whereas basal cells do not seem to depend
on fibroblast instigation. On the other hand, supernatants from breast cancer
cells induce the expression of TGM2, encoding for tissue transglutaminase 2, a
multifunctional protein also involved in modulation and deposition of extracellular
matrix (ECM) and up-regulated in inflammation and wound repair.
An ECM gene signature helps
to identify the class of risk of
breast carcinoma. Type ECM3
in grade III tumors identifies
patients with worse survival
Accordingly, an ECM gene signature helps to identify the class of risk of breast
carcinoma. In particular, type ECM3 in grade III tumors identifies patients with
worse survival. This finding from Elda Tagliabue’s Group has been extended and, in
collaboration with the University of Pisa, they found the highest stiffness in ECM3
grade III tumors. Proteomic analysis of soluble extracts from these tumors analyzed
for the elastic modulus by two-dimensional differential gel electrophoresis coupled
with MALDI mass spectrometry revealed several unique spots which characterize
these high grade tumors.
Most studied in the tumor microenvironment, the fibroblast, can be variably activated
regardless the distance from tumor cells. Primary fibroblast cultures have been
established by the group of Luca Roz in Gabriella Sozzi’s Unit from surgical specimens
either adjacent or distant from the cancer area, and functionally tested for supporting
lung tumor xenografts growth in immunodeficient mice, an effect often associated
with activation of the Epithelial to Mesenchymal Transition (EMT) program. Protumorigenic properties were also observed by culturing normal lung fibroblasts,
suggestive of their ability to generate markers for risk assessment after sensing
variations in the lung microenvironment.
Stromal markers with potential prognostic significance have been identified in a large
IHC study using univariate analyses and more complex risk models developed by the
Clinical Epidemiology and Trial Organization Unit (Elena Landoni and Luigi Mariani)
and will be validated in a large retrospective clinical series selected by Giuseppe
Pelosi and Ugo Pastorino.
58
In vitro, tumor fibroblast co-cultures established that physical contact between
cells or their produced ECM induced the most aggressive behavior. Nevertheless,
tumor-fibroblast cross-talk can also occur through information passed by miRNAs,
as shown by Paolo Gandellini in Nadia Zaffaroni’s Unit. Normal epithelium releases
miR-205 which neutralizes the pro-oxidant, pro-inflammatory, and pro-tumorigenic
vicious circle between cancer and associated fibroblasts. Another miRNA, namely
miR-210, if up-regulated in fibroblasts, further promotes tumor aggressiveness
thereby fuelling the tumor with energy-rich metabolites, recruiting endothelial
precursor cells, and stimulating HUVEC capillary morphogenesis.
Normal epithelium releases
miR-205 which neutralizes
the pro-oxidant, proinflammatory, and protumorigenic vicious circle
between cancer and the
associated fibroblasts
Moreover, Licia Rivoltini and Collaborators have shown that the myeloid cell
component of the tumor microenvironment contributes to melanoma progression.
The tumor releases exosomes, which are able to convert monocytes into myeloidderived suppressor cells (MDSC). This conversion is mediated by specific proteins
(e.g. CCL2 and TGFβ) and selected miRNAs (mir155, 125 and 146) coexisting within the
melanoma exosomes passed into monocytes upon contact. Signs of this exosomemediated MDSC conversion can be found in the peripheral blood of melanoma
patients in clear association with a more aggressive disease, suggesting that the
pathway is active in vivo and that it can be exploited for prognostic or therapeutic
purposes.
Taken together, these studies delineate a variety of microenvironmental signals
among which suitable prognostic markers or markers for early diagnosis can be
identified.
59
NEW DRUGS AND
PERSONALIZED
MEDICINE
NEW DRUGS AND
PERSONALIZED MEDICINE
PROGRAM MEMBERSHIP
M.C. GARASSINO (COORDINATOR),
S. DI COSIMO, D. LORUSSO, P. PEREGO, G. SOZZI,
E. TAGLIABUE, M. IORIO, N. ZAFFARONI
It’s far more important to know what person the disease
has than what disease the person has.
Hippocrates
The term “personalized medicine” describes the approach of providing “the right
patient with the right drug at the right dose at the right time.” Personalized medicine
or “precision medicine” may be defined as the tailoring of medical treatment to
individual characteristics, needs, and preferences of a patient during all stages of
care, including prevention, diagnosis, treatment, and follow-up.
Emerging data from clinical studies suggest that the use of targeted agents in
patients with targetable molecular aberrations improves clinical outcomes. Despite
an increasing number of studies, gaps remain in identifying driver molecular
alterations in patients with multiple aberrations and molecular networks that affect
tumor development, metastatic spread, and drug resistance/response. Personalized
medicine requires continuous scientific breakthroughs and technological
improvements that are able to integrate preclinical, pathological, and clinical
information. The INT is currently working on integrating knowledge at preclinical,
clinical, and epidemiological levels with a large number of new drugs under
investigation.
The main areas of research are focused on identification of new targets, identification
of new biomarkers, and testing new drugs in small populations.
At the preclinical level, some examples of research regarding new drugs and efforts
towards personalized medicine are provided below.
The efficacy of novel peptide
inhibitors of CXCR4 in blocking
metastatic dissemination and
preventing CSC enrichment
induced by standard
chemotherapy is being
evaluated
The Tumor Genomics Unit (Gabriella Sozzi) is investigating the potential of miRNAs
as novel tools for early detection and therapy of lung cancer. In particular, mir-660,
one of the 24 miRNAs of a diagnostic signature, when over-expressed inhibited tumor
growth in immunodeficient mice xenografted with human lung cancer cells. The
MDM2 gene, a key regulator of p53 function, was identified as a new direct target of
mir-660, thereby supporting its role as a tumor suppressor miRNA, and suggesting
replacement of mir-660 as a new therapeutic approach for p53 wild-type lung cancer
treatment (O. Fortunato et al. CDD 2014; O. Fortunato et al. Biomed Res Int. 2014).
The evolving paradigm of cancer stem cells (CSC) now suggests the existence of
heterogeneous subsets of cells that are able to guide different steps of tumor
initiation and metastatic progression, thus providing new therapeutic targets and
prognostic biomarkers. The Tumor Genomics Unit is working on the identification
of specific subsets of lung metastatic cells, e.g. CD133+CXCR4+ modulated by tumor
microenvironment and associated with poor prognosis. The efficacy of novel
peptide inhibitors of CXCR4 in blocking metastatic dissemination and preventing
CSC enrichment induced by standard chemotherapy is being evaluated. The in vivo
capacity of all-trans retinoic acid (ATRA) to force the CSC fraction to differentiate
toward a cisplatin susceptible phenotype was also examined.
In collaboration with the Thoracic Oncology Unit (Marina C. Garassino) and Medical
Oncology Department, the identification of KRAS mutations in lung cancer with a
more aggressive phenotype is ongoing. KRAS mutations are thought to confer a
more aggressive phenotype in lung cancer, although clinical observations are often
controversial to support this evidence. Since a fraction of these patients have worse
prognosis than those with wild-type KRAS, the research group investigated if the
co-presence of KRAS and LKB1 mutations can confer a more unfavorable prognosis.
Furthermore, this population accounts for at least 10% of all NSCLC patients and
might be treated with combinations of drugs including metformin.
On a similar hypothesis, the Thoracic Oncology Unit and Oncology Department, in
collaboration with several European institutions (University of Ulm, IRCCS Mario
Negri, University of Athens) are working on the possibility that patients harboring
mutated KRAS have an unbalancing in DNA repair at several levels. Theoretically,
60
these patients can be excluded from therapy with platinum compounds. In the last
year within the consortium we identified and published a biomarker polymerase Beta
from the BER system which could be tested as a biomarker of platinum resistance
(Base excision repair-mediated resistance to cisplatin in KRAS(G12C) mutant NSCLC
cells.(Caiola E, Oncotarget 2016).
TN tumors, defined based
on the absence of HER2 and
hormone receptor expression,
have the ability to generate
blood lacunae lined by tumor
cells
The Molecular Target Unit of Experimental Oncology and Molecular Medicine
Department (DOSMM) (Elda Tagliabue) is actively working to gain insight into the
molecular pathways that are relevant for progression and response to therapy of
breast carcinomas, especially those with HER2 overexpression and triple-negative
(TN) features. In collaboration with the AIRC Start Up Unit (Marilena V. Iorio), they
demonstrated that TN tumors, defined based on the absence of HER2 and hormone
receptor expression, have the ability to generate blood lacunae lined by tumor cells.
This feature is associated with poor outcome and PDGFRβ- and FGFR2-mediated
pathways and has been identified as relevant in mediating this characteristic, thus
potentially representing valid targets for specific therapy of this breast cancer
subgroup.
Concerning the identification of a robust predictor marker of the benefits of
trastuzumab, the Molecular Targeting Unit uncovered the relevance of a splice
isoform of the HER2 receptor which lacks exon 16 (D16HER2) in susceptibility of
HER2-positive breast tumors to trastuzumab treatment. Specifically, they provided
evidence in transgenic mice that expression of D16HER2 is sufficient to accelerate
mammary tumorgenesis and improve the response to trastuzumab. D16HER2 was
optimally functional through a link to SRC activation (pSRC). Clinically, HER2-positive
BCs from patients who received trastuzumab exhibited a positive correlation in
D16HER2 and pSRC abundance, consistent with results on mice. Moreover, patients
expressing high pSRC or an activated “D16HER2 metagene” were found to derive the
greatest benefit from trastuzumab treatment.
The estimated association
between gene expression
and relapse-free survival
allowed the development of
a trastuzumab risk (TRAR)
model based on a 41-gene
signature
In addition, in collaboration with the Medical Oncology Department (Serena
Di Cosimo), they analyzed by DASL technology in archival tumor blocks from
HercepTest 3+/2+ FISH-positive patients treated with adjuvant trastuzumab at INT.
The estimated association between gene expression and relapse-free survival
allowed the development of a trastuzumab risk (TRAR) model based on a 41-gene
signature. Application of the TRAR model to tumors treated with neo-adjuvant
trastuzumab indicated that it is predictive of trastuzumab response, but not to
chemotherapy alone. Pathway analysis revealed that TRAR-low tumors expressed
genes of the immune response, with significantly higher CD8-positive cells detected
immunohistochemically compared to TRAR-high tumors. Based on these results, a
study aimed to explore whether the TRAR model is useful for predicting/monitoring
therapeutic response to different anti-HER2 agents has been recommended for
endorsement by the Steering Committee of the phase III, randomized trial NeoALTTO including women treated with trastuzumab or the EGFR/HER2 tyrosine kinase
inhibitor lapatinib, either alone or in combination.
The Molecular Pharmacology Unit (Nadia Zaffaroni) actively worked on the
molecular alterations implicated in sustaining tumor cell survival that may provide
opportunities for new drug development. In particular, XPO1/CRM1, which mediates
nuclear protein export, is targeted by selective drugs (e.g. selinexor) that inhibit
highly metastatic cell aggressiveness in prostate carcinoma models, and reduced
bone metastasis and cell spread in orthotopic models (GL Gravina et al. J Hematol
Oncol. 2014). G-quadruplex (G4) structures occur in different regions of the genome.
Naphthalene dimide derivatives emerged as G4 ligands that are able to impair
tumor cell proliferation by interfering with telomere maintenance mechanisms
and inhibiting the expression of oncogenes bearing G4-forming sequences in
their promoters. A platinum complex (TriplatinNC) with non-covalent DNA binding
produced p53-independent nucleolar targeting in tumor cells and a shift in the
antitumor drug structure-activity paradigms.
Furthermore, in an attempt to provide the molecular basis for personalized drug
combinations to be clinically exploited and to define biomarkers for patient selection,
the following was demonstrated: a) efficacy of namitecan/topotecan-cetuximab
combinations in squamous cell carcinoma as a function of EGFR gene copy number
(M De Cesare et al. Clin Cancer Res. 2014); b) synergistic interaction between the RET
inhibitor sunitinib and cisplatin in RET-driven medullary thyroid cancer (A Lopergolo
et al. J Clin Endocrinol Metab. 2014); c) chemosensitizing effect by the survivin
suppressant YM155 in DR5-expressing triple-negative breast cancer exposed to
membrane TRAIL; d) synergistic interaction of sanguinarine/arsenic trioxide/TRAIL in
platinum-resistant NSCLC cells (L Gatti et al. J Pharmacol Exp Ther. 2014); e) increased
61
ovarian carcinoma cell sensitivity to platinum compounds by pharmacological
targeting of the ERK1/2 pathway in selected molecular backgrounds (G Cossa et al.
Cancer Lett. 2014), and f) therapeutic potential of vorinostat in combination with
temozolomide in mutant BRAF melanoma models (L Gatti et al. Oncotarget. 2014).
A large part of new drugs
under investigation in several
diseases are represented by
immune checkpoint inhibitors
At the clinical level, in the Medical Oncology Department several new drugs are
under investigation, aimed towards a personalized medicine approach. Most are
directed towards targeted sub-populations. In breast cancer, the Medical Oncology
Department has the unique chance to treat patients not only with the milestone of
breast cancer therapy represented by anthracycline and taxane, but also with novel
and promising agents, including eribulin and the taselisib inhibitor of PIK3CA alpha
in a neoadjuvant setting. In tight collaboration with pathologists and researchers at
the Experimental Oncology and Molecular Medicine Department (DOSMM), residual
cancer samples from breast cancer patients treated with primary systemic therapy
are being analyzed with the Ion AmpliSeq Comprehensive Cancer Panel for mutational
analysis of more than 400 genes and validation of detected mutations by digital PCR.
Furthermore, in collaboration with DOSMM and the Senology Unit, circulating miRNAs
able to predict outcome and guide treatment of breast cancer patients are being
examined.
For gynecological tumors, several investigations are ongoing. For ovarian cancer,
where knowledge of phenotypes and presence of BRCA mutations is important,
aberrant methylation and HER2 status are useful to identify the subpopulations for
individualized treatment. In particular, trabectedin is under investigation in BRCA
mutated and BRCAness phenotypes, temozolamide in MGMT hypermethylated
ovarian cancer, trastuzumab in mucinous ovarian cancer, and the PARP inhibitor
rucaparib and antiangiogenic agent bevacizumab in the first-line treatment of
ovarian cancer. In addition, immunotherapy (MK-3475-anti PLD 1 Inhibitor) is under
investigation in recurrent, platinum-resistant BRCA mutated ovarian cancer.
A large part of new drugs under investigation in several diseases are represented by
immune checkpoint inhibitors.
In principle, every Department and every Unit is attempting personalized approach
in both clinical practice and research. Therefore, these are only examples and are
not representative of the entire institutional contribution. The chapters referring to
specific Units provide more complete understanding of the research projects and
clinical trials focused on personalized medicine.
62
ORGAN
REPLACEMENT &
RECONSTRUCTION
LIVER
TRANSPLANTATIO
ORGAN REPLACEMENT
& RECONSTRUCTION:
LIVER TRANSPLANTATION
PROGRAM MEMBERSHIP
C. SPOSITO (COORDINATOR)
V. MAZZAFERRO, J. COPPA, S. BHOORI, E. REGALIA,
C. SPREAFICO, A. MARCHIANÒ
Indications for liver transplantation (LT) are multifold and
can be classified into end-stage liver disease, acute liver
failure, and certain benign and malignant liver tumors.
LT should be considered for any patient in whom anticipated overall survival (OS)
exceeds life expectancy of the underlying disease or where a significant increase in
quality of life can be achieved. These criteria may also be valid for many patients with
primary liver tumors or hepatic metastases. However, LT for malignant diseases is a
medical and ethical challenge with regard to long-term oncologic outcomes under
immunosuppressive therapy and with regard to allocation due to organ shortage. In
the future, ongoing improvements in multimodality cancer therapy may widen the
indications for LT in malignant diseases.
LT is the only solid organ transplant performed for cure of malignancy. At INT, a median
of 35 LTs are performed each year. LT is a part of the process of cure for some specific
tumors (hepatocellular carcinoma, metastatic neuroendocrine tumors, and some rare
malignancies): both the process of cure associated with LT and subsequent follow-up
are managed by a multidisciplinary taskforce that involves surgeons, hepatologists,
radiologists, anesthesiologists, oncologists, and a dedicated nursing staff.
Liver transplantation for hepatocellular carcinoma
LT is the only solid organ
transplant performed for cure
of malignancy. At INT, a median
of 35 LTs are performed each
year
LT is the only curative treatment option for patients with irreversible acute or chronic
liver failure and, in the last four decades, it has developed from an experimental
approach with very high mortality to an almost routine procedure with excellent shortand long-term survival rates. From the time of its initial development, LT appeared
as the ideal cure for primary liver tumors, in particular hepatocellular carcinoma
(HCC) arising from established liver cirrhosis, because it had the ability of curing at
the same time both the tumor and the underlying liver disease. Early unsatisfactory
results emphasized that only a highly selected patient population would benefit from
transplantation, as survival of patients is directly related to the stage of HCC at the
time of LT (1). This was a field for the development of the prospective study by Vincenzo
Mazzaferro and coworkers conducted at INT, which in 1996 showed that by applying a
priori restrictive criteria for selection of HCC candidates for LT (namely a single nodule
≤5 cm or 2-3 nodules ≤3 cm, each with no macrovascular invasion at pre-transplant
imaging), it was possible to obtain long-term results that were better than any other
therapy applied for HCC (2). These so-called Milan Criteria (MC) were subsequently
validated by many other groups reporting 5-year survival rates of 70% or better, and
were used worldwide as selection guidelines (3).
Only approximately 30% of
HCCs are diagnosed at an
early stage (namely within
the MC), and therefore the
large majority of patients
can be offered only palliative
treatments
On January 2015, the National Transplant Center (CNT) published the report on the
outcomes of LT in Italy performed in the period from 2000 to 2012. During this period,
12,471 LTs were performed at 22 Italian Centers. Of these, 370 were performed at INT,
and the 1- and 5-year survival rates were 95.4% and 84.4%, respectively, among the
best in Italy. The median 1- and 5-year survival rates throughout the country were, in
fact, 85.9% and 73.7%, respectively.
HCCs meeting the MC have been confirmed to be a separate prognostic category
associated with good outcomes after LT: however, only approximately 30% of HCCs
are diagnosed at early stage (namely within the MC), and therefore the large majority
of patients can be offered only palliative treatments. Several experiences suggested
that such restrictive criteria may exclude LT patients with a more extended disease,
but still in the range of a possible cure. This is a debated issue which has been
ongoing for about two decades with a large number of proposals alternative to the
published MC, most of which are based on retrospective evaluations of postoperative
pathology (4). Up to now, none have managed to replace the MC which hence have
been termed “conventional criteria”, while any criteria beyond the size-and-number
assigned to HCCs within the MC, are deemed as “extended” (Fig. 1).
63
Actually, the Liver Transplant Unit of INT directed by Prof. Mazzaferro has concluded
a large data collection at three Transplant Centers (INT Milan, S. Orsola Malpighi
Bologna, Niguarda Hospital Milan) in order to define, with a competitive risk analysis,
which are the pre-LT oncologic and biological features that affect post-LT cancerrelated survival. The statistical analysis is ongoing, and in the next few months a new
perspective to expand LT criteria for HCC will likely be divulgated.
Another possible way of expanding the criteria for LT for HCC is through downstaging
treatments (5-6). In 2011, our group designed a multicenter randomized clinical trial
(RCT) to investigate whether or not LT following a successful downstaging may
provide a survival benefit with respect to pure downstaging procedures. This was the
first RCT ever that sought to evaluate the outcomes of LT in patients with HCC. The
protocol “Controlled Expansion of Conventional Criteria for Liver Transplantation in
Hepatocellular Carcinoma Through Downstaging Procedures: a Randomized Trial” or
“XXL trial” has involved the most important Italian Centers dealing with LT, and patient
enrolment ended on December 31th, 2014. At INT, the XXL trial enrolled a total of 35
patients. Of the 26 patients who were randomized, 13 underwent LT while 13 patients
were treated according to the best available care. Preliminary results showed similar
3-year survival rates of 64.9% in the LT group and of 64% in the No LT group (p=0.81).
Conversely, LT patients showed significantly fewer tumor recurrences as compared to
the No LT group, being recurrence-free survival at 3-years 87% in the LT group and 0%
in the No LT group, respectively. Actually, it is likely that follow-up period is too short to
observe significant differences in terms of survival. However, considering recurrencefree survival as a surrogate endpoint of the efficacy of LT for HCC patients responding
to downstaging, these results highly support the study hypothesis and may open the
doors for an expansion of LT selection criteria after successful downstaging.
Liver transplantation for metastatic neuroendocrine tumors
LT patients showed
significantly fewer tumor
recurrences as compared
to the No LT group, being
recurrence-free survival at
3-years 87% in the LT group
and 0% in the No LT group,
respectively
Neuroendocrine tumors (NETs) originate from different parts of the widespread
neuroendocrine system. Heterogeneity of biological features and clinical
outcomes present significant challenges for diagnosis and treatment (7). Delayed
diagnosis is common and tumors are often discovered when liver metastases
have occurred often associated with the paraneoplastic “carcinoid syndrome” (8).
Limited therapeutic options are available for these patients, and liver metastases
represent the leading cause of death. Therefore, the perspective enabled by liver
transplantation has been repeatedly explored, but selection biases and variegated
resource allocation issues have made the interpretation of results difficult. At INT, a
systematic application of restrictive criteria for selecting transplant candidates with
liver metastases from NETs was started in 1995 (9).
INT Criteria for Liver Transplantation in Patients with Liver Metastases from NET are:
• Confirmed histology of low-grade (G1-G2) neuroendocrine tumor;
• Primary tumor drained by the portal system and removed with all extrahepatic
deposits in a separate curative resection prior to transplant consideration;
• Metastatic diffusion to <50% of the total liver volume;
• Stable disease/response to therapies for at least 6 months prior to transplant
consideration;
• Age < 60 (relative criteria)
Since then, all patients presenting with tumors fulfilling such criteria have been
considered for liver transplantation and eventually enlisted according to waitlist capability, patient compliance, and absence of contraindications. In 2015, our
research has been focused on investigating survival outcomes of a series of patients
with metastatic NETs who underwent LT at INT according the aforementioned criteria,
collected over 20 years. Moreover, we sought to evaluate if LT provides a significant
survival benefit compared to a therapeutic strategy that does not include LT. The
results of our investigations have been recently published in the American Journal
of Transplantation, and are currently the only prospective study to compare the long
term outcomes of LT vs. a non-transplant strategy (10).
Of 280 patients referred for transplantation, a prospective cohort of 88 NETs with
restrictive tumor characteristics was selected on the aforementioned pre-determined
criteria. Allocation to transplant (n=42) versus no transplant treatment (n=46)
depended on wait-list availability, patient disposition, and age considerations. Longterm outcomes were compared between groups after matching made through multiple
Cox models and adjustment for propensity score built on logistic models based on
patient age, stage of primary tumor, and serum chromogranin A. Survival benefit
was the difference in mean survival between liver transplant versus non-transplant
64
options. Transplant patients were younger (40.5 vs. 55.5 years; p<0.001). There was
no difference in tumor burden. No patient was lost to follow-up or died without
recurrence. Marginal quality grafts were used in 86% of transplants; 89% of nontransplanted patients received systemic therapies. Median follow-up was 122 months.
LT for metastatic NETs under
restrictive criteria provides an
excellent long-term outcome;
survival benefit increases
over time in transplanted
patients with respect to nontransplant options
The transplant group had a significant advantage over non-transplant at 10 years for
survival (88.8% vs. 22.4%; p<0.001) and time-to-progression (13.1% vs. 89%; p<0.001).
After adjustment for propensity score, survival advantage in transplanted patients was
maintained (HR: 10.67; 95%CI: 3.48-32.72; p<0.001). Adjusted transplant survival benefit
was 6.82 months and 38.43 months at 5 and 10-years, respectively (p<0.001) (Figure 1).
We demonstrated that LT for metastatic NETs under restrictive criteria provides
an excellent long-term outcome, and that survival benefit increases over time in
transplanted patients with respect to non-transplant options, justifying enlistment
of these patients as recognized exceptions.
References
Figure 1
Visual representation of transplant benefit for
patients with liver metasteses from GEP NET
(Continuous line: transplant strategy; Dotted line:
non transplant strategy).
1. Ringe B, Wittekind C, Bechstein WO, Bunzendahl H, Pichlmayr R. The role of liver transplantation in
hepatobiliary malignancy. A retrospective analysis of 95 patients with particular regard to tumor stage
and recurrence. Ann Surg 1989;209(1):88-98
2. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F et al. Liver transplantation for the
treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334(11):693-9.
3. Befeler AS, Hayashi PH, Di Bisceglie AM. Liver transplantation for hepatocellular carcinoma.
Gastroenterology 2005;128(6):1752-64.
4. Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L et al. Predicting survival after liver
transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective,
exploratory analysis. Lancet Oncol 2009;10(1):35-43.
5. Majno PE, Adam R, Bismuth H, Castaing D, Ariche A, Krissat J et al. Influence of preoperative transarterial
lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients
with cirrhosis. Ann Surg 1997;226(6):688-701.
6. Bhoori S, Sposito C, Germini A, Coppa J, Mazzaferro V. The challenges of liver transplantation for
hepatocellular carcinoma on cirrhosis. Transpl Int 2010;23(7):712-22.
7. K
ulke MH, Siu LL, Tepper JE, Fisher G, Jaffe D, Haller DG et al. Future directions in the treatment of
neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical
trials planning meeting. J Clin Oncol 2011;29(7):934-43.
indi G, D’Adda T, Froio E, Fellegara G, Bordi C. Prognostic factors in gastrointestinal endocrine tumors.
8. R
Endocr Pathol 2007;18(3):145-9.
9. Coppa J, Pulvirenti A, Schiavo M, Romito R, Collini P, Di BM et al. Resection versus transplantation for liver
metastases from neuroendocrine tumors. Transplant Proc 2001;33(1-2):1537-9.
10. Mazzaferro V, Sposito C, Coppa J, Miceli R, Bhoori S, Bongini M, et al. The Long-term Benefit of Liver
Transplantation for Hepatic Metastases from Neuroendocrine Tumors. Am J Transplant. 2016, epub
ahead of print.
65
PATIENT-DERIVED
XENOGRAFTS
PATIENT-DERIVED XENOGRAFTS
PROGRAM MEMBERSHIP
G. SOZZI (COORDINATOR),
M. MORO, N. ZAFFARONI
A growing body of work
suggests that patient-derived
xenografts (PDX) represent
a more informative cancer
model, providing a faithful
representation of the patient’s
original tumor
Characterization of these
mouse models confirmed that
they closely recapitulate the
parental primary tumors in
terms of tumor histology and
expression of specific markers
for several passages in mice
66
Studies based on cell lines have been found to be
poor predictors of clinical effects, and thus in many
cases clinical translation of results has failed. A major
determinant for the poor performance of cell lines is the
observation that they do not reflect the entire complexity
and heterogeneity of primary tumors.
In fact, tumors contain not only tumor cells but also stromal cells of different
types. Furthermore, tumor cells within a tumor might be heterogenous, in some
cases organized along a differentiation hierarchy, and in other cases organized
as different subclones with differing molecular characteristics reflecting ongoing
clonal evolution. Taken together, the different cells in a tumor form a complex
tissue-like structure. Therefore, preclinical models that more precisely reflect these
characteristics are needed. A growing body of work suggests that patient-derived
xenografts (PDX) represent a more informative cancer model, providing a faithful
representation of the patient’s original tumor.
PDX AT TUMOR GENOMICS UNIT (Gabriella Sozzi and Massimo Moro)
We have recently developed in vivo lung cancer PDX models by directly implanting
fragments of the patient’s primary tumor in the flank of immunocompromised mice.
We have so far successfully grafted 45 non-small cell lung cancer PDXs (26 ADC,
12 SCC), among which 13 PDXs were obtained from LDCT screen-detected (MILD
and bioMILD studies) patients. Additional PDXs are being continuously established.
Characterization of these mouse models confirmed that they closely recapitulate
the parental primary tumors in terms of tumor histology and expression of specific
markers for several passages in mice. Interestingly, the prevalent histological pattern
(i.e. acinary or papillary for AC) was generally maintained , although a progressive
drift towards a solid pattern for some models was noticed. Moreover, the percentage
of stroma and necrosis within PDXs reflected the characteristics of the primary
tumor, in contrast to classical xenografts, obtained from cell line injection, which
developed subcutaneous tumors with very low stromal content . Of note, the parental
tumor’s stromal cells are gradually substituted by murine cells. In order to use
these models for testing novel treatments, we set up metabolic imaging in vivo of
PDXs using weekly [18F]FDG-PET and performing coronal and 3D-reconstruction at
different days. We noted good correlation of metabolic activity between patient’s
tumors and PDXs thus supporting the use of these “human in mouse” models for
functional studies.
Moreover, PDXs are similar to a patient’s tumor also in terms of the content of
Cancer Initiating Cells (CICs); this feature allowed us to study the in vivo ability of
all-trans retinoic acid (ATRA) to force the CICs fraction to differentiate to a more CDDP
susceptible phenotype.
Our Unit is also actively involved in a collaborative project on pediatric
rabdomyosarcoma with the team of Dr Andrea Ferrari (Pediatric Unit). This project
aims to investigate genetic alterations in druggable genes, such as ALK, MET, and
others, to identify novel target treatments for this incurable disease. Within this
collaboration, we have started to develop PDXs from pediatric rhabdomyosarcoma
patients and have successfully grafted 1 PDX derived from a child harboring a fusion
positive, ALK positive alveolar rhabdomyosarcoma.
PDX AT MOLECULAR PHARMACOLOGY UNIT (Nadia Zaffaroni)
SFT PDX has been used
to comparatively assess
the activity of different
available antiangiogenic
compounds, and to develop
novel drug combinations of
conventional and targeted
agents
Thanks to a strict collaboration with surgeons and pathologists, we generated a
small panel of PDXs in SCID mice through the direct implant of surgical specimens
obtained from patients carrying rare diseases, including Diffuse Malignant Peritoneal
Mesothelioma (DMPM) and solitary fibrous tumor (SFT), for which preclinical
models are currently unavailable. Since PDXs retain the molecular, genetic, and
histologic heterogeneity of their donor tumors (Figure A), they represent enhanced
preclinical models compared to established cell line-derived xenografts, and provide
information on tumor biology useful for identifying novel therapeutic targets and
mechanisms of resistance suitable for specific inhibition with pharmacological and/
or genetic tools. Such findings appear of utmost importance for several tumor types,
such as DMPM and SFT, for which limited therapeutic options are clinically available.
To date, 4 orthotopic DMPM PDXs, which properly recapitulate the dissemination
pattern in the peritoneal cavity of human DMPM and the occurrence of ascites
(Figure B), and 1 s.c. dedifferentiated-SFT PDX have been successfully grafted.
Additional PDXs are currently being established. DMPM PDXs have already been used
to preclinically develop novel CDK1, Hsp90, and XPO-1/CRM1 inhibitors (Figure C),
and are currently employed to validate selected miRNAs shown to be deregulated
in clinical DMPM as novel therapeutic targets through the use of miRNA mimics
and LNA-based inhibitors. The SFT PDX has been used to comparatively assess the
activity of different available antiangiogenic compounds, indicating regorafenib as
the best drug for the disease (Figure D), and to develop novel drug combinations of
conventional and targeted agents (Figure E).
Figure Legend
A) SFT primary tumor morphology (i.e.,
patternless growth, collagen deposition,
moderate cellularity) and PDX morphology
consistent with a high-grade dedifferentiated
SFT. B) A representative photograph showing
the DMPM growth pattern following
xenotransplantation in the peritoneal cavity of a
SCID mouse. Arrow indicates the tumor mass and
widespread tumor nodes. C) Orthotopic tumor
weight distribution in control and CRM1 inhibitor
(selinexor) treated mice. Photographs of tumors
from five representative mice per experimental
group are reported. D) SFT PDX treated with
antiangiogenic compounds, and E) cytotoxic
drugs, singly administered and in combination.
67
PEDIATRIC TUMORS
PROGRAM MEMBERSHIP
M. MASSIMINO (COORDINATOR),
PEDIATRIC
TUMORS
A. FERRARI, M. CASANOVA, R. LUKSCH,
F. SPREAFICO, C. A. CLERICI, D. PEROTTI
Patient management is based on a multidisciplinary
approach that includes prevention (counselling and
genetic testing), diagnosis (with specific histological
and radiological expertise), treatment (including
interdisciplinary activity with the Pediatric Surgical
Unit and the Pediatric Radiotherapy Unit, a Bone
Marrow Transplantation service and a team dedicated
to experimental therapy in patients with relapsing/
refractory solid tumors), psychosocial support, and long
term survivors program (for the follow-up of iatrogenic
sequaele). Dedicated age-specific facilities and projects
for adolescents (the Youth Project) have been developed
and represent a model to promote the normalcy of our
patients.
Brain tumors are the leading
cause of cancer-related
mortality and morbidity in
pediatric age
We have opened the
medulloblastoma PNET 5
trial dedicated to standard
and low biological risk
medulloblastoma
Brain tumors are the leading cause of cancer-related mortality and morbidity in
pediatric age. We have opened the medulloblastoma PNET 5 trial dedicated to
standard and low biological risk medulloblastoma and we are expected to open
SIOP ependymoma 2 trial early next year, whose scientific coordinator is a member
of this Unit. After the publication of the results of our institutional trial on diffuse
intrinsic pontine glioma (DIPG), we have opened a new phase 2 randomized trial
comparing to different radiotherapy schedule and maintaining the same systemic
treatment with nimotuzumab, an anti-EGFR monoclonal antibody, and vinorelbine.
This trial will be soon extended to other pediatric oncology centers. In collaboration
with Sapienza University in Rome and Genetics Unit of S. Anna Hospital in Rome
we have retrieved, from 43 cases identified of DIPG for whom biopsy had been
performed between 1987 and 2014, 24 samples from 12 different Pathology Units.
We evaluated 17 cases by immunohistochemistry (IHC) for the expression of H3F3A
K27M, H3K27me3 and EZH2, an histone methyltransferase responsible for H3K27
methylation. Moreover, in 20 cases we also performed sequencing to detect
H3F3A/HIST1H3B histonic mutations K27M/G34R-V. We demonstrate the high
frequency of H3F3A/HIST1H3B mutations by IHC and sequencing in DIPG consistent
with MRI diagnosis, thus confirming the consistency of imaging with biological
markers. A study of biopsy surrogate serum biomarkers (mainly Hh pathway
ligands) in DIPG is ongoing, as well as a miRNA profile. Results so far gathered in 12
patients (out of 32 available so far) monitored for up to 18 months from beginning
of therapy, indicate that all three Hh ligands can be found in serum of all patients
(at 100-1000 pg/mL range) and that these molecule show frequent changes in level
during treatment. Some of these changes appear to be related with response to
treatment, and additional samples will be evaluated to allow a robust statistical
analysis of data. Primary data analysis yielded a matrix containing 330 detectable
miRNA. A preliminary report on association with progression-free survival allowed
us to identify a signature of 10 miRNAs that is able to stratify high and low risk
patients (HR=4.33, 95%CI 1.49-12.54; p=4.27E-05). In order to understand the rule of
the miRNAs present in our signature, two activities are required and will be object
of future research:
1. Validation of our 10 miRNA signature. This is an essential step to confirm the
accuracy of our model in predicting the outcome in DIPG children treated with
nimotuzumab vinorelbine combination. In order to ascertain whether the
expression of the 10 circulating miRNA is linked to pontine glioma, a cohort of
cases not related to neurological malignancies has to be selected and tested for
expression of the 10 miRNAs.
68
2. Functional role of miRNA. Most of the miRNA present in our signature were
only recently annotated in miRBase (miRBase_v19.0; August 2013). Really few
information is available on their biological functions. For this reason we propose to
investigate their functional role. As a result of collaboration with McGill University
in Montreal, we have obtained preliminary analysis of specific DIPG mutation,
after selecting 10 patients (5 long-term survivors and 5 fast-progressors) with the
largest series of serum samples. We are in the process of correlating these analytic
results with patients disease course and final outcome.
Combining a unique dataset
of CSFs from pediatric CNS
tumors with a novel enabling
nanotechnology allowed us
to identify promising CSF
proteins, possibly relating to
metastatic status
A prospective frozen cerebrospinal-fluid (CSF) biobank from children/adolescents
with brain tumors and non-Hodgkin lymphoma (controls) was established, as CSF is
a very valuable source of biomarkers for brain tumors and other diseases affecting
the CNS, which could offer new important insights for diagnosis, prognosis, and
novel treatments. The CSF biobank has over 200 samples from 130 patients and 32
controls with lymphomas. CSF samples from 27 children with brain tumors and 13
controls were processed with core-shell hydrogel nanoparticles and then analyzed
with reverse-phase liquid chromatography/electrospray tandem mass spectrometry
(LC-MS/MS). To identify the candidate relevant proteins, a first selection procedure
was applied by using Fisher’s exact test and/or univariate logistic regression model.
To validate the discovery observations, we used Reverse Phase Protein Array (RPPA),
Western blot (WB) and ELISA in the training set (technical validation) and in an
additional larger independent set of CFSs samples (60 cases and 14 controls, internal
validation). Among the 559 non redundant proteins identified by LC-MS/MS, 147 were
not present in the known CSF database (http://www.biosino.org). Fourteen of 26
top-candidate proteins were chosen for validation by WB, RPPA and ELISA methods,
on the base of antibody availability and reliability. Six proteins (PCOLCE, COL1A1,
GFRalpha2, ITIH4, NPDC1, IGFBP4) were eventually validated. All of them reported a
good capability to discriminating metastatic cases from controls. Combining a unique
dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology
allowed us to identify promising CSF proteins, possibly relating to metastatic status.
Proteins linked to collagen synthesis (generation of extracellular matrix) seemed to
deserve attention.
The Pediatric Oncology Unit also continues the National Coordination for stage
4 and poor prognosis neuroblastoma (NBL) trial that is a particular engagement
including intensive chemotherapy, autologous hemopoietic stem cell transplantation,
surgery, radiotherapy, and immunotherapy with anti-GD2, a hard phase of the
overall strategy, for which some patients are referred from other centers for the
well-known experience gained at our Unit. In the pipeline, there is an immunotherapy
project involving the creation of tumor specific CARs (chimeric antigenic receptors)
that maintain the antigenic specificity of the antibody which has generated and the
transmembrane part of the T receptor. In NBL, CARs against GD2 antigen trasduced
in activated T-cell or EBV-specific CTL have been used in protocols of adoptive
immunotherapy and have shown strong anti-neoplastic activity. We aim to identify
new tumoral targets such as NY-ESO-1. Another target, called PRAME, has shown
immunogenicity in vitro and is expressed by advanced stage neuroblastoma.
The Unit is a referral Centre
for pediatric bone tumors
and joints the national and
international treatment
programs of Italian Sarcoma
Group (ISG) for Ewings and
osteosarcoma
The Pediatric Oncology Unit is a referral Centre for pediatric bone tumors and joints
the national and international treatment programs of Italian Sarcoma Group (ISG) for
Ewings and osteosarcoma. The Unit has the responsibility of the treatment protocol
of ISG for metastatic Ewing sarcoma at onset.
Thanks to the involvement in the ITCC -Innovative Therapies for Children with
Cancer- network, we offered our relapsing patients a significant number of further
line therapies with new drugs contributing to some clinical success. We published
on Clinical Cancer Research a paper identifying a five gene-signature selecting
medulloblastoma patients who can respond to the SHH inhibitor LDE225, which
was then applied in a phase 2 trial (protocol coordinated in Italy by our Unit). Two
studies for first-line (randomization for the addiction of bevacizumab to standard
therapy in metastatic patients) and relapsed rhabdomyosarcoma (randomization
for the inclusion of temozolomide to standard vincristine/irinotecan) have been
concluded (our Institution being the leader center in Italy), as well as the first-line
randomized trial for malignant glioma with or without bevacizumab where our center
was the national coordinator and the largest recruiting center worldwide (14 out of
120 patients in over 80 open centers). As largest enrolling center, we also recruited
two adolescents in a phase I study of vemurafenib for unresectable and stage IIIC
or IV tumor carrying BRAFV600 mutations. We have continued the screening and
enrollment in two phase I pediatric - first in child - studies with LDK378, an ALK
inhibitor (only Italian center in the study) nab-paclitaxel (our Unit is the national
69
coordinator). We also began the enrollment of the phase 1 study of lenvatinib and of
the anti-PDL1 drug Atezolizumab (first center opened and enrolling worldwide).
Members of the Pediatric Oncology Unit are part of the Executive Committee of ITCC
and part of the Clinical Research Council (CRC) of SIOP-Europe (International Society
of Pediatric Oncology – Europe)
The Youth Project has
promoted the creation of a
new scientific Italian society:
SIAMO, Società Italiana
Adolescenti con Malattie
Oncoematologiche
The Youth Project, a clinical, social, and political awareness project to help cope with
the poor prognosis of adolescents and young adults affected by pediatric tumors,
has promoted the creation of a new scientific Italian society: SIAMO, Società Italiana
Adolescenti con Malattie Oncoematologiche (www.progettosiamo.it), that unifies
the efforts of AIEOP (Associazione Italiana Ematologia e Oncologia Pediatrica),
FIAGOP (parents association), AIOM (Associazione Italiana Oncologia Medica), and
SIE (Società Italiana Ematologia) towards better care with inclusion in controlled
trials and tailored post-treatment return to normal life with fertility, psychology,
sport, education, and job programs. There is a strong national and international (e.g.
ENTYAC – European Network on Teenagers and Young Adults with Cancer) movement
led by one of us to highlight this problem and modify patient access to care and
clinical behaviors that will be the aim of future efforts.
This last aspect is pioneered in our “cured patients” clinic which receives around
300 patients a year taking into account the late effects reported after the impact of
cancer and iatrogenic sequelae. An interview related to job and social activities is
also accompanied by specific clinical questions, visit, and care. When needed, guided
referral to other childhood or adult specialists is made. In the last year, particular care
has been given to premature ovarian failure risks and subsequent female infertility.
We aim to study, by dosing anti-mullerian hormone (AMH), prematural ovarian failure
in a pilot series of girls who will be assessed at the beginning of therapy, 6 months
after, and 2 years later. Candidates will be those with osteosarcoma, lymphoma,
localized medulloblastoma, or localized rhabdomyosarcoma.
The occurrence of familiar
cases of WT has been
analyzed by whole exome
sequencing and genetic
variants have been validated
by classic sequencing
For Wilms’ tumor (WT), the most common kidney tumor in children, we will continue
National Coordination of both clinical and biological trials with a tumor bank
containing over 350 tumor, blood, and urine samples, and activities concerning
referral for particularly difficult cases from surgical or radiotherapy standpoints. The
analysis of new putative genes involved in WT has been completed. The occurrence
of familiar cases of WT has been analyzed by whole exome sequencing and genetic
variants have been validated by classic sequencing. In 58 non-pre-treated tumors,
gene expression data have been correlated to relapse. Genomic and genetic
anomalies in primary and recurrent tumors have been investigated. The aim for
near future is to extend the analysis of genetic heterogeneity of primary tumors and
investigate events possibly related to recurrence.
Our Unit is also in charge of National Coordination for germ cell tumors, metastatic
Ewing sarcoma, soft tissue sarcomas (plus the coordination of the European EpSSG
NRSTS committee and protocols) and very rare pediatric tumors (coordination of the
Italian TREP project – Tumori Rari Età Pediatrica - and the European EXPeRT project –
European Cooperative Study Group on Pediatric Rare Tumors).
With particular reference to rhabdomyosarcoma, we are performing cytogenetic/
genetic analysis (Targeted Next Generation Sequencing, t-NGS) to find new molecular
alterations and possibly new therapeutic targets. To prove the existence, feasibility,
and vulnerability of these targets, pre-clinical models will be prepared. This will
be obtained through cell culture preparation from surgical samples of pediatric
rhabdomyosarcomas which will be submitted to several pharmacologic inhibitors.
We also aim to prepare in vivo xenograft models to confirm the possibility of tumor
cell inhibition.
In the field of children and adolescent soft-tissue sarcomas of interest, we also
have a project to study a selected series of children and young adults with sarcoma
with the same histology but different patient ages at diagnosis. The aim of this
research is to understand if the prognostic differences which were already clinically
observed between younger – more favorable – and older patients are justified by
different molecular alterations. We will use a high-throughput t-NGS with IonTorrent
AmpliSeqTM Comprehensive Cancer Panel to identify recurrent gene mutations.
Moreover, we will use comparative genomic hybridization to identify deletions and
amplifications.
In the field of psychological and psychodynamic studies and support, we
contributed to the realization of the general guidelines on the prescription of
psychopharmacological treatments in pediatric onco-hematology edited by AIEOP
70
and SIPO (Società Italiana di Psico-Oncologia) and we are working to the operational
guidelines. We also have ongoing studies about the integration of spiritual support in
oncological cures, the quality of life of bone tumor patients at diagnosis and during/
after treatment, the action-observation-therapy for patients with post-cerebral
tumor morbidities, the effects of patient communication during phase I/II trials and
effects of continuous sport training during oncological treatment.
71
PROSTATE CANCE
PROGRAM
PROSTATE CANCER PROGRAM
PROGRAM MEMBERSHIP
R. VALDAGNI, N. ZAFFARONI
PARTICIPATING UNITS
SCIENTIFIC DIRECTORATE
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
Depending on the state of
disease, there are several
therapeutic options and,
for selected patients,
observational strategies,
namely active surveillance (AS)
and watchful waiting
The Prostate Cancer (PC) Program is a translational
multidisciplinary (MD) and multiprofessional (MP)
program started in September 2004.
Endorsed by the Scientific Director, the PC Program has a decade long tradition of
MD and MP approaches to the disease and expertise in epidemiology, experimental
oncology, molecular pharmacology, pathology, imaging, urologic surgery, radiotherapy,
medical oncology, palliative and supportive care, and psychology. The goals of the
PC Program are: i) to outline and implement research strategies for the malignancy,
including the study of mechanisms of PC development and progression as well as
the identification/validation of novel therapeutic targets; ii) to promote clinical and
experimental studies, also in collaboration with national and international partners;
iii) to have a MD and MP team of specialists manage PC patients ; iv) to run MD clinical
activities; v) to organize educational activities (i.e. Seminars, MD and MP Team Meetings,
conferences for clinicians, general practitioners, patients); and vi) to optimize the human
and technological resources within a disease-focused MD and MP 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 and, for selected patients, observational
strategies, namely active surveillance (AS) and watchful waiting. Radical therapies,
namely surgery, radiotherapy, and brachytherapy, show no clear differences in cancer
control rates in the same stage, but can induce adverse effects and negatively impact
the patients’ quality of life. On these assumptions, patients should receive objective,
comprehensive information about the disease, therapeutic and observational strategies,
and therapy-induced side effects. At the same time, patients and their significant others
should be accompanied in the decision-making process, which might be a particularly
difficult phase. To address the complexity of the disease, the PC Program has managed
PC patients multidisciplinarily and multiprofessionally since its beginning in 2004. The
MD and MP organizational model was formalized under the name of Prostate Cancer
Unit (PCU) in 2009 and updated in 2013. The latest version includes specifics on the MD
activities, the core and non-core personnel, the procedures regulating the access to the
MD activities and the interaction among services and units.
The MD clinical activities run by the PCU include the following:
• weekly first consultations for newly referred PC patients (345 MD visits in 2015 plus
108 patients with advanced or metastatic disease directly addressed to Medical
Oncology to accelerate the access to care) with the concurrent participation of
urologist, radiation oncologist, and psychologist; a 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);
• biweekly follow-up visits for patients on AS and watchful waiting (706 visits in 2015):
urologist and radiation oncologist perform monodisciplinary visits with patients
continuing in the observation; a psychologist is on demand; urologist, radiation
oncologist, and psychologist meet patients in a MD setting when the observational
setting needs to be discontinued and therapeutic options proposed;
• weekly Multidisciplinary Team Meetings, a CME activity aimed to share decisions and
paths of care on PC patients, tailor therapeutic and observational strategies, manage
PC patients holistically, consider quality of life and psychological issues, enroll
patients in trials, and verify adherence to guidelines and quality assurance. In 2015,
302 cases were discussed.
The PC Program is acknowledged worldwide to have important expertise 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 has 2 protocols open for enrollment (total number of patients included
72
since 2005: 748), it is the top recruiting center in the PRIAS (Prostate cancer Research
International: Active Surveillance) consortium with 482 patients until December 2015,
and coordinates the 10 Italian Institutions participating in PRIAS under the name of
SIUrO PRIAS ITA. Significant attention is paid to the quality of life of patients on AS,
which is the focus of a research project run by the PC Program dedicated psychologists.
Considering the acknowledgements of expertise in the area, the PC Program chief
psychologist was appointed chair of an international Task Force on Quality of Life in AS
promoted and supported by the European School of Oncology.
The PC Program is the only Italian center invited to participate in the Global PC AS
Initiative funded by Movember Foundation, aimed to unite the world’s leading research
and clinical groups focusing on AS to develop a new therapeutic guidelines for men
diagnosed with low risk PC by integrating clinical, imaging, and biomarker data in the
global central database GAP3.
Aware of the importance of translational research, the PC Program activated a biobank
in 2005 and collects blood, urine, and tissue samples from different categories of PC
patients, in order to have biological material for translational research.
Highlights
Urgently needed is the
improvement of selection
criteria for AS by testing novel
biological markers
Research is focused on multiple areas, such as the interpretation of survival differences
over time, rational design of novel single drug and combination approaches exploiting
tumor-associated molecular alterations and development of nanocarrier-based
strategies for selective drug delivery in translatable and predictive preclinical PC
models, identification of epithelial and stromal microRNAs regulating PC progression
and metastasis as well as long non-coding RNAs governing prostate epithelial biology
and tumor development, dissection of the role of mast cells and extracellular matrix
proteins in prostate carcinogenesis, molecular characterization of indolent PC, quality
of life of patients on AS, toxicity and quality of life of patients treated with radiotherapy,
new drugs and drug combinations for locally advanced and metastatic PC, and new
radiotherapy fractionation schemes.
Urgently needed is the improvement of selection criteria for AS, which are currently
suboptimal and rely exclusively on clinical and pathological parameters, by testing
novel biological markers. In this context, studies are aimed to identify somatic genomic
aberrations in circulating cell-free DNA as well as circulating miRNAs associated with
disease reclassification (up-grading) in PC patients on AS, based on the assumption
that such alterations i) represent surrogate markers of the different tumor foci
concomitantly present in the patient, and ii) can provide risk refinement to standard
clinical-pathological features. Upon confirmation of the results in independent patient
cohorts, the final aim of this study will be the integration of selected circulating
biomarkers in an updated and improved model for prediction of indolent PC. In addition,
the identification/validation of such biomarkers will pave the way to the development
of non-invasive approaches for disease monitoring during AS.
The development of a non-invasive method to diagnose PC is long overdue. On this
basis, we started collaborative research with the Bruno Kessler Foundation and
the University of Trento that aims to measure volatile compounds in urine samples
and identify and distinguish emission spectra in urine from PC patients and healthy
specimens. If preliminary evaluation is positive, the substances contained in urine
from PC patients will be more specifically identified in a larger group to implement the
technique and produce low cost and non-invasive diagnostic kits.
Since 2008 the PC Program has promoted research in the field of predictive modeling
of clinically significant endpoints. After starting with the prediction of gastrointestinal
acute and late toxicity after radical radiotherapy for PC, the know-how in this
field was used to design and activate the first multicenter Italian trial (DUE01Disfunzione Urinaria ed Erettile) devoted to predicting urinary toxicity and erectile
functioning after radiotherapy and a large international collaboration (including
Australian, French and Danish centers) dedicated to external validation of models. A
collaboration with the National Research Council is now designed to the introduction
of radiomic variables into such models. The methodology developed was recently
also applied to predictive modeling of poor quality of life for men on AS. In 2014, the
PC Program started its participation in the multicenter international project (funded
by the European Union’s Seventh Framework Programme) “REQUITE - Validating
Predictive Models and Biomarkers of Radiotherapy Toxicity to Reduce Side-Effects
and Improve Quality of Life in Cancer Survivors”, which is aimed to validate known
predictors of adverse reactions after radiotherapy for PC, breast and lung cancer,
and to develop the statistical models that are clinically useful. This multi-center
observational study will collect blood samples and standardized data longitudinally
73
from 5,300 cancer patients. It is expected that 380 patients will be enrolled at our
Institute, 148 patients were included in 2015.
Keywords
Translational research, multidisciplinary approach, experimental therapeutics
Selected recent publications
1. Bokhorst LP, Alberts AR, Rannikko A, Valdagni R, Pickles T, Kakehi Y, Bangma CH, Roobol MJ; PRIAS study
group. Compliance Rates with the Prostate Cancer Research International Active Surveillance (PRIAS)
Protocol and Disease Reclassification in Noncompliers. Eur Urol 2015 Nov;68(5):814-21
2. Valdagni R, Van Poppel H, Aitchison M, Albers P, Berthold D, Bossi A, Brausi M, Denis L, Drudge-Coates L,
De Santis M, Feick G, Harrison C, Haustermans K, Hollywood D, Hoyer M, Hummel H, Mason M, Mirone V,
Müller SC, Parker C, Saghatchian M, Sternberg CN, Tombal B, van Muilekom E, Watson M, Wesselmann S,
Wiegel T, Magnani T, Costa A. Prostate Cancer Unit Initiative in Europe: A position paper by the European
School of Oncology. Crit Rev Oncol Hematol 95(2):133-43, 2015.
3. Cozzarini C, Rancati T, Carillo V, Civardi F, Garibaldi E, Franco P, Avuzzi B, Esposti CD, Girelli G, Iotti C,
Palorini F, Vavassori V, Valdagni R, Fiorino C. Multi-variable models predicting specific patient-reported
acute urinary symptoms after radiotherapy for prostate cancer: Results of a cohort study. Radiother
Oncol. 2015 Aug;116(2):185-91.
4. Doldi V, Callari M, Giannoni E, D’Aiuto F, Maffezzini M, Valdagni R, Chiarugi P, Gandellini P, Zaffaroni N.
Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a
prominent role for interleukin-6 in fibroblast activation. Oncotarget. 2015 Oct 13;6(31):31441-60.
5. Beretta GL, Folini M, Cavalieri F, Yan Y, Fresch E, Kaliappan S, Hasenöhrl C, Richardson JJ, Tinelli S, Fery A,
Caruso F, Zaffaroni N. Unravelling “off-target” effects of redox-active polymers and polymer multilayered
capsules in prostate cancer cells. Nanoscale. 2015 Apr 14;7(14):6261-70.
ACTIVE SURVEILLANCE IN PROSTATE CANCER
Since the early 2000s, AS is worldwide being offered to selected patients with
particularly favorable prognostic factors in alternative to radical prostatectomy,
radiotherapy and brachytherapy, these are the gold standard radical approaches which
may, however cause side effects that can potentially impact on patients’ quality of
life. AS is being proposed by the PC Program Multidisciplinary Clinic Team at INT since
March 2005.
Eligible patients are
examined and selected
during multidisciplinary
consultation with urologist,
radiation oncologist, and
psychologist and confirmed
in the interdisciplinary and
multiprofessional team
meeting dedicated to case
discussion
The first AS protocol started as a single-center cohort study named SAINT
(Sorveglianza Attiva INT) in 2005. In November 2007, we joined PRIAS (Prostate cancer
Research International: Active Surveillance), a multicenter prospective observational
study coordinated by the Erasmus University Medical Center (Rotterdam, The
Netherlands). Due to the limited understanding of PC aggressiveness at diagnosis,
the current protocols, which are both open, are slightly different in terms of inclusion
criteria. They accept patients with histologically confirmed adenocarcinoma of the
prostate, suitable for radical treatments, untreated, with initial PSA (iPSA) ≤10ng/
ml, clinical stage (T category) ≤T2a (2002 TNM, no T1a and T1b in PRIAS), and Gleason
Score (GS) ≤3+3. SAINT allows inclusion of patients with ≤25% positive cores as long
as the maximum core length containing cancer is ≤50%. In contrast, inclusion in PRIAS
requires PSA density <0.2 ng/ml/cc and maximum 2 positive cores with GS 3+3 (if a
multiparametric MRI, including targeted biopsies on suspected areas, is performed
at inclusion, no limit in the number of positive cores; in case of saturation biopsies,
number of positive cores up to 15% of the cores with a maximum of 4 when >26 cores
are taken).
Eligible patients are examined and selected during multidisciplinary consultation with
urologist, radiation oncologist, and psychologist (the medical oncologist is on demand
for castration-resistant, advanced and metastatic PC patients) and confirmed in the
interdisciplinary and multiprofessional team meeting dedicated to case discussion.
In addition to curative options (radical prostatectomy, external beam radiation,
brachytherapy), patients with low and very low PC are offered AS after confirmation of
sizing and grading of diagnostic biopsy by the uro-pathologist of the PC Unit.
Patients on AS are monitored over time with PSA, digital rectal examination, and
repeated biopsies. The latter are aimed to periodically confirm the histological
characteristics of disease and discontinue patients when > 3+3 GS is found and patients
are considered reclassified. SAINT and PRIAS apply slightly different follow-up schemes
with respect to the timing of rebiopsy. SAINT schedules biopsies at 12 and 24 months
after diagnosis and then every 2 years, while in PRIAS biopsies are taken at 1, 4, and
7 years. Between March 2005 and December 2015, 748 patients were enrolled in AS,
268 in SAINT, and 480 in PRIAS. Over time, 365 patients were discontinued, mainly due
to changes in histological parameters: upgrading (GS >6) and/or upsizing (number of
positive cores exceeding the criteria for AS and/or maximum core length containing
cancer >50% in SAINT). Active treatment-free survival (ATFS) curves, assessed by the
Kaplan-Meier method, show discontinuation rates (Figure 1).
74
Figure 1
Kaplan-Meier curve of ATFS
(all causes)
The group of patients on AS at INT is the largest in Italy and one of the largest
worldwide. In fact, the PC Program is the top recruiting center in the PRIAS
consortium. The cohort represents a good reservoir for investigation on the
pathogenesis and natural history of PC as patients are free from treatment
manipulations. In this regard, research is urgently needed to improve selection and
monitoring criteria for AS. To date, patients have been identified and
followed based on clinical and pathological
parameters, which are suboptimal.
Several problematic issues are the focus
of our research:
• Is it possible to predict reclassification
or progression and detect the presence
of GS 4 in an early stage?
• Is it possible to identify patients with
indolent/insignificant cancer?
• Can new reliable tools (biomarkers
and imaging instruments such as
multiparametric MRI) be implemented
to distinguish indolent from aggressive
and potentially evolving prostate
cancer?
• How is quality of life with an untreated
cancer?
• What is the long-term outcome of
patients on AS?
In the attempt to answer these
questions, multiple studies are being
proposed to AS patients.
Starting November 2008, the PROCABIOINT side study is collecting biological
material (blood) prospectively (at
inclusion in AS and then once a year
during follow-up). This biobank has
made possible the activation of studies focused on improving selection criteria for
AS. The preclinical research group, directed by Dr Nadia Zaffaroni (Vice Director of
the PC Program), is evaluating novel circulating biomarkers. The aim is to develop
non-invasive approaches for disease monitoring during AS. There are two fields of
interest:
We are currently evaluating
microRNA (miRNA) profiles
in plasma samples obtained
from patients in AS
Circulating microRNAs. We are currently evaluating microRNA (miRNA) profiles in
plasma samples obtained from patients at inclusion in AS. The aim is to correlate
them with clinical outcome and assess whether specific miRNAs/miRNA signature
are able to predict disease reclassification/progression better and/or in advance
compared to conventional markers. Samples from 258 eligible patients were
divided into training set (144 samples) and testing set (114 samples). Training set
plasma samples were profiled using the OpenArray Technology. The relationship
between patients clinical status –“indolent (still on AS)” versus “non indolent (who
discontinued AS due to upgrading at the repeated biopsy)”– and miRNA expression
in the training set was preliminarily investigated in univariate fashion to select
candidate miRNAs. Fifteen miRNAs, contributed by either stromal or tumor cells, were
identified as potential biomarkers being associated to patient outcome. Such results
are currently being confirmed in the testing set using the same technical approach.
Upon confirmation of results in an independent patient cohort, the final aim of this
study will be the integration of selected miRNAs in an updated and improved model
for prediction of truly indolent PC.
Genomic aberrations in circulating cell-free DNA. Since the genomic lesions that
characterize indolent PC are currently unknown, the search for point mutations and
copy number aberrations has been initially carried out in positive core biopsies from
a subset of 60 AS patients by a whole exome sequencing approach with the aims
of identifying specific DNA alterations associated with disease reclassification/
progression during AS. Preliminary evidence suggests that DNA lesions typically
found in GS=3+3 PC from prostatectomy samples are preferentially or exclusively
present in core biopsies from patients who discontinued AS due to disease upgrading
75
The search for point
mutations and copy
number aberrations has
been initially carried out
in positive core biopsies
from a subset of 60 AS
patients by a whole exome
sequencing approach
at the repeated biopsy. We also planned to test the feasibility of assessing DNA
lesions found in GS=3+3 core biopsies, as well as other genomic aberrations
characteristics of higher grade/more advanced tumors, in circulating cell-free DNA
by an ultra-deep targeted sequencing approach in plasma/serum samples from AS
pts. Preliminary results obtained in a subset of samples confirmed the possibility to
obtain DNA suitable, in terms of quality and quantity, to generate libraries from both
plasma and serum samples. Relevant cell-free DNA aberrations will be then validated
in independent series of tumors from patients followed in the context of PRIAS in
other medical centers by using the targeted sequencing approach.
Starting September 2007, a research project run by dedicated psychologists of the
PC Program is centered on the quality of life (QoL) of patients on AS. If avoidance of
therapy-induced side effects and a positive impact on QoL are among the advantages
of AS, it can be argued that the idea of “living” with an untreated cancer might be
associated with high levels of psychological distress and anxiety which would impair
QoL and eventually lead men to discontinue AS. Patients enrolled in PRIAS and SAINT
are asked to complete standardized self-reported questionnaires assessing QoL
at inclusion and 6 times during a 5-year follow-up period (10, 12, 24, 36, 48, and 60
months). About 75% of patients enrolled in AS accepted to participate in the QoL
study. Assessment of QoL in PC patients is most often based on the presence of
symptoms, but although physical impairment represents one of the main concerns,
patients’ well-being should be considered by taking into account equally important
factors such as overall health status, coping strategies, emotional well-being, and
social interactions. As such, we used different assessment tools to tackle different
aspects of patients’ QoL in order to have a comprehensive evaluation of patients’
perceived well-being. Our data, consistent with studies published by other research
groups across Europe, North America, and Australia, showed that the idea of living
with an untreated cancer does not represent a relevant psychological burden for
patients. Only a minority of patients are more likely to be exposed to the risk of poor
QoL due to vulnerability factors that include specific personality traits, lack of a
partner, and inadequate communication with physicians.
In addition, to demonstrate that AS is a valid alternative to radical therapies in low
and very low risk PC patients and that long-term outcome is favorable, data on
follow-up are being collected from patients who discontinued AS and underwent
surgery, radiotherapy, and brachytherapy.
76
MULTIDISCIPLINA
RESEARCH
IN THORACIC
ONCOLOGY
THORACIC ONCOLOGY
MULTIDISCIPLINARY RESEARCH
PROGRAM MEMBERSHIP
U. PASTORINO
PARTICIPATING UNITS
THORACIC SURGERY
MEDICAL ONCOLOGY
RADIOTHERAPY
PNEUMOLOGY
ENDOSCOPY
RADIOLOGY
ANATOMIC PATHOLOGY
NUCLEAR MEDICINE
A multidisciplinary approach in Thoracic Oncology has
been demonstrated to be one of the most important
parameters of quality of care in patient management.
Correct diagnosis, interaction, and definition of a therapeutic plan are key elements
for an effective and efficient approach to every patient, from the simplest to the most
complex.
To achieve this goal, a multidisciplinary group of specialists with specific experience
in thoracic pathologies has been instituted since 2011 that meets weekly to discuss
clinical cases. The group includes specialists in thoracic surgery, medical oncology,
radiotherapy, pneumology, endoscopy, radiology, anatomic pathology, and nuclear
medicine. All patients who need a multidisciplinary approach are simultaneously
visited in clinic my the team of the involved specialists. Also diagnoses are set up
in a multidisciplinary fashion with dedicated resources in order to provide fast
histological diagnoses and staging and to active smoking cessation programmes.
The results of this activity have been progressive standardization of the diagnostictherapeutic approach in complex cases, implementation of a working team, and
training of medical personnel.
The multidisciplinary staff meets at the Thoracic Surgery Unit every Monday for two
hours.
This program became active in October 2011. Since then, over 1,400 clinical cases
have been discussed. The meeting is accreditated by the Regional Healthcare System
for Continuing Education for the training offered.
Keywords
Multidisciplinary approach, Quality of care, Training of medical personnel
77
A MULTIDISCIPLIN
APPROACH
FOR THYROID
PATHOLOGIES AN
CANCER
THYROID PATHOLOGIES AND
CANCER: A MULTIDISCIPLINARY
APPROACH
PROGRAM MEMBERSHIP
G. GALMOZZI, E. SEREGNI
PARTICIPATING UNITS
MEDICAL DIRECTORATE
NUCLEAR-MEDICINE
OTOLARYNGOLOGY SURGERY
RADIOLOGY AND DIAGNOSTIC IMAGING
ANATOMIC PATHOLOGY
LABORATORY MEDICINE
EXPERIMENTAL ONCOLOGY AND MOLECULAR
MEDICINE: MOLECULAR MECHANISMS;
HEAD AND NECK CANCER MEDICAL ONCOLOGY
PEDIATRIC ONCOLOGY
Thyroid alterations, i.e. endocrine dysfunctions and
nodular pathologies, are frequently diagnosed in clinical
practice. The wider use of neck ultrasound and laboratory
tests can trigger intensive treatment with the risk of
increasing costs and morbidity. Despite the availability of
several guidelines for management of thyroid pathologies,
different approaches are observed in daily practice. For
this reason, a multidisciplinary project was started at the
INT in 2005 to harmonize and coordinate the activities of
different specialists towards a unique and well established
clinical framework.
Objectives
The objectives of the project can be summarized as follows:
•R
educe the time interval between diagnosis and treatment for each patient,
minimize diagnostic errors, unnecessary or repeated examinations, and the
fragmentation of approaches and variability of judgment among clinicians.
• Improve clinical skills among different specialists.
• Improve the efficiency and qualification in institutional organization pathways.
•C
onfer to the multidisciplinary team a more structured organization with greater
decisional autonomy in order to achieve more effectively and quickly the goals fixed
within the Institutional global strategy
Activities
The multidisciplinary project adopts different tools to achieve the above objectives.
Among these:
• Internal guidelines for management of thyroid disease (diagnostic and therapeutic
protocols).
During 2015 more than 1000
clinical visits were performed
in the multidisciplinary clinic
•M
ultidisciplinary clinical for outpatients: in this structure otolaryngologist
specialists, endocrinologists, and nuclear medicine physicians operate to define the
most appropriate diagnostic work-up and treatment for the individual patient.
•M
ultidisciplinary board: during these boards different specialists (surgeons,
pathologists, radiologists, nuclear medicine physicians, endocrinologists) discuss
in a collegial manner all post-surgical patients and all patients to be submitted to
thyroid surgery.
•D
efinition of a Diagnostic Therapeutic Care Pathway (PDTA) for patients with thyroid
disease.
•C
ollaboration with extra-institutional thyroid cancer centres.
Relevant output
• As in 2014, also during 2015 more than 1,000 clinical visits were performed in
the multidisciplinary clinic and many patients underwent thyroid surgery or
radiometabolic treatment with radioiodine for thyroid carcinoma.
•S
everal studies are now ongoing regarding, for instance, radioiodine therapy,
the clinical impact of skeletal metastases in patients with thyroid carcinoma, the
78
clinical significance of a synchronous diagnosis of papillary thyroid carcinoma
and medullary thyroid carcinoma and the identification of new target molecules in
thyroid carcinogenesis.
• Imaging techniques have been improved by introducing in clinical practice of a new
high performance SPECT/TC scanner (see Figure 1).
• Furthermore, the multidisciplinary approach to thyroid cancer allowed the
Institute to be considered in the developing of two relevant Italian guidelines:
1) “the Italian consensus on diagnosis and treatment of differentiated thyroid
cancer: Join statement of Italian Endocrinology Society (SIE), Italian Association of
Nuclear Medicine (AIMN) and Italian Society of Endocrine Surgery (SIEC)”; 2) “Italian
Association of Medical Oncology (AIOM) guideline on thyroid carcinoma”.
Keywords
Multidisciplinary approach, thyroid cancer, laboratory tests, guidelines
Figure 1
Improved diagnostic accuracy by introducing
SPECT/TC imaging.
Radioiodine uptake in thyroid bed and in
metastatic cervical lymph nodes in patient
underwent thyroidectomy for papillary
carcinoma. Note as SPECT/TC, in respect to
conventional whole body imaging, is able to
differentiate between normal tissue and cancer.
79
DEPARTMENTS
AND UNITS
SURGERY
DIRECTOR OF DEPARTMENT
VINCENZO MAZZAFERRO
vincenzo.mazzaferro@istitutotumori.mi.it
GASTROINTESTINAL,
HEPATOPANCREATOBILIARY SURGERY,
AND LIVER TRANSPLANTATION
VINCENZO MAZZAFERRO
COLORECTAL SURGERY
ERMANNO LEO
BREAST SURGERY
MARCO GRECO
Until September 2015
VINCENZO MAZZAFERRO
Interim from October 2015
MELANOMA AND SARCOMA
MARIO SANTINAMI
DIAGNOSTIC AND THERAPEUTIC
ENDOSCOPY
ENZO MASCI
SURGERY
PEDIATRIC SURGERY
LUIGI PIVA
T
he Department of Surgery
is composed of 12 Units,
organized for homogeneity
of performance, with 240 inpatient
beds and 14 outpatient beds. The
Department treats oncological diseases
that affect all areas of the body except
for the brain, providing elective and
emergency surgical activity, in ordinary
inpatient and day hospital regimens,
and specialistic oupatient activity for
diagnosis and follow-up. Routine clinical
activity ensures a high standard of
care for all surgically-treated patients,
providing conservative surgery (organ/
function preserving or minimally
invasive) for early stage disease and
combined treatment modalities for
advanced disease.
VINCENZO MAZZAFERRO
Interim until March 2015
MARCO GUZZO
Interim from March 2015
GYNECOLOGIC ONCOLOGY
FRANCESCO RASPAGLIESI
THORACIC SURGERY
UGO PASTORINO
UROLOGIC SURGERY
ROBERTO SALVIONI
LASER THERAPY
ANNA COLOMBETTI
DAY SURGERY
ALDO BONO
81
GASTROINTESTINAL,
HEPATOPANCREATOBILIARY SURGERY,
AND LIVER TRANSPLANTATION
VINCENZO MAZZAFERRO, Head of the Unit
Clinical activity
Research activity
Networking
The Unit is focused on the
treatment of tumors of the
upper gastrointestinal tract,
including liver and pancreas,
and neuroendocrine tumors (NET).
Within the Unit, a liver transplantation
(LT) program is active, which is known
worldwide. The Unit is operational 24
hours per day and is equipped with
instrumentation for semi-intensive
hospitalization.
The most relevant clinical
research projects concern:
The Hepatocellular
Carcinoma (HCC) Genomic
Consortium is a scientific
platform created in 2005 devoted to the
study of the molecular pathogenesis
of liver cancer. It includes Mount Sinai
School of Medicine (New York, USA),
Hospital Clinic (Barcelona, Spain), The
Broad Institute of Harvard and MIT
(Boston, USA) and INT
To date, almost 600 liver
transplantations (LT) have been
performed in oncologic patients, with
a survival rate of 80% at 5 years after
intervention.
About 800 patients per year are
hospitalized in the Unit, and treated
either by means of surgical or
locoregional procedures as part of a
multidisciplinary oncologic strategy.
Over 600 surgical interventions have
been performed for hepatic metastases
from colorectal tumors, as part of an
innovative and coordinated protocol.
The Unit is a worldwide referral Center
for the treatment of hepatocellular
carcinoma (HCC), since it provides
innovatively a wide range of therapeutic
strategies for this disease. Among these,
liver surgery is increasingly carried out
by means of laparoscopic technique,
and Y90 radioembolization has been
developed for the treatment of non
surgical HCC.
Liver transplantation in oncology.
In 2015 the Unit led a multicenter
international study collecting more
than 1,500 patients who underwent
liver transplantation for hepatocellular
carcinoma; aim of the study, by means
of a competitive risk analysis, was to
define which are the pre-LT oncologic
and biological features that affect postLT cancer-related survival.
In 2015 the Group finalized the first
prospective study to demonstrate
a significant survival benefit of liver
transplantation for patients with liver
metastases from neuroendocrine
tumors.
Systemic and locoregional treatments
for primary tumors of the liver. Several
international phase II and III studies
started or were running in 2015: ARQ087
as second line treatment for intrahepatic
cholangiocarcinoma; tivantinib vs
placebo for HCC progression after
sorafenib treatment; nivolumab vs
sorafenib as first line treatment of HCC;
sorafenib vs Y90RE for HCC with portal
vein thrombosis.
Oncogenic drivers and signaling
pathways in HCC The European project
HEPTROMIC (www.heptromic.eu) based
on cancer genomics was awarded with
a European Commission grant (FP-7
Health grant No. 259744-2). The project
was coordinated by Dr. Llovet and
includes the participation of 6 research
centers [M. Esteller (Spain), J. ZucmanRossi (France), V. Mazzaferro (Italy), L.
Zender (Germany), T. Golub (Harvard,
USA)] and 2 small-medium enterprises
involved in the transfer of knowledge to
industry
ROL - Rete Oncologica Lombarda (Dr
Mazzaferro is the scientific advisor for
the extension of Clinical Management
Guidelines for HCC)
Integrated medical and surgical
strategies for hepatic metastases
GASTROINTES
HEPATOPANC
AND LIVER TR
The Unit is a national referral Center for
study and treatment of patients with
gastroenteric neuroendocrine tumors,
for which a wide range of therapies are
used within a multidisciplinary context
that was recently certified by the
European Neuroendocrine Tumor Society
(ENET).
82
New types of video-assisted
interventions for pathologies of the
stomach and upper digestive tract
Development of supporting systems to
improve the quality of life in patients
with organ transplants and analysis of
the risk-benefit ratio in patients with
gastroenteric tumors
Keywords
Selected publications (2013-2015)
Liver surgery,
liver transplantation,
pancreatic surgery,
neuroendocrine tumors,
hepatocellular carcinoma,
radioembolization
Mazzaferro V, Sposito C, Bhoori S, Romito R, Chiesa C, Morosi
C, Maccauro M, Marchianò A, Bongini M, Lanocita R, Civelli E,
Bombardieri E, Camerini T, Spreafico C. Yttrium-90 radioembolization
for intermediate-advanced hepatocellular carcinoma: a phase
study. Hepatology. 2013 May;57(5):1826-37
2
Sposito C, Mariani L, Germini A, Flores Reyes M, Bongini M, Grossi G, Bhoori S,
Mazzaferro V. Comparative efficacy of sorafenib versus best supportive care in
recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J
Hepatol. 2013 Jul;59(1):59-66
Coppa J, Citterio D, Cotsoglou C, Germini A, Piccioni F, Sposito C, Mazzaferro V.
Transhepatic anterior approach to the inferior vena cava in large retroperitoneal
tumors resected en bloc with the right liver lobe. Surgery. 2013 Nov;154(5):1061-8
Cillo U, Burra P, Mazzaferro V, Belli L, Pinna AD, Spada M, Nanni Costa A, Toniutto P;
I-BELT (Italian Board of Experts in the Field of Liver Transplantation). A Multistep,
Consensus-Based Approach to Organ Allocation in Liver Transplantation: Toward a
“Blended Principle Model”. Am J Transplant. 2015 Oct;15(10):2552-61
Staff
Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, Cai J, Poon RT, Han KH,
Tak WY, Lee HC, Song T, Roayaie S, Bolondi L, Lee KS, Makuuchi M, Souza F, Berre MA,
Meinhardt G, Llovet JM; STORM investigators. Adjuvant sorafenib for hepatocellular
carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind,
placebo-controlled trial. Lancet Oncol. 2015 Oct;16(13):1344-54
HEAD
Mazzaferro Vincenzo, MD
CLINICAL RESEARCH STAFF
Carlo Battiston, MD, Sherrie Bhoori, MD, Jorgelina
Clara Coppa, MD, Christian Cotsoglou, MD,
Alessandro Germini, MD, Andrea Pulvirenti, MD,
Enrico Regalia, MD (Liver Translplant, Director),
Raffaele Romito, MD, Carlo Sposito, MD
RESIDENTS
Michele Droz Dit Busset, Luca Lamperti, Michele
Mazzola, Fiammetta Soggiu
STINAL,
CREATOBILIARY
RANSPLANTAT
RESEARCH STAFF
Bongini Marco Angelo, MD, Davide Citterio, MD,
Flores Reyes Maria De Los Angeles, MD, Cecilia
Muscarà, MD, Francesca Romana Ponziani, MD,
Mauro Alessandro Scotti, MD, Daniela Sia, MD
DATA MANAGERS
Federica Brunero, Simona Giovanna Marchesi
ADMINISTRATIVE PERSONNEL
Daniela Guarneri, Emilia Mausoli, Giuseppina
Carla Sciora
NURSES
Paola Balzano, Adriana Blanco, Anna Teresa
Bugada, Morena De Santis, Yesica Del Rio
Mendez, Milda Di Giacomo, Angela Mihaela
Farcas, Stefania Fici, Francesca Maiorano,
Giuseppe Marena, Antonia Masiello, Monica
Mitarotonda, Patrizia Perotto Ghi, Daniele
Pezzera, Patrizia Rota, Paola Serafin, Rossina
Sitta, Stefania Sperandio, Cristina Stracquadaini,
Patrizia Valentini
HEALTHCARE ASSISTANTS
Isabella Damasi, Nicoletta Damiani, Rosa De
Felice, Annamaria Pancari, Angela Vittorina
Restaini, Vincenza Spina, Anna Vecchio
BIBLIOMETRIC INDICATORS
OF THE UNIT
25
PUBLICATIONS
216.036
IMPACT FACTOR
10
PUBLICATIONS AS FIRST/LAST AUTHOR
74.722
IMPACT FACTOR AS FIRST/LAST AUTHOR
2-55, 10
UNIT H-INDEX RANGE, MEDIAN
83
COLORECTAL SURGERY
ERMANNO LEO, Head of the Unit
Clinical activity
Research activity
Networking
The Unit is a recognized
European referral center for
colorectal tumors. The case
load of colorectal surgeries is
about 600 per year. Our Unit is chiefly
focused on distal rectum tumors. High
standards of care for the management
of these patients have been established,
including highly specialized surgical
techniques and multidisciplinary
treatment programs. During 2015,
about 200 rectal resections were
performed. Approximately 50% of these
cases were distal tumors at high-risk
for abdominoperineal resection and
definitive ostomy which were managed
by sphincter preserving surgical
procedures. A further area of expertise
covers local recurrences of rectal
cancer and rare ano-rectal tumors,
such as melanoma and squamous cell
carcinoma.
The most relevant clinical
and translational research
programs focus on colorectal
cancer (CRC) and rare peritoneal surface
malignancies, such as pseudomyxoma
peritonei (PMP) and diffuse malignant
peritoneal mesothelioma (DMPM).
Two randomized trials are ongoing to
assess the role of cytoreductive surgery
(CRS) and HIPEC in the treatment of
CRC peritoneal metastases, and to
test an approach involving secondlook surgery and HIPEC (vs. standard
follow-up) in CRC patients at high risk
for the development of peritoneal
metastases. This year we have closed
the enrollment of a prospective trial
to assess an individualized approach
of systemic chemotherapy and
molecular-targeted therapies, based
on the molecular characterization and
chemosensitivity profile on primary
cultures in DMPM patients treated by
CRS/HIPEC (supported by a grant of the
Health Ministry). A prospective study
is ongoing to determine the prognostic
role of microRNA and other biologic
factors in PMP patients using tissue the
microarray (TMA) technology (supported
by a grant of the National Organization
for Rare Disorders, NORD). A third
randomized trial is ongoing to test the
effect of intra-abdominal pressure
on the pharmacokinetics and tissue
diffusion of drugs during the HIPEC
(supported by a grant of the Italian
Association for Cancer Research, AIRC).
The Colorectal Cancer
Unit is involved in the Rete
Oncologica Lombarda (ROL).
We have contributed to define clinical
management guidelines for colorectal
cancer (both early and advanced
stage), and for colorectal peritoneal
metastases.
Special attention is paid to patients
affected by gastrointestinal hereditary
tumors, who are treated and followedup by a dedicated team in collaboration
with the Hereditary Digestive Tract
Tumor Unit. Since 2012, the Peritoneal
Surface Malignancy (PSM) Program
was included into the Colorectal
Unit. This Program is focused on
the treatment of pseudomyxoma
peritonei, peritoneal mesothelioma, and
peritoneal metastases from colorectal
cancer. More than 800 procedures
of surgical cytoreduction associated
with hyperthermic intraperitoneal
chemotherapy (HIPEC) performed so
far. The PSM Program has pioneered
the development of peritoneal
surface oncology, and has become an
international referral center for these
diseases.
The Peritoneal Surface Malignancy
(PSM) Program is a member of the
Peritoneal Surface Oncology Group
International (PSOGI). Our PSM
Program is the coordinating center
of two PSOGI international registries
collecting patients all over the world
affected by two rare peritoneal surface
malignancies: pseudomyxoma (PMP)
and diffuse malignant peritoneal
mesothelioma (DMPM): 2,451 PMP
patients, and 1,162 DMPM patients have
been included in these registries.
The Colorectal Cancer Unit is a PSOGI/
ESSO recognized training center for the
European School of Peritoneal Surface
Oncoloy (EPSO).
COLORECTAL
84
Keywords
Colon, rectum, cancer, anal
melanoma, squamous cell
carcinoma, local recurrence,
colo-rectal adenocarcinoma,
HIPEC, peritoneal carcinomatosis,
sphincter preserving, nerve sparing,
colo-anal anastomosys, FAP, colectomy,
rectal resection
Deraco M, Cabras A, Baratti D, Kusamura S. Immunohistochemical
Evaluation of Minichromosome Maintenance Protein 7 (MCM7),
Topoisomerase IIα, and Ki-67 in Diffuse Malignant Peritoneal
Mesothelioma Patients Using Tissue Microarray.
Ann Surg Oncol. 2015 Dec;22(13):4344-51
Kusamura S, Moran BJ, Sugarbaker PH, Levine EA, Elias D, Baratti D, Morris DL, Sardi
A, Glehen O, Deraco M; Peritoneal Surface Oncology Group International (PSOGI).
Multicentre study of the learning curve and surgical performance of cytoreductive
surgery with intraperitoneal chemotherapy for pseudomyxoma peritonei. Br J Surg.
2014 Dec;101(13):1758-65
Baratti D, Kusamura S, Iusco D, Bonomi S, Grassi A, Virzì S, Leo E, Deraco M.
Postoperative complications after cytoreductive surgery and hyperthermic
intraperitoneal chemotherapy affect long-term outcome of patients with peritoneal
metastases from colorectal cancer: a two-center study of 101 patients. Dis Colon
Rectum. 2014 Jul;57(7):858-68
Vitellaro M, Sala P, Signoroni S, Radice P, Fortuzzi S, Civelli EM, Ballardini G, Kleiman
DA, Morrissey KP, Bertario L. Risk of desmoid tumours after open and laparoscopic
colectomy in patients with familial adenomatous polyposis. Br J Surg. 2014
Apr;101(5):558-65
Baratti D, Kusamura S, Cabras AD, Bertulli R, Hutanu I, Deraco M. Diffuse malignant
peritoneal mesothelioma: long-term survival with complete cytoreductive surgery
followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Eur J Cancer. 2013
Oct;49(15):3140-8
Staff
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
ADMINISTRATIVE
Roberta Aceto
NURSES
Fabiana Bettoni, Lucia Caracciolo, Rut Cittadin,
Angela Colamonaco, Stefania Labori, MagdalenaAlonso Manuel, Marica Melis, Vanessa Neri,
Maria Palma, Mirtha Ybazeta Ramos, Riccardo
Vacca
OF THE UNIT
10
PUBLICATIONS
32.107
IMPACT FACTOR
5
14.931
SURGERY
Monica Anzaghi, Isabella Damasi, Nunzia Di
Perna, Fabio Lizzano, Maria Petrosina
2-34, 21
85
BREAST SURGERY
MARCO GRECO, Head of the Unit (until September 2015)
VINCENZO MAZZAFERRO, Head of the Unit (Interim from October 2015)
Clinical activity
Research activity
Keywords
The clinical activity of the Unit
includes diagnosis, primary and
adjuvant therapy, and followup. Treatment is performed
by multidisciplinary teams involving
Units and Departments. More in detail,
11,000 patients accessed to out-patients
services, ranging from the out-patients
first examination to pre-operative
counseling to therapeutic planning,
or follow-up of operated patients. In
cooperation with the Medical Genetics
Unit, an approach tailored for women at
high genetic risk has been developed.
Long-standing results in
T1N0 breast cancer, from two
different randomized clinical trials
comparing axillary dissection with
observation in patients under and over
65 years of age, respectively, were
published.
Breast Cancer, breast
reconstructive and
plastic surgery, axillary
management, oncoplastic
surgery
Almost 1,100 patients underwent main
surgery for breast cancer, ranging
from breast conservative surgery to
mastectomy (ev. NAC- or Skin-sparing)
with plastic intervention for breast
modeling or reconstruction. More than
300 patients underwent minor surgery
for benign and suspicious malignant
breast diseases.
Plastic and Reconstructive Surgery
The Plastic and Reconstructive Surgery
Unit carries out both surgical and
research activities. The main focus
of the Unit is oncoplastic surgery.
Surgical reconstructive procedures
are performed for mastectomy and
for tumors of the head and neck, soft
tissues, thorax, and other types of
oncological ablations as well as surgical
intervention and repair for skin tumors.
The Department carries out the
following types of surgeries:
• Breast and soft tissue reconstruction;
• Microsurgical reconstruction;
• Germ cell transplantation;
dvanced techniques for wound
•A
healing.
A further study comparing FDG-PET
with sentinel lymph node biopsy for
identifying different biological and
prognostic breast cancer populations
was also published.
Among several joint studies started
in the last years with other Units
and Departments we completed the
evaluation of PET as imaging tool
for early prediction of pathologically
response in patients with locally
advanced breast cancer treated with
neoadjuvant chemotherapy, as well
as the evaluation of NAC-sparing
mastectomy after neo-adjuvant
chemotherapy, the relationship between
breast cancer and metabolic syndrome,
the breast conservative surgery in
elderly patients with or without postoperative radiotherapy. Furthermore,
we actively participate to multicentric
clinical randomized trial comparing
sentinel node biopsy vs. observation in
early breast cancer (SOUND).
Following a recent pilot study at the INT
on the feasibility of Selective Axillary
Dissection (SAD) which preserves the
lymphatic drainage of the arm, we
started a randomized clinical trial to
assess the prevention of lymphedema
adopting selective axillary dissection.
BREAST SURG
86
Staff
HEAD
Marco Greco, MD
(until September 2015),
Vincenzo Mazzaferro, MD
(Interim from October 2015)
Crippa F, Agresti R, Sandri M, Mariani G, Padovano B, Alessi A, Bianchi
G, Bombardieri E, Maugeri I, Rampa M, Carcangiu ML, Trecate G, Pascali
C, Bogni A, Martelli G, de Braud F. 18F-FLT PET/CT as an imaging tool for
early prediction of pathological response in patients with locally advanced
breast cancer treated with neoadjuvant chemotherapy: a pilot study. Eur J Nucl Med
Mol Imaging. 2015 May;42(6):818-30
Domenico Piromalli, MD (Senology outpatient
clinic and day hospital, Director); Umberto
Cortinovis, MD (Plastic and Reconstructive
Surgery, Director); Roberto Agresti, MD; Silvia
Bohm, MD; Alberto Rudy Conti, MD; Cristina
Ferraris, MD; Massimiliano Gennaro, MD; Maria
Ilaria Grosso, MD; Gabriele Martelli, MD; Novella
Bruno, MD; Joseph Ottolenghi, MD; Angela Elenia
Pennati, MD; Egidio Riggio, MD; Andrea Spano, MD
RESIDENTS
Caterina Tartaglione, MD
RESEARCH STAFF
Stefano Avvedimento, MD; Barbara Ballestra,
Biol Sci D; Eleonora Guzzetti, MD; Cristina La
Tessa, MD; Ilaria Maugeri, MD; Mario Rampa, MD
Angela Allegri
NURSES
Irene Alessandrini, Giovanni Cavaliere, Myriam
P. Conti, Maria Carla Puddu, Michele Rossello,
Gelsomina Sasso, Francesco A. Spagnolo,
Samantha F. Castelli, Cinzia Gentilini, Marisa
Labò, Giovanna Melia, Caterina Pireddu, Irene
Rossi, Raffaella Tupputi
Martelli G, Boracchi P, Guzzetti E, Marano G, Lozza L, Agresti R, Ferraris C, Piromalli
D, Greco M. Omission of radiotherapy in elderly patients with early breast cancer: 15Year results of a prospective non-randomised trial. Eur J Cancer. 2015 Jul;51(11):135864
Agresti R, Martelli G, Sandri M, Tagliabue E, Carcangiu ML, Maugeri I, Pellitteri C, Ferraris
C, Capri G, Moliterni A, Bianchi G, Mariani G, Trecate G, Lozza L, Langer M, Rampa M,
Gennaro M, Greco M, Menard S, Pierotti MA. Axillary lymph node dissection versus no
dissection in patients with T1N0 breast cancer: a randomized clinical trial (INT09/98).
Cancer. 2014 Mar 15;120(6):885-93
Agresti R, Crippa F, Sandri M, Martelli G, Tagliabue E, Alessi A, Pellitteri C, Maccauro
M, Maugeri I, Barbara P, Rampa M, Moscaroli A, Ferraris C, Carcangiu ML, Bianchi G,
Greco M, Bombardieri E. Different biological and prognostic breast cancer populations
identified by FDG-PET in sentinel node-positive patients: results and clinical
implications after eight-years follow-up. Breast. 2014 Aug;23(4):334-40
Martelli G, Boracchi P, Orenti A, Lozza L, Maugeri I, Vetrella G, Agresti R. Axillary
dissection versus no axillary dissection in older T1N0 breast cancer patients: 15-year
results of trial and out-trial patients. Eur J Surg Oncol. 2014 Jul;40(7):805-12
Nadia Casati, Francesca Maiorana, Iolanda
Panipucci, Annunziata Rugolo, Esther Noemi
Ybazeta Ramos
GERY
OF THE UNIT
13
PUBLICATIONS
39.165
IMPACT FACTOR
4
14.730
1-35, 7
87
MELANOMA AND SARCOMA
MARIO SANTINAMI, Head of the Unit
Clinical activity
Research activity
Networking
The Melanoma Unit performed
clinical and dermatoscopic
examination and followup for more than 15,000
patients. More than 682 patients
were hospitalized during 2015 to
undergo surgery for melanoma. About
1,500 conventional surgeries and 30
electrochemotherapy procedures
were performed in day surgery setting.
Substantial focus is on pediatric
melanomas and melanocytic tumors
of uncertain malignant potential
(MELTUMP) that typically occur in
children and adolescents.
The Melanoma Unit mantains
a perspective database
collecting more than 7,000
melanoma patients who were treated at
our Institution from 2000 to date. Taking
advantage of our large case-series we
are collaborating with the MD Anderson
Cancer Center to formulate the new AJCC
classification. Several clinical trials in
adjuvant setting were performed during
2015 (See the chapter Ongoing Clinical
Studies).
ROL - Rete Oncologica
Lombarda
The Sarcoma Unit is a national referral
facility for soft tissue sarcomas of the
extremities and trunk, retroperitoneal
sarcoma, gastrointestinal stromal tumor
(GIST), and desmoid type fibromatosis. In
2015, 310 primary tumor were surgically
treated. About 1,500 patients were
referred for consultation, and about
5,000 follow-up visits were performed.
An institutional database is maintained
by the Sarcoma Unit, collecting data of
over 7,900 patients affected by sarcoma
treated in the last 30 years. International
studies are ongoing focused on localized
high-risk sarcomas of the extremities
and trunk wall, retroperitoneal sarcoma,
sporadic desmoids-type, fibromatosis
and GIST (see the Ongoing Clinical
Studies chapter).
MELANOMA A
88
Keywords
Melanoma, sarcoma,
retroperitoneal sarcoma,
GIST, fIbromatosis
C.R. Rossi, N. Mozzillo, A. Maurichi, S. Pasquali, P. Quaglino, L.
Borgognoni, N. Solari, D. Piazzalunga, L. Mascheroni, G. Giudice, S.
Mocellin, R. Patuzzo, C. Caracò, S. Ribero, U. Marone and M. Santinami.
The number of excised lymph nodes is associated with survival of
melanoma patients with lymph node metastasis. Annals of Oncology 25, 240-46,
2014
Rossi CR, Mozzillo N, Maurichi A, Pasquali S, Macripò G, Borgognoni L, Solari N,
Piazzalunga D, Mascheroni L, Giudice G, Mocellin S, Patuzzo R, Caracò C, Ribero S,
Marone U, Santinami M. Number of excised lymph nodes as a quality assurance
measure for lymphadenectomy in melanoma. JAMA 149(7). 700-6, 2014
. Maurichi, R. Miceli, T. Camerini, L. Mariani, R. Patuzzo, R. Ruggeri, G. Gallino, E.
A
Tolomio, G. Tragni, B. Valeri, A. Anichini, R. Mortarini, D. Moglia, G. Pellacani, S. Bassoli,
C. Longo, P. Quaglino, N. Pimpinelli, L. Borgognoni, D. Bergamaschi, C. Harwood, O.
Zoras, and M. Santinami Prediction of Survival in Patients With Thin Melanoma:
Results From a Multi-Institution Study JCO, 2014
Eggermont AM, Suciu S, Rutkowski P, Marsden J, Santinami M, Corrie P, Aamdal S,
Ascierto PA, Patel PM, Kruit WH, Bastholt L, Borgognoni L, Bernengo MG, Davidson
N, Polders L, Praet M, Spatz A. Adjuvant Ganglioside GM2-KLH/QS-21 Vaccination
Versus Observation After Resection of Primary Tumor >1.5 mm in Patients With Stage
II Melanoma: Results of the EORTC 18961 Randomized Phase III Trial J Clin Onc. 31(30).
3831-7. 2013
Staff
HEAD
Mario Santinami, MD
Alessandro Gronchi MD (Surgery for Sarcoma,
Director), Chiara Colombo MD, Marco Fiore MD,
Gianfrancesco Gallino MD, Andrea Maurichi MD,
Daniele Moglia MD, Roberto Patuzzo MD, Stefano
Radaelli MD, Roberta Ruggeri MD,
RESIDENTS
Dario Callegaro MD, Andrea Pierluigi Fontana MD
RESEARCH STAFF
Valentina Girgenti MD, Roberto Grillo MD, Ilaria
Mattavelli MD, Elena Tolomio MD
DATA MANAGERS
Giulia Elisa Bonarini, Adele Di Fazio
Annabella Di Florio, Lorella Rusi, Maria Antonia
Vescera
NURSES
Annamaria Biondo, Annarita Carluccio, Alessio
Cremonesi, Nello Curatolo, Giovanna Lomartire,
Loridana Marino, Linda Musuraca, Erika
Panigada, Giuseppina Pede, Lucia Preto, Denise
Sirianni, Claudia Maria Sonzogni, Monica Ullio,
Liliane Venafra, Addolorata Volpe
OF THE UNIT
30
PUBLICATIONS
182.382
IMPACT FACTOR
14
73.790
AND SARCOMA
RESEARCH NURSES
Gabriella Nicolò
Roberta Allenza, Floarea Dorca, Tereza Mina,
Silvana Mirante, Francesca Ruiu, Antonietta
Tomasicchio
1-46, 15
89
DIAGNOSTIC AND
THERAPEUTIC ENDOSCOPY
ENZO MASCI, Head of the Unit
Clinical activity
The Unit is focused on
diagnosis and endoscopic
treatment of gastroenteropancreatic cancer and
palliation of advanced gastrointestinal
tumors. Our interest is on advanced
endoscopic imaging modalities, such
as high definition chromoendoscopy
and confocal endomicroscopy. New
imaging techniques for endoscopic
surveillance in patients with hereditary
gastrointestinal cancer are being
developed to evaluate the role of
endomicroscopy in management of
duodenal polyps (and adenomas of the
papilla of Vater).
Calandrella D, Romito LM, Elia AE, Del Sorbo F, Bagella CF, Falsitta M,
Albanese A. Causes of withdrawal of duodenal levodopa infusion in
advanced Parkinson disease. Neurology 2015;84:1669-1672
Arena M, Virdis M, Morandi E, Viaggi P, Pisani A, Opocher E, Masci E.
Blue rubber bleb nevus syndrome: Combined surgical and endoscopic treatment.
Endoscopy 2015;47 Suppl 1 UCTN:E372-E373
Billè A, Giovannetti R, Calarco G, Pastorino U. Tailored stent for bronchial stump
fistula closure and omentoplasty for infection control: A combined approach with low
morbidity. Tumori 2014;100:157e-159e
Vitellaro M, Sala P, Signoroni S, Radice P, Fortuzzi S, Civelli Em, Ballardini G, Kleiman
Da, Morrissey KP, Bertario L . Risk of desmoid tumours after open and laparoscopic
colectomy in patients with familial adenomatous polyposis. British Journal Of Surgery
2014;101:558-565
We focus on the development of new
endoscopic procedures for treatment
of early neoplasia and surgical
complication management.
We perform mucosal and submucosal
dissection, endoscopic retrograde
colangiopancreatography,
cholangioscopy, and both diagnostic
and therapeutic endoscopic ultrasounds
(EUS) with more than 700 EUS
procedures per year.
In collaboration with the Unit of
Hereditary Digestive Tract Tumors, we
coordinate the endoscopic surveillance
of patients at high risk for familial or
syndrome predisposing digestive tract
tumors.
DIAGNOSTIC
THERAPEUTI
ENDOSCOPY
The Unit participates in the Local Health
Service of Milan program for colorectal
cancer screening. We are involved in
a multicenter trial aimed to identify
circulating biomarkers (miRNAs) for
subjects with a genetic profile of high
risk for colorectal cancer.
Our Unit is involved in the diagnosis
and treatment of neuroendocrine
tumors certified by the European
Neuroendocrine Tumor Society and we
join a multidisciplinary team focused on
upper gastrointestinal cancer.
OF THE UNIT
Staff
HEAD
Enzo Masci, MD
Giovanni Ballardini, MD; Giuseppe Calarco, MD;
Gabriele Delconte, MD; Massimo Falsitta, MD;
Andrea Mancini, MD, Teresa Staiano, MD
ADMINISTRATIVES
Concetta Adele Di Quattro, Annamaria Mercuri
NURSES
Vittorio Mauro (Coordinator), Francesco Bottani,
Raffaele Calò, Daniele Lo Curcio, Roberto Fiocco,
Licata Stefano, Raffaele Quagliuolo, Giovanni
Sammartino
Salvatore Morfeo, Luigi Magnifico
90
2
PUBLICATIONS
13.339
IMPACT FACTOR
1
5.053
5-25, 6
PEDIATRIC SURGERY
LUIGI PIVA, Head of the Unit
Clinical activity
Research activity
Networking
The Pediatric Surgery Unit was
created in 2005 and collaborates
with pediatric oncologists to
provide high standard treatments
for the most frequent solid, non CNS,
tumors in children and adolescents. The
main clinical research areas are renal
tumors, Wilms’ tumor, neuroblastoma,
teratomas and malignant germ cell
tumors.
The Pediatric Surgery Unit is
involved in different Working
Group of the Associazione Italiana
di Ematologia ed Oncologia Pediatrica
(AIEOP) that groups over 50 Italian
center in a network
European Expert Pediatric
Oncology Reference
Network for Diagnostics
and Treatment (EXPO-r-NET)
The Pediatric Oncology Unit is the referral
center of the Associazione Italiana
Ematologia e Oncologia Pediatrica (AIEOP)
for pediatric renal tumors and the national
coordinating center for clinical protocols
and molecular studies. Surgeons of this
Unit take charge of both institutional
patients and children coming from other
Hospitals. In the new protocol of the Renal
Tumor Study Group of the International
Society of Pediatric Oncology (SIOP RTSG)
this Unit will be identified as one of the
reference Center at European level for
surgeries of high complexity.
Tumori Rari dell’Età Pediatrica (TREP)
Società scientifiche italiane Insieme
per gli Adolescenti con Malattie Oncoematologiche (SIAMO )
Collaboration with the Children’s
Hospital V. Buzzi of Milan
Collaboration with the Pediatric Surgery
Unit of the Fondazione IRCCS Ospedale
Maggiore of Milan
Europian Pediatric Soft Tissue Sarcoma
Study Group (EpSSG )
European Cooperative Study Group on
Pediatric Rare Tumors (EXPeRT)
Staff
Keywords
HEAD
Luigi Piva, MD
Pediatric surgery,
solid tumors
Our Institute is the Italian coordinating
center of the ongoing European Protocol
for high-risk neuroblastoma.
Another area of expertise is represented
by pediatric patients affected by teratoma
and malignant germ cell tumor with
localized disease (ovary, testicular and
extragonadal tumor) which are treated
according to the AIEOP TCGM 2004
protocol.
In collaboration with the Unit of Hereditary
Digestive Tract Tumours, during 2015, 7
adolescent patients affected by Familial
Adenomatous Polyposis undergone
laparoscopic prophylactic colectomy.
Giannatempo P, Greco T, Mariani L, Nicolai N, Tana S, Farè E, Raggi D,
Piva L, Catanzaro M, Biasoni D, Torelli T, Stagni S, Avuzzi B, Maffezzini
M, Landoni G, De Braud F, Gianni Am, Sonpavde G, Salvioni R, Necchi A.
Radiotherapy or chemotherapy for clinical stage IIA and IIB seminoma:
A systematic review and meta-analysis of patient outcomes. Annals Of Oncology
2015;26:657-668
Necchi A, Mariani L, Di Nicola M, Lo Vullo S, Nicolai N, Giannatempo P, Raggi D, Farè
E, Magni M, Piva L, Matteucci P, Catanzaro M, Biasoni D, Torelli T, Stagni S, Bengala C,
Barone C, Schiavetto I, Siena S, Carlo Stella C, Pizzocaro G, Salvioni R, Gianni Am. Highdose sequential chemotherapy (HDS) versus PEB chemotherapy as first-line treatment
of patients with poor prognosis germ-cell tumors: mature results of an Italian
randomized phase II study. Annals Of Oncology 2015;26:167-172
PEDIATRIC
SURGERY
OF THE UNIT
11
PUBLICATIONS
35.512
IMPACT FACTOR
21-21, 21
Raggi D, Mariani L, Giannatempo P, Lo Vullo S, Giardiello D, Nicolai N, Piva L, Biasoni
D, Catanzaro M, Torelli T, Stagni S, Maffezzini M, Calareso G, Magni M, Di Nicola M,
Verzoni E, Grassi P, Procopio G, De Braud F, Pizzocaro G, Salvioni R, Necchi A. Prognostic
reclassification of patients with intermediate-risk metastatic germ cell tumors:
Implications for clinical practice, trial design, and molecular interrogation. Urologic
Oncology-seminars And Original Investigations 2015;33:332.e19-332.e24
Nicolai N, Bianchi E, Donati I, L’acqua C, Brunelli C, Biasoni D, Catanzaro M, Stagni S, Piva
L, Torelli T, Necchi A, Raggi D, Giannatempo P, Faré E, Colecchia M, Langer M, Borreani C,
Salvioni R. Quality of life and pain control following laparoscopic retroperitoneal lymph
node dissection in early-stage nonseminoma. Tumori 2015;101:650-656
Terenziani M, Spreafico F, Gotti G, Biasoni D, Piva L, Collini P. Bilateral testicular germ
cell tumors. Journal Of Pediatric Surgery 2014;49:1341.
91
VINCENZO MAZZAFERRO, Head of the Unit (Interim until February 2015)
MARCO GUZZO, Head of the Unit (Interim from March 2015)
Clinical activity
Research activity
Keywords
The Otolaryngology Surgery
Unit is involved in the treatment
of all types of tumors that
affect the oral cavity, pharynx,
larynx, cervical esophagus and trachea,
nose and paranasal sinuses, salivary
glands, thyroid and parathyroid.
The Unit collaborates with the
Radiology, Pathology, Radiotherapy,
and Medical Oncology Department.
This collaboration makes it possible
to offer a multidisciplinary evaluation
and to plan the individualized and
effective treatment, with the goal to
optimize post-treatment quality of
life, management of treatment sideeffects, early diagnosis and treatment
of disease recurrences. Besides, the
Unit has close collaborations with
neurosurgeons at C. Besta Neurological
Institute. The reconstructions required
during the extensive resections needed
for treatment of head and neck tumors
are carried out together with plastic
surgeons in order to provide high
standards in terms of preservation of
function and esthetics, including the use
of free flaps. The Otolaryngology Surgery
Unit also collaborates with the Nuclear
Medicine and Endocrinology Department
for diagnosis, treatment, and follow-up
of thyroid and parathyroid pathologies
as part of the Thyroid Project. In the last
year we improved speech rehabilitation
of laryngectomized patients using the
tracheoesophageal voice, transoral laser
microsurgery for laryngeal cancer and
neuromonitoring in thyroid and parotid
surgery.
The Otolaryngology Surgery
Unit is involved in many clinical
studies in collaboration with the
Medical Oncology and Radiotherapy
Department, as listed below:
Head and neck cancer,
free flaps, transoral
laser microsurgery,
intraoperative neuromonitoring,
tracheoesophageal speech, pre-operative
chemotherapy
- Multidisciplinary approach for poor
prognosis sinonasal tumors: Phase
II study of chemotherapy, surgery,
photon and heavy ion radiotherapy
integration for more effective and less
toxic treatment in operable patients SINTART1
- 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 -SINTART2
- 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
- Neoadjuvant afatinib based treatment
strategies followed by surgery in
squamous cell carcinoma of the
head and neck: an EORTC NOCI-HNCG
window study – EORTC 90111-24111
- Health and economic outcomes of
two different follow up strategies in
effectively cured advanced head and
neck cancer
OTOLARYNGO
92
Staff
Chiaravalli S, Guzzo M, Bisogno G, De Pasquale MD, Migliorati R, De
Leonardis F, Collini P, Casanova M, Cecchetto G, Ferrari A. Salivary
gland carcinomas in children and adolescents: the Italian TREP project
experience. Pediatric Blood & Cancer 2014;61:1961-1968
HEAD
Vincenzo Mazzaferro, MD
(Interim until February 2015)
Marco Guzzo, MD
(from March 2015)
Luzzati AD, Shah SP, Gagliano FS, Perrucchini GG, Fontanella W, Alloisio M.
Four- And five- Level en bloc spondylectomy for malignant spinal tumors. Spine
2014;39:E129-E139
Sarah Colombo, MD; Walter Fontanella, MD;
Tullio Mattia Ibba, MD; Natalia Rita Pizzi, MD;
Madia Pompilio, MD; Stefano Riccio, MD
Podda Mg, Terenziani M, Gandola L, Collini P, Pizzi N, Marchianò A, Morosi C, Luksch
R, Ferrari A, Casanova M, Spreafico F, Polastri D, Meazza C, Catania S, Schiavello E,
Biassoni V, Massimino M. Thyroid carcinoma after treatment for malignancies in
childhood and adolescence: From diagnosis through follow-up. Medical Oncology
2014;31:121
Orlandi E, Takanen S, Giandini T, Iannacone E, Fontanella W, Locati L, Carrara M,
Bossi P, Bergamini C, Granata R, Tombolini V, Ibba T, Licitra L, Pignoli E, Fallai C.
Postoperative radiotherapy with volumetric modulated arc therapy of lacrimal gland
carcinoma: Two case reports and literature review. Future Oncology 2014;10:21112120
Grigolato R, Pizzi N, Brotto MC, Corrocher G, Desando G, Grigolo B. Magnesiumenriched hydroxyapatite as bone filler in an ameloblastoma mandibular defect.
International Journal Of Clinical And Experimental Medicine 2015;8:281-288
RESEARCH STAFF
Roberto Bianchi, MD; Michele Caputo, MD;
Guglielmo Larotonda, MD
TECHNICIANS
Filomena Labori
Sabrina Zazzera
NURSES
Carla Caldarera, Alice Casali, Petronilla
D’Agostino, Floriana Dimo, Giorgio Fumi, Giorgio
Inverni, Tiziana Longo, Carmelina Minio, Lia G.
Nicolosi, Laura Ongari, Federica Prudenzano,
Raffaella Repetto, Maura Rimoldi, Mariastefania
Selva, Salvatore Sirigu
Nadia P. Duca, Pablita Endaya, Vanessa Inzillo,
Gianluca Severgnini
OF THE UNIT
1
PUBLICATIONS
1.277
IMPACT FACTOR
2-15, 6
OLOGY SURGER
93
GYNECOLOGIC ONCOLOGY
FRANCESCO RASPAGLIESI, Head of the Unit
Clinical activity
Research activity
Networking
The Unit deals mainly with all
primary and secondary tumors
of the female genital tract. The
clinical activity comprises three
area of expertise: surgical, medical
and diagnostic area and includes all
aspects of gynecological cancers
management: diagnosis, surgery,
chemotherapy and follow-up. The Unit
carries out over 1,200 procedures each
year in DH surgery, including conization,
laser therapy, hysteroscopy and
photodynamic therapy for Paget disease.
Over 600 major surgical procedures
were performed, including complex ones
(debulking and exenteration). Advanced
Mini-invasive surgery regarding
diagnosis, staging and treatment of all
gynecological cancers, is also carried
out. In addition, over 23,000 outpatient
visits concerning first entry gynecologic
oncology evaluation, familial cancer, HPV
multidisciplinary office, follow-up visits
and 1st and 2nd level ultrasound were
performed.
The Unit is considered a
referral center for clinical and
surgical research in gynecological
cancers. Twenty-seven clinical trials
have been conducted (1 phase I,
11phase II, 14 phase III). Of these, 9 were
non-profit clinical trials and 18 were
sponsored trials. Regarding the surgical
research, 12 phase II studies were
conducted on the following techniques:
Surgical lymphnodal staging; Nerve
sparing radical surgery; Debulking
surgery employing new devices;
Advanced mini-invasive surgery with
new 3D technology; Fertility-sparing
surgery; Sentinel node technique;
Photodynamic treatment of recurrent
Paget’s vulvar disease; Radio-guided
Surgery.
The Gynecologic Oncology
Unit is founder center of the
Multicenter Italian Trialists
in Ovarian cancer and gynecological
malignancies (MITO) group. The MITO
group is the largest group in Italy
involved in the clinical and translational
research in gynecological cancers,
accounting for about 150 Italian centres.
The Director of the Unit is member of the
board of MITO group. At international
level, MITO is part of ENGOT (European
Network of Gynaecological Oncological
Trial group), the European network of
Centers involved in gynecological cancer
research and the Gynecological Cancer
Intergroup (GCIG), counting 23 groups
worldwide.
The medical part of the Unit is devoted
to the oncological treatment of
gynecological malignancies (ovarian,
uterine and cervical cancers). Over 3,000
chemotherapies and 3,801 oncological
visits have been done. Most part of
treatments are performed in an outdoor
setting. The unit is considered in Italy
and abroad as a referral center for
second opinion in the medical treatment
of gynecological malignancies.
Innovative strategies of care have been
implemented, such as neoadjuvant dose
dense chemotherapy in locally advanced
cervical cancer and antiangiogenic
therapies.
Evaluation of innovative treatment in
ovarian cancer represents the principal
area of our research; some of the
results were presented last year at
ASCO during the plenary gynecological
cancer session, addressing the
role of antiangiogenic agents in
endometrial cancer. Twenty-seven
scientific papers have been published
in 2015 in peer-reviewed journals.
Four monographic courses on the
treatment of gynecological malignancies
for specialists, one course on the
methodology of clinical trials, a 2-days
precepthorship in gynecology oncology
and three courses on gynecological
malignancies for general practitioner
physicians were performed in 2015. All
these events, received ECM credits.
The Unit is an active member of the
SIOG (Italian Society of Gynaecological
Oncology), the national society of
gynecologist oncologists, with two
members of the Unit being part of its
Board.
GYNECOLOGIC
94
Keywords
Gynecologic surgery,
oncology, clinical trials
Bogani G, Chiappa V, Lorusso D, Raspagliesi F. Treatment of Recurrent
Endometrial Carcinoma: Progress Toward a More Personalized
Approach. J Clin Oncol. 2015 Oct 20;33(30):3516
Ditto A, Martinelli F, Bogani G, Lorusso D, Carcangiu M, Chiappa V, Reato
C, Donfrancesco C, De Carrillo KJ, Raspagliesi F. Long-term safety of fertility sparing
surgery in early stage ovarian cancer: comparison to standard radical surgical
procedures. Gynecol Oncol. 2015 Jul;138(1):78-82
Papadia A, Bellati F, Ditto A, Bogani G, Gasparri ML, Di Donato V, Martinelli F, Lorusso
D, Benedetti-Panici P, Raspagliesi F. Surgical Treatment of Recurrent Endometrial
Cancer: Time for a Paradigm Shift. Ann Surg Oncol. 2015 Dec;22(13):4204-10
Pignata S, Lorusso D, Scambia G, Sambataro D, Tamberi S, Cinieri S, Mosconi AM,
Orditura M, Brandes AA, Arcangeli V, Panici PB, Pisano C, Cecere SC, Di Napoli M,
Raspagliesi F, Maltese G, Salutari V, Ricci C, Daniele G, Piccirillo MC, Di Maio M,
Gallo C, Perrone F; MITO 11 investigators. Pazopanib plus weekly paclitaxel versus
weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced
ovarian cancer (MITO 11): a randomised, open-label, phase 2 trial. Lancet Oncol. 2015
May;16(5):561-8
Staff
HEAD
Francesco Raspagliesi, MD
Pignata S, Scambia G, Katsaros D, Gallo C, Pujade-Lauraine E, De Placido S, Bologna
A, Weber B, Raspagliesi F, Panici PB, Cormio G, Sorio R, Cavazzini MG, Ferrandina G,
Breda E, Murgia V, Sacco C, Cinieri S, Salutari V, Ricci C, Pisano C, Greggi S, Lauria R,
Lorusso D, Marchetti C, Selvaggi L, Signoriello S, Piccirillo MC, Di Maio M, Perrone F;
Multicentre Italian Trials in Ovarian cancer (MITO-7); Groupe d’Investigateurs Nationaux
pour l’Etude des Cancers Ovariens et du sein (GINECO); Mario Negri Gynecologic Oncology
(MaNGO); European Network of Gynaecological Oncological Trial Groups (ENGOT-OV-10);
Gynecologic Cancer InterGroup (GCIG) Investigators. Carboplatin plus paclitaxel once
a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a
randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2014 Apr;15(4):396405
Giorgio Bogani, MD; Valentina Chiappa, MD;
Antonino Ditto, MD; Domenica Lorusso, MD;
Fabio Martinelli,MD; Marina Merola, MD; Mauro
Signorelli, MD; Flavia Zanaboni, MD
RESIDENTS
Cristina Donfrancesco, Francesca Lecce, Ilaria
Sabatucci
RESEARCH STAFF
Stefano Lepori, MD; Giuseppa Maltese, MD;
Stefania Perotto, MD; Dario Recalcati, MD; Cono
Scaffa, MD
Gabriele Cantini, Cinzia Marretta, Dominique
Ronzulli, Rosella Zennoni
NURSES
Patricia Acosta Rojas, Placida Battaglia,
Marcantonio Boccola, Michele Capobianco,
Teresa D’Antonio, Pamela De Carolis, Eleonora
Ferrini, Lorenzina Greco, Eva Guitti, Stefania
Maria Labori, Luisa Mancini, Antonio Micello,
Marianna Miranda, Federica Pes, Ylenia Ponti,
Paolo Re, Maria Saracino, Viviana Villa
OF THE UNIT
22
PUBLICATIONS
119.529
IMPACT FACTOR
15
53.235
C ONCOLOGY
Roberta Allenza, Sonia Donata Altieri, Leni
Natalia Munante Valdez, Cecilia Lorena
Muzzupappa, Laura Rapone, Guglielmina Riccio,
Laura Somma, Franca Tancredi
1-29, 8
95
THORACIC SURGERY
UGO PASTORINO, Head of the Unit
Clinical activity
Research activity
Networking
Thoracic Surgery Unit is
characterized by minimally
invasive approaches, complex
surgical procedures with
organ replacement and reconstruction,
involving different surgical specialists,
multidisciplinary therapeutic selection,
scientific research on early lung cancer
detection, and continuous education.
bioMILD trial: Plasma
microRNA profiling as first
line screening test for lung cancer
detection: a prospective study.
Passtrial: a multicentric
randomized clinical
trial is ongoing to
evaluate the results of pleurectomy/
decortication after chemotherapy versus
chemotherapy in malignant pleural
mesothelioma.
Clinical activity is focused on pulmonary,
mediastinal, chest wall and esophageal
tumors. Considering primary lung
cancers, the mainstay of treatment is
lobectomy or segmentectomy by 3D
VATS in over 50% of cases, to reduce
postoperative pain, complications
and hospital stay. For locallyadvanced lung tumors, lung-sparing
procedures (bronchoplasty and/
or angioplasty) are adopted to avoid
the removal of the entire lung. In the
domain of secondary lung tumors,
the Thoracic Surgery Unit cooperates
with different INT Units (Medical and
Pediatric Oncology, Sarcoma Unit),
performing metastasectomy by
parenchyma-sparing procedures. In
the context of chest wall tumors, an
innovative technique for tridimensional
reconstruction (“rib-like” technique) have
been successfully employed in almost
100 patients, allowing optimal functional
results even in case of entire removal of
chest and lung. Considering malignant
pleural mesothelioma, a multicentric
randomized clinical trial (PASS trial)
is ongoing to evaluate the results
of pleurectomy/decortication after
chemotherapy versus chemotherapy
alone. Esophageal surgery is also
performed with a 3D VATS approach.
In March 2013 we launched a large
scale prospective study (phase 4
according to guidelines of biomarkers
development) to test the efficiency of a
combined LDCT-MSC approach as firstline screening tests in a large cohort of
4,000 smokers, 50 yrs or older. In the
study design, the combination of the
results of these two tests determine
the subsequent diagnostic route. Status
update of the trial was: total registered
9,236, enrolled 4,300, eligibile subjects
5,772. We successfully completed
at the end of 2015 the accrual and
executed baseline LDCT-MSC analyses
of 4,119 subjects thus respecting the
time line of the project. Overall 6,800
MSC tests (including baseline, repetion
for technical issues i.e.hemolysis
and recalls) and 5,922 LDCT analyses
(baseline and recalls) were performed.
Mean age of the 4,119 accrued subjects
is 60 years, with 2,503 males and 1,616
females. 3,261 of the subjects are active
smokers, 858 former-smokers. Average
pack-years for smokers is 46 p/y.
Fourteen Italian Institutes participate to
this study: San Luigi Orbassano, Torino;
Fondazione IRCCS Ospedale Maggiore
Policlinico, Ospedale Fatebenefratelli e
Oftalmico, Ospedale San Paolo, Ospedale
Niguarda, Milano; Azienda USL Piacenza;
Ospedale Centrale di Bolzano; A.O.
Nazionale SS. Antonio e Biagio e Cesare
Arrigo, Alessandria; A.O. Papa Giovanni
XXIII, Humanitas Gavazzeni, Bergamo;
Fondazione IRCCS San Matteo, Pavia;
Azienda U.L.S.S. n. 21, Legnano (VR);
P.O.V. Cervello, Palermo; Santa Maria
della Misericordia Perugia.
Statistical analyses of the results of this
trial will be concluded within 2018, with
a minimum follow up time of 3 years for
all the 4,119 subjects and will include
evaluation of sensitivity/specificity/
Negative Predictive Value (NPV)/Positive
Predictive Value (PPV)/false positive
rate of MSC alone, LDCT alone and their
combination as well as association with
all clinico-pathological parameters
(tumor type, stage, mortality rate).
THORACIC SU
96
Keywords
3D VATS,
lung-sparing procedures,
metastasectomy,
tridimensional reconstruction,
multidisciplinary approach,
lung cancer early detection
and prevention,
translational research
Pelosi G, Fabbri A, Tamborini E, Perrone F, Testi AM, Settanni G, Busico
A, Centonze G, Braidotti P, Bulfamante G, De Braud F, Garassino M,
Pastorino U. Challenging Lung Carcinoma with Coexistent ΔNp63/p40
and Thyroid Transcription Factor-1 Labeling Within the Same Individual
Tumor Cells. J Thorac Oncol. 2015 Oct;10(10):1500-2
Pelosi G, Fabbri A, Papotti M, Rossi G, Cavazza A, Righi L, Tamborini E, Perrone F,
Settanni G, Busico A, Testi MA, Maisonneuve P, De Braud F, Garassino M, Valeri B,
Sonzogni A, Pastorino U. Dissecting Pulmonary Large-Cell Carcinoma by Targeted
Next Generation Sequencing of Several Cancer Genes Pushes Genotypic-Phenotypic
Correlations to Emerge. J Thorac Oncol. 2015 Nov;10(11):1560-9
Pastorino U, Duranti L, Scanagatta P, Leo F, Piccioni F, Collini P, Gronchi A.
Thoracopleuropneumonectomy with Riblike Reconstruction for Recurrent Thoracic
Sarcomas. Ann Surg Oncol. 2014 Jan 24
Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, Bravi F, Roz L, Conte D, Grassi M,
Sverzellati N, Marchiano A, Negri E, La Vecchia C, Pastorino U. Clinical Utility of a
Plasma-Based miRNA Signature Classifier Within Computed Tomography Lung Cancer
Screening: A Correlative MILD Trial Study. J Clin Oncol. 2014 Mar 10;32(8):768-73
Duranti L, Gronchi A, Stacchiotti S, Fiore M, Casali PG, Collini P, Pelosi G, Galeone C,
Pastorino U. Localised thoracic sarcomas: Outcome improvement over time at a
single institution. Eur J Cancer. 2013 May 14
Staff
HEAD
Ugo Pastorino, MD
Leonardo Duranti, MD; Paolo Nicola Camillo
Girotti, MD; Mara Gisabella, MD; Giovanni Leuzzi,
MD; Paolo Scanagatta, MD; Luca Domenico
Tavecchio, MD
RESIDENTS
Alessandra Mazzucco, MD; Luigi Rolli, MD
RESEARCH STAFF
Giuseppe Garofalo, MD; Lara Girelli, MD; Stefano
Sestini, MD; Paola Suatoni, Biol Sci D
OF THE UNIT
Tiziana Negri
Research Projects area: Elena Bertocchi
(coordinator), Gaia Ancona, Chiara Banfi,
Annamaria Calanca, Claudio Citterio, Claudio
Jacomelli, Carolina Ninni
24
NURSES
Federica Pirovano (charge nurse), Brice Marcial
Atiomeguim, Francesco Auletta, Marcella
Bernardo, Claudia Costa, Antonino De Vita,
Raffaele Di Nino, Margherita Fersurella, Viviana
Liccardo, Daniele Marino, Hilda Aliaga Martinez,
Anna Maria Panareo, Antonio Carmelo Pantano,
Antonella Prete, Maria Luisa Quitadamo
URGERY
Angela Di Luglio, Nekpen Eguavoen, Gloria
Veronica Nunez Barros, Svitlana Shulzhenko,
Maria Grazia Sonzini, Pamela Karolina Soto
Fernandez
PUBLICATIONS
125.912
IMPACT FACTOR
11
26.667
1-52, 5
97
UROLOGIC SURGERY
ROBERTO SALVIONI, Head of the Unit
Clinical activity
Research activity
Networking
Multidisciplinary urological
cancer management is our best
focus.
During 2015, we participated
in several international trials
of immunotherapy and/or targeted
therapies in urothelial carcinoma,
testicular cancer and penile squamous
cell carcinoma. As regards urothelial
cancer, some of these phase II and III
trials are likely to provide breakthrough
changes in the therapeutic landscape
(see publications attached). We have
been frontline center in developing
a number of immune checkpoint
inhibitors in bladder cancer, including
atezolizumab, pembrolizumab,
nivolumab, durvalumab, avelumab,
either alone or in combination with
other immunotherapeutic compounds or
chemotherapy and radiation. Multimodal
management of urothelial cancer and
the development of new drugs in this
disease do represent two strategic
research topics of the Fondazione.
We strengthened
our commitment in
collaborating with the
Italian Rare Cancer Network, and we
developed important collaborations
with the European Cancer Patient
Coalition with the aim of promoting a
bladder cancer patient awareness in the
European framework. We have achieved
important collaborative publications on
multicenter international retrospective
studies in rare tumors like the teratoma
with malignant transformation.
The Urologic Oncology Unit
is one of the largest in the Italy, with
special surgical expertise in testicular
and penile cancers. A multidisciplinary
group constitutes the clinical faculty,
which includes urologists and medical
oncologists working together in the
same Department. Another topic that
is being strengthened in our Unit is the
minimally-invasive surgical approach
as well as non-surgical techniques
like cryoablation for localized renal
masses. Finally, we have pursued the
development of the Italian bladder
cancer patient advocacy group PaLiNUro
(Pazienti Liberi dalle Neoplasie
Uroteliali).
In parallel, we are pursuing the
sponsorship of a number of academic
studies for the above neoplasms,
coupled with international retrospective
studies, mainly in rare genitourinary
diseases, as it is indicated in the
references as well. A growing
commitment in collaborating with the
biostatisticians of the Fondazione INT is
pursued.
UROLOGIC SU
98
Keywords
Multidisciplinary approach,
peri-operative therapy,
urothelial Carcinoma,
testicular cancer, penile cancer,
renal cell cancer, prostate cancer
Necchi A, Mariani L, Di Nicola M, et al. High-dose sequential
chemotherapy (HDS) versus PEB chemotherapy as first-line treatment
of patients with poor prognosis germ-cell tumors: mature results of an
Italian randomized phase II study. Ann Oncol 2015;26:167-72
Necchi A, Nicolai N, Mariani L. Modified cisplatin, etoposide, and ifosfamide (PEI)
salvage therapy for male germ-cell tumors. Long-term efficacy and safety outcomes.
Ann Oncol 2013 Jul 16
Nicolai N, Bianchi E, Donati I, L’Acqua C, Brunelli C, Biasoni D, Catanzaro M, Stagni
S, Piva L, Torelli T, Necchi A, Raggi D, Giannatempo P, Faré E, Colecchia M, Langer
M, Borreani C, Salvioni R. Quality of life and pain control following laparoscopic
retroperitoneal lymph node dissection in early-stage nonseminoma. Tumori. 2015
Nov-Dec;101(6):650-6
Raggi D, Mariani L, Giannatempo P, Lo Vullo S, Giardiello D, Nicolai N, Piva L, Biasoni
D, Catanzaro M, Torelli T, Stagni S, Maffezzini M, Calareso G, Magni M, Di Nicola
M, Verzoni E, Grassi P, Procopio G, De Braud F, Pizzocaro G, Salvioni R, Necchi A.
Prognostic reclassification of patients with intermediate-risk metastatic germ cell
tumors: Implications for clinical practice, trial design, and molecular interrogation.
Urol Oncol. 2015 Jul;33(7):332.e19-24
Nicolai N, Necchi A, Raggi D, Biasoni D, Catanzaro M, Piva L, Stagni S, Maffezzini M,
Torelli T, Faré E, Giannatempo P, Pizzocaro G, Colecchia M, Salvioni R. Clinical outcome
in testicular sex cord stromal tumors: testis sparing vs. radical orchiectomy and
management of advanced disease. Urology. 2015 Feb;85(2):402-6
Staff
HEAD
Roberto Salvioni, MD
Nicola Nicolai, MD (Testicular Surgery, Director),
Davide Biasoni, MD; Mario Achille Catanzaro, MD;
Massimo Maffezzini, MD; Silvia Stagni, MD; Tullio
Torelli, MD
RESIDENTS
Lorenzo Angelini, MD; Francesco Cattaneo, MD;
Alberto De Gobbi, MD
TECHNICIANS
Elena Cristiani, Isabella Vurchio
Maria Giovanna Bodini
NURSES
Rosa Anna Candigliota, Maria Lucia Cennamo,
Anna Maria Cercaci, Zino Ferro, Jessica Gualtieri,
Francesca Marelli, Lucia Mesiano, Arturo
Monetta, Valentina Musarò, Giuseppa Napoli,
Veronica Patricia Rojas, Raffaella Rossi, Graziella
Russo, Rita Sciancalepore, Annalisa Simone
URGERY
Rocio Del Pilar De La Cruz Velesmoro, Olimpia
Liberatore, Anna Mastroianni
OF THE UNIT
17
PUBLICATIONS
69.030
IMPACT FACTOR
9
21.695
5-23, 9
99
LASER THERAPY
ANNA COLOMBETTI, Head of the Unit
Clinical activity
Research activity
Networking
The Unit features 5 lasers for
a total of 23 wavelengths,
allowing for both conservative
and ablative therapies. Selective
photothermolysis laser treatment
is performed for keloids, pigmented
and vascular lesions; laser ablation
technique is used for mucosal and skin
cancers lesions requiring histological
evaluation.
The Laser Therapy
Unit is considered the
national reference center for
neurofibromas and cafe-au-lait spots in
Neurofibromatosis disease (NF1).
Our approach is
multidisciplinary, and
patient cares are performed
in collaboration with the Human
Genetics Institute of IRCCS Policlinico
of Milan, the “C. Besta” neurological
institute of Milan and the Vascular
Surgery Unit of IRCCS “G.Gaslini” of
Genoa
We have developed an intralesional
innovative technique to treat selected
vascular lesions and giant nevi.
Our clinical activity is mainly focused on
the following conditions:
Tumor lesions: melanoma in-transit
metastases in patient not eligible to
other therapy,cutaneous and mucosal
localizations of Kaposi’s sarcoma,skin
carcinomas of critical anatomical areas
as eyelids,nostrils and ear,precancerous
lesions such as actinic keratosis.
Keywords
Laser, skin cancer,
neurofibromatosis,
angiodysplasia,
giant melanocytic nevi
Vascular lesions: flat-type congenital
capillary angiodysplasia, angiomas,and
venous lymphatic angiodysplasia.
Nevi: giant melanocytic nevi.
Traumatic and post-burn hypertrophic
scars and keloids, radiodermatitis: in
addition to laser therapy we associate in
particular cases the lipofilling technique
with implant of adipose tissue, to restore
skin trophism and volume.
Cutaneous localizations originating
from complex syndromes, such as
adenomas in tuberous sclerosis,
angiodysplasias related to S turgeWeber syndrome.
During 2015, about 2,000 patients were
treated with laser therapy, more then
1,500 of which were in an ambulatory
setting.
LASER
THERAPY
The pediatric patients were treated
with laser procedures under general
anesthesia.
Staff
HEAD
Anna Colombetti, MD
RESEARCH STAFF
Federica Brenta, MD; Mario Zeno Raso, MD
Maria Rosaria Aceto
NURSES
Emilia D’Arrigo
Domenica Giuseppina Loprete
100
OF THE UNIT
2-2, 2
DAY SURGERY
ALDO BONO, Head of the Unit
Clinical activity
Research activity
Keywords
The Day Surgery Unit is
devoted to surgical procedures
performed in ambulatory and
Day Hospital settings. The unit
includes 10 beds, 2 operating rooms
for general surgical activities, and
one operating room for laser surgery.
Surgical activity deals with different
lesions involving skin, soft tissues,
breast, as well lesions in gynecologic,
urologic, and head and neck areas.
During the year 2015, 5,537 surgical
procedures were per formed. Of
these, 2,040 were performed in a Day
Hospital setting, and 3497 patients
underwent outpatient surgery. Besides
normal surgical activity, specialized
procedures were performed such as
electrochemotherapy of secondary skin
tumors (in collaboration with Melanoma
and Sarcoma Unit) and fat injection
or lipostructure with the Coleman
technique to lessen local skin and subcutaneous damage (in collaboration with
Plastic and Reconstructive Unit).
Clinical research activity is,
at present, mainly performed in
cooperation with the Melanoma and
Sarcoma Unit. The aim of this activity
is to better define the initial clinical
features of early melanoma to bring
about curative surgery. In particular,
many studies have been performed
on the following topics: melanoma
in situ, small melanoma, childhood
m elanoma, amelanotic melanoma,
horizontal growth phase melanoma,
nodular melanoma, spectrophotometry
of melanoma, automated computerized
diagnosis of melanoma. Recently,
we have developed the concept of
micro-melanoma: a melanoma with a
diameter equal to or less than 3 mm.
The detection of these small lesions
is important as, although close to the
limit of clinical relevance, they are “de
facto” malignant. A further scientific
cooperation is currently ongoing with
the Unit of Immunotherapy of Human
Tumors, dealing, in particular, with blood
measurements of circulating miRNA in
patients bearing cutaneous melanoma.
Outpatient surgery, early
melanoma, small melanoma
Staff
HEAD
Aldo E. Bono, MD
RESEARCH STAFF
Biancamaria Scoppio, MD
Maria Rosa Bignamini, Loredana Orezzi, Anna
Corella
NURSES
Giovanna R. Colaci, Roberta Colombo, Francesco
Filippazzo, Mariangela Lena, Pina P. Mele,
Domenica R. Violi, Marina A. Zocchi
Antonella Bordoni, Rosa Selvati, Silvia Cara
DAY
SURGERY
1. Ferrari A, Bisogno G, Cecchetto G, Santinami M, Maurichi A, Bono
A, Vajna De Pava M, Pierani P, Bertolini P, Rossi CR, De Salvo GL.
Cutaneous melanoma in children and adolescents: The Italian rare
tumors in pediatric age project experience. Journal Of Pediatrics
2014;164:376-820
OF THE UNIT
21-21, 21
101
MEDICAL ONCOLOGY
FILIPPO DE BRAUD
filippo.debraud@istitutotumori.mi.it
MEDICAL ONCOLOGY 1
FILIPPO DE BRAUD
ADULT MESENCHYMAL TUMOR
MEDICAL ONCOLOGY 2
PAOLO G. CASALI
The Medical Oncology Department
comprises various clinical medical
units and one centralized day hospital;
outpatients visits are performed in
dedicated rooms.
The Department is organized in the
following Units:
MEDICAL
ONCOLOGY
HEAD AND NECK CANCER
MEDICAL ONCOLOGY 3
LISA LICITRA
T
he Department provides for
comprehensive cancer treatments
in adults with solid tumors and
performs research focusing on new drug
development and treatment strategies.
Opportunities are maximized for interdepartmental and inter-institutional
collaborations to ensure the forefront of
patient care and oncology research.
CARDIOLOGY
PATRIZIA PIOTTI
MEDICAL DAY HOSPITAL
ROBERTO BUZZONI
RESPIRATORY PATHOPHYSIOLOGY
ROBERTO BOFFI
Medical Oncology 1: new drugs
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, prostatic, bladder,
testis and penis cancer), solid tumors
immunotherapy.
Adult Mesenchymal Tumor Medical
Oncology 2: clinical research and care in
sarcomas and peritoneal mesothelioma.
Head and Neck Cancer Medical Oncology
3: clinical research and care in cancer,
thyroid and salivary glands cancer.
Cardiology: evaluation of patients
addressed to surgery and medical
treatments. Follow up of cardiovascular
toxicities due to antineoplastic
treatments.
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,
genitourinary tumors).
New generation targeted therapy
and immunotherapy for malignant
melanoma, lung cancer, gastrointestinal
tumors, prostate cancer, breast cancer
and neuroendocrine tumors.
Cardiologic surveillance to assess the
cardiotoxicity of new experimental
drugs (monoclonal antibodies, receptor
tyrosine kinase inhibitors, BRAF
inhibitors, MEK inhibitors).
Research interest focused on electronic
cigarettes and their health effects
in terms of second-hand exposure
and concerning the physiological
consequences of the “rib-like” technique,
a semi-rigid tridimensional prosthesis
reproducing the shape of native ribs for
sarcoma patients.
INT is certified as a Center of
Excellence by the European Society of
Neuroendocrine Tumors (ENET).
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.
Respiratory Pathophysiology: evaluation
of patients addressed to surgery,
and medical treatments; follow up of
pulmonary toxicities due to chemoradiotherapy; hospital-based tobacco
control policies as well as outpatient and
inpatient smoking cessation clinic.
103
MEDICAL ONCOLOGY 1
FILIPPO DE BRAUD, Head of the Unit
Clinical activity
Research activity
Networking
Our mission is to improve
clinical care and outcomes of
medical treatment of cancer
through multidisciplinary
management, personalized medicine
and development of new drugs and
strategies by the Units fully dedicated
to lung cancer, mesothelioma and
thimoma, gastrointestinal tract cancers,
genitourinary tumors, melanoma and
breast cancer. Major areas of interest
are:
We develop treatments using
new molecular compounds,
and investigate new therapeutic
strategies, with particular attention to
the immune system, for solid tumors.
This is carried out by a Unit fully
dedicated to new drug development
(phase I and Ib studies) and promotion
of translational research projects, as
well as conducting non sponsored and
sponsored phase II/III trials. The Unit is
strictly connected to a well-equipped
preclinical laboratory focused on
translational medicine to test novel
therapeutic approaches.
The Unit, collaborating
with ROL (Rete Oncologica
Lombarda) accomplished a
the update of the National guidelines for
melanoma, kidney, prostate and gastric
cancer.
New drugs development (phase I and Ib
studies) and promotion of translational
research projects.
Translational research on prognostic
and/or predictive biomarkers in
most solid tumors (upper and lower
gastrointestinal tracts, non-small
cell lung cancer, malignant pleural
mesothelioma and thymoma, melanoma,
genitourinary tumors).
In 2015, 54 trials were activated: 3,081
new patients were visited and 1,095
entered into clinical trials.
High-dose chemotherapy supported
by autologous hematopoietic stem cell
transplant in testicular cancer.
The facilities available at Medical
Oncology include a 28-bed inpatient
ward, a day hospital area, 10 consulting
rooms, and 2 research laboratories for
pharmacokinetic, pharmacodynamic,
and preclinical studies. A Clinical
Research Team is fully dedicated to
Phase I studies in solid tumors.
The Lung team signed a consortium
agreement with the University of Ulm,
the University of Athens and the Istituto
Regina Elena to work on KRAS and
DNA repair (Transcan) A long-standing
collaboration is still ongoing with the
Breast Cancer Working Group of the
Michelangelo Foundation, aimed to
conduct Phase II/III trials in breast
cancer, and with WIN (Worldwide
Innovative Networking) with the aim to
conduct studies in personalized cancer
medicine.
TYME is a dedicated network for thymic
malignancies. The network is working
with referral centers in Italy and it is
creating a common database, linked
with italian registries and with other
networks such as Rythic in France.
Adjuvant systemic treatments of breast
cancer: identification and selection
of subsets of patients to be treated
differently according to the molecular
profile of their disease.
Active involvement in research on
antiemetic drugs.
The Unit is part of NIBIT (Network
Italiano per la Bioterapia dei Tumori)
for the application of nationwide
immunotherapy studies and for
educational activities.
Staff
HEAD
Filippo Guglielmo de Braud,
MD, Full Professor
PERMANENT CLINICAL RESEARCH STAFF
MEDICAL DOCTORS (MD)
Massimo Antonio Di Nicola, (Immunotherapy
and New Treatments in Medical Oncology,
Director); Marina Chiara Garassino, (Thoracic
Medical Oncology, Director); Giuseppe Procopio,
(Urogenital Medical Oncology, Director); Giulia
Valeria Bianchi; Giuseppe Capri; Luigi Celio;
Sara Cresta; Michele Del Vecchio; Maria Di
Bartolomeo; Serena Di Cosimo; Michele Magni;
Gabriella Mariani; Andrea Necchi; Marco Platania;
Sara Pusceddu; Elena Verzoni; Nicoletta Zilembo
BIOLOGIST (BIOL. SCI. D.)
Antonia Martinetti
Maria Agnese Di Sarno, Gerardo Esposito, , Sara
Pastor Manosa, Vincenzo Scarascia, Cristina
Tamburelli, Anna Tamburro
Naziriet Asfaha Zere, Oliviero Bertanzetti, Ana
Maria Farcas, Rivelino Walter Nava Bello, Maria
Bernardina Reyes Olivas
Barbara Formisano, Giuseppa Iannaci
RESEARCH STAFF ON GRANT
Francesco Agustoni; Rosa Berenato; Marta
Caporale; Giulia Carlo Stella; Carolina
Cimminiello, MD; Silvia Damian; Lorenza Alessia
Di Guardo; Katia Fiorella Dotti; Matteo Duca;
Benvenuto Ferrari; Francesco Gelsomino; Patrizia
Giannatempo; Paolo Grassi; Giuseppe Lo Russo;
Marianna Macerelli; Paola Mariani; Federica
Morano; Filippo Pietrantonio; Claudia Proto;
Lorenzo Sica; Diego Signorelli; Milena Vitali
MEDICAL ONC
RESEARCH NURSES
Benedetta Bardazza; Alessandra Castano
NURSES
Filomena Lavecchia (Coordinator) Carlos Ivan
Angeles Valdez, Arianna Bolis, Elvira Bressanelli,
Marisa Caggegi, Laura Castellon Duque, Doris
Cesareo, Angela De Leone, Ilenia De Quattro,
104
BIOLOGISTS (BIOL. SCI. D.)
Monica Ganzinelli; Roberta Mennitto; Anna
Rossini; Giusi Ruggiero; Elisa Sottotetti
Keywords
New drugs,
clinical research,
translational research
Larkin J, Del Vecchio M, Ascierto PA, Krajsova I, Schachter J, Neyns B,
Espinosa E, Garbe C, Sileni VC, Gogas H, Miller WH Jr, Mandalà M, Hospers
GA, Arance A, Queirolo P, Hauschild A, Brown MP, Mitchell L, Veronese L,
Blank CU. Vemurafenib in patients with BRAF(V600) mutated metastatic
melanoma: an open-label, multicentre, safety study. Lancet Oncol. 2014 Apr;15(4):43644
Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini
J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F; PROFILE 1014 Investigators.
First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med.
2014 Dec 4;371(23):2167-77
Brahmer J1, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S,
Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O,
Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C,
Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced SquamousCell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS,
Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F,
Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin
J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators.
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015
Nov 5;373(19):1803-13
Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N,
Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M,
Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi
H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for
refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19
RESEARCH NURSES
Gloria Colangelo, Edoardo Tulli Baldoin
NURSES
Jennifer Avenido, Alessandro Lorenzo
DATA MANAGERS (BIOL. SCI. D.)
Valentina Sinno (Coordinator); Liana Bevilacqua;
Ilaria Bossi; Angela Brissa; Nicola Di Genova;
Rosaria Gallucci; Silvia Sesana; Margherita
Sorrentino; Eleonora Sparacio; Claudia Stefanetti;
Irene Vetrano
Paola Bignotti, Anna Dentico, Maria Teresa
Lorella Garanzelli, Carla Ghisani, Concetta
Iannucci, Susanna Maggi, Katya Mantoan, Silvia
Merlo
RESIDENTS STAFF
COLOGY
Stefano Cavalieri; Maria Silvia Cona; Elena Farè;
Giovanni Fucà; Giulia Galli; Martina Imbimbo;
Claudia Maggi; Alessia Mennitto; Monica Niger;
Giorgia Peverelli; Michele Prisciandaro; Daniele
Raggi; Alessandra Raimondi; Raffaele Ratta;
Claudio Vernieri
OF THE UNIT
111
PUBLICATIONS
797.302
IMPACT FACTOR
57
246.896
1-45, 7
105
ADULT MESENCHYMAL TUMOR
MEDICAL ONCOLOGY 2
PAOLO G. CASALI, Head of the Unit
Clinical activity
Research activity
Networking
The Adult mesenchymal tumor
& Rare cancer Medical Oncology
Unit deals with adult patients
with soft tissue and bone
sarcomas and peritoneal mesothelioma.
It operates within the institutional
multidisciplinary Sarcoma Tumor Board.
The Unit is involved in
updating the European Society
for Medical Oncology (ESMO)
Clinical Practice Guidelines on soft
tissue (STS) and bone sarcomas, and
Gastrointestinal Stromal Tumors (GIST).
The Unit carries out, or participates in,
institutional research projects, national
and international clinical trials, both
industry-sponsored and investigatordriven. Overall, in 2015 the Unit
participated in 33 clinical studies with 42
patients enrolled.
- The Unit coordinates the
Italian Network on Rare
Cancers (RTR), a project
aimed at distantly sharing cases of
adult patients with rare solid cancers
to improve quality of care and reduce
patient migration.
Institutional facilities include a 6-bed
inpatient ward, a day-hospital area, 3
outpatient rooms.
In 2015, the Unit carried out:
- 4,164 outpatient visits (771 first
consultations and 3,393 visits on
patients on treatment or follow-up)
- 394 admitted patients
- about 800 consultations on new cases
were clinically shared with other Italian
centers within the Italian Network on
Rare Cancers.
The Unit collaborates with different
Patient Advocacy groups (AIG,
Chordoma Foundation, LAM, Epitheliod
Hemangioendothelioma Edvocacy
Group)
- World Sarcoma Network
- euroSARC (European Clinical Trials in
rare Sarcomas within an integrated
Translational Trial Network)
The Unit keeps a strong focus on:
- translational research on prognostic
and/or predictive biomarkers in STS,
GIST, rare bone tumors (chordoma,
giant cell tumor), mesenchymal locally
aggressive tumor (desmoids, giant
cell tumor of the tendon sheats/
PVNS, LAM), and malignant peritoneal
mesothelioma;
- targeted therapy for STS, GIST, rare
bone tumors (chordoma, giant cell
tumor);
- histology-driven medical therapy
of soft tissue sarcomas, both in the
neoadjuvant and in advanced setting;
- development of new cell lines and
xenograft models of selected sarcoma
subtypes to investigate the differential
activity of new and old drugs and
mechanisms for response;
- improve the knowledge of the natural
history and biology of each sarcoma
subtype integrating clinical data
and molecular analysis/integrated
genomics approach.
ADULT MESEN
TUMOR MEDI
106
Keywords
Sarcoma,
rare tumors, translational
research, methodology
Stacchiotti S and Sommer J, on behalf of a Chordoma global consensus
group. Building a global consensus approach to chordoma: a position
paper from the medical and patient community. Lancet Oncol 2015, 16:7183.
alassini E, Ferrari S, Verderio P, De Paoli A, Martin Broto J, Quagliuolo V, Comandone
P
A, Sangalli C, Palmerini E, Lopez-Pousa A, De Sanctis R, Bottelli S, Libertini M, Picci
P, Casali PG, Gronchi A. Feasibility of Preoperative Chemotherapy With or Without
Radiation Therapy in Localized Soft Tissue Sarcomas of Limbs and Superficial Trunk in
the Italian Sarcoma Group/Grupo Español de Investigación en Sarcomas Randomized
Clinical Trial: Three Versus Five Cycles of Full-Dose Epirubicin Plus Ifosfamide. J Clin
Oncol. 2015 Nov 1;33(31):3628-34
Casali PG, Le Cesne A, Poveda Velasco A, Kotasek D, Rutkowski P, Hohenberger P,
Fumagalli E, Judson IR, Italiano A, Gelderblom H, Adenis A, Hartmann JT, Duffaud F,
Goldstein D, Broto JM, Gronchi A, Dei Tos AP, Marréaud S, van der Graaf WT, Zalcberg
JR, Litière S, Blay JY. Time to Definitive Failure to the First Tyrosine Kinase Inhibitor
in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European
Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma
Group Intergroup Randomized Trial in Collaboration With the Australasian GastroIntestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group,
and Spanish Group for Research on Sarcomas. J Clin Oncol. 2015; 33:4276-83
Stacchiotti S, Tortoreto M, Baldi GG, Grignani G, Toss A, Badalamenti G, Cominetti D,
Morosi C, Dei Tos AP, Festinese F, Fumagalli E, Provenzano S, Gronchi A, Pennacchioli
E, Negri T, Dagrada GP, Spagnuolo RD, Pilotti S, Casali PG, Zaffaroni N. Preclinical and
clinical evidence of activity of pazopanib in solitary fibrous tumour. Eur J Cancer. 2014;
50:3021-8
Staff
Stacchiotti S, Pantaleo MA, Astolfi A, Dagrada GP, Negri T, Dei Tos AP, Indio V, Morosi
C, Gronchi A, Colombo C, Conca E, Toffolatti L, Tazzari M, Crippa F, Maestro R, Pilotti S,
Casali PG. Activity of sunitinib in extraskeletal myxoid chondrosarcoma. Eur J Cancer.
2014; 50:1657-64
HEAD
Paolo G. Casali, MD
Rossella M. Bertulli, MD; Elena Palassini, MD;
Silvia Stacchiotti, MD
RESIDENTS
Salvatore Provenzano, MD
RESEARCH STAFF
Vittoria Colia, MD; Elena R. Fumagalli, MD;
Michela Libertini, MD; Giovanna R. Sanfilippo, MD
OF THE UNIT
32
NCHYMAL
ICAL ONCOLOG
DATA MANAGERS
Federica Favales, Paola Pistillo, Chiara Villa
Anabela Di Giovanni, Elisabetta Prati
NURSES
Roberta Albasini, Rosa Vita Attolino, Luigia Cerra,
Ilaria Serafina Chiofalo, Cinzia Concetta Cocca,
Giuseppe L’Abbate, Antonio Lucenti, Filippo
Monno, Erminia Nardo, Vincenza Natola, Ilenia
Nigro, Elena Maria Omati, Michela Saracino,
Fabio Scoletta, Luigi Tamburrino, Gianni Nicola
Virgilio, Patrizia Galantin
Angela Abatangelo, Rosa Maria Farro Alvarez,
Brenilda Marlene Fuentes Delgado, Giuseppe
Gaglio, Virginia Marini, Fabrizio D’Amico
PUBLICATIONS
207.472
IMPACT FACTOR
12
94.645
2-58, 17
107
HEAD AND NECK CANCER
MEDICAL ONCOLOGY 3
LISA LICITRA, Head of the Unit
Clinical activity
Research activity
Staff
The Unit offers to head and
neck cancer patients the
most appropriate diagnostic,
treatment and care path
characterized by multidisciplinarity and
latest evidence. Although this pathology
is defined as “rare”, we are actively
involved in several research protocols at
national and international levels which
enables patients to have access to the
best treatment available and to the most
innovative drugs for their disease type.
The Head and Neck Medical
Oncology Unit has been
involved in 47 trials concerning the
following setting:
HEAD
Lisa Licitra, MD
- Curative treatment (6 trials)
RESIDENTS
Donata Galbiati, MD
During the 2015 the Head and Neck
Cancer Unit performed a substantial
number of visits, including outpatient,
inpatient, follow-up and first visits. In
particular, for the outpatient visits we
carried out
- Biological studies (2 trials)
- Recurrent/metastatic disease (9 trials)
- Thyroid cancer (12 trials)
- Non melanoma skin cancer (2 trials)
- Salivary glands cancer (4 trials)
- Quality of life and supportive care (12
trials)
A total 406 patients were enrolled in
clinical trials during 2015.
Paolo Bossi, MD; Laura D. Locati, MD
RESEARCH STAFF
Salvatore Alfieri, MD; Cristiana Bergamini, MD;
Carlo Resteghini, MD; Roberta Granata, MD
DATA MANAGERS
Federica Favales, Paola Pistillo
Pamela Cassini, Paola Esposti, Francesca Rabito,
Francesca Mazzetti
HEAD
AND NECK
CANCER
MEDICAL
ONCOLOGY
- 330 Multidisciplinary first visits
- 938 Multidisciplinary follow-up visits
- 3,140 Medical oncology out-patient
visits
We carried out 332 inpatient visits and a
total of 610 hospitalizations.
Keywords
Head and Neck Cancer,
thyroid cancer,
salivary gland cancer
Basset-Seguin N, Hauschild A, Grob JJ, Kunstfeld R, Dréno B, Mortier L,
Ascierto PA, Licitra L, Dutriaux C, Thomas L, Jouary T, Meyer N, Guillot
B, Dummer R, Fife K, Ernst DS, Williams S, Fittipaldo A, Xynos I, Hansson
J. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a
pre-planned interim analysis of an international, open-label trial. Lancet Oncol. 2015
Jun;16(6):729-36
Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, Clement PM,
Gauler T, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G Jr, de Souza Viana L,
Keilholz U, Del Campo JM, Cong XJ, Ehrnrooth E, Cohen EE; LUX-H&N 1 investigators.
Afatinib versus methotrexate as second-line treatment in patients with recurrent or
metastatic squamous-cell carcinoma of the head and neck progressing on or after
platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3
trial. Lancet Oncol. 2015 May;16(5):583-94
Osman AA, Neskey DM, Katsonis P, Patel AA, Ward AM, Hsu TK, Hicks SC, McDonald TO,
Ow TJ, Alves MO, Pickering CR, Skinner HD, Zhao M, Sturgis EM, Kies MS, El-Naggar A,
Perrone F, Licitra L, Bossi P, Kimmel M, Frederick MJ, Lichtarge O, Myers JN. Evolutionary
Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and
Neck Cancer Patients. Cancer Res. 2015 Apr 1;75(7):1205-15.
De Cecco L, Bossi P, Locati L, Canevari S, Licitra L. Comprehensive gene expression
meta-analysis of head and neck squamous cell carcinoma microarray data defines a
robust survival predictor. Ann Oncol. 2014 Aug;25(8):1628-35
Bossi P, Lo Vullo S, Guzzo M, Mariani L, Granata R, Orlandi E, Locati L, Scaramellini G,
Fallai C, Licitra L. Preoperative chemotherapy in advanced resectable OCSCC: longterm results of a randomized phase III trial. Ann Oncol. 2014 Feb;25(2):462-6
108
OF THE UNIT
31
PUBLICATIONS
165.832
IMPACT FACTOR
8
24.495
1-30, 8
CARDIOLOGY
PATRIZIA PIOTTI, Head of the Unit
Clinical activity
Research activity
Staff
The Cardiology Unit carries
out cardiac evaluation of
patients undergoing surgical
interventions or chemoradiotherapy for cancer in order to define
individual cardiovascular risk and predict
the need of monitoring complications.
During the 2015, the
Cardiology Unit has been
involved in over 200 clinical trials for
the monitoring of cardiovascular toxicity
related to anti-neoplastic treatments, in
collaboration with other clinical Units
of INT.
HEAD
Patrizia Piotti, MD
Patients candidates for surgery and/
or medical therapy, are subjected to
diagnostic tests and therapies for
ischemic heart disease, hypertension,
valvular heart disease, arrhythmias, and
congestive heart failure before and/
or during the course of their cancer
treatment. Preoperative evaluation of
cardiac risk, perioperative assessment
and monitoring are performed according
to the latest International Guidelines.
Regular cardiologic surveillance to
assess the cardiotoxicity of new
experimental drugs is carried out for
all ongoing Phase I, II, and III clinical
studies (monoclonal antibodies,
receptor tyrosine kinase inhibitors, BRAF
inhibitors, MEK inhibitors).
Iryna Arendar, MD; Marina Crivaro, MD; Patrizia
Greco, MD; Carlo Materazzo, MD
TECHNICIANS
Rita Carulli, Michele Iannelli
Maria Alessandra Ceccarini, Maria Grazia
Marchetti, Lucia Menzione
Keywords
Cardiotoxicity,
cardiologic assessment
NURSES
Sabrina Barrotta, Graziella Borlenghi, Vincenzo
Mandurino, Rosella Murru, Luisa Sala
Miria Faccini, Salvatore Uccelli
In 2015, 24,963 (17,473 for inpatients
and 7,490 for outpatients) cardiologic
procedures have been performed.
Two thousand and forty three cardiac
examinations, including EKG and
Echo-color Doppler, were exclusively
dedicated to experimental protocols.
revitali P, Fumagalli L, Ammatuna M, Materazzo C, Colombo C,
P
Langer M. Coronary spasm under combined epidural-general anesthesia.
Case report. Experimental & Clinical Cardiology 2014;20:1997-1999
Celik S, Lestuzzi C, Cervesato E, Dequanter D, Piotti P, De Biasio M, Imazio M. Systemic
chemotherapy in combination with pericardial window has better outcomes in
malignant pericardial effusions. Journal Of Thoracic And Cardiovascular Surgery
2014;148:2288-2293
i Bello V, La Carrubba S, Antonini Canterin F, Di Salvo G, Caso P, La Canna G, Erlicher
D
A, Badano L, Romano MF, Zito C, Vriz O, Conte L, Carerj S, Research Group Of The
Italian Society Of Cardiovascular Echography (Siec), Milan, Italy {Materazzo C}. Role of
electrocardiography and echocardiography in prevention and predicting outcome of
subjects at increased risk of heart failure. European Journal Of Preventive Cardiology
2015;22:249-262
OF THE UNIT
1
PUBLICATIONS
3.319
IMPACT FACTOR
2-9, 6
CARDIOLOGY
109
MEDICAL DAY HOSPITAL
ROBERTO BUZZONI, Head of the Unit
Clinical activity
Research activity
Networking
Our Unit features rooms for
outpatient visits, waiting
room, hospital rooms, oral
medication dispensing rooms,
and short infusional therapy rooms. The
oncological diseases treated are the
following: breast cancer, gastrointestinal
tumors, head/neck carcinomas,
malignant melanoma, sarcomas, and
neuroendocrine tumors. About 300
patients are seen daily, and, of these,
about 100 undergo medical treatment.
The Medical Day Hospital Unit
is involved in several ongoing
trials, sponsored and spontaneous.
Our Institution, in Italy and in Europe, is a
reference Center in the management of
these heterogeneous neoplasms whose
incidence is increasing worldwide.
Cooperation with the
European Neuroendocrine
Tumors Society - by
sharingour database counting more
than 1,650 patients with a diagnosis of
neuroendocrine tumor.
Short duration therapies are performed
in a large room with 11 dedicated chairs.
Another room is dedicated to
management of central line in order
to minimize the risk of complications
related to these devices. There are about
60-65 of these treatments per day.
There are 6 daily hospitalization rooms
for a total of 18 beds and 5 chairs. In
addition, there is a room dedicated
to mini-invasive treatments such as
thoracentesis, paracentesis, lumbar
puncture, bone marrow, and cutaneous
biopsies. Research nurses are also
involved in the collection of blood
samples. In 2015, the total number of
treatments in the Day Hospital unit was
8140. For short therapies plus catheters,
there were 14550 procedures.
MEDICAL DAY
110
Keywords
Research,
day hospital,
therapies
Pusceddu S, De Braud F, Festinese F, Bregant C, Lorenzoni A, Maccauro
M, Milione M, Concas L, Formisano B, Leuzzi L, Mazzaferro V, Buzzoni R.
Evolution in the treatment of gastroenteropancreatic-neuroendocrine
neoplasms, focus on systemic therapeutic options: A systematic review.
Future Oncology 2015;11:1947-1959
Paz Ares L, Mezger J, Ciuleanu TE, Fischer JR, Von Pawel J, Provencio M, Kazarnowicz
A, Losonczy G, De Castro G Jr, Szczesna A, Crino L, Reck M, Ramlau R, Ulsperger E,
Schumann C, Miziara JE, Lessa AE, Dediu M, Balint B, Depenbrock H, Soldatenkova V,
Kurek R, Hirsch FR, Thatcher N, Socinski MA, Inspire Investigators {Buzzoni R, Zilembo
N}. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients
with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label,
randomised, controlled phase 3 study. Lancet Oncology 2015;16:328-337
Ferrari LA, Fanetti G, Rossi FG, Brambilla MC, Re B, Buzzoni R. Are antineoplastic drug
acute hypersensitive reactions a submerged or an emergent problem? Experience of
the Medical Day Hospital of the Fondazione IRCCS Istituto Nazionale Tumori. Tumori.
2014 Jan-Feb;100(1):9-14
Buzzoni R, Pusceddu S, Bajetta E, De Braud F, Platania M, Iannacone C, Cantore M,
Mambrini A, Bertolini A, Alabiso O, Ciarlo A, Turco C, Mazzaferro V. Activity and safety
of RAD001 (everolimus) in patients affected by biliary tract cancer progressing after
prior chemotherapy: A phase II ITMO study. Annals Of Oncology 2014;25:1597-1603
Staff
Pusceddu S, De Braud F, Concas L, Bregant C, Leuzzi L, Formisano B, Buzzoni R.
Rationale and protocol of the MetNET-1 trial, a prospective, single center, phase II
study to evaluate the activity and safety of everolimus in combination with octreotide
LAR and metformin in patients with advanced pancreatic neuroendocrine tumors.
Tumori 2014;100:286e-289e
HEAD
Roberto Buzzoni, MD
Laura Anna Maria Ferrari, MD
RESEARCH STAFF
Daniela Femia, MD; Gabriella Luisa Dinoi, PhD
TECHNICIANS
Arcangela Accadia, Vincenzina Arnone, Silvana
Celauro, Claudia Cocciolo, Fabio Di Bartolo, Maria
Rosa Forte, Giovanna Maria Montecalvo, Maria
Rosaria Moscatiello, Diego Putzu, Domenica
Spartano, Raffaele Zicconi
DATA MANAGERS
Laura Concas, M. Sc.
Anna Rosa Cabiddu, Gianfranco De Pol, Antonella
Bifano, Alba Patrizia Gobbi
NURSES
Daria Caterina Albini, Chiara Bernasconi,
Patrizia Brambati, Antonella Chiesa, Domenica
Comberiati, Lucia D’Agnessa, Laura Di Vico,
Viviana Donatiello, Claudia Facchinetti, Anna
Frisario, Lucia Giordano, Mirella Jugovaz, Lorena
Lavorca, Massimo Limonta, Francesca Maffione,
Elena Natalina Nuti, Maria Sterpeta Paolillo,
Francesca Pisano, Maria Neve Pisanu, Nicolò
Nuccio Rampello, Elena Maria Sala, Laura Sala,
Sonia Sanapo, Deborah Zordan, Patrizia Valente
OF THE UNIT
4
PUBLICATIONS
53.126
IMPACT FACTOR
1
2.477
Y HOSPITAL
Maria Cosimina Fadda, Anna Maria Meloni, Rita
Enrica Trovato, Daniela Fino, Anna Maria Leone,
Margherita Napoletano, Santina Ucciardo
1-24, 15
UNIT H-INDEX RANGE, MEDIAN TRUTTURA
111
RESPIRATORY
PATHOPHYSIOLOGY
ROBERTO BOFFI, Head of the Unit
Clinical activity
Research activity
Keywords
The Respiratory
Pathophysiology Unit is
commited to provide the highest
quality of care to all forms of
lung diseases. Our areas of expertise
cover chronic obstructive pulmonary
disease (COPD), tobacco control policies
and interventions and pre-operative
cardiopulmonary exercise tests in
patients admitted to thoracic surgery.
The Respiratory
pathophysiology and Tobacco
Control Unit has been involved in
several research activities:
lung cancer, COPD,
pulmonary toxicity,
pulmonary function, smoke,
electronic cigarette, smoking
cessation, environmental tobacco smoke
In 2015, we performed 600 first
visits and 500 follow-up visits to
pneumological outpatients.
We have also provided 650 smoking
cessation interventions, including
integrated pharmacological and
psychological support, addressed to
outpatients (230 new smokers), with a
25% of smoking cessation rate at one
year and to 150 inpatients (with a 40%
of smoking cessation rate at the first
re-evaluation).
- The TackSHS Project (Horizon 2020):
tackling secondhand tobacco smoke
and e-cigarette emissions: exposure
assessment, novel interventions,
impact on lung diseases and economic
burden in different European
populations.
- Environmental pollution comparison
of e-cigarettes, heat-not-burn tobacco
products and conventional cigarettes
- A combined smoking cessation
intervention within a lung cancer
screening trial: a pilot observational
study
- Impact of outdoor second-hand
cigarette smoke on air quality
- Hospital doctors’ smoking behaviour
and attitude towards smoking
cessation interventions for patients
We also continue our ongoing research
focused on electronic cigarettes and
their health effects in terms of secondhand exposure.
RESPIRATORY
PATHOPHYSIO
112
Staff
HEAD
Roberto Boffi, MD
De Marco C, Invernizzi G, Bosi S, Pozzi P, Di Paco A, Mazza R, Ruprecht
AA, Munarini E, Boffi R. The electronic cigarette: potential health benefit
or mere business? Tumori. 2013 Nov-Dec;99(6):299e-301e.
Alessandra Busia, MD
RESEARCH STAFF
Anna Chiara Ogliari, MD, Paolo Pozzi, MD, Elena
Munarini, Psy D
uprecht AA, De Marco C, Pozzi P, Munarini E, Mazza R, Angellotti G, Turla F,
R
Boffi R. Comparison between particulate matter and ultrafine emission by electronic
and normal cigarettes in real-life conditions. Tumori. 2014 Jan-Feb;100(1):e24-7.
NURSES
Maria Antonietta Chiricosta
Saffari A, Daher N, Ruprecht A, De Marco C, Pozzi P, Boffi R, Hamad SH, Shafer MM,
Schauer JJ, Westerdahl D, Sioutas C. Particulate metals and organic compounds from
electronic and tobacco-containing cigarettes: comparison of emission rates and
secondhand exposure. Environ Sci Process Impacts. 2014 Oct;16(10):2259-67.
HEALTH CARE ASSISTENT
Sara Franca Santoro
Munarini E, Marabelli CM, Pozzi P, Boffi R. Extended varenicline treatment in a serious
cardiopathic smoker: a case report. Journal of Medical Case Reports. 2015 Mar;9:29.
Alessandra Ceccarini, Maria Grazia Marchetti
Pozzi P, Munarini E, Bravi F, Rossi M, La Vecchia C, Boffi R, Pastorino U. A combined
smoking cessation intervention within a lung cancer screening trial: a pilot
observational study. Tumori. 2015 May-Jun;101(3):306-11.
TECHNICIANS
Simona Montalti, Vito Fabio Valente
Y
OLOGY
OF THE UNIT
2
PUBLICATIONS
1.269
IMPACT FACTOR
2
1.269
1-12, 3
113
HEMATOLOGY
AND PEDIATRIC
ONCO-HEMATOLO
HEMATOLOGY AND
PEDIATRIC ONCO-HEMATOLOGY
PAOLO CORRADINI
Professor of Hematology, University of Milan
paolo.corradini@istitutotumori.mi.it
HEMATOLOGY AND ALLOGENEIC BONE
MARROW TRANSPLANTATION
PAOLO CORRADINI
PEDIATRIC ONCOLOGY
MAURA MASSIMINO
IMMUNOHEMATOLOGY AND
TRANSFUSION MEDICINE (SIMT)
FERNANDO RAVAGNANI
CLINICAL PSYCHOLOGY
CLAUDIA BORREANI
CARLA I. RIPAMONTI
T
he Department of Hematology
and Pediatric Onco-Hematology
comprises five clinical divisions:
1) the Hematology Unit, a leader
in hematological malignancies
care and research. It controls 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; 2) the Pediatric
Oncology Unit, devoted to the treatment
and study of typical infancy, adolescent
and young adult solid tumors and
hematological malignancies. This Unit
focuses on prevention, early diagnosis
and management of long-term cancerand treatment-induced effects. Clinical
activities include dedicated medical care,
educational and sport programs; 3) 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 (a donor
center, apheresis center, and HLA
typing laboratory are part of this Unit).
This Unit is responsible for collecting
and processing hematopoietic stem
cells and performs the necessary
analyses required for bone marrow
transplantation procedures; 4) the
Supportive Care in Cancer 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 the complete care of
patients starting from diagnosis. The
treatments offered are compliant with
guidelines of the WHO, MASCC, ESMO,
and AIOM; 5) the Clinical Psychology
Unit, supporting patients with lifethreatening 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.
115
HEMATOLOGY AND ALLOGENEIC
BONE MARROW TRANSPLANTATION
PAOLO CORRADINI, Head of the Unit
Clinical activity
Research activity
Networking
The Unit of Hematology and
Bone Marrow Transplant (ETMO)
is principally engaged in the
clinical care and treatment of
adult patients with onco-hematological
diseases. It is focused on the use of
innovative treatments that include
target therapies and advanced stem
cells transplantation techniques. For
the activity of bone marrow transplant,
which comprises autologous, allogeneic
from family or unrelated donor,
compatible or partially compatible, the
Unit is accredited by JACIE (International
Joint Accreditation Committee). During
the 2015, we performed 98 transplants,
of which 70 were autologous and 28
allogeneic. ETMO is currently conducting
50 clinical trials from phase I to phase
III studies testing new combination of
drugs and monoclonal antibodies for
the treatment of lymphoid and myeloid
malignancies, enhancing the antitumour activity while reducing the toxic
effects. Of note, our Unit coordinates: (a)
an innovative trial known as 2-JULIET.
For the first time in Italy, patients with
Diffuse Large B-cell Non-Hodgkin’s
Lymphoma (DLBCL) relapsed or
refractory to first-line therapy, and not
candidate for autologous transplant, will
have access to a highly effective antitumor cell therapy. A new technology,
known as CAR-T cells, involves the
genetic manipulation of patient’s T
lymphocytes that are reprogrammed
to recognize and attack the CD19 cell
surface protein present on cancer cells.
Preliminary results demonstrated
amazing results for pediatric and adult
patients with acute lymphoblastic
leukemia, and very favorable disease
responses also for patients suffering
from DLBCL; (b) the peripheral T-cell
Lymphoma phase I-II study (PTCL-13)
employing the new drug Romidepsin.
Ongoing clinical and biological
studies are aimed at:
REL - Rete Ematologica
Lombarda
Evaluating the efficacy of
new targeted therapies alone
or in combination with standard
chemotherapy to allow individualized
treatment options for patients
affected by multiple myeloma,
indolent and aggressive non-Hodgkin’s
lymphoma, acute myeloid leukemia,
myelodysplastic and myeloproliferative
disorders.
Wellcome Trust Sanger
Institute, Cambridge UK
Massive sequencing technologies
are employed to identify genetic
lesions/mechanism(s) driving tumor
aggressiveness and/or chemorefractoriness and to define new targets.
Pre-clinical models are used to test
efficacy of novel combinations.
Improving allogeneic hematopoietic
cell transplantation as treatment for
hematological malignancies. Specifically
laboratory and clinical studies are
designed to broaden the availability
of transplantation, to decrease the
incidence and severity of graftversus-host disease, and to reduce the
incidence of disease recurrence post
transplant.
Exploiting novel biomarkers for the early
recognition/stratification of patients
requiring intensified treatment options
or those unlikely to respond to standard
chemo-immunotherapies.
HEMATOLOGY
ALLOGENEIC B
TRANSPLANT
116
Introducing new molecular methods
for the diagnosis and monitoring of
hematological malignancies. We are
applying a next generation sequencing
strategy to monitor B cell malignancies
and clonal evolution in MM patients
using circulating DNA. We have
introduced and developed molecular
tests for detection of mutations with
diagnostic impact.
Keywords
Hematopoietic stem cell
transplantation, lymphoid
malignancies, myeloid
malignancies
Carniti C, Gimondi S, Vendramin A, Recordati C, Confalonieri D, Bermema
A, Corradini P, Mariotti J. Pharmacologic Inhibition of JAK1/JAK2 Signaling
Reduces Experimental Murine Acute GVHD While Preserving GVT Effects.
Clin Cancer Res. 2015 May 14. pii: clincanres.2758.2014
Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti
S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano
L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone
G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous
transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014
Sep 4;371(10):895-905
Staff
HEAD
Paolo Corradini, MD
Niccolò Bolli, MD, PhD; Liliana Franca Devizzi,
MD; Anna Dodero, MD; Lucia Farina, MD, PhD;
Anna Guidetti, MD; Paola Matteucci, MD;
Vittorio Montefusco, MD; Alberto Mussetti, MD;
Giulia Perrone, MD; Francesca Rezzonico, MD;
Francesco Spina, MD, PhD; Simonetta Viviani, MD
Guidetti A, Carlo-Stella C, Locatelli SL, Malorni W, Mortarini R, Viviani S, Russo D,
Marchianò A, Sorasio R, Dodero A, Farina L, Giordano L, Di Nicola M, Anichini A,
Corradini P, Gianni AM. Phase II Study of Perifosine and Sorafenib Dual-Targeted
Therapy in Patients with Relapsed or Refractory Lymphoproliferative Diseases. Clin
Cancer Res. 2014 Nov 15;20(22):5641-51
orradini P, Marchetti M, Barosi G, Billio A, Gallamini A, Pileri S,Pimpinelli N, Rossi G,
C
Zinzani PL, Tura S. SIE-SIES-GITMO guidelines for the management of adult peripheral
T- and NK-cell lymphomas, excluding mature T-cell leukemias. Ann Oncol. 2014 Apr 9
orradini P, Vitolo U, Rambaldi A, Miceli R, Patriarca F, Gallamini A, Olivieri A,
C
Benedetti F, Todeschini G, Rossi G, Salvi F, Bruno B,Baldini L,Ferreri A, Patti C, Tarella
C, Pileri S, Dodero A. Intensified chemo-immunotherapy with or without stem cell
transplantation in newly diagnosed patients with peripheral T-cell lymphoma.
Leukemia. 2014; 28(9):1885-91
RESIDENTS
Marco Capecchi, MD; Chiara Caprioli, MD;
Nicoletta Cieri, MD; Serena Camilla Dalto, Chiara
De Philippis, Maria Chiara Di Chio, Elena Farè,
Giulia Galli, Livia Leuzzi, Francesco Maura, Luca
Pappalettera, Martina Pennisi, Tommaso Radice,
Martina Soldarini
RESEARCH STAFF
Cristiana Carniti, PhD; Alessandra Cavanè, PhD;
Silvia Gimondi, PhD; Antonio Vendramin, PhD
Y AND
BONE MARROW
TATION
RESEARCH FELLOWS
Giulia Biancon, Med Biotech D; Sara Rizzitano,
Med Biotech D
DATA MANAGERS
Anisa Bermema, PhD; Debora Degl’Innocenti,
PhD; Daniela Tomaiuolo, Med Biotech D
Giusi Iannaci, Marialuisa Longhi
SCIENTIFIC-ADMINISTRATIVE PERSONNEL
Anna De Filippo, PhD; Elena Maggioni
NURSES
Rosa Abate, Matteo Biondelli, Sonia Citro,
Alessandro De Nisi, Riccardo De Stefano, Giorgia
Gobbi (coordinator), David Guiote Pertierra,
Donatella Luongo, Elisabetta Martinelli, Simona
Mazzella, Francesco Murana, Leonardo Orsini,
Alfonso Parisi, Rita Russo, Serafina Tomasicchio,
Giuseppe Torregrossa, Anna Vernone
RESEARCH NURSE
Ilaria Lo Russo
Nunzio Bovello, Carmelo Fedele, Evelina Palella,
Jose Noboa Velasco,
OF THE UNIT
28
PUBLICATIONS
184.953
IMPACT FACTOR
5
20.540
1-50, 12
117
PEDIATRIC ONCOLOGY
MAURA MASSIMINO, Head of the Unit
Clinical activity
Research activity
Networking
Our activity is based on the
treatment and study of tumors
typical of infancy, adolescence,
and young adulthood with
about 20% of patients over 18 years
of age at diagnosis. This Unit is the
largest for accrual of solid tumors in
Italy. During 2015, 253 new patients
were diagnosed and treated. Our
clinical activities are managed in both
inpatient and outpatient regimens, also
involving social support, education,
sport continuation, cured patient followup, fertility preservation programs,
and throughout psychological support
for children, adolescent and families.
A palliative care program is also
operational, using both institutional
and external resources. Nearly 100
major surgical acts (apart for 60 needle
or tru-cut biopsies) and over 150
radiation treatments were performed
for malignant tumors. Post-operative
courses were cared inside the Unit as
well as a total of 33 autologous bonemarrow transplantations performed
for high-risk or relapsed solid tumors.
Over 80% of treated children were
enrolled in controlled clinical trial
mostly on a National or European
background in the collaborative trials
of AIEOP (Associazione Italiana di
Oncologia ed Ematologia Pediatrica) or
SIOP (International Society of Pediatric
Oncology) with chairmanship of the Unit
researchers in many of these protocols,
such as brain tumors, soft tissue
sarcoma, Wilms’ tumor, neuroblastoma,
germ cell tumors, osteo- and Ewing
sarcoma, pediatric rare tumors.
Given the active involvement
in the network ITCC (Innovative
Therapies for Children with Cancer)
(one member of our Unit is part of the
Executive Committee), we can offer to
relapsing patients a number of further
line therapies involving new drugs. For
this reason, we have been identified,
together with the twin Pediatric Unit in
Monza, as a National reference Center
for phase I-II Pediatric studies.
Member of AIEOP (Italian
Society of Pediatric
Oncology and Hematology)
that groups over 50 Italian centers in a
National network
The Youth Project is dedicated to
adolescent patients (15-19 years) and to
those young adults (up to 25-29 years)
affected by pediatric-type tumors.
SIOP (International Society of Pediatric
Oncology), same as above, at European
level mostly (one member of the Unit is
part of the Clinical Research Council CRC
of SIOP-Europe)
The study of biopsy surrogate serum
biomarkers and miRNA profiles in DIPG
(Diffuse Intrinsic Pontine Glioma) is
ongoing, through a validation cohort,
based on what has already been
found, in a new parallel trial (AIRC and
Fondazione Celeghin grants).
A biomolecular study aiming to compare
miRNA profiles and genic expression
in pediatric rhabdomyosarcoma vs
adolescent-young adult RMS (the
latter generally characterized by worse
prognosis).
We are developing in cooperation
with other Institutions in Italy an
immune-based approach, employing
genetically modified T cells , to express
chimeric proteins to specifically target
neuroblastoma (Osp Bambin Gesù Rome
grant)
Continuation of a project investigating
the cerebrospinal fluid proteome
obtained from central nervous system
pediatric tumors using bait loaded
hydrogel nanoparticles and mass
spectrometry (Health Minister grant,
private charity support)
Currently, in 2015 there are 29 academic
and 10 sponsored trials open to accrual.
Rete TREP (Tumori Rari dell’Età
Pediatrica)
SIAMO (Società scientifica italiana
Insieme per gli Adolescenti con Malattie
Onco-ematologiche)
LESG (Late Effect Study Group) and
Pancare International Network
SG (Italian Sarcoma Group)
ITCC (Innovative Therapies for Children
with Cancer)
EpSSG (European pediatric Soft Tissue
Sarcoma Study Group)
SIOPEN-r-NET (International Society
of Paediatric Oncology European
Neuroblastoma Research Network) ,
EuroEWING Consortium (international
clinical trials to improve survival from
ewing sarcoma)
EXPeRT (European Cooperative Study
Group on Pediatric Rare Tumors)
EXPO-r-NET (European Expert Paediatric
Oncology Reference Network for
Diagnostics and Treatment)
COG (Children Oncology Group) as
external
AHOPCA (Central American Association
of Pediatric Hematology and Oncology),
ENTYAC (European Network for
Teenagers and Young Adults)
Moreover: Neurological Institute Carlo
Besta, Università La Sapienza Roma,
G. Pini Institute, Institut Léon Berard
(Lyon), Hamburg University, Mc Gill Univ
(Montreal), Sickkids Hosp (Toronto)
PEDIATRICS O
118
Keywords
Solid tumors, prognosis,
adolescents, trials,
phase I-II
Viprey VF, Gregory WM, Corrias MV, Tchirkov A, Swerts K, Vicha A,
Dallorso S, Brock P, Luksch R, Valteau-Couanet D, Papadakis V, Laureys
G, Pearson AD, Ladenstein R, Burchill SA. Neuroblastoma mRNAs predict
outcome in children with stage 4 neuroblastoma: a European HR-NBL1/
SIOPEN study. J Clin Oncol. 2014 Apr 1;32(10):1074-83
Massimino M, Biassoni V, Miceli R, Schiavello E, Warmuth-Metz M, Modena P,
Casanova M, Pecori E, Giangaspero F, Antonelli M, Buttarelli FR, Potepan P, Pollo
B, Nunziata R, Spreafico F, Podda M, Anichini A, Clerici CA, Sardi I, De Cecco L, Bode
U, Bach F, Gandola L. Results of nimotuzumab and vinorelbine, radiation and reirradiation for diffuse pontine glioma in childhood. J Neurooncol. 2014 Jun;118(2):30512
Staff
HEAD
Maura Massimino, MD
Michela Casanova, MD; Andrea Ferrari, MD;
Roberto Luksch, MD; Cristina Piera Meazza, MD;
Filippo Spreafico, MD; Monica Terenziani, MD
RESIDENTS
Luca Bergamaschi, MD; Calogero Mazzara, MD
RESEARCH STAFF
Veronica Biassoni, MD; Serena Catania, MD;
Stefano Chiaravalli, MD; Maria Chiara Magni,
MD; Carla Moscheo, MD; Marta Giorgia Podda,
MD; Nadia Puma, MD; Enrico Roberto Riva, MD;
Luisa Roncari, MD; Elisabetta Schiavello, MD;
Marco Chisari, MD; Barbara Giacon, Psychologist;
Giovanna Sironi, Laura Veneroni, Psychologist
Dome JS, Graf N, Geller JI, Fernandez CV, Mullen EA, Spreafico F, Van den HeuvelEibrink M, Pritchard-Jones K. Advances in Wilms Tumor Treatment and Biology:
Progress Through International Collaboration. J Clin Oncol. 2015 Sep 20;33(27):29993007
Ferrari A, De Salvo GL, Brennan B, van Noesel MM, De Paoli A, Casanova M, Francotte
N, Kelsey A, Alaggio R, Oberlin O, Carli M, Ben-Arush M, Bergeron C, Merks JH, Jenney
M, Stevens MC, Bisogno G, Orbach D. Synovial sarcoma in children and adolescents:
the European Pediatric Soft Tissue Sarcoma Study Group prospective trial (EpSSG
NRSTS 2005). Ann Oncol. 2015 Mar;26(3):567-72
erenziani M, Massimino M, Magazzù D, Gandola L, Capri G, Carcangiu ML, Catania S,
T
Di Russo A, Gennaro M, Meazza C, Podda M, Schiavello E, Valagussa P. Management
of breast cancer after Hodgkin’s lymphoma and paediatric cancer. Eur J Cancer. 2015
Sep;51(13):1667-74
TECHNICIANS
Elena Barzanò, Antonia Biasi, Maria Grazia
Cremona, Andrea Elia Gazzi, Angelo Prati, Delia
Rimoldi, Valeria Salsi, Matteo Silva
SOCIAL WORKER
Giovanna Casiraghi
DATA MANAGERS
Eleonora Desirèe Boccuto, Luna Boschetti, Chiara
Secco
Mattia Bussi, Gabriella Angela Vighi
NURSES
Maria Angela Armiraglio, Iris Anna Baranella,
Morena Berti, Daniela Bruno, Cristina Comelli,
Patrizia Conti, Maria Domenica Costeri, Lucia
Curreli, Laura De Porras Payà, Ruggero Fauro,
Marta Ferrante, Carmelo Fiorello, Giuseppe
Forzini, Marinella Gaidolfi, Rossana Ghezzi, Laura
Maria Ida Lottaroli, Simone Macchi, Rossana
Marra, Manuela Angela Oriani, Elisa Procopio,
Silvana Saverino, Giovanna Elisa Triglia, Daniela
Valsecchi, Monica Villa
OF THE UNIT
38
PUBLICATIONS
170.788
IMPACT FACTOR
17
49.598
ONCOLOGY
Anna Maria Bilanzuoli, Beatriz Alberta Rivera
Delgado De Al, Rosanna Loi, Rita Marina
Tamburro, Stella Maria Uzzardi
1-35, 9
119
IMMUNOHEMATOLOGY AND
TRANSFUSION MEDICINE (SIMT)
FERNANDO RAVAGNANI, Head of the Unit
Clinical activity
Research activity
Networking
The Immunohematology and
Transfusion Medicine Service
(SIMT) provides clinical services
to support patients in need
of blood component therapy, cellular
therapy and therapeutic apheresis. The
Unit is involved in handling all aspects
of donor recruitment for whole blood
products, apheresis products, and the
auto-transfusion program collects.
The laboratory performed
analysis for patients enrolled
in clinical trials and in research
projects.
We collaborate with
Politecnico of Milan, in
order to supply blood
donor samples necessary to perform
experimental test to encapsulate
molecules in red blood cell.
During 2015, the Unit determined
eligibility on 490 potential blood donors
and collected a total of 7,890 donations
of whole blood and by apheresis,
platelet-pheresis or plasmapheresis.
Therapeutic apheresis procedures to
treat patients with blood diseases,
including photopheresis and plasma
exchange procedures, are also
performed routinely (433 procedures).
Since February 2015, the preparation and
the validation of blood components have
been performed by Ospedale Niguarda
in compliance with “State-Regions
Agreement 16/12/2010”.
Since June 2015, the Unit provides all
clinical services to support patients of
Istituto Neurologico Besta in need of
blood components.
The Unit includes specialized
laboratories (about 14,000 tests/year):
IMMUNOHEM
AND TRANSFU
MEDICINE (SIM
- Immunohematology, performing
analyses for antibody identification,
antigenic typing and hemolytic
autoimmune disease;
- European Federation of
Immunogenetics certified and
accredited HLA Laboratory, performing
typing of patients and donors;
- Serology laboratory has introduced
methotrexate assay in order to provide
quantitative measurement of the drug;
- Molecular virology laboratory
improved the activity.
120
Keywords
Transfusion medicine,
HLA, virology
Taverna F, Coluccia P, Arienti F, Birolini A, Terranova L, Mazzocchi
A, Rini F, Mariani L, Melani C, Ravagnani F. Biological quality control
for extracorporeal photochemotherapy: Assessing mononuclear cell
apoptosis levels in ECP bags of chronic GvHD patients. Journal Of Clinical
Apheresis 2015;30:162-170
Piccioni F, Casiraghi C, Fumagalli L, Kusamura S, Baratti D, Deraco M, Arienti F, Langer
M. Epidural analgesia for cytoreductive surgery with peritonectomy and heated
intraperitoneal chemotherapy. International Journal Of Surgery 2015;16:99-106
Pardini B, Verderio P, Pizzamiglio S, Nici C, Maiorana MV, Naccarati A, Vodickova L,
Vymetalkova V, Veneroni S, Daidone MG, Ravagnani F, Bianchi T, Bujanda L, Carracedo
A, Castells A, Ruiz Ponte C, Morreau H, Howarth K, Jones A, Castellví Bel S, Li L,
Tomlinson I, Van Wezel T, Vodicka P, Radice P, Peterlongo P, Epicolon Consortium .
Association between CASP8 -652 6N del polymorphism (rs3834129) and colorectal
cancer risk: Results from a multi-centric study. Plos One 2014;9:e85538
Necchi A, Miceli R, Pedrazzoli P, Giannatempo P, Secondino S, Di Nicola M, Farè E,
Raggi D, Magni M, Matteucci P, Longoni P, Milanesi M, Paternò E, Ravagnani F, Arienti
F, Nicolai N, Salvioni R, Carlo Stella C, Gianni AM. Predictors of CD34+ cell mobilization
and collection in adult men with germ cell tumors: Implications for the salvage
treatment strategy. Clinical Genitourinary Cancer 2014;12:196-2020
Farina L, Rezzonico F, Spina F, Dodero A, Mazzocchi A, Crippa F, Alessi A, Dalto S,
Viviani S, Corradini P. Serum thymus and activation-regulated chemokine level
monitoring may predict disease relapse detected by pet scan after reduced-intensity
allogeneic stem cell transplantation in patients with hodgkin lymphoma. Biology Of
Blood And Marrow Transplantation 2014;20:1982-1988
Staff
HEAD
Fernando Ravagnani, MD
Flavio Arienti, MD; Annalisa Birolini, MD; Paola
Coluccia, MD; Carmela Guarino, MD; Claudia
Lombardo, Biol Sci D; Arabella Mazzocchi, Biol Sci
D; Laura Rosalia Maria Terranova, MD
MATOLOGY
USION
MT)
CLINICAL RESEARCH FELLOWS
Francesca Rosita Taverna, Biol Sci D
TECHNICIANS
Cinzia Luigia Biasuz, Alvaro Bompadre, Laura
Maria 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 Pietro Tattanelli,
Ornella Zanaboni
Orietta Clelia Polisena, Elide Spinelli, Giovanni
Veronese, Maria Cristina Zanetti
NURSES
Salvatore Alcamo, Marisa Dentella, Filomena
Fedele, Rita Fiorito, Patrizia Galantin, Cristina
Irene Lasala, Monica Pedretti, Carmela Santolla
HEALTH CARE ASSISTANTS
Antonella Atzeni, Stella Di Tommaso, Maria
Altomare Somma, Maria Tamburriello
OF THE UNIT
2
PUBLICATIONS
3.322
IMPACT FACTOR
1
1.791
1-28, 16
121
CLINICAL PSYCHOLOGY
CLAUDIA BORREANI, Head of the Unit
Clinical activity
Research activity
Keywords
Clinical activity aims at
enhancing quality of life and
well-being of people facing
with cancer. Depending on
the level of psychological suffering,
a psychological plan is created and it
may involve the patient as well as those
close by, who are also influenced by the
disease.
The research activity
investigates the psychological,
social, behavioural and ethical
aspects of cancer. Our research group
is especially involved in understanding:
the psychological impact of cancer
and its treatment; how and why this
gives rise to unmet psychosocial and
supportive care needs for patients and
their families; what interventions can be
put in place to reduce the distress and
improve quality of life and wellbeing.
Psycho-oncology,
global approach,
communication
This comprehensive plan is
accomplished by providing expert
clinical intervention such as individual
psychological counselling, short
psychotherapies, verbal and psychobodily groups, psycho-educational
groups and family therapies. The
Psychology Unit also operates in strict
collaboration with all the medical and
scientific professionals to provide,
in particular, training on how to
communicate and relate to patients and
their families.
During 2015, 3,169 clinical consultations
(concerning 2,650 outpatients and 519
inpatients) have been carried out, while
120 patients have been assisted by the
adult social service.
Several sessions of psycho-educational
groups have been conducted: a) the
MOIRA program: psychotherapeutic
groups employing narrative medicine
techniques, mindfulness practices and
meaning oriented psychotherapies;
b) the Itaca program, which involves
patients and their relatives in
educational and psychological support
groups; c) multidisciplinary clinical
project specifically addressed to
support cancer patients undergoing
liver transplant and to support clinical
decision making in BRCA1-2 carriers.
During 2015 the following studies were
conducted:
•E
xpectations, feelings and preferences
of patients and physicians involved
in the informed consent process
for clinical trials participation:
development of a model
•O
bservational study to assess the
impact of aromatase inhibitors on the
psychological dimension of breast
cancer patients
•P
sychological determinants of
preventive strategies’ choice in
BRCA1/2 carriers
valuation of cancer patient’s
•E
psychological distress during
hospitalization
CLINICAL PSY
122
Staff
HEAD
Claudia Borreani, Psy D
Roli A, Borreani C, Bosisio M, Bianchi E, Montefusco V, Gobbi G, Platania
M, Lavecchia F, Milanesi M, Anselmi V, Melani C, De Leo G. The OECI
model: the experience of INT Milan with a focus on the integration of
psycho-oncology support. Tumori. 2015 Dec 31;101 Suppl 1:25-32
Carlo Alfredo Clerici, MD; Marco Bosisio, Psy D
RESIDENTS
Roberta Caradonna, Psy D; Rossella Petrigliano,
Psy D
RESEARCH STAFF
Elisabetta Bianchi, Psy D; Laura Gangeri, Ped D;
Margherita Greco, Psy D; Luciana Murru, Psy D;
Patrizia Trimigno, Psy D
SOCIAL WORKER
Silvia Bettega, Valeria Maffi
Teresa Maria Cariglia
Scrignaro M, Bianchi E, Brunelli C, Miccinesi G, Ripamonti CI, Magrin ME, Borreani
C. Seeking and experiencing meaning: exploring the role of meaning in promoting
mental adjustment and eudaimonic well-being in cancer patients. Palliat Support
Care. 2015 Jun;13(3):673-81
Borreani C, Manoukian S, Bianchi E, Brunelli C, Peissel B, Caruso A, Morasso G, Pierotti
MA. The psychological impact of breast and ovarian cancer preventive options in
BRCA1 and BRCA2 mutation carriers. Clin Genet. 2014 Jan;85(1):7-15
Giannini A, Miccinesi G, Prandi E, Buzzoni C, Borreani C; ODIN Study Group. Partial
liberalization of visiting policies and ICU staff: a before-and-after study. Intensive
Care Med. 2013 Dec;39(12):2180-7
OF THE UNIT
13
PUBLICATIONS
13.151
IMPACT FACTOR
6
4.632
YCHOLOGY
3-12, 4
123
CARLA I. RIPAMONTI, Head of the Unit
Clinical activity
Research activity
Networking
The Supportive Care in
Cancer Unit (SCCU) provides
planned interventions and
real time answers to medical
emergencies after telephone request
by treating patients suffering from
iatrogenic toxicity (i.e., anemia and
thrombocytopenia, severe electrolyte
abnormalities, mucositis, dehydration
caused by gastrointestinal toxicity,
viral, bacterial and fungal infections,
symptomatic hypercalcemia and
hypocalcemia) according to ESMO,
MASCC, WHO guidelines.
In 2015 the main areas of
research were:
The SCCU research
activity is performed in
collaboration with other
Units within the Fondazione IRCCS INT
and with both National and International
external organizations/Centers. It
involves only patients on active cancer
treatment following a pharmacological
and non-pharmacological pattern of
treatment.
In 2015, there were 6,000 visits, 4,500
infusions of drugs or hydration, 1,200
transfusions of hemoderivatives and
800 treatments with bisphosphonates
and denosumab. The therapies were
practiced to patients with any primary
solid or hematologic malignancies as
outpatient, outpatient complex activity
(MAC) or day hospital (DH).
Areas of excellence: 1. All patients are
assessed for the presence and intensity
of physical and emotional symptoms,
spiritual and social concerns; hope,
dignity and communication needs by
means of validated assessment tools.
2. The Unit is the point of reference for
transfusions of hemoderivatives in the
out-patient setting.
relationship among hope, spirituality,
physical and emotional symptom of
patients cared at the SCCU (non profit
study)
nmet need of patients on active
u
oncologic treatments (non profit study)
ginger as anti nausea: multicenter,
randomized, double blind, controlled
vs placebo to assess the activity of
Ginger in the management of nausea
in patients on chemotherapy (cod prot
HF01-12-69)
observational prospective study on
the characteristic and the treatment of
fatigue in cancer patients in Italy (non
profit study)
experimental study on the use of
ginseng vs placebo in the treatment of
fatigue in patients with head and neck
cancer during follow-up (non profit
study)
The Unit is involved in International and
National research projects, as well as in
academic and non-academic educational
activities all over the world.
The Unit collaborates with World
Health Organization (WHO), European
Society for Medical Oncology (ESMO),
Multinational Association of Supportive
Care in cancer (MASCC), International
Association for Hospice and Palliative
Care (IAHPC), Institute for the Study and
Prevention of Cancer (ISPO-Florence),
Biomedical Campus (Rome); and the
University of Milano and Bologna.
randomized study to assess the efficacy
and tolerability of weak opioids vs low
dose oral morphine (non profit study)
intercycle nausea and vomiting in
patients treated with moderate and high
emetogenic chemotherapy (non profit
study)
SUPPORTIVE
IN CANCER (S
124
Keywords
Treatment-related toxicity,
supportive care,
out-patients
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-wwkly 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 013;14: 66370
Carla Ida Ripamonti, Daniela AP Sichetti, Caterina Fanizza, Elena Gianni Tognoni,
Marilena Romero on the behalf of ECAD_O Working Group. Is pain reporting to health
care professionals age-related? A cross sectional multicenter study in a hospital
serring. Expert Opin. Pharmacother 2013; 14(15): 2011-2017
Bertoldo F, Silvestris F, Ibrahim T, Cognetti F, Generali D, Ripamonti CI et al. Targeting
bone metastatic cancer: role of the mTOR patway. BBA Cancer Reviews (Biochim
Biophys Acta) 2014; Feb 5; 1845/2: 248-254
Ripamonti C, Bossi P, Santini D, Fallon M. Pain related to cancer treatments and
diagnostic procedures: a no man’s land? Annals of Oncology 2014; 25/6: 1097-1106
Distelhorst SR, Cleary JF, Ganz PA, Bese N, Camacho-Rodriguez R, Cardoso F, Ddungu
H, Gralow JR, Yip CH, Anderson BO; Breast Health Global Initiative Global Summit on
Supportive Care and Quality of Life Consensus Panel Members. Optimisation of the
continuum of supportive and palliative care for patients with breast cancer in lowincome and middle-income countries: executive summary of the Breast Health Global
Initiative, 2014. Lancet Oncol. 2015 Mar;16(3):e137-47
OF THE UNIT
CARE
SCCU)
Staff
HEAD
Carla Ida Ripamonti MD
RESEARCH STAFF
Patricia Di Pede, MD; Maria Adelaide Pessi, MD
NURSES
Laura De Taddei, Elisabetta Martinelli, Pietro
Giuseppe Toma
HEALTH CARE ASSISTANTS
Fabio Lizzano, Chiarina Pireddu,
8 Volunteers of Italian League Against Cancer
(LILT Milan section)
6
PUBLICATIONS
35.088
IMPACT FACTOR
1
1.269
11-45, 28
125
ANESTHESIA,
INTENSIVE CARE,
PAIN THERAPY
AND PALLIATIVE C
ANESTHESIA, INTENSIVE CARE,
PAIN THERAPY
AND PALLIATIVE CARE
MARTIN LANGER
Professor of Anesthesia and Critical Care Medicine
University of Milan
martin.langer@istitutotumori.mi.it
CLINICAL ANESTHESIA AND INTENSIVE
CARE
MARTIN LANGER
PALLIATIVE CARE, PAIN THERAPY, AND
REHABILITATION
AUGUSTO T. CARACENI
CLINICAL NUTRITION
CECILIA GAVAZZI
T
he Department has a key
position in the hospital, and
collaborates closely with all
other Clinical Departments for the
treatment of cancer patients. The most
demanding collaboration is certainly
the perioperative treatment of surgical
patients, but efficacious treatment of
pain and symptom relief in the advanced
phase of illness are increasingly
recognized as a right of patients and
quality of life is important as is the
duration of life.
Educating students in anesthesia,
critical care medicine, palliative care,
pain medicine and clinical nutrition
in postgraduate and master courses
and promoting research in this field is
important as is doing so in the clinical
activity.
127
CLINICAL ANESTHESIA
AND INTENSIVE CARE
MARTIN LANGER, Head of the Unit
Clinical activity
Research activity
Networking
INT runs an intense surgical
program (7,240 Operating Room
procedures in 2015 with a mean
surgical time of 1.8 hrs), and is
a referral center for sarcoma, thorax
and retroperitoneum rare tumors, solid
tumors in pediatric patients and major
liver surgery.
As we believe that research is
an essential component of the
good clinical practice, we participate
in some of the surgical projects as well
as running our own specific research.
Both the previous described
studies concerning
anesthetic management of
patients undergoing thoracic surgery,
are multicenter studies coordinated
by the Italian Society of Anesthesia
(SIAARTI).
Besides OR and non-OR anesthesia
(radiological and endoscopic procedures
and placement of long term vascular
accesses), particular attention is paid
to the postoperative analgesia carried
out by the Acute Pain Service that takes
care of patients on continuous epidural
infusion or patient-controlled opioid
analgesia.
During the 2015 the Intensive Care Unit
underwent a long renovation period (July
to October) which reduced the ICU beds
from 6 to 3. This renovation, however,
led to very important improvements
concerning both the structure and the
technical equipment. In spite of the
temporary reduction of the number of
beds, 449 patients were admitted (95%
of admission from OR or surgical wards)
with a mean SAPS 2 score (Simplified
Acute Physiology Score) of 23±11 and
an ICU mortality of 2.6%. The overall
in-hospital mortality of the patients
admitted to the ICU was 4.6%. The
observed in-hospital mortality was
significantly lower than the expected
mortality according to the national GIViTI
network risk calculation.
Our training program for residents
is well established and allows 6-8
trainees yearly to become familiar with
the preoperative assessment, clinical
anesthesia, postoperative intensive care
and acute pain treatment.
In 2015 we completed the enrolment
of >2,200 patients in our OR – infection
prevention study.
“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% povidoneiodine”, which involves also OR nurses
and will help to optimize surgical skin
preparation.
The ICU is collaborating with the
national network GIViTI, an extended
ICU network investigating performance
in order to promote better and safer
treatment. In 2015 our performance
index regarding observed / expected inhospital mortality resulted better than
the mean performance of similar units
(O/E 0.54; 95%CI= 0.28-0.80).
Other scheduled studies address
the respiratory function of patients
undergoing chest wall resection and
rib-like prosthesis in the preoperative,
postoperative and long term follow up
assessment, in order to investigate the
outcome of one of the most innovative
procedures.
Patient management during and
shortly after thoracic surgery is also
investigated in two more Italian
multicenter studies:
a) “protective one lung ventilation (4 ml/
kg per breath) versus conventional
(6 ml/kg breath) ventilation during
lobectomy or pneumonectomy”;
b) “reversal of rocuronium blockade
after thoracic surgery: comparison
of sugammadex vs neostigmin in a
double blinded study”. Both studies
are enrolling patients.
Staff
HEAD
Martin Langer, MD
Daniela Codazzi, MD (Intensive care, Director)
Mario Ammatuna MD, Anna Cardani MD, Roberta
Casirani MD, Valerio Costagli, Pasqualina
Costanzo MD, Ilaria Donati MD, Giuditta Lodovica
Fallabrino MD, Marco Faustini MD, Luca
Fumagalli MD, Edward A. Haeusler MD, Renato
C.F. Manzi MD, Antonio Maucione MD, Silvana
Migliavacca MD, Lucia Miradoli MD, Gabriele
Papagni MD, Laura Persiani MD, Federico Piccioni
MD, Andrea Poli MD, Paola F. Previtali MD, Paolo
L. Proto MD, Giacomino Rebuffoni MD, Giuseppe
Rigillo MD, Maurilia F. Rizzi MD, Emiliano Tognoli
MD, Irene Vecchi MD, Alessandro Zanon MD
CLINICAL ANE
AND INTENSIV
RESIDENTS
Martina Amini MD, Silvia Aresi MD, Alice Ascari
MD, Filippo Bernasconi MD, Chiara Borromeo
MD, Stefano Cornara MD, Irene Galluccio MD,
Giacomo Iapichino MD, Michele Introna MD,
Mario Macrì MD, Stefania Milani MD, Federico
Mondin MD, Giulia Nenna MD, Maria Chiara
Paleari MD, Massimiliano Pirrone MD, Elisa
Serusi MD, Matteo Spalluto MD, Cristina Carin
Sparacino MD, Giulia T.A. Tramontano MD,
Gregorio Spagnolin MD
128
Keywords
anesthesia, intensive
care, postoperative pain
treatment;
Guenzani S, Previtali P, Piccioni F, Allemano MC, Catania S, Langer
M: Pneumothorax Complicating Port-a-Cath and Groshong Catheter
Positioning in Children: Our Experience before Routine UltrasoundGuided Puncture. Open Journal of Anesthesiology, 2013, 3, 345- 48
Piccioni F, Martini L, Bogno L, Rivetti I, Tramontano GTA, Carbonara M, Ammatuna
M, Langer M: An acceleromyographic train-of-four ratio of 1.0 reliably excludes
respiratory muscle weakness after major abdominal surgery: a randomized doubleblind. Can J Anaesth] 2014 Jul; Vol. 61 (7), pp. 641-9.
Piccioni F, Fumagalli L, Garbagnati F, Di Tolla G, Mazzaferro V, Langer M. Thoracic
paravertebral anesthesia for percutaneous radiofrequency ablation of hepatic
tumors. J Clin Anesth. 2014 Jun;26(4):271-5
Poole D, Chieregato A, Langer M, Viaggi B, Cingolani E, Malacarne P, Mengoli F, Nardi
G, Nascimben E, Riccioni L, Turriziani I,Volpi A, Coniglio C, Gordini G, on behalf of the
Trauma Update Working Group: Systematic Review of the Literature and EvidenceBased Recommendations for Antibiotic Prophylaxis in Trauma: Results from an Italian
Consensus of Experts. PLoS One November 2014 | Volume 9 | Issue 11 | e113676
Piccioni F, Mariani L, Negri M, Casiraghi C, Belli F, Leo E, Langer M. Epidural analgesia
does not influence anastomotic leakage incidence after open colorectal surgery for
cancer: A retrospective study on 1,474 patients. J Surg Oncol. 2015 Jul 29
RESEARCH STAFF
Elias Ceravola MD
TECHNICIANS
Maria Irene Cipolletta, Giovanni Di Bari, Nunzia
Di Perna, Gerardo Gizzi, Gianbattista Grazioli,
Monica Mastrogiovanni, Lucia Vellotti, Elisabetta
Zedda
Antonella Nanna, Antonella Nieddu, Nagore
Nieto Lecuona, Anna Orrù, Hipolito Viviano Otani,
Samanta Palmisano, Maria Raffaela Pezone,
Cecilia Pifarotti, Ornella Piredda, Flavia Francesca
Ravasi, Esther Reinoso Crespo, Stefania Ronca,
Maria Jolanda Rosso, Massimo Sanseverino,
Salvatore Santucciu, Sara Sciamanna, Annalisa
Suppa, Filippo Venezia, Silvia Zanotto, Laura
Elisabetta Anselmi, Maria Paola Augello, Marco
Biollino, Beatrice Dibenedetto, Angelo Di Caro,
Paola Fiorentino, Michele Gasparini, Carmen
Greco, Tiziana Iodice, Ndiono Masha Kintaba,
Yuliya Kovhan, Emilia Lonetti, Maria Giovanna
Longo, Ana Isabel Lorenzo Acebes, Katia Masala,
Marica Melis, Monica Mingrino, Anna Maria
Morricella, Andrea Mulas, Chiara Polito, Achille
Simonetti, Paolo Vailati
ESTHESIA
VE CARE
Stefania Bettinardi, Fiorina Cantisani
NURSES
Maria Chiara Allemano, Rosalia Aloe, Elisabetta
Anchora, Marina Balbi, Marco Balconi, Gilda
Barletta, Silvana Bertoli, Gabriella Bianchessi,
Renata Bordonali, Katia Botrugno, Rossella
Brambilla, Debora Buenaventura Boada, Julia
Dasein Burgos Baena, Romano Castellari, Liviu
Dumitru Corbu, Maria Brindusa Corbu, Elena
Cotellessa, Silvia Cuccaro, Matrona De Felice,
Maria Della Croce, Simonetta Delrio, Andrea
Dibiase, Marina Djokic, Luca G. Falcone, Federica
Fiorini, Claudio A. Gasparro, Angelo Giannuzzi,
Rosanna Giumbo, Marcella Gozzo, Elisabeta Ileana
Kertez, Mara Dina Luisoni, Ezio Luzzi, Marianela
Paola Maienza, Margherita Assunta Marzo, Anna
Rita Mazzotta, Tatiana Maria Monfredini, Rosita
Rosa Maria Benevento, Mario Castronovo,
Barbara Patrizia D’Agostin, Denise De Bastiani,
Vincenzo Dellaquila, Annucia Delrio, Antonietta
Giuseppina Fantilli, Maria Maestri, Vincenzo
Marotta, Stefania Masella, Giuseppe Messana,
Marcello Murgia, Maria Concetta Pisasale, Diego
Risuglia, Elisabetta Ione Saccaggi, Carmelo
Antonio Scrofani, Rosa Maria Tirone, Dario
Tonelli, Cristina Marras, Erick Papa, Elena Scotti
OF THE UNIT
12
PUBLICATIONS
35.702
IMPACT FACTOR
9
18.209
1-23, 5
129
PALLIATIVE CARE, PAIN THERAPY,
AND REHABILITATION
AUGUSTO T. CARACENI, Head of the Unit
Clinical activity
Research activity
Networking
The Palliative Care, Pain Therapy
and Rehabilitation Unit provides
multidimensional care to
patients (pts) with advanced
disease and to cancer survivors.
Research areas:
The PC unit is part of:
Health care improvement based
on the development of guidelines
for symptom management and of
integrated care pathways (Quality of
care at the end of life: a comparison
of patients enrolled in a RCT of early
systematic best palliative care versus
on request palliative care consultation
- Italian Health Ministry Research 20112012)
the European Palliative
Care Research Centre.
The overall aim of the scientific
collaboration between the two
institutions is to increase evidence-base
knowledge for the improvement of PC
for cancer patients and their families
and to promote implementation of
evidence into clinical practice through
development of treatment guidelines
and of integrated care pathways;
Palliative care (PC) is the comprehensive
specialized care for pts with advanced
cancer and provides: outpatients visits
and day hospital, admission to hospice
for frail pts with a particular focus on
end of life care, consult service within
the Institute in order to liaise with other
clinical units to improve symptom
control and plan care strategies and
home care program for pts who wish to
spend their last periods of life at home.
During 2015, 996 pts were admitted
to day-hospital and 832 new pts were
examined in the PC clinic. Overall,
6,125 follow-ups and 6,852 symptom
assessments were performed.
The 10 bed hospice-unit admitted 223
pts for symptoms control, respite and
end-of-life care. The home care program
followed 151 pts.
Inpatients consult service monitored 557
pts and performed 2,089 calls. Specific
cancer rehabilitation interventions are
available for chronic lymphedema, pelvic
floor rehabilitation, pain and disability
following surgery and for children
undergoing antineoplastic treatments.
In 2015, the rehabilitation Unit was
consulted for 1,135 new outpatients and
delivered 4,293 treatment courses.
A neurology service is available for pts
with neurological complications. In 2015,
588 new pts were seen by neurologists
and 451 follow-ups were performed.
Translational research in cancer
pain control, including genetics and
prognostication (MOLO 13 studyAIRC IG 2014 Id.15314; The palliative
radiotherapy and inflammation studyPRAIS)
Symptom Assessment and
classification: Episodic pain assessment
and classification, an international
Delphi study; Italian oncologic pain
multisetting - multicentre survey (IOPSMS)
Testing efficacy and tolerability of
PC therapies: Sublingual fentanyl
versus subcutaneous morphine: a
randomized double-blind placebo
controlled trial; duration of analgesia
of single vs. double matrix transdermal
fentanyl patch; A phase II, multicentre,
randomized controlled study in pts with
inoperable malignant bowel obstruction
treated with lanreotide autogel 120 mg
in combination with standard care vs.
standard care alone (IMBO)
Rehabilitation: Pilot study on
decongestive therapies for the
treatment of lymphedema of the lower
limbs; Experimental study on the use
of optic scanner in the measurement
of upper limb lymphedema; Validation
of 3D laser scanner in limb volume
measurement in healthy volunteers
the European Association for
Palliative Care Research Network. The
collaboration is within the project to
update the EAPC guidelines on the use of
opioids for cancer pain management and
to integrate them with a series of new
topics to broaden their scope to cancer
pain management;
the European Commission Initiative on
Breast Cancer coordinated by the Joint
Research Group, JRC. Member of the
Quality Assurance Scheme Development
Group in order to integrate PC in the
breast cancer clinical pathway.
PALLIATIVE CA
AND REHABIL
130
Keywords
Palliative care,
rehabilitation, pain,
symptom control,
quality of life
Hui D, Bansal S, Strasser F, Morita T, Caraceni A, Davis M, Cherny N,
Kaasa S, Currow D, Abernethy A, Nekolaichuk C, Bruera E. Indicators of
integration of oncology and palliative care programs: an international
consensus. Ann Oncol. 2015 Sep;26(9):1953-9
Zecca E, Manzoni A, Centurioni F, Farina A, Bonizzoni E, Seiler D, Perrone T, Caraceni
A. Pharmacokinetic study between a bilayer matrix fentalyl patch and a monolayer
matrix fentanyl patch: single dose administration in healthy volunteers. Br J Clin
Pharmacol. 2015 Jul;80(1):110-5
Staff
HEAD
Augusto T. Caraceni, MD
Augusta Balzarini, MD; Fabio Formaglio, MD;
Fulvia A. Gariboldi, MD; Cinzia A. Martini, MD;
Luigi Saita, MD; Ernesto Zecca, MD
RESIDENTS
Francesca Beacco, MD; Maria Curinga, MD;
Annarita De Vivo, MD; Silvia Lo Dico, MD; Roberta
Massari, MD; Stefania Monsellato, MD
RESEARCH STAFF
Paola Bracchi, MD; Cinzia Brunelli, MSc; Tiziana
Campa, MD; Silvia Grecchi, MD; Andrea Magni,
MD; Alessandra Pigni, MD; Francesca Ricchini,
MD; Carmela P. Sigari, MD; Laura Campanello,
PhyD; Cecilia Mandelli, PsyD; Andrea Manzoni,
MD; Simonetta Zappata, PedD
Brunelli C, Bennett MI, Kaasa S, Fainsinger R, Sjøgren P, Mercadante S, Løhre ET,
Caraceni A; European Association for Palliative Care (EAPC) Research Network;
International Association for the Study of Pain (IASP) Cancer Pain Special Interest
Group. Classification of neuropathic pain in cancer patients: A Delphi expert survey
report and EAPC/IASP proposal of an algorithm for diagnostic criteria. Pain. 2014
Dec;155(12):2707-13
Costantini M, Romoli V, Leo SD, Beccaro M, Bono L, Pilastri P, Miccinesi G, Valenti
D, Peruselli C, Bulli F, Franceschini C, Grubich S, Brunelli C, Martini C, Pellegrini F,
Higginson IJ; Liverpool Care Pathway Italian Cluster Trial Study Group. Liverpool Care
Pathway for patients with cancer in hospital: a cluster randomised trial. Lancet. 2014
Jan 18;383(9913):226-37
Corli O, Montanari M, Greco MT, 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 Jul;17(6):858-66
TECHNICIANS
Marco Carminati, Gian Luigi Cislaghi
PHYSIOTERAPISTS
Livia I. Emerenzian Bedodi, Maria Grazia Blandini,
Chiara Bottani, Simona Breggiè, Elena Caldirola,
Paola Campanini, Lucia M. Cavallini, Anna B.
Cotza, Liviana Craba, Heike Feddersen, Cinzia
A. Ficcarelli, Donato F. Ficchì, Alida M.E. Grossi,
Chiara Piazza, Patrizia Placucci, Raffaella Sensi,
Beatrice Simoncini, Rossella Volta
Emanuela Brusati, Loredana D’Urso, Chiara
Vinuzzi
OF THE UNIT
15
ARE, PAIN THE
LITATION
NURSES
Barbara Acquisto, Giuseppe Baiguini, Sara
Bianchi, Anna Biondo, Giuseppina Bottigliero,
Olmina Di Florio, Massimo Di Francesco,
Antonella B. Ferraresi, Vincenzina Ferraro,
Carmen Rosa Garcia Cuesta, Anna Maria
Mazzucchelli, Nives Porta, Edoardo Rossetti,
Arianna Rossi, Federica S. Rusconi, Annunziata
Sammarro, Gianluigi Schena, Martina Timarani,
Peny Vargas Reategui, Elisabetta Volpato
RESEARCH NURSE
Edoardo Tulli Baldoin
Luigi Abbrescia, Libera Cipolletti, Denise De
Ronzo, Valentina Failla, Salvatore Genovese,
Maria Rosaria Lia, Nataliya Maksymova, Brunella
Martinelli, Teresa Natali, Teresa Pace
PUBLICATIONS
49.173
IMPACT FACTOR
1
3.878
1-42, 11
131
CLINICAL NUTRITION
CECILIA GAVAZZI, Head of the Unit
Clinical activity
Research activity
Networking
Malnutrition is well known to
be a negative prognostic factor
in the final prognosis of cancer
patients, increasing treatment
toxicities, morbidity and mortality. Goal
of the unit is the prevention and the
cure of malnutrition in order to improve
tolerance and response to cancer
therapy and quality of life. In agreement
with national and international
guidelines, a nutritional screening is
performed on all patients with high risk
of malnutrition, mainly patients affected
by gastrointestinal and head and neck
cancer and patients candidates to
major surgery. Malnourished patients
are then included in a nutrition support
programme and they are treated with
artificial nutrition whenever necessary.
Development of an algorithm
for the correct nutrition therapy
in cancer patients. International
guidelines for nutrition support in
cancer patients do not address to
specific cancer type, stage and oncologic
treatment. Therefore, the main goal
of the project is the development and
implementation of algorithms for the
correct nutrition therapy in different
type of cancer and phases of oncologic
course. Algorithms are developed after
review of related bibliography and
validated on at least 30 patients with
specific cancer types.
The Unit is part of “Rete
Lombarda NAD”, a network
of Clinical Nutrition Centre
responsible for patients treated with
home artificial nutrition.
In 2015, approximately 350 patients have
been included in a nutrition support
programme, 1,881 day of nutrition
therapy has been administered in
hospitalized patients and 94 patients
have continued artificial nutrition at
home for more than three months.
Thirty-five per cent of supported
patients were affected by upper
GI cancer, 25% by head and neck
cancer, while sarcoma in adults and
paediatric patients were reported
in 18% of nutritionally supported
patients. Patients affected by upper
GI cancer have been supported with a
personalized nutrition program from
diagnosis to the end of planned chemoradiotherapy, successfully maintaining
a good nutritional status and an
acceptable quality of life.
The Unit is part of the working group
“Nutrition in oncology” AIOM -SINPE
(Italian Association of Medical Oncology
– Italian Society of Artificial Nutrition
and Metabolism), which is assigned
to develop recommendations and
educational sessions for the correct
nutritional support in cancer patients.
Nutritional Screening with bioelectrical
impedance. Prospective, observational,
multicentre study in newly detected
cancer patients candidate to
chemotherapy. Major aim of this study is
to evaluate the prognostic value of the
bioelectrical impedance phase angle,
as an indicator of nutritional status, on
oncologic toxicity.
CLINICAL NUT
132
Keywords
Malnutrition, nutrition
therapy, quality of life
Kusamura S, Baratti D, Hutanu I, Gavazzi C, Morelli D, Iusco Dr,
Grassi A, Bonomi S, Virzi S, Haeusler E, Deraco M. The role of baseline
inflammatory-based scores and serum tumor markers to risk stratify
pseudomyxoma peritonei patients treated with cytoreduction (CRS) and
hyperthermic intraperitoneal chemotherapy (HIPEC). Ejso 2015;41:1097-1105
Bozzetti F, Santarpia L, Pironi L, Thul P, Klek S, Gavazzi C, Tinivella M, Joly F, Jonkers C,
Baxter J, Gramlich L, Chicharro L, Staun M, Van Gossum A, Lo Vullo S, Mariani L. The
prognosis of incurable cachectic cancer patients on home parenteral nutrition: A
multi-centre observational study with prospective follow-up of 414 patients. Annals
Of Oncology 2014;25:487-493
Pietrantonio F, Maggi C, Fanetti G, Iacovelli R, Di Bartolomeo M, Ricchini F, Deraco
M, Perrone F, Baratti D, Kusamura S, Tamborini E, Castano A, Consonni Pv, Bossi I,
Gavazzi C, Milione M, Pelosi G, De Braud F. Folfox-4 chemotherapy for patients with
unresectable or relapsed peritoneal pseudomyxoma. Oncologist 2014;19:845-850
Staff
HEAD
Cecilia Gavazzi, MD
Serena Della Valle, MD
RESIDENTS
Vanessa La Vela, MD
TRITION
RESEARCH STAFF
Michela Bassano, RD
OF THE UNIT
1
PUBLICATIONS
3.009
NURSES
Franca Filincieri, Carmelina Maiorana,
Lorena G. Riva
IMPACT FACTOR
TECHNICIANS
Silvia Colatruglio, RD
1-17, 9
133
DIAGNOSTIC
IMAGING
AND
RADIOTHERAPY
DIAGNOSTIC IMAGING
AND RADIOTHERAPY
ALFONSO MARCHIANÒ
alfonso.marchiano@istitutotumori.mi.it
RADIATION ONCOLOGY 1
RICCARDO VALDAGNI
CARLO FALLAI
DIAGNOSTIC AND INTERVENTIONAL
RADIOLOGY
ALFONSO MARCHIANÒ
NUCLEAR MEDICINE
FLAVIO CRIPPA
MEDICAL PHYSICS
EMANUELE PIGNOLI
Until October 2015
ALFONSO MARCHIANÒ
Interim since November 2015
T
he 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 hightechnology facilities and supports the
implementation of biologic imaging and
image-guided contouring radiotherapy.
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.
135
RICCARDO VALDAGNI, Head of the Unit
Clinical activity
Research activity
Networking
Radiation Oncology 1 (RTO1)
provides radical and palliative
radiation (RT) to patients
with breast, genitourinary,
gastrointestinal and lung cancers,
bone and soft tissue sarcomas,
lymphomas, and pediatric cancers,
with a multidisciplinary approach and
according to national and international
guidelines or research protocols. In 2015,
1,749 patients were treated. Based on
tumor site or patient age, treatments
were as follows: breast 480 (27.4%),
genitourinary 247 (14.1%), pediatric 158
(9%), bone and soft tissue sarcomas
105 (6%), gastrointestinal 97 (5.5%),
hematological 96 (5.5%), lung 82
(4.7%), skin 2 (0.1%). RTO1 also offers
symptomatic/palliative RT. In 2015, 482
(27.5%) patients have been treated with
palliative intent. To limit the discomfort
of this fragile subset of patients, a new
outpatient clinic has been activated
for a fast track start of symptomatic
RT. Particular attention and efforts are
dedicated to improve new technologies
in daily clinical practice, such as IMRT,
VMAT and IGRT in each specific clinical
setting. Calypso 4D Localization System,
a tool that utilizes radiofrequency waves
to align the prostate very precisely
before and during each treatment
session, was utilized in 73 patients.
Adoption of the Calypso System in other
clinical settings is on progress. Standard,
moderate or extreme hypofractionation
are routinely used.
RTO1 focuses its research
activity on the following
areas: radio-toxicity, through
the development and validation of
predictive models and the evaluation
of gene profiles in breast, prostate and
lung cancers; palliative radiotherapy, by
the development of predictive models
of outcome, through the evaluation of
inflammatory biomarkers; the role of RT
in the multidisciplinary setting, through
the application of clinical protocols
where irradiation is used in combination
with surgery and/or chemotherapy;
RT techniques and fractionations,
such as partial breast irradiation (PBI)
delivered by Cyberknife, or SBRT boost
in prostate cancer patients, with the
use of VMAT. Pediatric RT activity is
focused on ameliorating outcome of
oncologic treatments in the youngest
by adopting international clinical
studies in GCP, also aiming at identifying
biological prognostic factors, and by
investigating effects of different RT
doses absorbed by tissues, such as the
nervous one, that are very susceptible to
radiation damages in the pediatric and
adolescence age.
RTO1 collaborates with
Istituto Neurologico
Besta; Istituto Europeo
di Oncologia; Centro Nazionale di
Adroterapia Oncologica; Ospedale San
Raffaele; Italian National Research
Council-Institute of Molecular
Bioimaging and Physiology; Politecnico
di Milano; Associazione Italiana di
Ematologia and Oncologia Pediatrica;
Société International d’Oncologie
Pediatrique;German Cancer Research
Centre; Mount Sinai School of Medicine;
Maastricht Radiation Oncology;
University of Manchester; University of
Montpellier; Centre Regional Hospitalier
Universitaire of Lille; Erasmus Medical
Center, Rotterdam; John Hopkins
University, Baltimore; University School
of Medicine of Kagawa; Memorial Sloan
Kettering Cancer Center, NY; PMCC,
Toronto; Sunnybrook Health Sciences
Center, Toronto; University College,
London; The Royal Marsden, London;
University of California, San Francisco.
RADIATION ON
136
Keywords
Radiotherapy,
predictive Models of radioinduced toxicity, validation of
predictive models, IGRT, new
technologies, multidisciplinarity,
quality of life
Maggio A, Magli A, Rancati T, Fiorino C, Valvo F, Fellin G, Ricardi U,
Munoz F, Cosentino D, Cazzaniga LF, Valdagni R, Vavassori V. Daily
sodium butyrate enema for the prevention of radiation proctitis in
prostate cancer patients undergoing radical radiation therapy: results of
a multicenter randomized placebo-controlled dose-finding phase 2 study. Int J Radiat
Oncol Biol Phys 2014; 89(3):518-24
Cozzarini C, Rancati T, Carillo V, Civardi F, Garibaldi E, Franco P, Avuzzi B, Esposti CD,
Girelli G, Iotti C, Palorini F, Vavassori V, Valdagni R, Fiorino C. Multi-variable models
predicting specific patient-reported acute urinary symptoms after radiotherapy for
prostate cancer: Results of a cohort study. Radiother Oncol 2015; 116(2):185-91
Staff
HEAD
Riccardo Valdagni, MD, PhD
Laura A.M. Lozza, MD, (Breast cancer
Radiotherapy, Director), Lorenza Gandola, MD,
(Pediatric Radiotherapy, Director), Sergio Villa,
MD, (Genitourinary Radiotherapy, Director),
Barbara Avuzzi, MD, Nice Bedini, MD, Anna
Di Russo, MD, Claudia Sangalli, MD, Fulvia M.
Soncini, MD
RESIDENT
Michela Dispinzieri, MD
Terenziani M, Massimino M, Magazzù D, Gandola L, Capri G, Carcangiu ML, Catania S,
Di Russo A, Gennaro M, Meazza C, Podda M, Schiavello E, Valagussa P. Management
of breast cancer after Hodgkin’s lymphoma and paediatric cancer. European Journal
Of Cancer 2015; 51:1667-1674
Martelli G, Boracchi P, Guzzetti E, Marano G, Lozza L, Agresti R, Ferraris C, Piromalli
D, Greco M. Omission of radiotherapy in elderly patients with early breast cancer: 15year results of a prospective non-randomised trial. European Journal of Cancer 2015;
51, 1358-1364
Palassini E, Ferrari S, Verderio P, De Paoli A, Martin Broto J, Quagliuolo V, Comandone
A, Sangalli C, Palmerini E, Lopez Pousa A, De Sanctis R, Bottelli S, Libertini M, Picci
P, Casali PG, Gronchi A. Feasibility of preoperative chemotherapy with or without
radiation therapy in localized soft tissue sarcomas of limbs and superficial trunk in
the Italian sarcoma group/grupo español de investigación en sarcomas randomized
clinical trial: Three versus five cycles of full-dose epirubicin plus ifosfamide. Journal
Of Clinical Oncology 2015; 33:3628-3634
RESEARCH STAFF
Davide G. Bosetti, MD, Maria Carmen De Santis,
MD, Barbara Diletto, MD, Marzia Franceschini,
MD, Elisa D. Mantero, MD, Sara Morlino, MD,
Emilia Pecori, MD
TECHNICIANS
Claudio Boccadamo, Giuseppina M. Bonanno,
Alberto Buzzetti, Carmelo Campolo, Federica
Caputo, Gabriele Carabelli, Pasquale Contessa,
Lucio Donatone, Rosa Fortunato, Sarah C.
Frasca, Franca Gaetano, Emanuela Gatti,
Sonia Gili, Manuela Guerra, Paola E. Pierobon,
Antonio Spartano, Francesca Spartano, Rossella
Tamburelli, Carla G. Valenti
PROJECT MANAGER
Mariarita C. Cassese
CLINICAL TRIAL MANAGER
Simona Alessandra Gay
DATA MANAGER
Laura Andreoli
Donatella G. Orlandi, Patrizia Riva
NURSES
Donata Bertolesi, Pasquale Brunacci, Flavia
Montalto, Maria E. Visentin
OF THE UNIT
18
PUBLICATIONS
106.297
IMPACT FACTOR
1
4.027
NCOLOGY 1
RESEARCH NURSES
Edoardo Tulli Baldoin
Grazia Arpaia, Raffaela Diaferio, Romana Rosaria
Fiolo, Giuseppe Murru, Sebastiano Sicilia, Maria
Cristina Terenghi
1-30, 5
137
CARLO FALLAI, Head of the Unit
Clinical activity
Research activity
Networking
Inpatients activity
Ginecologic cancer. Gynadart:
“Adaptive” and MRI guided
Brachytherapy in the exclusive
treatment of locally advanced cervix
cancer according to the European
excellence standards: study of
the treatment quality in terms of
applicability, clinical and dosimetric
outcomes.(INT 53/15, CE approval
26/2/2015) GD Del. 28/08/2015. In
2015, 19 patients with locally advanced
cervix cancer (FIGO IB2-IVA) underwent
brachytherapy , with MRI used for
treatment planning before each session.
Participation into the head
and neck cancer PDTA
(Diagnostic therapeutic
pathways) elaboration with ROL
(Lombardy Oncologic Network) and
AIOCC (Italian Head and Neck Oncologic
Society).
Radiation Oncology 2 has a
section with eight beds for
patients needing hospitalization
for radiotherapy or radio-chemotherapy
procedures, supportive therapy, and
interventional manoeuvres. During
2015, there were 314 hospitalizations.
Of these, 254 patients underwent
radiotherapy procedures.
Outpatients activity
Radiotherapy of Head and Neck Cancer is
an essential part of the activities of the
Head and Neck Cancer Multidisciplinary
Group. All patients are subjected to
CT simulation, generally with contrast
medium, and personalized positioning
devices (masks). In 2015, 191 patients
affected with head and neck cancer were
irradiated curatively (161) or palliatively.
All patients treated with curative intent
were treated with VMAT.
The radiation treatment of gynecologic
cancers is also an essential part of
our activities. During 2015, 87 patients
were treated with curative intent and
43 with palliative intent with external
beam radiotherapy (VMAT) and/or
High-Dose Rate brachytherapy (HDRBCT). Seventy-seven patients had
brachytherapy as part of their treatment.
Overall, mostly in the cervix cancer, 128
cycles of concurrent chemotherapy were
given.
Brachytherapy for prostate cancer
consists of one or two sessions of
interstitial HDR-BCT under continuous
ultrasound guidance depending on
whether used as a boost or as exclusive
treatment. Twelve procedures were
performed in 2015.
Head and neck cancer. SINTART 1 – 2:
Multidisciplinary approach for bad
prognosis sinonasal tumors : a phase
II study about integration of surgery,
chemotherapy, radiotherapy with
photons and/or heavy ions looking for
more efficient and less toxic treatment
both in operable or inoperable patients.
(approved 27/4/2015, del. n. 230/F
session n. 43).
For heavy ions, a cooperation was
agreed on with the CNAO center in Pavia.
Overall, 15 patients were enrolled in the
trial in 2015, 6 in the operable and 9 in
the inoperable group.
Prophilactic treatment with MDD001
to reduce the radiation dermatitis
in patients undergoing curative
radiotherapy for head and neck cancer:
41 patients accrued in 2015.
A predictive model to stratify patients
according to treatment related toxicity
and survival after radio-chemotherapy
for head and neck cancer: 10 patients
accrued in 2015.
RADIATION ON
138
Keywords
Head and neck cancer;
gynecologic cancer;
brachytherapy
Alterio D, Ciardo D, Preda L, Argenone A, Caspiani O, Micera R, Ruo Redda
MG, Russi EG, Bianchi E, Orlandi E, Bacigalupo A, Busetto M, Cante D,
Deantonio L, De Sanctis V, Franco P, Lastrucci L, Marucci L, Merlotti A,
Molteni M, Pajar F, Rampino M, Santoro L, Ferrari A, Bazzani F, Caputo
M, Laudati A, Borzillo V, Falivene S, Simoni N, Vigo F, Iannacone E, Reali A, Bonanni A,
Leone M, Giannello L, Taglianti RV, Orecchia R. Contouring of the Pharyngeal Superior
Constrictor Muscle (PSCM). A cooperative study of the Italian Association of Radiation
Oncology (AIRO) Head and Neck Group. Radiother Oncol. 2014 Sep;112(3):337-42
Orlandi E, Giandini T, Iannacone E, De Ponti E, Carrara M, Mongioj V, Stucchi C, Tana
S, Bossi P, Licitra L, Fallai C, Pignoli E. Radiotherapy for unresectable sinonasal
cancers: dosimetric comparison of intensity modulated radiation therapy with
coplanar and non-coplanar volumetric modulated arc therapy. Radiother Oncol. 2014
Nov;113(2):260-6
Orlandi E, Tomatis S, Potepan P, Bossi P, Mongioj V, Carrara M, Palazzi M, Franceschini
M, Bergamini C, Locati L, Iannacone E, Guzzo M, Ibba T, Crippa F, Licitra L, Pignoli
E, Fallai C. Critical analysis of locoregional failures following intensity-modulated
radiotherapy for nasopharyngeal carcinoma. Future Oncol. 2013 Jan;9(1):103-14
Schindler A, Denaro N, Russi EG, Pizzorni N, Bossi P, Merlotti A, Spadola Bissetti
M, Numico G, Gava A, Orlandi E, Caspiani O, Buglione M, Alterio D, Bacigalupo A, De
Sanctis V, Pavanato G, Ripamonti C, Merlano MC, Licitra L, Sanguineti G, Langendijk JA,
Murphy B. Dysphagia in head and neck cancer patients treated with radiotherapy and
systemic therapies: Literature review and consensus. Crit Rev Oncol Hematol. 2015
Nov;96(2):372-84
Tana S, Avuzzi B. [Seminona of stage I: strategies compared]. Urologia. 2013 JulSep;80(3):207-11
Staff
HEAD
Carlo Fallai, MD
Annamaria Cerrotta, MD; Ester Orlandi, MD; Silvia
Tana, MD
RESIDENTS
Simona Naimo, MD; Gabriella Rossi, MD
RESEARCH STAFF
Monica A. Garcia, MD; Nicola A. Iacovelli, MD;
Brigida Pappalardi, MD
TECHNICIANS
Paolo D’Agnese, Carmelo Di Marco, Piera Fusar
Poli, Dayana Pignata, Ciro Pintaudi, Rossella P.
Tamburelli
Paola Sabatino
NURSES
Roberta Albasini, Rosa Attolino, Luigia Cerra,
Ilaria Chiofalo, Cinzia Cocca, Giuseppe L’Abbate,
Antonio Lucenti, Filippo Monno, Erminia
Nardo, Vincenza Natola, Ilenia Nigro, Elena
Omati, Michela Saracino, Fabio Scoletta, Luigi
Tamburrino, Gianni Virgilio
OF THE UNIT
4
PUBLICATIONS
18.267
IMPACT FACTOR
1-14, 8
NCOLOGY 2
Angela Abatangelo, Lucia Di Murro, Rosa Farro,
Brenilda Fuentes, Giuseppe Gaglio, Virginia
Marini, Tatiana Parolo
139
DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY
ALFONSO V. MARCHIANÒ, Head of the Unit
Clinical activity
Research activity
Keywords
At the end of 2015 the two
existing radiological Unit have
been merged in the current
Diagnostic and Interventional
Radiology Unit. Diagnostic oncology
and interventional-oriented radiology
represent the core activity of the
Unit. The Unit includes traditional
radiology, breast imaging, CT, MRI and
ultrasound. Breast imaging has all the
diagnostic and interventional tools
needed in an advanced comprehensive
cancer center: 2 Full Field Digital
Mammography units equipped with
breast tomosynthesis, 3 breast
ultrasound units, 1 stereotactic table
and a VABB system (Vacuum Assisted
Breast Biopsy) for percutaneous imageguided biopsies. Two CT scanners are
available, both with fast multislice
scanning capacity and about 25,000
diagnostic examinations per year and
a substantial number of interventional
radiologic procedures are carried out.
Interventional radiology activities
include long-term venous central
catheter placement, embolization,
and chemoembolization for regional
cancer treatment. Intralesional ablation
with various technologies, such as the
chemo-interventional procedures are
successfully performed. During 2015,
over 1,200 vascular and non-vascular
interventional procedures, over 500
long-term venous central catheters,
and over 1,100 percutaneous biopsies in
various body districts were performed.
During 2015, the process of necessary
technological upgrade of the department
has been continued and an additional
MRI 1.5 T unit was installed.
The Unit has a number of
ongoing collaborations at the
national and international levels.
The Unit is continuously improving
and working in this issue with ongoing
collaboration with the Radiotherapy
Unit for treatment planning for uterine
cancer with a research feasibility
study. Furthermore, response to
treatment is under investigation for
breast cancer and oropharyngeal
squamous cell carcinoma. The Unit
is involved in several multicenter
ongoing MRI studies; fields of scientific
interest are: pediatric MRI, focused on
neurooncology, soft tissue sarcomas,
oronasopharyngeal carcinoma, and
colorectal cancer. The lung cancer
screening program (bioMILD) with “low
dose” spiral CT continued in 2015. An
international multicentric study on the
treatment of inoperable hepatocellular
carcinoma with intra-arterial injection of
yttrium-90 radiolabeled microspheres
is ongoing in collaboration with Units of
Nuclear Medicine and Gastrointestinal
and Hepatopancreatobiliary Surgery and
liver Transplantation.
Interventional radiology,
screening,
breast biopsy
RADIOLOGY 2
AND INTERVE
RADIOLOGY)
140
Staff
HEAD
Alfonso V. Marchianò, MD
Morosi C, Stacchiotti S, Marchianò A, Bianchi A, Radaelli S, Sanfilippo
R, Colombo C, Richardson C, Collini P, Barisella M, Casali PG, Gronchi
A, Fiore M. Correlation between radiological assessment and
histopathological diagnosis in retroperitoneal tumors: analysis of 291
consecutive patients at a tertiary reference sarcoma center. Eur J Surg Oncol. 2014
Dec;40(12):1662-70
Rodolfo Lanocita (Interventional Ultrasound
Unit), Carlo Morosi (Pediatric Imaging Unit),
Gianfranco P. Scaperrotta (Breast Radiology
Unit), Davide Scaramuzza (Traditional Radiology
Unit), Carlo Spreafico (Gastrointestinal
Interventional Radiology Unit), Daniele Vergnaghi
(Magnetic Resonance Unit), Giuseppina Calareso,
MD, Tommaso Cascella, MD, Enrico M. Civelli,
MD, Giuseppe Di Tolla, MD, Claudio Ferranti,
MD, Laura F. Frigerio, MD, Giorgio Greco, MD,
Alberto Laffranchi, MD, Monica Marchesini, MD,
Antonella Messina, MD, Monica Salvetti, MD,
Laura Suman, MD, Paolo Potepan, MD, Giovanna
Trecate, MD
RESEARCH STAFF
Alessandra Casale, MD, Francesca G. Greco, MD,
Alessandra Primolevo, MD, Marta Vaiani, MD,
Sara Viganò, MD
RESIDENTS
Luke Bonello, MD, Emanuela Capalbo, MD,
Francesco Cartia, MD, Maria Cosentino, MD,
Giuseppe Di Pisa, MD, Henrida Kule, MD, Roberta
Magnani, MD, Silvana Sdao, MD, Adriana Vella,
MD
Spreafico C, Morosi C, Maccauro M, Romito R, Lanocita R, Civelli EM, Sposito C,
Bhoori S, Chiesa C, Frigerio LF, Lorenzoni A, Cascella T, Marchianò A, Mazzaferro
V. Intrahepatic Flow Redistribution in Patients Treated with Radioembolization.
Cardiovascular and Interventional Radiology 2015;38:322-328
Spreafico C, Cascella T, Facciorusso A, Sposito C, Rodolfo L, Morosi C, Civelli
EM, Vaiani M, Bhoori S, Pellegrinelli A, Marchianò A, Mazzaferro V. Transarterial
Chemoembolization for Hepatocellular Carcinoma with a New Generation of Beads:
Clinical-Radiological Outcomes and Safety Profile. Cardiovascular and Interventional
Radiology 2015;38:129-134
Chiesa C, Mira M, Maccauro M, Spreafico C, Romito R, Morosi C, Camerini T, Carrara M,
Pellizzari S, Negri A, Aliberti G, Sposito C, Bhoori S, Facciorusso A, Civelli E, Lanocita R,
Padovano B, Migliorisi M, De Nile Mc, Seregni E, Marchianò A, Crippa F, Mazzaferro V.
Radioembolization of hepatocarcinoma with 90Y glass microspheres: development of
an individualized treatment planning strategy based on dosimetry and radiobiology.
European Journal Of Nuclear Medicine And Molecular Imaging 2015;42:1718-1738
TECHNICIANS
Gaetano Annunziata, Marilena Barbiero, Pietro
Basile, Luisa Colombo, Luciana Dedei, Enrico F.
Depedri , Maria Ferrarello, Cristina Folini, Maria
Rosaria Fossaceca, Roberto Gallo, Giuseppina
Gentile, Maria Giovanna Grossi, Luca Lanzilotti,
Antonietta Laturra, Maria Pia Mannella, Tina
Mastrostefano, Luca Musumeci, Roberto Nioi,
Carmelina Pannone, Nicola Pulerà, Stefania Sala,
Anna Tavola, Luciana G. Tanzini, Vanni Tirella,
Giulia Truppi, Valeria Tosi, Maurizio Zattoni
2 (DIAGNOSTIC
ENTIONAL
Ornella Venegoni
DATA MANAGER
Fabrizio Baggio
NURSES
Pietro Ciccarese, Laura Fagnani, Mirella
Ferruccio, Addolorata Mauro, Nadia Nicoletti,
Loredana Palella, Roberta S. Populin, Pietrina
Sanna, Rosanna Scarpa
Marco Andreon, Maria Blumetti, Paola Bottiglieri,
Maria Cristina Gizzi, Tiziana Marzo, Antonio
Labori, Giacomo G. Leone
OF THE UNIT
22
PUBLICATIONS
89.578
IMPACT FACTOR
5
10.201
1-25, 10
141
NUCLEAR MEDICINE
FLAVIO CRIPPA, Head of the Unit
Clinical activity
Research activity
Networking
The Unit is fully-inclusive
nuclear medicine facility with
integrated sections where
various procedures for imaging
and therapy are performed in adult
and pediatric cancer patients. For
nuclear medicine therapies, patients
can be hospitalized in isolated and
protected rooms inside the Unit. An
endocrine outpatient clinic is available.
The Unit staff is a multidisciplinary
team formed by graduate and postgraduate specialists (engineers,
chemists, physicists, biologists, nuclear
medicine physicians), technicians and
nurses. The main technical equipments
of the Unit are a 17 MeV cyclotron, 2
radiochemistry laboratories for the
production of beta- and gammaemitter radiopharmaceuticals, 1 bone
densitometry scan, 2 stand-alone
gamma cameras, 1 SPECT/CT scanner, 2
PET/CT scanners. A laboratory equipped
with a micro-PET system for pre-clinical
imaging of small animals tumor models
is available.
The main clinical research
activities involved:
IATRIS - Task Force “Imaging
and Tracers”
PET/CT imaging for cancer prognostic
characterization and therapy response
assessement in various clinical models;
New methological approaches to
visualize metastatic lymph nodes;
Optimization of intra-arterial
radioembolization of HCC with Y-90
glass microspheres using individualized
dosimetry methods;
Comparison of 99mTc-MAA pre-therapy
versus 90Y peri-therapy microspheres
dosimetry;
Optimization of new 99mTc SPECT-CT
reconstruction methods for simulation
imaging in radioembolization;
Optimization of Y-90 and Lu-177
somatostatin analogues preparation for
NET radiometabolic therapy.
The 2015 clinical activity of the Unit was
as follow: about 10,000 conventional
scintigraphic and PET/CT procedures
and about 2,000 bone densitometry
scans have been performed. About
400 nuclear medicine treatments with
appropriate radiopharmaceuticals have
been performed in patients affected
by thyroid cancer (33% of treatments)
and other type of malignancies (67% of
treatments), including neuroendocrine
tumors, lymphomas, malignant
neuroectodermal tumours, primary liver
cancer and bone metastases; about
3,800 outpatient clinical examinations
have been performed.
NUCLEAR ME
142
Keywords
Metabolic Imaging,
hybrid Imaging,
PET/CT, therapy response,
nuclear medicine
therapy, radiopharmaceuticals,
radioembolization, Y-90 microspheres
dosimetry
S. Stacchiotti, E. Tamborini, S. Lo Vullo et al. Phase II study on lapanitib in
advanced EGFR-positive chordoma. Ann Oncology 24:1931-1936, 2013
P. Giannatempo, A. Alessi, R. Micheli et al. Interim F-18 Fluorodeoxyglucose
Positron Emission Tomography for early metabolic assessment of
therapeutic response to chemotherapy for metastatic transitional cell carcinoma. Clin
Genitourinary Cancer 12(6):433-439, 2014
L. Farina, F. Rezzonico, F. Spina et al. Serum thymus and activation-regulated
chemokine level monitoring may predict disease relapse detected by PET scan
after reduced-intensity allogenic stem cell transplantation in patients with Hodgkin
Lymphoma. Biol Blood Marrow Transplantation 20: 1982-1988, 2014
F. Crippa, R. Agresti, M. Sandri et al. F-18-FLT PET/CT a an imaging tool for early
prediction of pathological response in patients with locally advanced breast cancer
treated with neoadjuvant chemotherapy: a pilot study. Eur J Nucl Med Mol Imaging
42:818-830, 2015
C. Chiesa, M. Mira, M. Maccauro et al. Radioembolization of hepatocarcinoma with
Y-90 glass microspheres: development of an individualized treatment planning
strategy based on dosimetry and radiobiology. Eur J Nucl Med Mol Imaging 42:17181738, 2015
Staff
HEAD
Flavio Crippa, MD
Alessandra Alessi, MD (Clinical PET, Director);
Ettore Seregni, MD (Nuclear therapy and
endocrinology, Director); Gianluca Aliberti, MD;
Anna Bogni, Biol Sci D; Maria Rita Castellani, MD;
Carlo Chiesa, Phys D, Alice Lorenzoni, MD; Marco
Maccauro, MD; Claudio Pascali, Chem D; Gianluca
Serafini, MD
RESIDENTS
Carlotta B. Colombo, MD; Laura Olivari, MD;
Marta Mira, Phys D
RESEARCH STAFF
Barbara Padovano, MD; Federica Pallotti, MD;
Claudio Cucchi, Chem D; Elisa Galli, Chem D, Luca
Laera, Chem D
TECHNICIANS
Grazia Aprigliano, Davide Bassani, Sergio Bavusi,
Antonella Colombo, Gianenrico Cucchetti,
Maria Di Francesco, Martino Faedi, Deborah
Mansi, Veronica Nasari, Luigia Parello, Rossana
Pavesi, Matteo Ragazzoni, Roberto Segreti, Lidia
P.M. Spano, Rosella G. Spina, Monica Testoni,
Consuelo Zanette
Rosangela Ghilardi
EDICINE
NURSES
Maria Cristina De Somma, Carmela Fallacara,
Dario Longo, Calogero Oliveri, Aurelio A.
Scarabelli, Rita Sicari
Madeleine Borda, Fabrizio D’Amico, Maria
Concetta Pirrotta
OF THE UNIT
8
PUBLICATIONS
38.106
IMPACT FACTOR
2
10.766
1-33, 10
143
MEDICAL PHYSICS
EMANUELE PIGNOLI, Head of the Unit (Until October 2015)
ALFONSO V. MARCHIANÒ, Head of the Unit (Interim since November 2015)
Clinical activity
Research activity
Networking
Clinical activity of the Medical
Physics Unit is mainly for
patients who received
radiotherapy. Our activity
consisted in the study, planning, and
optimization of the radiation treatments
for every new patient. In 2015 a total of
2,431 patients were treated of which: 115
were treated by brachytherapy and 2316
by external beam radiotherapy.
Main area of research:
Referee center for the
quality control of treatment
plans of medulloblastoma
pathology in children. Creation of a
dedicated cloud platform to allow
plans reviews before the beginning
of the treatment in 14 italian centers
participating to PNET5 protocol.
In addition, a mandatory activity
for the Medical Physics Unit is to
participate in quality assurance
programs for both radiotherapy and all
radiological equipments. A lab is active
to manage dosimetry, film-badge and
thermoluminescent (TL) dosimeters,
for controlling personnel exposed to
ionizing radiation. In the 2015, our lab
processed more than 8,500 films and
1,660 TL dosimeters. The service also
provides support to specific dosimetric
questions in radiation therapy, for in vivo
dosimetry, or in some diagnostic checks
on X-ray equipment.
Retrospective and prospective
study of white and gray matter
alterations visible with DTI after focal
radiotherapy for childhood brain
cancer to correlate radiotherapy doses,
neurocognitive outcome and behavioral
problems.
A large study is started to identify the
more suitable physical parameters
of medical displays for a faithful
reproduction of medical images and to
quantify possible bias in medical images
interpretation.
Evaluation of the intra-fraction prostate
motion during radiotherapy sessions by
means of the Calypso electromagnetic
system (Varian Medical Systems):
quantification of the motion induced by
patients’ breathing.
Use of Cone-Beam CT scan anchored
to the radiotherapy linac to monitor
patients anatomic changes during
the course of radiotherapy, in order to
perform a treatment replanning when
target volumes deformations and
tissues shrinkage lead to significant
changes in the dose distribution.
In collaboration with the Centre for
Medical Radiation Physics, University
of Wollongong (Australia), study of
instruments and methods to perform
in vivo dosimetry in gynecological and
prostate HDR brachytherapy.
Within the collaboration with the
Prostate Program Unit, development of
non-linear classification models for the
prediction of rectal toxicity following
prostate radiotherapy.
Multi-institutional research project
“Carbon ions boost followed by pelvic
photon radiotherapy for high risk
prostate cancer”, with the aim to test the
feasibility and safety of a new treatment
schedule for high risk prostate cancer,
based on the delivery of a carbon ions
boost to the prostate followed by pelvic
intensity modulated radiation therapy.
A prospective study of the native
fluorescence of blood plasma in patients
with colorectal cancer is ongoing.
A multidisciplinary approach for poor
prognosis sinonasal tumors where
radiotherapy with mixed X-ray and
particle beams are used for more
effective and less toxic treatment in
inoperable and operable patients.
Optimization of the treatment workflow
for external beam radiotherapy and
MRI-guided HDR brachytherapy of cervix
cancer.
MEDICAL PHY
144
Keywords
Radioterapy treatment plan,
dosimetry, quality assurance
Orlandi E., Tomatis S., Potepan P., Bossi P., Mongioj V., Carrara M., Palazzi
M., Franceschini M., Bergamini C., Locati L., Iannacone E., Guzzo M., Ibba
T., Crippa F., Licitra L., Pignoli E., Fallai C.: Critical analysis of locoregional
failures following intensity-modulated radiotherapy for nasopharyngeal
carcinoma. Future Oncol 2013; 9: 103-114
Carillo V., Cozzarini C., Rancati T., Avuzzi B., Botti A., Borca V.C., Cattari G., Civardi
F., Esposti C.D., Franco P., Girelli G., Maggio A., Muraglia A., Palombarini M., Pierelli
A., Pignoli E., Vavassori V., Zeverino M., Valdagni R., Fiorino C.: Relationships
between bladder dose-volume/surface histograms and acute urinary toxicity after
radiotherapy for prostate cancer. Radiother Oncol 2014; 111: 100-105
Carrara M., Tenconi C., Guilizzoni R., Borroni M., Cavatorta C., Cerrotta A., Fallai C.,
Gambarini G., Vedda A., Pignoli E.: Stem effect of a Ce3+ doped SiO2 optical dosimeter
irradiated with a 192Ir HDR brachytherapy source. Radiat Phys Chem 2014; 104: 175179
Orlandi E., Giandini T., Iannacone E., De Ponti E., Carrara M., Mongioj V., Stucchi C., Tana
S., Bossi P., Licitra L., Fallai C., Pignoli E.: Radiotherapy for unresectable sinonasal
cancers: Dosimetric comparison of intensity modulated radiation therapy with
coplanar and non-coplanar volumetric modulated arc therapy. Radiother Oncol 2014;
113: 260-266
Safavi-Naeini M, Han Z, Alnaghy S, Cutajar D, Petasecca M, Lerch ML, Franklin DR,
Bucci J, Carrara M, Zaider M, Rosenfeld AB.: BrachyView, a novel in-body imaging
system for HDR prostate brachytherapy: Experimental evaluation. Med Phys. 2015
Dec;42(12):7098-107
Staff
HEAD
Emanuele Pignoli, Med Phys D
(Until October 2015)
Alfonso V. Marchianò, MD
(Interim since November 2015)
Marta R. Borroni, Med Phys D; Mauro Carrara,
Med Phys D; Valeria Mongioj, Med Phys D;
Emanuele Pignoli, Med Phys D; Claudio G. Stucchi,
Med Phys D
RESEARCH STAFF
Claudia Cavatorta, Phys D; Tommaso Giandini,
Med Phys D; Manuela Lualdi, Med Phys D; Silvia
Meroni, Med Phys D
RESIDENTS
Francesca Bonfantini, Phys D; Anna Cavallo, Phys
D; Davide Cusumano, Phys D; Giannicola Galetta,
Phys D; Simone A. Grisotto, Phys D; Marta Mira,
Phys D; Camilla Scabbio, Phys D; Chiara Tenconi,
Phys D
YSICS
OF THE UNIT
4
PUBLICATIONS
9.875
IMPACT FACTOR
1-16, 4
TECHNICIANS
Vito Cosentino, Luca C. Marrone, Ester
Mazzarella, Dario Postè
HEALTHCARE ASSISTANT
Giuseppina Esposito
145
PATHOLOGY AND
LABORATORY MEDICINE
GIUSEPPE PELOSI, MD
ANATOMIC PATHOLOGY 2
GIUSEPPE PELOSI
LABORATORY MEDICINE
DANIELE MORELLI
T
he mission of the Department is
to provide accurate diagnoses
and information of prognostic
and therapeutic value to clinicians.
The activities of Surgical Pathology,
Molecular Pathology, Cytopathology and
Autopsy Pathology are carried out in the
two Anatomic Pathology Units, while an
extensive activity of laboratory tests and
microbiological investigations is carried
out at the Laboratory Medicine Unit, all
based on state-of-the-art techniques
and quality certification (ISO9001;2008,
until 2017).
PATHOLOGY
AND
LABORATORY
MEDICINE
Professor of Pathology, University of Milan
giuseppe.pelosi@istitutotumori.mi.it
MARIA LUISA CARCANGIU
147
MARIA LUISA CARCANGIU, Head of the Unit
Clinical activity
Research activity
Networking
The Anatomic Pathology
1 Unit (ANP1) includes the
functional ‘Uropathology and
Adult Histopathology Unit’.
ANP1 is a national and international
reference service for breast pathology,
gynecopathology, thyroid pathology,
uropathology, colo-rectal pathology,
and neuroendocrine tumours. Routine
diagnoses are performed according to
international guidelines, including the
most updated immunohistochemical
and molecular analyses for prognostic
and predictive purposes in collaboration
with the Laboratories of the Anatomic
Pathology 2 Unit. An Autopsy
Pathology Sevice is also available.
Breast, gynecopathologic, thyroid,
uropathologic, and neuroendocrine
tumor cases are discussed in
multidisciplinary meetings. During 2015
in ANP1 and 2, 9,439 surgical specimens,
10,081 biopsies, and 3,382 second
opinion examinations were diagnosed.
ANP 1 Unit is actively involved
in many studies in collaboration
with other Departments of INT and
other referring Italian and international
centers. Tumours are studied with
morphology, immunohistochemistry,
molecular tests including FISH
(Fluorescence in situ Hybridization),
CISH (Chromogenic in situ Hybridization),
RT-PCR (RetroTranscription
Polymerase Chain Reaction), direct
sequencing and NGS (Next Generation
Sequencing) techniques. A special
focus is being pointed on the study of
microenvironment, immune contexture,
and epigenetic modifications, as long
as the integration of new prognostic
factors and potential terapeutic targets
in individualized treatments. The study
of pathologic response to neoadjuvant
therapies in vary histotypes and its
possible correlation with outcome is
another field of interest, as well as the
assessment of morphologic features in
needle biopsies for active surveillance
protocols in low-risk prostatic cancers.
ANP1 is involved in a
telepathology project of
the Sicily region together
with several referring Italian cancer
institutes.
ANP1 belongs to the educational network
of the Postgraduate Medical School in
Anatomic Pathology of the University of
Milan School of Medicine
ANATOMIC PA
148
Keywords
Diagnosis, therapy,
prognosis, predictive value,
morphology,
immunohistochemistry,
molecular pathology, cytofluorimetry,
breast pathology, gynecopathology,
thyroid pathology, uropathology,
colo-rectal pathology, neuroendocrine
tumors
Lughezzani G., Catanzaro M., Torelli T., Piva L., Biasoni D., Stagni S.,
Necchi A., Giannatempo P., Raggi D., Farè E., Colecchia M., Pizzocaro G.,
Salvioni R., Nicolai N. Relationship between lymph node ratio and cancerspecific survival in a contemporary series of patients with penile cancer
and lymph node metastases. Bju International 2015; 116(5):727-733
Schechter R.b., Nagilla M., Joseph L., Reddy P., Khattri A., Watson S., Locati L.d., Licitra
L., Greco A., Pelosi G., Carcangiu M.l., Lingen M.w., Seiwert T.Y., Cohen E.E. Genetic
profiling of advanced radioactive iodine-resistant differentiated thyroid cancer and
correlation with axitinib efficacy. Cancer Letters 2015; 359(2):269-274
Triulzi T., De Cecco L., Sandri M., Prat A., Giussani M., Paolini B., Carcangiu M.l., Canevari
S., Bottini A., Balsari A., Menard S., Generali D., Campiglio M., Di Cosimo S., Tagliabue E.
Whole-transcriptome analysis links trastuzumab sensitivity of breast tumors to both
HER2 dependence and immune cell infiltration. Oncotarget 2015; 6(29):28173-28182
Lucibello M., Adanti S., Antelmi E., Dezi D., Ciafrè S., Carcangiu M.l., Zonfrillo M.,
Nicotera G., Sica L., De Braud F., Pierimarchi P. Phospho-TCTP as a therapeutic target
of dihydroartemisinin for aggressive breast cancer cells. Oncotarget 2015; 6(7):527591
Cremolini C., Di Bartolomeo M., Amatu A., Antoniotti C., Moretto R., Berenato R.,
Perrone F., Tamborini E., Aprile G., Lonardi S., Sartore Bianchi A., Fontanini G., Milione
M., Lauricella C., Siena S., Falcone A., De Braud F., Loupakis F., Pietrantonio F. BRAF
codons 594 and 596 mutations identify a new molecular subtype of metastatic
colorectal cancer at favorable prognosis. Annals of Oncology 2015; 26(10):2092-7
Staff
HEAD
Maria Luisa Carcangiu, MD
Maurizio Colecchia, MD (Uropathology and Adult
Histopathology Unit, Director); Massimo Milione,
MD; Biagio Paolini, MD
RESEARCH STAFF
Ester Antelmi, Biol Sci D; Alessia Bertolotti, Biol
Sci D, Giovanni Centonze
TECHNICIANS
ROUTINE HISTOLOGY LAB: Renata Borchini,
Rita A. Carminati, Paolo Castioni, Alessandra
Chinosi, Maria Colantuono, Alessandra Elli, Elena
Fomiatti, Angelo Gaito, Matteo Marcuzzo, Marzia
Mietta, Margherita Mondini
OF THE UNIT
25
PUBLICATIONS
99.00
IMPACT FACTOR
1-47, 8
ADMINISTRATIVE PERSONNEL (ANP 1 AND 2)
Patrizia Cangioli, Margherita Cariglia, Maria
Teresa Codecasa, Maria Di Bartolomeo Cristina,
Roberto Ferrari, Maria Morelli, Alda R. Tosi, Enrica
Colzani (volunteer)
ATHOLOGY 1
HEALTH CARE ASSISTANTS (ANP 1 AND 2)
Cosima Anna Ciccarese, Massimo Festa, Paola
Tonielli, Anna Urbano
149
GIUSEPPE PELOSI, Head of the Unit
Clinical activity
Research activity
Networking
The Anatomic Pathology
2 Unit (ANP2) includes the
functional ‘Hematopathology
Unit’, ‘Soft Tissue and Bone
Pathology, Histopathology and Pediatric
Pathology Unit’, and the ‘Cytopathology
and Dermatopathology Unit’. ANP2
is a national and international
reference service for lung pathology,
hematopathology, soft tissue and
bone pathology, pediatric pathology (in
particular renal tumors), cytopathology,
dermatopathology, liver pathology,
gastroenteropancreatic pathology,
and head and neck pathology. Routine
diagnoses are performed according to
international guidelines, including the
most updated immunohistochemical
and molecular analyses for prognostic
and predictive purposes, performed
in the Immunohistochemistry and
Molecular Biology Laboratories of
the Unit. A Cytofluorimetry Service
is available. Hemathopathologic,
sarcomas, pediatric, liver tumor cases
are discussed in multidisciplinary
meetings. During 2015 9,439 surgical
specimens, 10,081 biopsies, and 3,382
second opinion examinations were
diagnosed in ANP1+2. In addition,
154 bone marrow smears, 15,488
cervico-vaginal smears, and 2,564
extra-cervicovaginal cytologic smears
were diagnosed; 8,540 molecular
tests were performed, including FISH
(Fluorescence in situ Hybridization),
CISH (Chromogenic in situ Hybridization),
RT-PCR (RetroTranscription Polymerase
Chain Reaction), direct sequencing and
NGS (Next Generation Sequencing)
techniques.
ANP2 Unit is actively involved
in many studies in collaboration
with other Departments of INT and
other referring Italian and international
centers. Tumours are studied with
morphology, immunohistochemistry,
FISH, CISH, cytofluorimetry, RT-PCR,
and sequencing. A special focus
is being pointed on the study of
microenvironment, immune contexture,
and epigenetic modifications, as long
as the integration of new prognostic
factors and potential terapeutic targets
in individualized treatments. The study
of pathologyc response to neoadjuvant
therapies in vary histotypes and its
possible correlation with outcome is
another field of interest. During 2015
translational research activities involved
all the specialties, including lung tumors,
hemathologic pathology, sarcomas,
pediatric tumours, melanoma, liver
tumors, pancreatic tumors, and
head and neck tumors. ANP2 actively
collaborates with the institutional
BioBanking Service.
ANP2 is involved in a
telepathology project of
the Sicily region together
with several referring Italian cancer
institutes.
ANP2 belongs to the educational
network of the Postgraduate Medical
School in Anatomic Pathology of the
University of Milan School of Medicine
Keywords
Diagnosis,
therapy, prognosis,
predictive value, morphology,
immunohistochemistry,
molecular pathology, cytofluorimetry,
lung pathology, hematopathology,
soft tissue pathology, bone pathology,
sarcoma, pediatric pathology,
dermatopathology, cytopathology,
gastrointestinal pathology hepatobiliary
and pancreatic pathology, head and neck
pathology
ANATOMIC PA
150
Staff
HEAD
Giuseppe Pelosi, MD
Zappasodi R., Ruggiero G., Guarnotta C., Tortoreto M., Tringali C.,
Cavanè A., Cabras A.d., Castagnoli L., Venerando B., Zaffaroni N., Gianni
A.m., De Braud F., Tripodo C., Pupa S.m., Di Nicola M. HSPH1 inhibition
downregulates Bcl-6 and c-Myc and hampers the growth of human
aggressive B-cell non-Hodgkin lymphoma. Blood 2015; 125(11):1768-71
Antonello D. Cabras, MD (Haematopathology
Unit, Director); Paola Collini (Soft Tissue and
Bone Pathology, Histopathology and Paediatric
Pathology Unit, Director); Gabrina Tragni, MD
(Dermatopathology and Cytopathology Unit,
Director); Marta Barisella, MD; Alessandra
Fabbri, MD; Alessandro Pellegrinelli, MD;
Pasquale Quattrone, MD; Angelica Sonzogni, MD;
Barbara Valeri, MD; Antonella Aiello, Biol Sci D;
Annunziata Gloghini, Biol Sci D; Federica Perrone,
Biol Sci D; Elena Tamborini, Biol Sci D; Maria Adele
Testi, Biol Sci D
RESIDENTS
Mara Cossa, MD; Simona Massa, MD; Salvatore L.
Renne, MD; Enea Zini, MD
RESEARCH STAFF
Antonino Belfiore, Biol Sci D; Silvia Brich, Biol Sci
D; Elena Conca, Biol Sci D; Barbara Cortelazzi, Biol
Sci D; Manuela Bimbatti, MD; Fabio L. Bozzi, Biol
Sci D; Adele Busico, Biol Sci D; Iolanda Capone,
Biol Sci D; Gian Paolo Dagrada, Biol Sci D; Ambra
V. Gualeni, Biol Sci D; Lucia Militti, Biol Sci D;
Tiziana Negri, Biol Sci D; Nicholas Paielli, Biol Sci,
D; Alessio Pellegrinelli, MD; Benedetta Picciani,
Biol Sci D; Giulio Settanni, Biol Sci D; Rosalin
Dolores Spagnuolo, Biol Sci D; Francesca Testa,
Biol Sci D; Laura Vittoria, Biol Sci D
raziano P., De Marinis F., Gori B., Gasbarra R., Migliorino R., De Santis S., Pelosi G.,
G
Leone A. EGFR-driven behavior and intrapatient T790M mutation heterogeneity of
non-small-cell carcinoma with squamous histology. Journal Of Clinical Oncology
2015; 33(31):e115-8
Gronchi A., Collini P., Miceli R., Valeri B., Renne S.l., Dagrada G., Fiore M., Sanfilippo R.,
Barisella M., Colombo C., Morosi C., Stacchiotti S., Casali P.g., Dei Tos A.p., Pilotti S.
Myogenic differentiation and histologic grading are major prognostic determinants in
retroperitoneal liposarcoma. American Journal Of Surgical Pathology 2015; 39(3):38393
Pelosi G., Fabbri A., Papotti M., Rossi G., Cavazza A., Righi L., Tamborini E., Perrone F.,
Settanni G., Busico A., Testi M.a., Maisonneuve P., De Braud F., Garassino M., Valeri
B., Sonzogni A., Pastorino U. Dissecting pulmonary large-cell carcinoma by targeted
next generation sequencing of several cancer genes pushes genotypic-phenotypic
correlations to emerge. Journal Of Thoracic Oncology 2015; 10(11):1560-9
Dugo M., Nicolini G., Tragni G., Bersani I., Tomassetti A., Colonna V., Del Vecchio M.,
De Braud F., Canevari S., Anichini A., Sensi M. A melanoma subtype with intrinsic
resistance to BRAF inhibition identified by receptor tyrosine kinases gene-driven
classification. Oncotarget 2015; 6(7):5118-33
PERSONNEL INVOLVED IN SPECIFIC RESEARCH
ACTIVITIES
Silvana Pilotti, MD (responsible for some GIST
and chordoma research projects)
TECHNICIANS
IMMUNOHISTOCHEMISTRY LAB: Miriam Barrera,
Maria Grazia Bonora, Luca Cesana, Daniela
De Bari, Francesca Dominoni, Maria Grazia
Facciorusso, Martina Filugelli, Daniela Galbiati,
Giovanna Garzone, Morena Gobbo, Rosa A.
Intorre, Teresa Labella, Alessia Mietta, Loretta
Missiato, Maria Luisa Moiraghi, Paola Murè,
Marta Orsenigo, Desirè Parimbelli, Silvia Redaelli,
Consiglia Sgura. CYTOPATHOLOGY LAB: Silvia
A. Colombo, Katia Ponzoni, Carla Riva, Mario B.
Ruggeri, Valentina Tricarico
ADMINISTRATIVE PERSONNEL (ANP 1 AND 2)
Patrizia Cangioli, Margherita Cariglia, Maria
Teresa Codecasa, Maria Cristina Di Bartolomeo,
Roberto Ferrari, Maria Morelli, Alda R. Tosi, Enrica
Colzani (volunteer)
HEALTH CARE ASSISTANTS (ANP 1 AND 2)
Cosima A. Ciccarese, Massimo Festa, Paola
Tonielli, Anna Urbano
OF THE UNIT
50
PUBLICATIONS
275.789
IMPACT FACTOR
13
48.800
ATHOLOGY 2
1-55, 10
151
LABORATORY MEDICINE
DANIELE MORELLI, Head of the Unit
Clinical activity
In 2015 the Laboratory
Medicine Unit carried out
about two million tests, which
have been conducted using
high-quality standards to assure
the best reliability of results, in turn
continuously monitored inside national
and international External Quality
Assessment (EQA) projects. Laboratory
Medicine Unit performs biological tests
and microbiological investigations
which contribute to the diagnosis,
prognosis and monitoring of oncologic
patients submitted to conventional and
experimental therapies inside clinical
trials.
Rossini A, Zanobbio L, Sfondrini L, Cavalleri A, Secreto G, Morelli D,
Palazzo M, Sommariva M, Tagliabue E, Rumio C, Balsari A. Influence of
fatty acid-free diet on mammary tumor development and growth rate in
HER-2/neu transgenic mice. J Cell Physiol. 2013 Jan;228(1): 242-9
Orlandi R, De Bortoli M, Ciniselli CM, Vaghi E, Caccia D, Garrisi V, Pizzamiglio S,
Veneroni S, Bonini C, Agresti R, Daidone MG, Morelli D, Camaschella C, Verderio P,
Bongarzone I. Hepcidin and ferritin blood level as noninvasive tools for predicting
breast cancer. Ann Oncol. 2014 Feb;25(2):352-7
Appierto V., Callari M., Cavadini E., Morelli D., Daidone M, Tiberio P. A LipemiaIndependent NanoDrop-Based Score to Identify Hemolysis in Plasma and Serum
Samples. Bioanalysis. 2014 May:6(9) 1215-1226
Kusamura S., Baratti D., Hutanu I., Gavazzi C., Morelli D., Iusco D.R,. Grassi A., Bonomi
S., Virzì S., Haeusler E., Deraco M. The role of baseline inflammatory-based scores and
serum tumor markers to risk stratify pseudomyxoma peritonei patients treated with
cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Eur J
Surg Oncol. 2015 May 16. pii: S0748-7983(15)00389-3
Maroni P., Bendinelli P., Morelli D., Drago L., Luzzati A., Perrucchini G., Bonini C.,
Matteucci E., Desiderio MA. High SPARC Expression Starting from Dysplasia,
Associated with Breast Carcinoma, Is Predictive for Bone Metastasis without
Enhancement of Plasma Levels. Int J Mol Sci. 2015 Nov 26;16(12):28108-28122
Staff
HEAD
Morelli Daniele, 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
RESIDENTS
Marta Giussani, Biol Sci D; Francesca Taverna,
Biol Sci D; Francesca Testa, Biol Sci D; Chiara C.
Volpi, Biol Sci D
OF THE UNIT
8
LABORATORY
MEDICINE
RESEARCH STAFF
Rossella Panella, Biol Sci D
TECHNICIANS
Giuseppina Ballabio, Rosella Bonfanti, Chiara
Brusati, Maria Rosa Carati, Maria Rosa Cattaneo,
Carlo Maggi, Roberta Marchetti, Valerio Motta,
Giovanni Nido, Giuseppa Perrucci, Pia S.M. Picco,
Marco Ranzani, Nicola Salvatore, Federica
Sozzani
Santa Zingone
Pierangela Carrino, Paola Preto
152
PUBLICATIONS
19.784
IMPACT FACTOR
2-19, 3
Y
EXPERIMENTAL
ONCOLOGY
AND
MOLECULAR
MEDICINE
EXPERIMENTAL ONCOLOGY
AND MOLECULAR MEDICINE
DEPARTMENT
MARIA GRAZIA DAIDONE
mariagrazia.daidone@istitutotumori.mi.it
BIOMARKERS
MARIA GRAZIA DAIDONE
MOLECULAR IMMUNOLOGY
MARIO PAOLO COLOMBO
MOLECULAR PHARMACOLOGY
NADIA ZAFFARONI
TUMOR GENOMICS
GABRIELLA SOZZI
IMMUNOBIOLOGY OF HUMAN TUMORS
ANDREA ANICHINI
IMMUNOTHERAPY OF HUMAN TUMORS
LICIA RIVOLTINI
MOLECULAR MECHANISMS
ANGELA GRECO
MOLECULAR MECHANISMS OF CELL
CYCLE CONTROL
DOMENICO DELIA
MOLECULAR THERAPIES
DELIA MEZZANZANICA
MOLECULAR TARGETING
ELDA TAGLIABUE
AIRC START UP UNIT
MARILENA IORIO
T
his 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.
Cancer complexity is addressed
through combined approaches,
which benefit from the availability of
adequate infrastructure resources,
state-of-the-art technology platforms,
and excellent expertise within each
Department Units, as well as from
established collaborations with INT
clinical Departments. The activity
of the Research Units is aimed to: i)
understand the molecular mechanisms
of transformation, tumor progression
and resistance to chemical and
physical agents; ii) identify and validate
molecular biomarkers/signatures (gene
and microRNA expression) as indicators
associated with diagnosis, prognosis
and monitoring of the disease and for
the development of highly sensitive
test assays suitable for possible clinical
applications; iii) identify molecular
targets potentially actionable and, using
NGS approaches, driver mutations able
to anticipate disease progression and
response to targeted treatments; iv)
develop rational new drug combinations
in different models and experimental
systems, including original patientderived xenografts established in mouse
models; v) decode the mechanisms
of interaction between the tumor
and its microenvironment during
the different phases of progression
and vi) understand the role of the
immune response in tumor control for
the identification of new therapeutic
strategies.
Substantial efforts have been dedicated
to approaches able to serially detect
function-related reliable biomarkers
reflecting early disease onset/
progression and treatment response
through noninvasive procedures,
amenable for longitudinal molecular
analysis. Liquid biopsy containing cells,
nucleic acids and proteins released
by primary and metastatic lesions,
reflecting their biological features and
allowing identification of clinically useful
biomarkers and treatment-induced
154
cancer adaption processes, have been
investigated in different solid tumors.
Such studies involved multidisciplinary
approaches, statistical and bioinformatic
methodologies, and integration among
the different high-throughput, highresolution techniques and functional
tests. Development of protocols/
operating procedures directed to the
transfer of information from research
to clinics, set up of reference “omics”
databases for in silico studies and
validations, and production of antibodies
for diagnostic in situ and imaging
fostered the translational aspects of all
activities. Investigations are carried out
using different preclinical experimental
models and validated on large series of
human biospecimens, taking advantage
of INT Biobank.
The Department supports investigators
with state-of-the-art core facilities,
with shared instrumentations,
dedicated trained specialists, and
also with the collaboration of experts
from the different Research Units. The
following core facilities are available,
which are certified to implement and
maintain a Quality Management System
which fulfills the requirements of ISO
9001:2008 standards.
Functional Genomics and Bioinformatics
(FGB). The FGB performs: study design;
RNA and DNA extraction and quality
controls; labeling and hybridization
methodologies required for high quality
analysis; libraries’ preparation and
quantification; data processing and
statistical analysis. The activities of the
FGB are conducted using the following
state-of-the-art equipment: QIAcube
and QIASymphonySP for nucleic acid
purification; Agilent Bioanalyzer and
Tapestation, Nanodrop, Qubit for
quantity and quality control of nucleic
acids; iScan (Illumina), SurePrint (Agilent)
and Gene Chip System 3000 (Affymetrix)
platforms for microarray analysis of
mRNA, miRNA and lncRNA expression,
ChIP-on-chip, DNA methylation, CGH
and CNV, SNPs; Quantstudio 12K with
OpenArray, Accufil and Automation
Robot for quantitative real-time PCR. For
NGS studies: Personal Genome Machine,
Ion S5XL, Ion Chef (Life Technologies) and
Next Seq 500 (Illumina) with dedicated
servers are available. Full computational
DEPARTMENT
analyses are performed using opensource software and dedicated licenses.
Identification and bio-functional
interpretation of promising biomarkers
are based on differential expression
analysis, pathway analysis (IPA, Qiagen)
with over-representation or gene set
enrichment approaches (GO and GSEA),
and integration of different kinds of data.
The samples manipulated by the FGB
and all experimental and bioinformatic
activities are tracked using dedicated
software provided by TwinHelix and IBM,
respectively. The scientific and technical
staff of the FGB have the appropriate
background, knowledge and skill in the
specific field of interest.
Proteomics/Mass Spectrometry
Laboratory, with Maldi-TOF and SeldiTOF instrumentations.
Immunohistochemistry: performs
histological and cytological processing
by a wide range of histological
techniques, immunohistochemistry, in
situ hybridization, and autoradiography.
Cell imaging facility: provides access
to the 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 up to 8 channel bright field
image collection, and live cell imaging.
Flow cytometry and cell sorting: using
state-of-the-art flow cytometric
instrumentation, and software analysis.
Microbiology service for plasmid DNA
purification; mutagenesis; bacterial
strains transformation and storage.
Laboratory animal facility: Animal
facilities authorized by the Italian
Ministry of Health.
Tissue and blood repository:
Departments of Pathology and
Experimental Oncology have
implemented and maintain a large
institutional biobank of frozen and
FFPE normal, tumor tissues and blood/
plasma/serum/buffy coats samples,
collected and stored within a short
time from removal following SOPs.
Thousands of well-annotated clinical
specimens of different tumor histotypes,
linked to dedicated databases of pathobiological and clinical information, are
currently available (>1200 new cases/
yearly). Patients sign an informed
consent which allows INT investigators
to use the leftover material of biological
samples collected during standard
surgical and medical procedures
for research purposes. Aliquots are
attributed to individual studies after
approval of Institutional Review Board
and specific requests to the Ethical
Committee. All leftover material is stored
in the Institutional BioBank for at least
20 years from the collection, including
residual material of specific project
studies.
Staff
STAFF SCIENTIST
Manuela Gariboldi, Biol Sci D, PhD
Marialuisa Sensi, Biol Sci D
RESEARCH ASSOCIATES
Silvana Canevari, Biol Sci D; Loris De Cecco, Biol
Sci D, PhD; Claudia Miranda, Biol Sci D, PhD;
Patrizia Pinciroli, Biol Sci D
POST DOCTORAL OR RESEARCH FELLOWS
Andrea Vanni Devecchi, Biotech Sci D; Vittoria
Disciglio, Biol Sci D; Matteo Dugo, Biotech D,
Bioinformatician; Marco Giannoccaro, Biotech
D; Maria Valeria Maiorana, Biol Sci D; Viktorija
Sokolova, Biol Sci D, PhD; Susanna Zanutto,
Biotech Sci D
TECHNICIANS
Gabriella Abolafio, Lucilla Ciorba, Loredana Cleris,
Lucia Gioiosa, Edoardo Marchesi, Gloria Morandi,
Ivan Muradore, Francesco Pastore, Donata Alda
Penso, Maria Teresa Radice, Antonio Scavo,
Lorena Ventura
LABORATORY MANAGEMENT TEAM
Enrico Ronchi, Domenico Di Fazio, Angelo Labori,
Salvatore Venturino
SUPPORTING PERSONNEL
Antonietta Calcagno, Antonietta Linda
Cimaglia, Angelo Farina, Giuseppina Liguori,
Agata Mancuso, Luisa Mona, David Penni,
Giovanna Ripoli, Maria Cristina Ripoli, Gisella
Rivadossi, Carlo Salandra, Claudio Santagostini,
Massimiliano Piero Scaranello, Rita Scozia
Simona Galuzzi, Luisa Rivetta
DEParray platform: combines imaging
technologies with the ability to
manipulate and recover individual, viable
rare cells from a heterogeneous sample
for subsequent culture or molecular
analysis.
Cytogenetics and molecular
cytogenetics 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.
155
BIOMARKERS
MARIA GRAZIA DAIDONE, Head of the Unit
Research activity
Research in this Unit aims to
identify and validate cancerrelated and actionable biomarkers
relevant for disease progression
and treatment response, through
an integration of molecular and cell
biology approaches, high-throughput
techniques and bioinformatic tools.
Studies, supported by grants from
AIRC and Ministry of Health, are
mainly focused on breast, bladder and
colorectal cancers for transcriptomic
and genomic characterizations of solid
and liquid biopsies, with efforts in
harmonizing pre-analytical, analytical
and interpretative factors to improve
accuracy and reproducibility towards
the development of sensitive and
specific tests for clinical application
(PlosOne 2015, Biomed Res Int 2015, BMC
Bioinformatics 2015).
Major achievements:
Candidate miRNAs identified by highthroughput analysis of primary nodenegative breast cancers and validated in
silico, showed:
• low expression of miR-100 as an
unfavourable prognostic factor
associated with genomic high grade
signature (Oncotarget 2015). In
basal-like cancers, miR-100 inhibits
maintenance and expansion of tumorinitiating cells, and favours their
differentiation, converting a basal-like
into luminal phenotype characterized
by functional ER and sensitivity to
hormonal therapy. Such findings
indicate a new possible therapeutic
strategy, which could make aggressive
breast cancers responsive to standard
treatments
• miR-30e* as a protective prognostic
factor independent of treatment in
the ER+/HER- and the HER2+ subtypes,
but not in triple negative tumors (Br J
Cancer, 2015). Such findings highlight
a relevant and subtype-specific role
for miR-30e* and demonstrated
that integrating gene signatures
and clinical-pathological features
with miRNAs can help for a better
prognostication.
Blood-based biomarkers as circulating
tumor cells (CTCs) and free nucleic acids
(e.g., circulating tumor DNA and miRNAs)
represent ideal non-invasive tools
released by primary and metastatic
lesions, reflecting their biologic features
and allowing identification of clinically
useful biomarkers and treatmentinduced cancer adaption processes. Our
investigations showed that:
ifferent approaches for CTC detection
•d
(positive-selection methods or
size-based unbiased enrichment)
probably identify distinct tumor
cell subpopulations, but need
standardization before investigating
their clinical validity and biological
specificity (Int J Biol Markers 2015)
pipeline to obtain technically and
•a
biologically reliable gene expression
profiles from at least 25 isolated CTCs
has been developed, which is suitable
for prospective studies and allows to
measure the expression of >29,000
genes (Clin Chem 2015)
• in patients with advanced
chemorefractory, RAS wild-type
colorectal cancer receiving anti-EGFR
therapies, early CTC fluctuations are
associated with patient outcome, may
predict treatment failure in advance
compared to imaging-based tools and
– if validated - allow optimization in
treatment planning (Int J Cancer 2015).
Networking
EurocanPlatform, an EC
funded project bringing
together 28 European
cancer Institutions and organisations
Newton (Advanced nanosystems
for a new era in molecular oncology)
consortium, supported by MIUR
Nanomax consortium, supported by CNR
BBMRI-ERIC (within the Common
Services for Biomolecular Resources);
BBMRI.it (Biobanking and BioMolecular
resources Research Infrastructure)
Active collaborations with:
Dipartimento di Scienze Farmacologiche,
Università degli Studi di Milano;
Department of Pathology and Public
Health, Università degli Studi di Verona;
Department of Surgical and Oncological
Sciences, Università di Palermo;
Università di Torino; Laboratorio
Nazionale CIB (LNCIB) Trieste; University
of Torino School of Medicine, Candiolo
Cancer Institute-FPO IRCCS-Candiolo;
Breast Unit, Istituti Ospitalieri, Cremona;
International Breast Cancer Study
Group (NeoALTTO trial); Leeds Institute
of Cancer Studies & Pathology at the
University of Leeds and Cambridge
Breast Cancer Research Unit, UK;
University Hospital Radiumhospitalet in
Oslo, Norway.
BIOMARKERS
156
S
Keywords
Breast cancer,
circulating tumor cells,
colorectal cancer, ctDNA,
gene expression, liquid biopsy,
microRNAs, target identification,
tumor progression
Callari M, Musella V, Di Buduo E, Sensi M, Miodini P, Dugo M, Orlandi R,
Agresti R, Paolini B, Carcangiu ML, Cappelletti V, Daidone MG. Subtypedependent prognostic relevance of an interferon-induced pathway
metagene in node-negative breast cancer. Mol Oncol. 2014 Oct;8(7):127889
Fina E, Callari M, Reduzzi C, D’Aiuto F, Mariani G, Generali D, Pierotti MA, Daidone MG,
Cappelletti V. Gene expression profiling of circulating tumor cells in breast cancer.
Clin Chem. 2015 Jan;61(1):278-89
Musella V, Pietrantonio F, Di Buduo E, Iacovelli R, Martinetti A, Sottotetti E, Bossi I,
Maggi C, Di Bartolomeo M, de Braud F, Daidone MG, Cappelletti V. Circulating tumor
cells as a longitudinal biomarker in patients with advanced chemorefractory, RASBRAF wild-type colorectal cancer receiving cetuximab or panitumumab. Int J Cancer.
2015 Sep 15;137(6):1467-74
D’Aiuto F, Callari M, Dugo M, Merlino G, Musella V, Miodini P, Paolini B, Cappelletti
V, Daidone MG. miR-30e* is an independent subtype-specific prognostic marker in
breast cancer. Br J Cancer. 2015 Jul 14;113(2):290-8
Angeloni V, Tiberio P, Appierto V, Daidone MG. Implications of stemness-related
signaling pathways in breast cancer response to therapy. Semin Cancer Biol. 2015
Apr;31:43-51
Staff
HEAD
Maria Grazia Daidone, Biol Sci D, PhD
STAFF SCIENTIST
Vera Cappelletti, Biol Sci D; Silvia Veneroni, Biol
Sci D
RESEARCH ASSOCIATES
Valentina Appierto, Biol Sci D, PhD; Maurizio
Callari, Med Biotech D, PhD
POST DOCTORAL AND RESEARCH FELLOWS
Valentina Angeloni, Ind Biotech D, PhD; Emanuela
Fina, Biol Sci D; Giuseppe Merlino, Med Biotech
D; Carolina Reduzzi, Biol Sci D; Paola Tiberio, Ind
Biotech D
TECHNICIANS
Elena Cavadini, Cinzia De Marco, Patrizia Miodini,
Rosita Motta
OF THE UNIT
22
PUBLICATIONS
106.626
IMPACT FACTOR
12
57.575
1-49, 11
Laura Zanesi
157
MOLECULAR IMMUNOLOGY
MARIO PAOLO COLOMBO, Head of the Unit
Research activity
The bone marrow provides
the continuous supply of
hematopoietic cells which, when
monitored in blood, can first signal
a state of disease. Infection, trauma
and cancer are all conditions that
prompt a boost in hematopoiesis to
cope with the need of many new white
blood cells in the periphery at site
of perturbation. These conditions of
emergency hematopoiesis require to
preserve the hematopoietic stem cells
(HSC) pool, whereas similar or partially
overlapping molecular circuits can also
confer aggressiveness in leukemia
clones. In this context we have studied
the Suppressor of Cytokine Signalling 2
(SOCS2). Combining analysis of human
HSC malignancies and studies on murine
HSC under steady state and stress
conditions, we have identified a dual
involvement of SOCS2 in the regulation
of HSC functions and a novel regulatory
mechanism for SOCS2 expression in HSC
(specifically: a STAT-independent but
MEF2C-dependent SOCS2 regulation)
(Cancer Res. 2015;75:2387-99).
Also, we have contributed to identify
a novel subsets of myeloid and
macrophage subsets, induced in
the bone marrow from a peripheral
cancer, based on their expression of
retinoic acid orphan nuclear receptor
gamma (RORC1). RORC1 orchestrates
myelopoiesis by suppressing negative
(SOCS3, Bcl3) and promoting positive
(C/EBPb) regulators of granulopoiesis,
as well as those of the monocytic/
macrophage lineage (IRF8 and PU.1)
(Cancer Cell. 2015;28:253-69). RORC1dependent myelopoiesis could be
targeted to prevent the induction of
tumor-promoting host macro- and
micro-environments.
Among the myeloid cells that in tissue
can participate in the healing process
and likewise in cancer progression, mast
cells (MC) have been poorly considered.
We have investigated their function in
colon inflammation and cancer in mice
either wild-type (WT) or MC-deficient
(KitWsh) reconstituted or not with bone
marrow-derived MCs either WT or
deficient for mouse mast cell protease 4.
We demonstrate that MC preferentially
localize in areas of mucosal healing
rather than damaged area where they
degraded interleukin (IL)-33, an alarmin
released by epithelial cells during tissue
damage such to reduce inflammation
and activate the healing process.
Differently from those intervening into
inflammatory damage healing, MC facing
transformed epithelial cells acquired
a pro-tumorigenic profile. Also, the
comparison with the equivalent human
disease underlined the paucity of MCs
in cases of detrimental inflammation
as occurring in active Inflammatory
Bowel Disease (IBD) and IBD-associated
colorectal cancers. Conversely, MCs
infiltrated areas that were mirroring
healing areas of the mouse epithelium
such as biopsies of remitting IBD and
of tumors arising spontaneously.
Indeed, the growth of sporadic
adenocarcinomas is driven by genetic
alterations and inflammation coevolves
with tumor-associated modifications of
tissues endowed with repair capacity
(Cancer Res. 2015;75:3760-70).
Networking
Collaboration with:
Tumor Immunology Unit,
Department of Health
Sciences, University of Palermo, Italy;
Department of Inflammation and
Immunology, Humanitas Clinical and
Research Center, Rozzano, Milan, Italy;
Department of Pharmaceutical Sciences,
Università del Piemonte Orientale
‘‘Amedeo Avogadro’’ Novara, Italy;
Department of Medical and Biological
Science, University of Udine, Italy;
Hematopathology Section, Department
of Hematology and Oncology, S. OrsolaMalpighi Hospital, University of Bologna,
Italy; Colorectal Cancer Genetics, Centre
for Digestive Diseases, Blizard Institute,
Barts and the London School of Medicine
and Dentistry, Whitechapel, London,
United Kingdom; Inserm UMRS-1149,
Paris, France; CNRS ERL 8252; Université
Paris Diderot, Sorbonne Paris Cite,
Laboratoire d’Excellence INFLAMEX,
Paris, France
MOLECULAR I
158
Keywords
Tumor microenvironment,
tumor immunology, myeloid
cells, inflammation
Sangaletti S, Tripodo C, Sandri S, Torselli I, Vitali C, Ratti C, Botti L,
Burocchi A, Porcasi R, Tomirotti A, Colombo MP, Chiodoni C. Osteopontin
shapes immunosuppression in the metastatic niche. Cancer Res.
2014;74:4706-19
Sangaletti S, Tripodo C, Vitali C, Portararo P, Guarnotta C, Casalini P, Cappetti B, Miotti
S, Pinciroli P, Fuligni F, Fais F, Piccaluga PP, Colombo MP. Defective stromal remodeling
and neutrophil extracellular traps in lymphoid tissues favor the transition from
autoimmunity to lymphoma. Cancer Discov. 2014; 4:110-29
Strauss L, Sangaletti S, Consonni FM, Szebeni G, Morlacchi S, Totaro MG, Porta C,
Anselmo A, Tartari S, Doni A, Zitelli F, Tripodo C, Colombo MP, Sica A. RORC1 Regulates
Tumor-Promoting “Emergency” Granulo-Monocytopoiesis. Cancer Cell. 2015; 28:25369
Rigoni A, Bongiovanni L, Burocchi A, Sangaletti S, Danelli L, Guarnotta C, Lewis A, Rizzo
A, Silver AR, Tripodo C, Colombo MP. Mast Cells Infiltrating Inflamed or Transformed
Gut Alternatively Sustain Mucosal Healing or Tumor Growth. Cancer Res. 2015;
75:3760-70
Vitali C, Bassani C, Chiodoni C, Fellini E, Guarnotta C, Miotti S, Sangaletti S, Fuligni F,
De Cecco L, Piccaluga PP, Colombo MP, Tripodo C. SOCS2 Controls Proliferation and
Stemness of Hematopoietic Cells under Stress Conditions and Its Deregulation Marks
Unfavorable Acute Leukemias. Cancer Res. 2015;75:2387-99
Staff
HEAD
Mario Paolo Colombo, Biol Sci D, PhD
STAFF SCIENTIST
Claudia Chiodoni, Biol Sci D, PhD; Silvia A.C. Miotti,
Biol Sci D
RESEARCH ASSOCIATES
Laura Botti, Biol Sci D; Sabina Sangaletti, Biol Sci
D, PhD
Silvia Galvan, Med Biotech D; Alessia Burocchi,
Biol Sci D, PhD; Luana Flamini, Biol Sci D; Elena
Jachetti, Ind Biotech D, PhD; Giorgio Mauri, Med
Biotech D, PhD; Tiziana Ada Renzi, Med Biotech
D, PhD; Alice Rigoni, Biol Sci D, PhD; Andrea M.
Tomirotti, Med. Biotech D, PhD Student; Ilaria
Torselli, Biol Sci D, PhD Student; Nadia Castioni,
Pharm Biotech D, PhD Student; Claudia Enriquez,
Vet Med Biotech D, PhD Student
OF THE UNIT
12
PUBLICATIONS
77.955
IMPACT FACTOR
7
28.781
IMMUNOLOGY
TECHNICIANS
Ivano Arioli, Claudia Bassani, Barbara Cappetti,
Renata Maria Ferri, Pierpaolo Pappalardo,
Mariella Parenza, Paola Portararo, Chiara Ratti
1-66, 7
Ester Grande
159
MOLECULAR PHARMACOLOGY
NADIA ZAFFARONI, Head of the Unit
Research activity
Research activities of the Unit
in 2015 focused on the following
areas:
Novel therapeutic targets:
G-quadruplexes (G4) represent
attractive targets due to their role in
gene expression regulation. We found
that, in tumor cell lines, a naphthalene
diimide derivative efficiently stabilized
G4 within the promoters of MYC, BCL2,
TERT and KIT, and decreased gene
expression levels to a different extent as
a function of the number of G4-forming
sequences within each promoter.
Through the use of selective inhibitors
of nuclear export, we demonstrated
the relevance of XPO1/CRM1 as a
novel therapeutic target in peritoneal
mesothelioma. Indeed, XPO1/CRM1
inhibition significantly impaired tumor
cell growth in vitro and in vivo, mainly as
a consequence of the interference with
survivin intracellular distribution and
function.
Novel anticancer agents: A novel class
of isoindoloquinoxalin imines was found
to inhibit tumor cell proliferation through
a pleiotropic mechanism involving i)
impairment of tubulin polymerization,
ii) DNA topoisomerase I poisoning, and
iii) perturbation of telomere architecture
with the detachment of TRF2 and hPOT1
proteins. Rationally designed allosteric
Hsp90 ligands, able to promote enzyme
activity and conformational dynamics,
were found to impair proliferation of
tumor cell lines, including variants
resistant to the ATP-competitive Hsp90
inhibitor 17-AAG. Novel conjugates of
the tripeptide integrin ligand Arg-GlyAsp (RGD) and paclitaxel (PTX) showed
remarkable cytotoxic activity in different
tumor cell lines. In addition, the most
promising derivative displayed a marked
in vivo antitumor activity, similar to that
of PTX but with a more favorable toxicity
profile.
Rationally designed drug combinations
and approaches to overcome resistance:
Based on findings correlating tumor
cell sensitivity to camptothecins to the
ability to activate an efficient G2/M
checkpoint, allowing degradation of the
mitotic kinase PLK1, we demonstrated
a synergistic interaction between
irinotecan and the PLK1 inhibitor BI2535,
which resulted in a high rate of cures in
mice harboring camptothecin-sensitive
or -resistant squamous cell carcinomas.
We also showed the ability of histone
deacetylase inhibitors to counteract the
invasive behaviour of cisplatin-resistant
NSCLC preclinical models through a
mechanism involving the increased
expression of the metastasis suppressor
gene KiSS1.
microRNA-based therapeutic strategies:
Through integrated microRNA and
gene expression profiling of patientderived cancer associated fibroblasts
and non-activated counterparts, we
provided insights into the molecular
mechanisms driving fibroblast activation
in prostate cancer, thus contributing to
identify novel hits (e.g. miR-133b) for the
development of therapeutic strategies
targeting the crucial interplay between
tumor cells and their microenvironment.
Nanodelivery systems: Intracellular
redox-responsive nanoparticles of
different chemical structure were
demonstrated to successfully deliver
siRNA-based therapeutics to prostate
cancer cells.
Our research projects were supported by
AIRC, Ministry of Health, Fondazione Italo
Monzino, Fondazione Bianca Garavaglia,
Fondazione Guido Berlucchi.
Networking
Collaborations with:
Dipartimento di
Biotecnologie Mediche e
Medicina Traslazionale, Universita’ degli
Studi di Milano; Dipartimento di Scienze
e Tecnologie Biologiche Chimiche e
Farmaceutiche, Universita’ di Palermo;
Dipartimento di Scienze del Farmaco,
Universita’ di Padova; Istituto per la
Sintesi Organica e la Fotoreattivita’ CNR, Bologna;
Istituto di Chimica del Riconoscimento
Molecolare - CNR, Milano;
CNR-INFM-Democritos National
Simulation Center and International
School for Advanced Studies, Trieste;
Centre for Integrative Biology, Universita’
di Trento;
Dipartimento di Scienze Biochimiche,
Università, Firenze;
Dipartimento di Scienze Cliniche
Applicate e Biotecnologiche, Universita’
degli Studi L’Aquila;
Department of Chemistry,Virginia
Commonwealth University, Richmond,
Virginia, US;
Department of Chemical and
Biomolecular Engineering, The University
of Melbourne, Parkville, Australia;
Department of Regenerative Medicine,
Houston Methodist Research Institute
(HMRI), Houston, Texas, US.
MOLECULAR P
160
Keywords
Therapeutic targets,
drug resistance,
preclinical drug development,
microRNAs
De Cesare M, Cominetti D, Doldi V, Lopergolo A, Deraco M, Gandellini
P, Friedlander S, Landesman Y, Kauffman MG, Shacham S, Pennati M,
Zaffaroni N. Anti-tumor activity of selective inhibitors of XPO1/CRM1mediated nuclear export in diffuse malignant peritoneal mesothelioma:
the role of survivin. Oncotarget. 2015;6(15):13119-32
Beretta GL, Folini M, Cavalieri F, Yan Y, Fresch E, Kaliappan S, Hasenöhrl C, Richardson
JJ, Tinelli S, Fery A, Caruso F, Zaffaroni N. Unravelling “off-target” effects of redoxactive polymers and polymer multilayered capsules in prostate cancer cells.
Nanoscale. 2015;7(14):6261-70
De Cesare M, Lauricella C, Veronese SM, Cominetti D, Pisano C, Zunino F, Zaffaroni
N, Zuco V. Synergistic antitumor activity of cetuximab and namitecan in human
squamous cell carcinoma models relies on cooperative inhibition of EGFR expression
and depends on high EGFR gene copy number. Clin Cancer Res. 2014;20(4):995-1006
Lopergolo A, Nicolini V, Favini E, Dal Bo L, Tortoreto M, Cominetti D, Folini M, Perego P,
Castiglioni V, Scanziani E, Borrello MG, Zaffaroni N, Cassinelli G, Lanzi C. Synergistic
cooperation between sunitinib and cisplatin promotes apoptotic cell death in human
medullary thyroid cancer. J Clin Endocrinol Metab. 2014;99(2):498-509
Gandellini P, Giannoni E, Casamichele A, Taddei ML, Callari M, Piovan C, Valdagni
R, Pierotti MA, Zaffaroni N*, Chiarugi P* (*co-last). miR-205 hinders the malignant
interplay between prostate cancer cells and associated fibroblasts. Antioxid Redox
Signal. 2014;20(7):1045-59
Staff
HEAD
Nadia Zaffaroni, Biol Sci D, PhD
STAFF SCIENTIST
Marco Folini, Biol Sci D, PhD; Cinzia Lanzi, Biol Sci
D; Paola Maria Chiara Perego, Biol Sci D, PhD
RESEARCH ASSOCIATES
Giovanni L. Beretta, Biol Sci D, PhD; Giuliana
Cassinelli, Pharm D; Michelandrea De Cesare,
Vet D; Paolo Gandellini, Biotech Sci D, PhD; Laura
Gatti, Biol Sci D, PhD; Marzia Pennati, Biol Sci D,
PhD; Valentina M. Zuco, Biol Sci D
Graziella Cimino Reale, Biol Sci D, PhD; Denis
Cominetti, Biol Sci D; Cristina Corno, Biol Sci D;
Valentina Doldi, Biotech Sci D; Alessia Lopergolo,
Biotech Sci D, PhD; Barbara Forte, Biotech Sci D
PHD STUDENTS
Rihan El Bezawy, Biotech Sci D; Noemi Arrighetti,
Biotech Sci D
OF THE UNIT
29
PUBLICATIONS
138.810
IMPACT FACTOR
15
67.632
PHARMACOLO
TECHNICIANS
Elisa Campi, Nives Carenini, Elisabetta Corna,
Laura Dal Bo, Enrica Maria Favini, Maria Stella
Tinelli, Monica Livia Tortoreto
2-40, 20
Laura Zanesi
161
TUMOR GENOMICS
GABRIELLA SOZZI, Head of the Unit
Research activity
The research activity of
the Unit is focused on the
molecular pathogenesis of lung
cancer, the most lethal type of cancer
with 5-year survival estimates around
15%. The research program includes
the analysis of (epi)genetic changes,
phenotypic analyses and functional
studies to elucidate the contribution of
the tumor and its microenvironment in
the carcinogenetic process. We also aim
to implement highly sensitive molecular
tests to improve early detection and
clinical management of lung cancer and
to develop novel therapeutic approaches
by exploiting biological targets. For
the therapeutic approaches original
patients-derived xenografts (PDXs) in
mouse models are established.
Major research activities:
miRNAs: sensors and players of
lung carcinogenesis. We tested the
prognostic performance of a plasma
miRNA risk classifier (MSC) and its
ability to monitor disease in screeningdetected patients. Five-year survival
was significantly different across the
three MSC risk levels independently
from tumor stage The MSC risk level
decreased after surgery in 80% of
disease free subjects while increased
in relapsing patients (Sestini S. 2015). A
unique prospective study (www.bioMILD.
org) is ongoing to test the efficiency
of a combined LDCT-MSC approach
as first-line screening tests in 4,000
volunteers. We have completed the
enrollment and LDCT-MSC analyses at
baseline of 4,114 subjects. The results
of this trial will prove the utility of MSC
test in routine clinical practice. We are
also studying the potential of miRNAs in
different aspects of lung cancer biology
and tested miRNAs as therapeutic
agent by creating neutral liposomes for
miRNAs delivery in PDXs. Preliminary
experiments showed successful
biodistribution.
Stromal cells as accomplices of
lung carcinogenesis. Using primary
cultures of lung fibroblasts from
patients we reported that response to
microenvironment cues is regulated
by balance between epithelial and
mesenchymal features in lung cancer
cells (Andriani F. 2015). In addition, gene
expression profiling showed similarities
and specificities of activated stroma in
different tumor types (lung, prostate and
breast) (Gandellini P. 2015) that could
represent novel microenvironmentbased prognostic markers and
therapeutic targets.
Characterization of cancer initiating
cells (CICs) in lung cancer. We
identified in PDX and tumors different
CIC subsets, responsible for primary
tumors generation (quiescent CD133+)
and disseminating CICs (slowly dividing
CD133+/CXCR4+) with metastasisinitiating potential whose detection in
primary tumors correlates with poor
clinical outcome (Moro 2015; Bertolini
2015). Testing the efficacy of novel
inhibitors of CXCR4 in preclinical model
of PDXs is ongoing. In addition we are
exploiting PDXs for functional and
phenotypic analysis of human lung CTC.
Networking
Program in Solid Tumors
and Biomarkers, Center
for Applied Medical Research (CIMA),
Navarra’s Health Research Institute
(IDISNA) and University of Navarra,
Pamplona, Spain. (Biomarkers)
Department of Molecular Immunology,
Virology and Medical Genetics, The Ohio
State University, Columbus, Ohio, USA.
(miRNAs)
Unit of Biophysics and Bioengineering,
School of Medicine, University of
Barcelona, Barcelona, Spain. (Lung
Fibroblasts)
Cancer Epigenetics and Biology Program,
Bellvitge Biomedical Research Institute,
L’Hospitalet de Llobregat 08907,
Barcelona, Spain. (Biomarkers)
Genetic Cancer Susceptibility Group,
International Agency for Research on
Cancer (IARC-WHO), Lyon, France. (Lung
Neuroendocrine Tumors)
Our studies are supported by AIRC
(Investigator Grants and 5X1000 Special
Program), Ministry of Health and NCI
grants.
TUMOR GENO
162
Keywords
Lung cancer,
microRNAs, genetic changes,
microenvironment, cancer
initiating cells, pre-clinical
experimental models
Sozzi G., et al. Clinical Utility of a Plasma-Based miRNA Signature
Classifier Within Computed Tomography Lung Cancer Screening: A
Correlative MILD Trial Study. J Clin Oncol 32, 768-773 (2014)
Fortunato O., et al. Mir-660 is downregulated in lung cancer patients and
its replacement inhibits lung tumorigenesis by targeting MDM2-p53 interaction. Cell
Death Dis. 5, e1564 (2014)
Bertolini G., et al. Microenvironment-Modulated Metastatic CD133+/CXCR4+/EpCAMLung Cancer-Initiating Cells Sustain Tumor Dissemination and Correlate with Poor
Prognosis. Cancer Res 75, 3636-3649 (2015)
Sestini S., et al. Circulating microRNA signature as liquid-biopsy to monitor lung
cancer in low-dose computed tomography screening. Oncotarget. 20, 32868-32877
(2015)
Moro M., et al. Combination Treatment with All-Trans Retinoic Acid Prevents CisplatinInduced Enrichment of CD133+ Tumor-Initiating Cells and Reveals Heterogeneity of
Cancer Stem Cell Compartment in Lung Cancer. J Thorac. Oncol. 10, 1027-1036 (2015)
Staff
HEAD
Gabriella Sozzi, Biol Sci D, PhD
STAFF SCIENTIST
Luca Roz, Pharm Sci D
RESEARCH ASSOCIATES
Francesca Andriani, Pharm Sci D; Patrizia
Gasparini, Biol Sci D, PhD; Massimo Moro, Biol Sci
D; Carla Verri, Biol Sci D
Giulia Bertolini, Med Biotech D, PhD; Mattia
Boeri, Biotech D, PhD; Cristina Borzi, Med Biotech
D; Antonina Bruccoleri, Med Biotech D; Linda
Calzolari, Ind Biotech D; Orazio Fortunato, Med
Biotech D, PhD
OMICS
TECHNICIANS
Giovanni Centonze, Davide Conte, Federica
Facchinetti, Mavis Mensah
OF THE UNIT
11
PUBLICATIONS
98.445
IMPACT FACTOR
4
22.113
2-48, 10
Cristina Zanini
163
IMMUNOBIOLOGY OF HUMAN TUMORS
ANDREA ANICHINI, Head of the Unit
Research activity
The main results of 2015, included:
Networking
The research activity of the
Unit is focused on improving
efficacy of immunotherapy and of
target-specific therapy of solid tumors
by biological, immunological and
molecular characterization of neoplastic
and normal tissues from cancer
patients. To this end, in collaboration
with clinicians of our Institute and with
research groups in Italy and abroad,
we aim at the identification of: a)
biomarkers of response; b) mechanisms
of resistance; c) new therapeutic
targets for developing combinatorial
treatments. Major pathologies of
interest were: cutaneous melanoma, non
small cell lung cancer (NSCLC), germ cell
tumors and pediatric gliomas.
Identification of a signaling pathway
controlled by the transcription factor
NFATc2 that promotes melanoma
de-differentiation and immune escape
(Perotti V, et al. Oncogene. 2015)
The main goals were:
BRAF-mutant melanomas with intrinsic
resistance to BRAF inhibitors can be
identified based on an EGFR-Hi ERBB3lo phenotype associated with a specific
gene expression profile (Dugo M, et al.
Oncotarget. 2015).
Lack of susceptibility to BRAF inhibitors
was associated with cross-resistance to
PI3K/mTOR blockade, but this phenotype
was efficiently counteracted by
association of MEK1/2 and PI3K/mTOR
inhibitors.
Pediatric Oncology Unit
and the McGill University,
Montreal, Canada, on a project aimed at
identification of molecular alterations in
diffuse intrinsic pontine glioma patients
by analysis of cfDNA in serum
Italian Institutions members of the I.M.I.
(Intergruppo Melanoma Italiano) on a
project aiming at defining biomarkers of
response and mechanisms of resistance
to immune checkpoint inhibitors in
melanoma
University of Catanzaro and with
Karolinska Institutet, Stockholm,
Sweden, on the role of NK cells in the
immune response to melanoma and in
the efficacy of immunotherapy
Melanoma: a) to characterize the
pathways controlled by master
immunoregulatory genes that suppress
the adaptive immune response; b) to
target TRAIL-R2 receptor on neoplastic
cells to redirect anti-tumor T cells; c) to
understand mechanisms of response
and resistance to immunotherapy
targeting CTLA-4 or PD-1/PD-L1; d)
to identify biomarkers of intrinsic
resistance to target-specific inhibitors;
e) to discover new combinatorial
treatments to overcome intrinsic
resistance to inhibitors of MAPK and
PI3K/mTOR pathways.
NSCLC: a) to characterize functional
PD-1+ anti-tumor T cells in the tumor
microenvironment as biomarkers
of active anti-tumor immunity; b) to
identify predictive factors of response to
immune checkpoint blockade therapy by
immune profiling of peripheral blood;
IMMUNOBIOL
OF HUMAN TU
Germ cell tumors: to verify the
immunological mechanism explaining
efficacy of treatment with Brentuximabvedotin.
Pediatric gliomas: to identify serum
biomarkers associated with response to
treatment and to exploit liquid biopsies
to identify tumor-specific Histone H3
mutations.
Our research is supported by AIRC
Investigator Grants and 5x1000 Special
Program; FIRC and Fondazione Berlucchi
Fellowships.
164
Keywords
Melanoma, NSCLC,
microenvironment, immune
response, target-specific
therapy
Loria R, Bon G, Perotti V, Gallo E, Bersani I, Baldassari P, Porru M,
Leonetti C, Di Carlo S, Visca P, Brizzi MF, Anichini A, Mortarini R, Falcioni
R. Sema6A and Mical1 control cell growth and survival of BRAFV600E
human melanoma cells. Oncotarget. 2015 Feb 20;6(5):2779-93
Dugo M, Nicolini G, Tragni G, Bersani I, Tomassetti A, Colonna V, Del Vecchio M, De
Braud F, Canevari S, Anichini A, Sensi M. A melanoma subtype with intrinsic resistance
to BRAF inhibition identified by receptor tyrosine kinases gene-driven classification.
Oncotarget. 2015 Mar 10;6(7):5118-33
Ali TH, Pisanti S, Ciaglia E, Mortarini R, Anichini A, Garofalo C, Tallerico R, Santinami
M, Gulletta E, Ietto C, Galgani M, Matarese G, Bifulco M, Ferrone S, Colucci F, Moretta
A, Kärre K, Carbone E. Enrichment of CD56(dim)KIR + CD57 + highly cytotoxic NK cells
in tumour-infiltrated lymph nodes of melanoma patients. Nat Commun. 2014 Dec
4;5:5639
Grazia G, Vegetti C, Benigni F, Penna I, Perotti V, Tassi E, Bersani I, Nicolini G, Canevari S,
Carlo-Stella C, Gianni AM, Mortarini R, Anichini A. Synergistic anti-tumor activity and
inhibition of angiogenesis by cotargeting of oncogenic and death receptor pathways
in human melanoma. Cell Death Dis. 2014 Oct 2;5:e1434
Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, Erba E, Uboldi
S, Zucchetti M, Pasqualini F, Nebuloni M, van Rooijen N, Mortarini R, Beltrame L,
Marchini S, Fuso Nerini I, Sanfilippo R, Casali PG, Pilotti S, Galmarini CM, Anichini A,
Mantovani A, D’Incalci M, Allavena P. Role of macrophage targeting in the antitumor
activity of trabectedin. Cancer Cell. 2013 Feb 11;23(2):249-62
OF THE UNIT
Staff
LOGY
UMORS
HEAD
Andrea Anichini, Biol Sci D
STAFF SCIENTIST
Roberta Mortarini, Biol Sci D
2
PUBLICATIONS
12.718
IMPACT FACTOR
Valentina Eleonora Perotti, Biol Sci D
Elena Tassi, Biotech Sci D
2
PH.D. STUDENTS
Giulia Grazia, Biotech Sci D
12.718
TECHNICIANS
Paola Lucrezia Baldassari, Ilaria Bersani,
Alessandra Molla, Gabriella Nicolini, Claudia
Vegetti
2-43, 11
Cristina Zanini
165
IMMUNOTHERAPY OF HUMAN TUMORS
LICIA RIVOLTINI, Head of the Unit
Research activity
The work of the Unit is
focused on multiple aspects
of tumor immunology and
immunotherapy in cancer patients.
The aim is to dissect pathways
involved in tumor progression, identify
immune-related prognostic/predictive
biomarkers, and define new therapeutic
tools of immunomodulation. A
substantial effort in devoted to clinical
trials testing immunological effects
of different therapeutic approaches
modulating host/tumor immune
interactions, in tight collaboration with
clinical departments.
Myeloid cell dysfunctions as systemic
biomarkers and therapeutic targets.
Aberrant immunosuppressive myeloid
cells, including MDSC (Myeloid-Derived
Suppressor Cells), are mobilized from
the bone marrow into blood of cancer
patients as consequence of tumor
conditioning or chronic inflammation.
We are working on defining a Myeloid
Index Score, a phenotypic blood test
to quantify systemic cancer immune
suppression showing prognostic/
predictive value in patients with
advanced melanoma. The study of the
molecular pathways underlying MDSC
generation has allowed to define a panel
of MDSC-related exosomal miRNAs that
is under evaluation as plasma biomarker
of cancer immune suppression. Through
an MDSC in vitro model allowing to
screen drugs interfering with myeloidtumor cross-talk, we selected proton
pump inhibitors as a promising drug
family to modulate tumor-associated
immune dysfunctions. A clinical trial to
test the immunomodulating activity of
PPI in melanoma patients is presently in
progress (Adesom2 trial).
pH regulators and immunity.
Hypoxia and local acidity are biochemical
cancer hallmarks. Tumor cells, as
well as immunosuppressive cells,
have evolved the ability to function in
an acidic environment, thanks to the
upregulation of pH regulators including
carbonic anhydrases and vATPase.
We are interested in understanding
whether this pathway may be source of
prognostic biomarkers or therapeutic
targets in hepatocellular carcinoma
(HCC), a particularly hypoxic and acidic
cancer histotype. The evidence that pH
regulators are highly expressed in HCC
and that a gene-signature linking acidity
to immunosuppression and tumor
aggressiveness is associated with poor
outcome, underlines the prognostic and
therapeutic value of this pathway in
liver cancer.
Networking
The Unit is actively involved
in:
Network Italiano di
BioImmunoterapia dei tumori (NIBIT)
Rete Oncologica Venezia
GOIM (Gruppo Oncologico Italia
Meridionale)
The Unit partecipates to the
Horizon2020 Program, the Precious
project and ‘MELANOSTRUM GWAS to
dbGaP’ GWAS Program NCI, USA. The
Unit also contributes to guidelines for
immunological monitoring through
MIATA PROGRAM and Society for
Immunotherapy of Cancer (SITC)
Impact of immunity on clinical efficacy
and resistance to target therapies.
Combining target therapies with
immunotherapy is a promising strategy
to increase disease control in cancer.
In melanoma, we are dissecting the
immunological implications of BRAF and
MEK inhibitors, to identify pathways of
potential synergism. Through a complex
set on in vitro experiments, we defined a
series of miRNA induced by therapy with
tyrosine kinase inhibitors (TKI), that are
responsible for the acquired resistance
of tumor cells to multiple proapoptotic
signals including those mediated by
immune effectors. The use of selective
antagomirs is under investigation as a
strategy to potentiate intrinsic tumor
sensitivity to Immune-mediated cell
death.
IMMUNOTHER
OF HUMAN TU
166
Keywords
Immunosuppression;
pH; myeloid cells;
immunoncology; immunerelated predictive factors
Castelli C, Triebel F, Rivoltini L, Camisaschi C. Lymphocyte activation
gene-3 (LAG-3, CD223) in plasmacytoid dendritic cells (pDCs): a molecular
target for the restoration of active antitumor immunity. Oncoimmunology.
2014 Dec 21;3(11)
Vallacchi V, Vergani E, Camisaschi C, Deho P, Cabras AD, Sensi M, De Cecco L, Bassani
N, Ambrogi F, Carbone A, Crippa F, Vergani B, Frati P, Arienti F, Patuzzo R, Villa A,
Biganzoli E, Canevari S, Santinami M, Castelli C, Rivoltini L, Rodolfo M. Transcriptional
profiling of melanoma sentinel nodes identify patients with poor outcome and reveal
an association of CD30(+) T lymphocytes with progression. Cancer Res. 2014 Jan
1;74(1):130-40
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 antigenspecific T cell response. Cancer Immunol Immunother. 2013 May;62(5):897-908
Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L. The acidity of tumor
microenvironment is a mechanism of immune escape that can be overcome by
proton pump inhibitors. Oncoimmunology. 2013 Jan 1;2(1):e22058
Staff
HEAD
Licia Rivoltini, MD
STAFF SCIENTIST
Chiara Castelli, Biol Sci D, PhD;
Monica M. Rodolfo, Biol Sci D
RESEARCH ASSOCIATES
Chiara Camisaschi Biol Sci D, PhD; Veronica
B. Huber, PhD; Samantha A. Pesce, Biol Sci D;
Viviana Vallacchi, Biol Sci D, PhD
RAPY
UMORS
OF THE UNIT
7
PUBLICATIONS
Angela De Laurentiis, Biol Sci D, PhD; Eriomina
Shahaj, Biol Sci D, PhD; Marcella Tazzari, Biol
Sci D, PhD; Alessandra Tuccitto, Biol Sci D, PhD;
Elisabetta Vergani, Biol Sci D, PhD
24.701
RESEARCH NURSE
Felicetta Giardino
TECHNICIANS
Valeria Beretta, Agata Cova, Paola Deho, Simona
Frigerio, Francesca Rini, Paola Squarcina
DATA MANAGER
Paola Frati
IMPACT FACTOR
2
7.303
2-59, 9
Grazia Convertino
167
ANGELA GRECO, Head of the Unit
Research activity
The Unit is involved in
studies aimed to identify of the
molecular mechanisms contributing
to pathogenesis of thyroid carcinoma.
Ongoing studies focus on: i) papillary
thyroid carcinoma (PTC), arising from
thyroid follicular epithelium and ii)
medullary thyroid carcinoma (MTC)
from parafollicular C cells. The goal
is identification of markers for early
detection, prognosis, follow-up, and
novel therapeutic targets. We employ
several approaches including: highthroughput analyses; functional studies
employing tumor derived cell lines and
primary thyrocytes as in vitro models of
thyroid carcinogenesis; characterization
of thyroid tumor case collections.
During 2015, we have progressed in
several projects.
Identification of thyroid tumor cell
vulnerability. We have previously
identified a set of genes whose inhibition
interferes with tumor, but not normal
thyroid cell viability. Among those, we
selected MASTL, CCND1 and COPZ1 genes
for deeper functional studies. We found
that their inhibition induced cell growth
inhibition also in several thyroid cancer
cell lines, regardless the histotype or
genetic lesion, thus proposing them
as attractive therapeutic targets for
thyroid cancer. (supported by: AIRC 11347
“Role of oncogene-induced senescence
and non-oncogene addiction in thyroid
carcinogenesis” 2012-2015; fellowship
Fondazione Umberto Veronesi 2015)
miRNA in PTC: pathways involved and
possible prognostic and therapeutic
impact. Through the integration of
different approaches we have identified
a list of 18 miRNAs differentially
expressed between PTC and normal
thyroid. Among these we focused on
miR-451a: we have demonstrated that
it exerts an oncosuppressor role in PTC,
and targets the AKT/mTOR pathway.
(Supported by Ministero della SaluteProgetto Strategico Istituzionale 5xmille
2014-16 “Studio dei MiRNA nel carcinoma
papillare della tiroide: pathways
coinvolti e possibili bersagli terapeutici”)
Next generation sequencing of PTC.
Using next generation sequencing
technologies we have determined
the genetic landscape of a PTC case
collection negative for the major PTCassociated genetic lesions.
Networking
Crosstalk between thyroid tumor
cells and macrophages. Using
senescent thyrocytes and thyroid
tumor cell lines as in vitro models of
early and late thyroid tumor stages,
we have performed a preliminary
characterization of the interaction with
tumor microenvironment components,
in particular macrophages. Both
senescent and tumor thyroid cells are
able to induce M2-like phenotype in
monocytes. M2 macrophages enhance
the migratory ability of tumor cells,
whereas M1 macrophages exert a prosenescence effect on normal thyrocytes.
(Supported by CARIPLO 2013-0893
Role of tumor microenvironment in
thyroid carcinogenesis onset and
progression:thyroid cells cross-talk with
macrophages 2014-2017)
INdAM Unit & Department of Information
Engineering, University of Brescia
Identification of specific tumor and
plasma miRNA profiles of metastatic
MTC patients. We have obtained gene
and miRNA expression profiles from MTC
primary tumors and matched lymph
node metastases vs normal thyroid, as
well as the profiles of circulating miRNA
from MTC patients, before vs after TK
inhibitor pharmacological treatment,
and vs healthy donors. In vitro model
using an MTC cell line harboring the
most frequent genetic alterations
present in these patients, RET-M918T,
treated with TK inhibitor, has been set up
and characterized both for expression
profiles of cellular transcriptoma and
for miRNA and protein of isolated
exosomes. Partially supported by Astra
Zeneca: “Molecular profile of metastatic
sporadic medullary thyroid cancer
(sMTC) patients and possible correlation
with vandetanib therapy” 2013-2015
The Unit collaborates with:
Lab. Cellular Immunology,
Clinical and Research
Institute HUMANITAS
Department of Pathophysiology and
Transplantation, Endocrine Unit
Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, Milan
Hematology Unit, Fondazione IRCCS Ca’
Granda, Ospedale Maggiore Policlinico,
Milan, Italy
Department of Clinical Sciences and
Community Health; University of Milan,
Milan, Italy
Nerviano Medical Sciences S.r.l.,
Department of Cell Biology, Oncology,
Nerviano
MOLECULAR
MECHANISMS
168
S
Keywords
Thyroid tumors;
miRNA;
oncogene-induced senescence;
tumor cell vulnerabilities
MC Anania, F Gasparri, E Cetti, I Fraietta, K Todoerti, C Miranda, M
Mazzoni, C Re, R Colombo, G Ukmar, S Camisasca, S Pagliardini, MA
Pierotti, A Neri, A Galvani, and A Greco. Identification of thyroid tumor cell
vulnerabilities through a siRNA-based functional screening. Oncotarget
2015, Oct 27;6(33):34629-48
Minna E, Romeo P, De Cecco L, Dugo M, Cassinelli G, Pilotti S, Degl’Innocenti D, Cinzia
Lanzi C, Casalini P, Pierotti MA, Greco A, and Borrello MG. 5. miR-199a-3p displays
tumor suppressor functions in papillary thyroid carcinoma. Oncotarget 2014 May
15;5(9):2513-28
Vizioli MG, Santos J, Pilotti S, Mazzoni M, Anania MC, Miranda C, Pagliardini S, Pierotti
MA, Gil J, and Greco A. Oncogenic RAS-induced senescence in human primary
thyrocytes: molecular effectors and inflammatory secretome involved. Oncotarget
2014 Sep 30;5(18):8270-83
Anania MC, Miranda C, Vizioli MG, Mazzoni M, Cleris L, Pagliardini S, Manenti G,
Borrello MG, Pierotti MA, Greco A. S100A11 overexpression contributes to the
malignant phenotype of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2013
October; 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 MA, Greco A, Borrello MG. DUSP6/MKP3 is overexpressed in papillary and poorly-differentiated thyroid carcinoma and contributes
to the neoplastic properties of thyroid cancer cells. Endocr Relat Cancer. 2013 Jan
21;20(1):23-37
OF THE UNIT
Staff
HEAD
Angela Greco, Biol Sci D, PhD
STAFF SCIENTIST
Italia Bongarzone, Biol Sci D, Maria Grazia
Borrello, Biol Sci D
Elena Cetti, Med Biotech D, Mara Mazzoni, Biol
Sci D; Emanuela Minna, Biol Sci D, Paola Romeo,
Med Biotech D; Luca Varinelli, Med Biotech D
TECHNICIANS
Maida De Bortoli, Sonia Pagliardini, Maria Grazia
Rizzetti, Elena Taverna
10
PUBLICATIONS
44.615
IMPACT FACTOR
6
26.748
1-39, 9
Silvia Grassi
169
OF CELL CYCLE CONTROL
DOMENICO DELIA, Head of the Unit
Research activity
This research unit is involved
in three main projects:
Analysis and dissection of the
ATM-dependent pathway in DNA
damage response (DDR) and genomic
stability in tumor cells and in cancerpredisposing neurodegenerative
syndrome. In 2015, we analyzed the role
of the DNA damage response protein
DBC1 in the repair of DNA breaks induced
by etoposide and ionizing radiation
treatments. Using U2OS cells, knockedout or silenced for DBC1, we discovered
that this protein is required for the
repair of heterochromatic DNA lesions.
Indeed, the absence of DBC1 hinders
the activation of the checkpoint kinase
Chk2 and thus the phosphorylation
of its substrate KAP1. The defective
phosphorylation of KAP1 prevents
heterochromatin relaxation which is
required to allow the access of repair
factors to the lesions.
Moreover, we discovered that DBC1
depletion reduces the growth of cancer
cells, but not that of non-neoplastic
cells. Gene expression profile analyses
revealed deregulation of genes involved
in ERK, AKT and NF-kB pathways in
DBC1-ablated cells. Accordingly, we
found that DBC1-depleted cancer cells,
but not normal cells, show reduced
activation of AKT, and furthermore AKT
hyperactivation by PTEN depletion can
rescue the defective proliferation of
DBC1-ablated cancer cells.
Role of the inhibitor of apoptosis
proteins (IAPs) in cancer aggressiveness
and metastasization. IAP levels are
often deregulated in cancer cells and
contribute to cancer development and
resistance to apoptosis. For this reason,
we have recently developed a library
of IAP-directed compounds, called
Smac mimetics (SM) to inhibit these
proteins and enhance the cytotoxic
activity of traditional chemotherapeutic
compounds. Our work provided
evidence that SMs not only increase
cancer sensitivity to treatment, but also
reduced the aggressiveness of cancer
cells by repressing the expression of
metastasis-related genes. This effect
is particularly evident in triple negative
breast cancer cells, which are highly
sensitive to SMs and are characterized
by high levels of Snai2. This transcription
factor contributes to metastasis
formation and resistance to anti-cancer
treatment. Furthermore, to understand
the molecular mechanisms that promote
cancer metastases, we engineered our
breast cancer models to knock-out the
genes of interest using the CRISPR/Cas9
technology.
Networking
Dipartimento di Bioscienze,
Università degli Studi di
Milano
Dipartimento di Chimica, Università degli
Studi di Milano
Department of Molecular Oncology,
King’s College London
Fibroblast contribution to lung
cancer aggressiveness. Using a highthroughput approach, we identified a
group of miRNAs that, when ectopically
expressed in fibroblasts, influence the
growth of the adjacent cancer cells.
Accordingly, we demonstrated that
these miRNAs modulate the secretome
of the fibroblasts and characterized a
miR16/FGFR1/HGF axis which results in
the stimulation of the cMet receptor of
cancer cells.
MOLECULAR M
OF CELL CYCL
170
Keywords
DNA damage
metastasis
tumor microenvironment
Conti A, Majorini MT, Elliott R, Ashworth A, Lord CJ, Cancelliere C,
Bardelli A, Seneci P, Walczak H, Delia D, Lecis D. Oncogenic KRAS
sensitizes premalignant, but not malignant cells, to Noxa-dependent
apoptosis through the activation of the MEK/ERK pathway. Oncotarget. 2015 May
10;6(13):10994-1008
Buscemi G, Ricci C, Zannini L, Fontanella E, Plevani P, Delia D. Bimodal regulation of
p21(waf1) protein as function of DNA damage levels. Cell Cycle. 2014;13(18):2901-12
Magni M, Ruscica V, Buscemi G, Kim JE, Nachimuthu BT, Fontanella E, Delia D, Zannini
L. Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis.
Nucleic Acids Res. 2014 Dec 1;42(21):13150-60
Carlessi L, Fusar Poli E, Bechi G, Mantegazza M, Pascucci B, Narciso L, Dogliotti E,
Sala C, Verpelli C, Lecis D, Delia D. Functional and molecular defects of hiPSC-derived
neurons from patients with ATM deficiency. Cell Death Dis. 2014 Jul 17;5:e1342
Lecis D, De Cesare M, Perego P, Conti A, Corna E, Drago C, Seneci P, Walczak H,
Colombo MP, Delia D, Sangaletti S. Smac mimetics induce inflammation and necrotic
tumour cell death by modulating macrophage activity. Cell Death Dis. 2013 Nov
14;4:e920
OF THE UNIT
5
MECHANISMS
LE CONTROL
Staff
HEAD
Domenico Delia, Biol Sci D
RESEARCH ASSOCIATES
Laura Zannini, Biol Sci D, PhD
Luigi Carlessi, Biol Sci D; Annalisa Conti, Biol Sci
D, PhD; Daniele Lecis, Biotech Sci D, PhD; Martina
Magni, Biol Sci D, PhD Student; Maria Teresa
Majorini, Biol Sci D, PhD Student; Michela Restelli,
Biol Sci D, PhD
TECHNICIANS
Enrico Carlo Fontanella
PUBLICATIONS
45.177
IMPACT FACTOR
2
12.718
1-45, 9
Silvia Grassi
171
MOLECULAR THERAPIES
DELIA MEZZANZANICA, Head of the Unit
Research activity
Achievements:
Networking
The Unit of Molecular
Therapies is involved in
translational research mainly
dedicated to respond to the unmet
clinical needs related to ovarian cancer:
late diagnosis, rapid progression,
frequent disease relapse, and
development of chemoresistance.
Besides ovarian cancer, other tumors
(prostate and thyroid cancers,
melanoma, lymphoma) are studied.
Identification of Gas6 ligand/Axl/integrin
pathway cross-talk and molecular
signature in the most aggressive ovarian
cancers.
The Unit is part of the
MITO group (Multicentre
Italian Trials in Ovarian
Cancer); Unit PI is the MITO translational
representative at the GCIC (Gynecological
Cancer Inter Group) and at ENGOT
(European Network of Gynaecological
Oncological Trial Groups).
The activity is organized into the
following lines of research in
collaboration with Surgery and
Pathology Departments and with
Functional Genomics Core Facility.
Molecular basis of tumor growth
and progression: the aim is to
decipher signal transduction
mediated by adhesion molecules
and microenvironment interaction in
3D models of cell lines and patientderived cells and its validation in clinical
settings.
Molecular bases of disease recurrence
in ovarian cancer: study of the
microRNA-driven regulatory networks
related to drug sensitivity/cellular
plasticity. Integration of data derived
from multiple level of analysis: gene
expression, miRNA, methylation, exome
sequencing. Evaluation of the impact of
metabolic alteration in ovarian cancer
aggressiveness.
Antibody engineering: development of
antibody-based diagnostic/therapeutic
tools; testing their efficacy in short term
patients’ derived cultures and patenting
the most promising tools for clinical
application.
Our research is supported by AIRC
Investigator and 5x1000 Special Program
Grants.
Molecular and functional
characterization of peptidomimetic
ligands to cell/cell adhesion-mediated
signal transdution in ovarian cancer
cells.
Identification of a miRNA predictor
of ovarian cancer early relapse and
definition of one of the miRNAs included
into the predictor (miR506) as master
regulator of cell plasticity and drug
sensitivity.
Identification of Choline Kinase,
involved in altered choline metabolism,
as a target to reduce ovarian cancer
aggressiveness and to increase drug
sensitivity.
Production of human antibody
fragments in different format whose
variable regions have been patented:
Human ScFv fragment to prostate
specific membrane antigen (PSMA)
for imaging and treatment of prostate
cancer; Chimeric Antigen Receptors with
anti alpha-folate receptor (FR) and antiPSMA specificity for T cells redirection;
functionalization of magnetic
nanoparticles with an anti-FR ScFv for
treatment and miRNA delivery; human
bispecific antibody (anti-TRAIL-R2\antiCD3) for T cells redirection.
Collaboration to the phase I clinical trial
NCT02546921: first in human study of
the new therapeutic antibody MOv18 IgE
anti alpha-FR, in patients with advanced
solid tumors.
Unit’s members actively collaborate
with:
Department of Theoretical and Applied
Sciences, Università degli Studi
dell’Insubria, Varese; CNR, Istituto di
Scienze e Tecnologie Molecolari, and
Centro Interdisciplinare Studi biomolecolari e applicazioni Industriali,
Milano; Istituto Italiano Tecnologia (IIT);
Nanomaterial for biomedicals, Genoa;
Istituto Italiano Tecnologia (IIT); Center
for Nano Science and Technology @
PoliMi; University of Turin; Department
of Molecular Biotechnology and Health
Sciences; Mayo Clinic, Jacksonville (USA);
Cancer Biology; University of Milan;
Department of Chemistry; Nerviano
Medical Sciences; Oncology; Centro
Oncologico di Riferimento, Aviano;
Experimental and Clinical Pharmacology;
Division of Experimental Oncology
2; IRCCS Istituto Pascale, Naples;
Urogynaecological Oncology; Functional
Genomics; Clinical Trial Office; Anatomy
Pathology; IRCCS S. Martino, Genoa;
Integrated Oncological Therapies;
Istituto Superiore Sanità, Rome; Cell
Biology and Neurosciences;
MD Anderson Cancer Center, Houston
(USA); Pathology; Gynecologic
Oncology and Cancer Biology; John
Hopkins University, Baltimore (USA);
Russell H. Morgan Department of
Radiology and Radiological Science;
Istituto Oncologico Veneto, Padoa;
Immunology and Molecular Oncology;
Kings College, London; Dermatology
Division of Genetics and Molecular
Medicine Faculty of Life Sciences
and Medicine; Institute of Biomedical
Sciences, Taiwan; Academia Sinica Taipei,
Taiwan; University of Pennsylvania
(USA); Dept of Path & Lab Medicine;
Radboud University Medical Center, NL;
Department of Radiology and Nuclear
Medicine; GlyTech, Inc Kyoto; University
of Bordeaux. Imagerie moléculaire et
thérapies innovantes en oncologie
MOLECULAR T
172
Keywords
ovarian cancer;
tumor progression;
antibody engineering
Granata A, Nicoletti R, Perego P, Iorio E, Krishnamachary B, Benigni F,
Ricci A, Podo F, Bhujwalla ZM, Canevari S, Bagnoli M, Mezzanzanica D.
Global metabolic profile identifies choline kinase alpha as a key regulator
of glutathione-dependent antioxidant cell defense in ovarian carcinoma.
Oncotarget. 2015;6(13):11216-30.
Quarta A, Bernareggi D, Benigni F, Luison E, Nano G, Nitti S, Cesta MC, Di Ciccio L,
Canevari S, Pellegrino T, Figini M. Targeting FR-expressing cells in ovarian cancer with
Fab-functionalized nanoparticles: a full study to provide the proof of principle from in
vitro to in vivo. Nanoscale. 2015;7(6):2336-51
Rea K, Pinciroli P, Sensi M, Alciato F, Bisaro B, Lozneanu L, Raspagliesi F, Centritto F,
Cabodi S, Defilippi P, Avanzi GC, Canevari S, Tomassetti A. Novel Axl-driven signaling
pathway and molecular signature characterize high-grade ovarian cancer patients
with poor clinical outcome. Oncotarget. 2015;6(31):30859-75
Lualdi M, Pedrini E, Rea K, Monti L, Scaldaferri D, Gariboldi M, Camporeale A, Ghia P,
Monti E, Tomassetti A, Acquati F, Taramelli R. Pleiotropic modes of action in tumor
cells of RNASET2, an evolutionary highly conserved extracellular RNase. Oncotarget.
2015;6(10):7851-65
Liu G, Yang D, Rupaimoole R, Pecot CV, Sun Y, Mangala LS, Li X, Ji P, Cogdell D, Hu
L, Wang Y, Rodriguez-Aguayo C, Lopez-Berestein G, Shmulevich I, De Cecco L,
Chen K, Mezzanzanica D, Xue F, Sood AK, Zhang W. Augmentation of response to
chemotherapy by microRNA-506 through regulation of RAD51 in serous ovarian
cancers. J Natl Cancer Inst. 2015;107(7)
Staff
HEAD
Delia Mezzanzanica, Biol Sci D
STAFF SCIENTIST
Mariangela Figini, Biol Sci D;
Antonella Anna Piera Tomassetti, Pharm Sci D
RESEARCH ASSOCIATES
Marina Bagnoli, Biol Sci D
Davide Bernareggi, Biol Sci D; Andrea Cacciamali,
Biol Sci D; Floriana Centritto, Biol Sci D; Barbara
Frigerio, Biol Sci D; Anna Granata, Biol Sci D;
Roberta Nicoletti, Med Biotech D; Katia Rea, Med
Biotech D; Alessandro Satta, Vet Biotech D
OF THE UNIT
15
PUBLICATIONS
85.794
IMPACT FACTOR
7
31.832
THERAPIES
TECHNICIANS
Paola Alberti, Annamaria Invernizzi, Elena Luison
1-24, 5
Silvia Portincasa
173
MOLECULAR TARGETING
ELDA TAGLIABUE, Head of the Unit
Research activity
Our research is currently
focused on breast cancer early
diagnosis and resistance to therapy
as an avenue toward enhancing cure
rate.
During 2015, the research activity of the
Unit focused on:
Mechanism(s) underlying the resistance
to HER2-targeted therapies. Through
whole-transcriptome analysis of
primary HER2+ BCs obtained from
patients treated with trastuzumabcontaining therapies, we developed a
trastuzumab risk model (TRAR) able
to identify patients with high and low
risk of relapse. Application of the TRAR
model to core biopsies from patients
treated with neo-adjuvant trastuzumab
indicated that it is predictive of
trastuzumab response. Pathway
analysis revealed that TRAR-low
tumors expressed genes of the immune
response, with higher numbers of CD8+
cells detected immunohistochemically
compared to TRAR-high tumors (Triulzi
& De Cecco et al., Oncotarget 2015). In
addition, we found that the synergistic
therapeutic effect between trastuzumab
and taxanes depends on the ability of
drug-induced stress to improve NK cell
effectiveness and thus trastuzumabmediated cytotoxicity. Accordingly,
NK cells from HER2+ BC patients after
treatment with taxane-containing
therapy expressed higher levels of
NKG2D activating receptor than before
treatment. This enhancement occurred
mainly in patients with low NKG2D
basal expression, suggesting that
taxanes concomitantly administered
with trastuzumab could maximize the
antibody effect, especially in patients
with low basal immune effector
cytotoxic activity (Di Modica et al.,
Oncotarget, 2016).
Evaluation of microenvironment
influence in tumor development and
progression. By exploring the possibility
that host-tumor interaction leads to
the release of exhaled compounds
detectable in breath, we approached
the discovery of new tools for the early
diagnosis of BC which may present a
problem, especially for high risk women
who need repeatedly flawless screening.
Analysis of breath data in a cohort of
BC patients and healthy volunteers
using mass-spectrometry identified
features able to discriminate BC patients
from healthy individuals with very high
sensitivity and specificity (MartinezLozano Sinue et al., J Breath Res. 2015)
. Consistent with the host-related
changes accompanying transformation,
we investigated whether the abnormal
production of extracellular matrix (ECM)
molecules fostered by the cross-talk
between an incipient BC clone and the
adjacent fibroblasts may lead to the
release of molecules that enter the
blood stream and represent an amplified
circulating marker of transformation.
Analyses of independent series of
human plasma samples supported
the usefulness of a combination
of circulating ECM molecules in
discriminating patients with malignant
from benign breast disease.
Networking
Collaboration with:
Hematology and Oncology
Division, Cornell University,
NY
Dept. of Cell and Molecular Biology,
Tulane University, New Orleans, LO
Department of Breast Surgery,Fudan
University Shanghai Cancer Center,
Shanghai, China
Dept. of Chemistry and Applied
Biosciences, ETH Zurich, Switzerland
Department of Bioengineering University
of Illinois at Urbana-Champaign, Urbana
The Scripps Research Institute, La Jolla,
CA
Translational Genomics Group Vall
d’Hebron Institute of Oncology,
Barcelona, Spain
European Laboratory for Non-linear
Spectroscopy, University of Florence,
(LENS), Sesto Fiorentino, Italy
Department of Biochemistry, University
of Western Ontario, Canada
Cancer therapy through TLR-induced
local innate immunity activation.
The lung immunosuppressive
microenvironment, essential to limit
response to inhaled antigens, favors
metastasis development. We found that
aerosol delivery of TLR agonists, able to
convert tumor-supporting macrophages
to tumoricidal effectors, reduced M2
macrophages in tumor-bearing lungs
and induced a significant anti-tumor
activity (Le Noci et al., Oncoimmunology,
2015).
MOLECULAR T
174
Keywords
Breast cancer,
HER2,
taregeted therapy,
tumor microenvironment
M. Giussani, G. Merlino, V. Cappelletti, E. Tagliabue, and M. G. Daidone.
Tumor-Extracellular matrix interactions: identification of tools
associated with breast cancer progression. Semin. Cancer Biol. 2015;
35:3-10
T. Triulzi, L. De Cecco, M. Sandri, A. Prat, M. Giussani, B. Paolini, M. L. Carcangiu, S.
Canevari, A. Bottini, A. Balsari, S. Ménard, D. Generali, M. Campiglio, S. Di Cosimo, and
E. Tagliabue. Whole-transcriptome analysis links trastuzumab sensitivity of breast
tumors to both HER2 dependence and immune cell infiltration. Oncotarget 2015;
6(29):28173-28182
T. Triulzi, M. Ratti, M. Tortoreto, C. Ghirelli, P. Aiello, V. Regondi, M. D. Modica, D.
Cominetti, M. L. Carcangiu, A. Moliterni, A. Balsari, P. Casalini, and E. Tagliabue. Maspin
influences response to doxorubicin by changing the tumor microenvironment
organization. Int J Cancer 2014; 134:2789-2797
L. Castagnoli, M. Iezzi, G. C. Ghedini, V. Ciravolo, G. Marzano, A. Lamolinara, R.
Zappasodi, P. Gasparini, M. Campiglio, A. Amici, C. Chiodoni, A. Palladini, P. Lollini,
T. Triulzi, S. Ménard, P. Nanni, E. Tagliabue, and S. M. Pupa. Activated d16HER2
homodimers and Src kinase mediate optimal efficacy for trastuzumab. Cancer Res.
2014; 74:6248-6259
T. Triulzi, P. Casalini, M. Sandri, F. Ratti, M. L. Carcangiu, M.P. Colombo, A. Balsari, S.
Ménard, R. Orlandi, and E. Tagliabue. Neoplastic and stromal cells contribute to an
extracellular matrix gene expression profile defining a breast cancer subtype likely to
progress. PLoS ONE 2013; 8:e56761
Staff
HEAD
Elda Tagliabue, Biol Sci D
STAFF SCIENTIST
Rosaria Orlandi, Biol Sci D;
Serenella M. Pupa, Biol Sci D
RESEARCH STAFF
Manuela Campiglio, Biol Sci D
RESEARCH ASSOCIATES
Marco Sandri, Stat Sci D; Valentina Ciravolo,
Biotech Sci D; Michele Sommariva, Biotech Sci D
Martina Di Modica, Biotech Sci D; Luca Forte, Biol
Sci D; Ada Koschorke, Biotech Sci D; Valentino Le
Noci, Biotech Sci D; Viola Regondi, Biotech Sci D;
Federica Turdo, Biol Sci D
PHD STUDENTS
Lorenzo Castagnoli, Biotech Sci D; Gaia C. Ghedini,
Biotech Sci D; Marta Giussani, Biotech Sci D;
Tiziana Triulzi, Biotech Sci D
OF THE UNIT
13
PUBLICATIONS
56.696
IMPACT FACTOR
7
30.181
TARGETING
TECHNICIANS
Pierangela Aiello, Patrizia Casalini, Cristina A.
Ghirelli
1-45, 8
Laura Mameli
175
AIRC START UP UNIT
MARILENA V. IORIO, Head of the Unit
Research activity
The goal of the Start Up
Unit is the identification and
the study of microRNAs involved
in the most relevant pathways driving
human breast cancer occurrence and
progression. The aim of our research is
not only the advancement of knowledge
in this field, by a clear definition of
the role of these small but powerful
molecules in this neoplasia, but also to
provide the experimental bases for their
possible use as therapeutic targets or
tools.
The so-called Triple Negative Breast
Cancers (TNBCs) represent a relatively
unknown area in breast cancer biology
and 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.
In collaboration with Dr Tagliabue,
we have recently described in TNBC a
feature peculiar of aggressive tumors,
the capability to undergo a tumorto-endothelium trans-differentiation
and reported that this phenomenon
is associated with poor prognosis in
TNBC (Plantamura I et al., 2014). In
2015, we completed a study describing
the opposite role of miR-9 and
miR-200c both in vitro and in vivo
on the phenomenon of endothelial
differentiation of TNBC. In detail, miR200c reintroduction and miR-9 inhibition
led to a significant reduction of the
number of “vascular lacunae”. Moreover,
the analysis of human specimens
allowed determining that miR-9 is
overexpressed in TNBC versus HER2+
and luminal tumors, and associated with
poor prognosis.
Still concerning miR-9 in TNBC, a
different study was carried out in 2015.
This project focuses on the interaction
between tumor and stromal cells; in
particular we demonstrated that miR-9
is released by tumor cells encapsulated
in exosomes that it contributes to the
conversion of NF (normal fibroblasts)
in CAF (cancer-associated fibroblasts),
increasing their migration and invasion
capability. Moreover, NFs-miR-9 (NF
transfected with miR-9) are in turn
able to release miR-9 and affect other
fibroblasts and even tumor cells,
increasing their aggressiveness by
direct targeting of E-cadherin. Our
results describe a regulatory loop where
miR-9 seems to be one of the “tools”
exploited by the tumor to modulate its
microenvironment.
Networking
Concerning the study of microRNAs
involved in HER pathway:
INMEGEN (Instituto National de Medicina
Génomica), Mexico City, Mexico
Our preliminary data demonstrate
a possible role of miR-205 in the
resistance to Trastuzumab in vitro,
and as a predictive biomarker in a
serie of 50 HER2+ patients treated in
adjuvant, where higher miR-205 levels
are associated with better outcome. To
confirm the effect of miR-205 in vivo,
we have analyzed the expression of
miR-205 in two HER2+ PDX tumors with
different sensitivity to Trastuzumab
(in collaboration with Xentech, Evry),
and found that the resistant model
shows lower miR expression than the
most responsive. We plan to propagate
the resistant model in SCID mice and
perform a combined treatment with
Trastuzumab + systemic or peritumoral
delivery of miR-205 mimics by lipidic
nanoparticles (Max Suppressor).
XENTECH (Evry, Paris, France)
Collaborations:
Tumor Immunology Unit,
Department of Health
Sciences,University of Palermo, Italy
Department of Molecular Virology,
Immunology and Medical Genetics, The
Ohio State University, Columbus (OH,
USA)
Salford University, Salford, UK
We successfully submitted a proposal to
obtain RNA samples from the NeoALTTO
clinical trial (which randomized patients
to neoadjuvant lapatinib, Trastuzumab,
or a combination of both drugs plus
paclitaxel) to evaluate microRNA
expression.
AIRC START U
176
Keywords
microRNAs,
breast cancer,
therapy
Plantamura I, Casalini P, Dugnani E, Sasso M, D’Ippolito E, Tortoreto M,
Cacciatore M, Guarnotta C, Ghirelli C, Barajon I, Bianchi F, Triulzi T, Agresti
R, Balsari A, Campiglio M, Tripodo C, Iorio MV and Tagliabue E. PDGFRβ
and FGFR2 mediate endothelial cell differentiation capability of triple
negative breast carcinoma cells. Mol Oncol 2014; Jul;8(5):968-81
Zappasodi R, Cavanè A, Iorio MV et al. Pleiotropic antitumor effects of the panHDAC inhibitor ITF2357 against c-Myc-overexpressing human B-cell non-Hodgkin
lymphomas. IJC 2014; Nov 1;135(9):2034-45
D’Ippolito E, Iorio MV. “MicroRNAs and Triple Negative Breast Cancer”. Int J Mol Sci.
2013 Nov 11;14(11):22202-20
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, Ramasamy S,
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
Mar;9(3):e1003311
De Cecco L, Berardi M, Sommariva M, Cataldo A, Canevari S, Mezzanzanica D, Iorio MV,
Tagliabue E, Balsari A. “Increased Sensitivity to Chemotherapy Induced by CpG-ODN
Treatment Is Mediated by microRNA Modulation”. PLoS One. 2013;8(3):e58849
Staff
UP UNIT
HEAD
Marilena V. Iorio, Biotech Sci D, PhD
Ilaria Plantamura, Biol Sci D, PhD
Sara Baroni, Biol Sci D, PhD
Alessandra Cataldo, Biotech Sci D, PhD
Elvira D’Ippolito, Biotech Sci D, PhD student
OF THE UNIT
2-20, 2
177
PREVENTIVE AND
PREDICTIVE MEDICINE
GIOVANNI APOLONE
Interim
direzionescientifica@istitutotumori.mi.it
EPIDEMIOLOGY AND PREVENTION
VITTORIO KROGH
ANALYTICAL EPIDEMIOLOGY AND
HEALTH IMPACT
MILENA SANT
EVALUATIVE EPIDEMIOLOGY
GEMMA GATTA
PREVENTIVE
AND
PREDICTIVE
MEDICINE
ENVIRONMENTAL EPIDEMIOLOGY
PAOLO CONTIERO
T
he 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.
CANCER REGISTRY
GIOVANNA TAGLIABUE
MEDICAL GENETICS
SIRANOUSH MANOUKIAN
HEREDITARY DIGESTIVE TRACT
TUMORS
GIUSEPPE PELOSI
Interim
MOLECULAR BASES OF GENETIC RISK
AND GENETIC TESTING
PAOLO RADICE
GENETIC EPIDEMIOLOGY AND
PHARMACOGENOMICS
TOMMASO A. DRAGANI
179
EPIDEMIOLOGY AND PREVENTION
VITTORIO KROGH, Head of the Unit
Research activity
The Epidemiology and
Prevention Unit is involved in
large prospective studies on the
association between diet, hormones,
nutrition, lifestyle, genetic factors,
and cancer risk: the EPIC (European
Prospective Investigation into
Cancer and Nutrition) and the ORDET
(hORmones and Diet in the Etiology of
breast Tumor) studies.
A further prospective study is TPM,
which evaluates the prognostic role
of androgens and related endocrinemetabolic factors in breast cancer.
The main results published in 2015 are
the following:
colorectal cancer: dietary antioxidant
capacity reduces the risk of colon
cancer but increases the risk of rectal
cancer; adherence to the WCRF/AICR
recommendations prior to diagnosis
improves survival after diagnosis;
ovarian cancer: the long-term use of
HRT increases survival in women with
this cancer; the number of pregnancies
and the use of oral contraceptives are
protective for the different subtypes of
this cancer;
breast cancer: lignans improve survival
among postmenopausal women but
reduces it among premenopausal
women; metabolic syndrome increases
the risk among postmenopausal women;
a diet rich in beta-carotene, riboflavin,
thiamin, vit. C and B6, fibre, Fe, Ca, K,
Mg, P and folate reduces overall, ER+
and PR+ breast cancer risk; caffeinated
coffee reduces the risk among
postmenopausal women;
gastric cancer: elevated serum iron
and ferritin reduce the risk; abdominal
obesity increases the risk;
hepatocellular carcinoma:
monounsaturated fat decreases the
risk; coffee and tea decrease the risk;
vegetables, but not fruit, decrease the
risk;
pancreatic cancer: elevated plasma
beta-carotene, zeaxanthin and alfatocopherol decrease the risk;
Networking
European Prospective
Investigation into Cancer
and Nutrition (EPIC)
research collaborative.
European Study of Cohorts for Air
Pollution Effects (ESCAPE) consortium
“Pooling Project of Prospective Studies
of Diet and Cancer” study consortium Harvard University - Boston - USA
renal cancer: moderate alcohol intake
decreases the risk.
The Unit is also involved in many
controlled clinical trials:
COS, a randomized controlled trial of diet
and physical activity in BRCA mutation
carriers.
TEVERE (Diana-4), a blinded randomized
controlled trial of diet and metformin for
primary prevention of breast cancer.
MeMeMe, a randomized controlled
trial of diet and metformin for primary
prevention of age-related chronic
diseases.
DIANA-5, a multicentric randomized
controlled trial of the effectiveness
of a diet based on Mediterranean and
macrobiotic recipes and principles,
associated with moderate physical
activity, in reducing additional breast
cancer events in women with early
stage invasive breast cancer at high risk
of recurrence because of metabolic or
endocrine milieu.
EPIDEMIOLOG
PREVENTION
endometrial cancer: coffee reduces the
risk;
differentiated thyroid carcinoma:
moderate alcohol intake reduces
papillary and follicular carcinoma risk;
elevated energy and polyunsaturated fat
intake increases the risk;
head and neck cancer: elevated
homocysteine levels increase squamous
cell carcinoma risk;
esophageal adenocarcinoma: abdominal
obesity increases the risk, general
obesity decreases the risk;
180
Keywords
Prospective studies,
diet, hormones,
metformin,
dietary intervention studies
Sieri S, Krogh V, Agnoli C, Ricceri F, Palli D, Masala G, Panico S, Mattiello
A, Tumino R, Giurdanella MC, Brighenti F, Scazzina F, Vineis P, Sacerdote
C. Dietary glycemic index and glycemic load and risk of colorectal cancer:
results from the EPIC-Italy study. Int J Cancer. 2015 Jun 15;136(12):2923-31
Vece MM, Agnoli C, Grioni S, Sieri S, Pala V, Pellegrini N, Frasca G, Tumino R, Mattiello
A, Panico S, Bendinelli B, Masala G, Ricceri F, Sacerdote C, Krogh V. Dietary Total
Antioxidant Capacity and Colorectal Cancer in the Italian EPIC Cohort. PLoS One. 2015
Nov 13;10(11)
Agnoli C, Grioni S, Sieri S, Sacerdote C, Ricceri F, Tumino R, Frasca G, Pala V, Mattiello A,
Chiodini P, Iacoviello L, De Curtis A, Panico S, Krogh V. Metabolic syndrome and breast
cancer risk: a case-cohort study nested in a multicentre italian cohort. PLoS One. 2015
Jun 1
Sieri S, Chiodini P, Agnoli C, Pala V, Berrino F, Trichopoulou A, Benetou V, Vasilopoulou
E, Sánchez MJ, Chirlaque MD, Amiano P, Quirós JR, Ardanaz E, Buckland G, Masala
G, Panico S, Grioni S, Sacerdote C, Tumino R, Boutron-Ruault MC, Clavel-Chapelon
F, Fagherazzi G, Peeters PH, van Gils CH, Bueno-de-Mesquita HB, van Kranen HJ,
Key TJ, Travis RC, Khaw KT, Wareham NJ, Kaaks R, Lukanova A, Boeing H, Schütze M,
Sonestedt E, Wirfält E, Sund M, Andersson A, Chajes V, Rinaldi S, Romieu I, Weiderpass
E, Skeie G, Dagrun E, Tjønneland A, Halkjær J, Overvard K, Merritt MA, Cox D, Riboli E,
Krogh V. Dietary fat intake and development of specific breast cancer subtypes. J Natl
Cancer Inst. 2014 Apr 9;106(5)
Agnoli C, Grioni S, Sieri S, Palli D, Masala G, Sacerdote C, Vineis P, Tumino R,
Giurdanella MC, 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 Mar 15;132(6):1404-11
Staff
HEAD
Vittorio Krogh, MD, MSc
STAFF SCIENTIST
Maria Gaetana Di Mauro, MD; Patrizia Pasanisi,
MD, MSc; Sabina Sieri, Biol Sci D; Anna Villarini,
Biol Sci D, MSc, PhD; Valeria Pala, Dr Sc Agr
RESEARCH ASSOCIATES
Franco Berrino, MD; Alessandra Borgo, Biol Sci
D; Alice Casagrande, Pharm D; Mauro Cortellini,
Biol Sci D; Giuliana Gargano, Biol Sci D, MSc; Giulia
Garrone, Chemist D; Samuele Pedraglio, Chemist
D; Elisabetta Venturelli, Biol Sci D; Claudia Agnoli,
Nutrition Tech D, MSc; Sara Grioni, Nutrition Tech
D
GY AND
Eleonora Bruno, Nutrition Tech D, MSc; Patrizia
Cogliati, Biol Sci D
TECHNICIANS
Adalberto Cavalleri, Daniela Del Sette Cerulli,
Anna D’Ambrosio, Giuseppe Fornaciari, Antonella
Maule
Patrizia Curtosi, Maria Grazia Guerrini, Fabrizia
Genoni, Manuela Bellegotti, Alberto Evangelista,
Paola Consorti
OF THE UNIT
117
PUBLICATIONS
661.786
IMPACT FACTOR
12
26.068
2-73, 13
181
ANALYTICAL EPIDEMIOLOGY
AND HEALTH IMPACT
MILENA SANT, Head of the Unit
Research activity
Activity focuses on
investigation of cancer
outcomes and survival across
regions and groups of patients, through
the collection, centralization and
analyses of data in population cancer
registries (CRs) and in hospital sets of
patients.
EUROCARE is monitoring cancer
patients survival in Europe since over
20 years. Its results provide a measure
of the efficacy of the European health
systems in cancer control, contributing
to set plans for reducing inequalities
in outcome and to evaluate the impact
of innovative treatments in the current
clinical practice (“effectiveness” vs
“efficacy”). In September 2015 the
EUROCARE-5 monograph containing 13
cancer specific papers was published in
the European Journal of Cancer.
In June 2015 the EUROCARE-6 call for
data was launched to collect survival
data of patients diagnosed up to 2012.
Through the EPAAC Joint action, the
study protocol was agreed with the
European Network of Cancer Registries
(ENCR) and the JRC (EU Commission).
HIGH RESOLUTION (HR) STUDIES aim
to describe and compare patterns of
cancer care across areas, groups of
patients and over time. They analyze
adhesion to clinical guidelines and their
effect on outcomes by collecting data
on diagnostic exams, stage, treatment,
bio-molecular tumour characteristics,
recurrences, also considering comorbidity, undesired effects of
treatments.
By the end of 2015, we received data
on 16,043 cancer cases (8,750 breast,
4,813 colorectal, 626 lung cancers,
1,134 melanoma and 720 lymphoma
cases), diagnosed in 2009-2013, from
24 population-based CRs, some funded
through HIGHCARE, others participating
voluntarily. Quality checks started in mid
2015, with contacts with CRs.
HIGHCARE also investigates the CRs
possibility to access biobanks in their
areas and envisages a pilot study to
validate a plasma derived microRNA
signature predictive of distant
metastatization in early stage breast
cancer.
Using Italian HR data, we started a pilot
study to investigate the influence of
socio-economic conditions on adhesion
to clinical guidelines.
Networking
EUROCARE- EUROpean
CAncer REgistry based
project on survival and care.
Network of 117 population-based cancer
registries in 31 countries. Coordination
and scientific secretariat.
ENCR-European Network of Cancer
Registries
JRC-EU Commission
CANCON Joint Action (coordinated by
Slovenia) will produce the guide “Quality
Improvement in comprehensive cancer
control”, covering best practices and
recommendations to governments on
screening, primary care, integrated care
and rehabilitation. Our unit participates
as an editor of the guide, in relation to
Health Information. After circulation of
chapters outlines (March 2015), drafts
were available in September 2015.
HR - High Resolution studies. Network
of more than 50 CRs.Patterns of cancer
care (colorectal, lung, breast cancers,
NHL, skin melanoma)
Institutional BREAST CANCER CLINICAL
REGISTRY continued the collection of
clinical data of all patients hospitalized
in the breast surgery unit. By the end
of 2015 the registry contained data of
4,750 patients, of which about 65%
had primary breast cancer. In 2015, 3
scientific articles were accepted using
breast cancer registry data. We started
constructing the lung cancer registry by
textual analysis of pathological reports,
to distinguish primary lung cancer
from metastasis, benign lesions, other
cancers.
AIRTUM Network of Italian Cancer
registries
HIGHCARE - ERANET TRANSCAN project
involving 7 countries
CONCORD Cancer survival in five
continents (London School of Hygene
and Tropical Medicine. Contribution to
analyses
GRELL Group of latin language cancer
registries
EUROCAN Platform “Structuring
translational cancer research
between cancer research centres in
Europe”. Participation in WP11 “Clinical
Epidemiology”.
CANCON European Joint Action
ANALYTICAL E
AND HEALTH
182
Keywords
Survival,
cancer outcome, registries,
patterns of care
Allemani C, Sant M, Weir Hk, Richardson Lc, Baili P, Storm H, Siesling
S, Torrella Ramos A, Voogd Ac, Aareleid T, Ardanaz E, Berrino F, Bielska
Lasota M, Bolick S, Cirilli C, Colonna M, Contiero P, Cress R, Crocetti
E, Fulton Jp, Grosclaude P, Hakulinen T, Izarzugaza Mi, Malmstrom P,
Peignaux K, Primic Zakelj M, Rachtan J, Safaei Diba C, Sánchez M J, Schymura MJ,
Shen T, Traina A, Tryggvadottir L, Tumino R, Velten M, Vercelli M, Wolf HJ, Woronoff AS,
Wu X, Coleman MP. Breast cancer survival in the US and Europe: A CONCORD highresolution study International Journal Of Cancer 2013, 132, 1170-1181
De Angelis R, SANT M, Coleman MP, Francisci S, BAILI P, Pierannunzio D, TRAMA A,
Visser O, Brenner H, Ardanaz E, Bielska Lasota M, Engholm G, Nennecke A, Siesling S,
Berrino F, Capocaccia R, Eurocare 5 Working Group. Cancer survival in Europe 19992007 by country and age: Results of EUROCARE-5-a population-based study. Lancet
Oncology 2014, 15, 23-34
Sant M, Minicozzi P, Mounier M, Anderson LA, Brenner H, Holleczek B, Marcos Gragera
R, Maynadié M, Monnereau A, Osca Gelis G, Visser O, De Angelis R, Eurocare 5 Working
Group. Survival for haematological malignancies in Europe between 1997 and 2008 by
region and age: Results of EUROCARE-5, a population-based study. Lancet Oncology
2014, 15, 931-942
Baili P, Torresani M, Agresti R, Rosito G, Daidone Mg, Veneroni S, Cavallo I, Funaro
F, Giunco M, Turco A, Amash H, Scavo A, Minicozzi P, Bella F, Meneghini E, Sant M.
A breast cancer clinical registry in an Italian comprehensive cancer center: An
instrument for descriptive, clinical, and experimental research. Tumori 2015, 101, 440446
Francisci S, Minicozzi P, Pierannunzio D, Ardanaz E, Eberle A, Grimsrud Tk, Knijn
A, Pastorino U, Salmerón D, Trama A, Sant M, Eurocare-5 Working Group. Survival
patterns in lung and pleural cancer in Europe 1999-2007: Results from the Eurocare-5
study. European Journal Of Cancer 2015, 51, 2242-2253
OF THE UNIT
19
EPIDEMIOLOGY
IMPACT
PUBLICATIONS
Staff
HEAD
Milena Sant, MD
RESEARCH STAFF
Hade Amash, MD;
Paolo Baili, Statistician, MSc;
Francesca Di Salvo, Statistician, PhD;
Elisabetta Meneghini, Physicist, MSc;
Pamela Minicozzi, Mathematician, PhD; Claudia
Vener, MD (visitor)
TECHNICIANS
Camilla Amati, Simone Bonfarnuzzo, Ilaria
Cavallo, Agata Cifalà, Francesco Funaro, Chiara
Margutti, Stefania Saltarelli, Alberto Turco
129.408
IMPACT FACTOR
10
46.272
1-37, 7
183
EVALUATIVE EPIDEMIOLOGY
GEMMA GATTA, Head of the Unit
Research activity
Rare tumors
Due to their low frequency,
rare cancers (RC) 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. The project
“Information network on rare cancers”
(RARECAREnet) is aimed to serve as the
reference source of information on RC
in Europe and contributes to ameliorate
diagnosis and treatment of RCs, to
foster research on RCs, to support the
establishment of CoE and to empower
patients. Thanks to the European funded
projects RARECARE and RARECAREnet,
this Institute has been committed to
coordinate the European Joint Action on
RCs.
Cancers in children, adolescents and
young adults (AYA)
Survival disparities have been observed
between countries and, with few
exceptions, survival was lowest in
Eastern Europe. Several reasons might
explain such inequalities. The lack
of healthcare resources is probably
the most important one, especially in
countries with limited drug supply. Other
reasons can be the lack of specialized
centers with multidisciplinary teams,
delayed diagnosis and treatment, poor
management of treatment and drug
toxicity. Cancers typically arising in
children have worse prognosis in AYA.
Although rare, cancers of the adults
can also affect AYA and children, but
there is considerable uncertainty on
their management. Agreed guidelines
for these rare events and specific health
plans should to be implemented in all
countries. The epidemiologic analyses
based on the large EUROCARE database
can be of help to monitor the impact
of public health actions aimed at
answering such needs. A survival study
on European AYA with cancer will be
published by Lancet Oncology.
Prostate cancers
In Italy, as in Western countries,
prostate cancer (PC) incidence is
presently reducing after a dramatic
increase. Mortality remained stable or
slightly increased and is now steeply
decreasing. The main reason for this is
given by the diffusion of the PSA, whose
spread started in the early 1990s, and
ultrasound-guided biopsy or needle
biopsies. The paper, with estimates
on PC trends (mortality, incidence and
prevalence) for Italy up to 2020, has
been published. With high-resolution
(HR) studies based on cancer registries
data we provided explanation on the
extent of the true improvement of
treatment. The study funded by the
AIRC and AMGEN showed that six-year
survival for PC patients significantly
improved, during 1996-2007, only in
high risk patients. Patients at low
and intermediate risk, highly affected
by overdiagnosis and with excellent
prognosis, did not show survival
improvement. Also, for metastatic
patients no progress has been observed,
in agreement with the absence of
effective treatment. The results
obtained from the Italian incidence and
mortality trend analysis and from the HR
study support the hypothesis that the
reduction of mortality is mainly due to
more effective treatments.
Networking
Istituto Superiore di Sanità
Rome - IT
RARECAREnet European
research consortium - EU
London School of Hygiene and Tropical
Medicine - UK
National Cancer Institute (Division of
Cancer Control and Population Sciences)
- Bethesda - USA
Centres for Disease Control and
Prevention (CDC) - Division of Cancer
Prevention and Control’s Epidemiology Atlanta - USA
EVALUATIVE
EPIDEMIOLOG
184
Keywords
Prostate cancer,
rare cancer,
children and young adults
Trama A, Foschi R, Larrañaga N, et al. Survival of male genital cancers
(prostate, testis and penis) in Europe 1999-2007: Results from the
EUROCARE-5 study. Eur J Cancer. 2015 Sep 6. pii: S0959-8049(15)007078.
Capocaccia R, Gatta G, Dal Maso L. Life expectancy of colon, breast, and testicular
cancer patients: an analysis of US-SEER population-based data. Ann Oncol. 2015
Jun;26(6):1263-8
Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, Dimitrova N, Jakab
Z, Kaatsch P, Lacour B, Mallone S, Marcos-Gragera R, Minicozzi P, Sánchez-Pérez
MJ, Sant M, Santaquilani M, Stiller C, Tavilla A, Trama A, Visser O, Peris-Bonet R;
EUROCARE Working Group. Childhood cancer survival in Europe 1999-2007: results of
EUROCARE-5-a population-based study. Lancet Oncol. 2014 Jan;15(1):35-47
Gatta G, Mallone S, van der Zwan JM, Trama A, Siesling S, Capocaccia R; EUROCARE
Working Group. Cancer prevalence estimates in Europe at the beginning of 2000. Ann
Oncol. 2013 Jun;24(6):1660-6
Gatta G, Rossi S, Foschi R, Trama A, Marcos-Gragera R, Pastore G, Peris-Bonet
R, Stiller C, Capocaccia R; EUROCARE Working Group. Survival and cure trends
for European children, adolescents and young adults diagnosed with acute
lymphoblastic leukemia from 1982 to 2002. Haematologica. 2013 May;98(5):744-52
OF THE UNIT
23
PUBLICATIONS
Staff
HEAD
Gemma Gatta, MD
STAFF SCIENTIST
Annalisa Trama, MD
GY
RESEARCH ASSOCIATES
Laura Botta, Statistician
Riccardo Capocaccia, Math
Roberto Foschi, Math
154.254
IMPACT FACTOR
4
17.874
2-51, 10
Rossana Berruti, Lucia Buratti
185
ENVIRONMENTAL EPIDEMIOLOGY
PAOLO CONTIERO, Head of the Unit
Research activity
The Unit’s principal tasks
are to analyze the effects of
exposure to environmental agents
on cancer development and cancer
prognosis; shed light on biological
process leading from exposure to cancer
from a population-based perspective
and characterize geographic areas in
terms of environmental and individual
risk factors that influence cancer
incidence and prognosis. The Unit is also
investigating the prevalence of factors
that affect disease prognoses. For
example, effect of fasting glucose levels
and comorbidities on the prognosis of
women with breast cancer.
Studies are carried out on cohorts from
the population-based Varese Cancer
Registry, which is high quality registry
with virtually complete data. Many of
these studies involve collaboration with
partners of the Open Registry Network,
thereby exploiting a population of
3,800,000 individuals in which 30,000
new cancer cases occur annually.
The Unit also investigates birth defects
and adverse reproductive outcomes,
selecting cohorts from the Lombardy
Birth Defects and Adverse Pregnancy
Outcomes Registry. The recently
completed Riscripro_Sentieri project,
funded by the Italian Ministry of Health,
documented reproductive health
and risk of congenital anomalies in
populations living in Italian National
Priority Contaminated Sites.
In 2015 the Unit performed a study on
the relationship between breast cancer
prognosis and atmospheric particulate
matter (PM2.5) in large cohort of women
with breast cancer. The study was
performed in collaboration with the
Cancer Registry Unit, the Department
of Physics and Atmospheric Science
of Dalhousie University (Canada) and
the Harvard-Smithsonian Center for
Astrophysics of Cambridge (USA).
A study assessing the health of people
living near a waste landfill was also
conducted. This was a retrospective
population-based study using maps
computed from pollutant dispersion
models, and routinely collected
information sources.
A pilot population-based study
was performed to investigate the
dissemination of surveillance programs
in persons at high risk of developing
hepatocarcinoma and to determine the
prevalence of cirrhosis and hepatitis (B
and C) in such persons.
The above-mentioned research projects
are population-based, sustainable
epidemiological studies, and have the
important characteristic that they
make use of electronic information
sources (hospital discharges, pathology
reports, death certificates, outpatient
consultations, and drug prescriptions)
collected routinely for administrative
or clinical purposes. However,
indiscriminate use of these information
sources, without a clear scientific
objective and without systematic data
quality checking, may lead to producing
biased results. The Unit, working with
the Cancer Registry Unit, is therefore a
leading partner in collaborative studies
involving the Open Registry Network
to develop more secure methods
and systems for using use routinelycollected electronic information sources.
Networking
Department of Physics
and Atmospheric
Science, Dalhousie
University, Halifax, Nova Scotia,
Canada and Harvard-Smithsonian
Center for Astrophysics, Cambridge,
Massachusetts, USA
International Clearinghouse for Birth
Defects Surveillance and Research
Environmental Health Sciences
Department IRCCS - Istituto di Ricerche
Farmacologiche “Mario Negri”
Open Registry Network
EPIC, European Prospective Investigation
into Cancer and Nutrition
RARECARE, Surveillance of Rare Cancer
in Europe
CONCORD, Global Programme for
Surveillance of Cancer Survival
EUROCARE, Survival of Cancer Patients
in Europe
IARC, International Agency for the
Research on Cancer
AIRTUM, the Italian Association of Cancer
Registries
National Center for Rare Diseases,
Istituto Superiore di Sanità, Rome, Italy
Institute of Clinical Physiology, National
Research Council, Unit of Environmental
Epidemiology and Disease Registries,
Pisa, Italy
ENVIRONMEN
EPIDEMIOLOG
186
Keywords
environmental pollutants,
cancers, birth defects,
prognosis, survival
Mohammad Ghanbari Ghozikali, Alessandro Borgini, Andrea Tittarelli,
Abdeltif Amrane,Kazem Naddafi, Mahmoud Mohammadyan,
Gholamreza Goudarzi, Roberto Bono and Behzad Heibati. Quantification
of the health effects of exposure to air pollution (NO2) in Tabriz, Iran.
Fresenius Environmental Bulletin; 11c, 2015
Tomba C, Elli L, Bardella MT, Soncini M, Contiero P, Roncoroni L, Locatelli M, Conte D.
Enteroscopy for the early detection of small bowel tumours in at-risk celiac patients.
Dig Liver Dis. 2014 May;46(5):400-4
Dik VK, Murphy N, Siersema PD, Fedirko V, Jenab M, Kong SY, Hansen CP, Overvad
K, Tjønneland A, Olsen A, Dossus L, Racine A, Bastide N, Li K, Kühn T, Boeing H,
Aleksandrova K, Trichopoulou A, Trichopoulos D, Barbitsioti A, Palli D, Contiero P,
Vineis P, Tumino R, Panico S, Peeters PH, Weiderpass E, Skeie G, Hjartåker A, Amiano
P, Sánchez MJ, Fonseca-Nunes A, Barricarte A, Chirlaque MD, Redondo ML, Jirström
K, Manjer J, Nilsson LM, Wennberg M, Bradbury KE, Khaw KT, Wareham N, Cross AJ,
Riboli E, Bueno-de-Mesquita HB. Prediagnostic intake of dairy products and dietary
calcium and colorectal cancer survival-results from the EPIC cohort study. Cancer
Epidemiol Biomarkers Prev. 2014 Sep;23(9):1813-23
Allemani C, Sant M, Weir HK, Richardson LC, Baili P, Storm H, Siesling S, TorrellaRamos A, Voogd AC, Aareleid T, Ardanaz E, Berrino F, Bielska-Lasota M, Bolick S,
Cirilli C, Colonna M, Contiero P, Cress R, Crocetti E, Fulton JP, Grosclaude P, Hakulinen
T, Izarzugaza MI, Malmström P, Peignaux K, Primic-Žakelj M, Rachtan J, Safaei Diba
C, Sánchez MJ, Schymura MJ, Shen T, Traina A, Tryggvadottir L, Tumino R, Velten M,
Vercelli M, Wolf HJ, Woronoff AS, Wu X, Coleman MP. Breast cancer survival in the US
and Europe: a CONCORD high-resolution study. Int J Cancer. 2013 Mar 1;132(5):1170-81
Contiero P, Berrino F, Tagliabue G, Mastroianni A, Di Mauro MG, Fabiano S, Annulli M,
Muti P. Fasting blood glucose and long-term prognosis of non-metastatic breast
cancer: a cohort study. Breast Cancer Res Treat. 2013 Apr;138(3):951-9
NTAL
GY
Staff
HEAD
Paolo Contiero
RESEARCH ASSOCIATES
Alessandro Borgini, B Sci
TECHNICIANS
Alessandra Scaburri, ScD
DATA MANAGERS
Alessandro Cau
OF THE UNIT
18
PUBLICATIONS
119.250
IMPACT FACTOR
1
6-18, 12
Martina Bertoldi ScD, Immacolata Favia
187
CANCER REGISTRY
GIOVANNA TAGLIABUE, Head of the Unit
Research activity
The Cancer Registry Unit is
concerned with the following
tasks and related research areas:
Management of the Varese Province
section of the Lombardy Cancer
Registry. This is the original Lombardy
Cancer Registry, that first began
collecting data in the 1970s. Since that
time it has continuously produced
population- based cancer incidence,
survival and mortality data. The
Registry’s data are sent periodically to
national and international databases
and are thus available for consultation
and inclusion in both large and small
scale analyses that resulted in several
scientific publications: in 2015, 59
scientific papers were published, also
based on population-based cancer data
produced by the Cancer Registry Unit.
Coordination of the Open Registry
network of cancer registries. The
network involves nine Italian cancer
registries covering a population of
four millions. To produce cancer
registry data and to manage their
databases, all these registries use the
Open Registry information system, a
software developed by the staff of the
INT’s Cancer Registry Unit. The same
staff assist in the implementation of
Open Registry systems and participate
in application projects. Network
coordination also takes the form of
operational and technical support,
provision of expertise, know-how,
instructions and advice (e.g. on
quality control, codification practice,
and evaluation of data consistency)
particularly for data sent to national and
international databases, and required for
research, training and updating.
Management of the Lombardy Birth
Defects Registry. This registry was
developed and set up by the staff of the
INT’s Cancer Registry Unit, to provide
population-based data on birth defects
and other adverse pregnancy outcomes,
and to enable investigation of the causes
of these events. The Lombardy Birth
Defects Registry, which has now been
operating for 14 years, is the first of its
type in Italy. It uses already available
sources of information and collects
data on a large population (over 14,000
births annually). Over 23,727 cases are
archived. Low-weight and preterm
births, spontaneous miscarriages and
ectopic deliveries are also registered, in
addition to recognized birth defects .
Networking
Cases are followed over time and
hospital admissions, outpatient
treatments, concomitant diseases, and
drug consumption, are also registered.
The focus of this population-based
registry (which reveals the real situation
better than hospital-based studies)
is to identify relationships between
adverse birth outcomes and cancer
diagnoses and treatments, potentially
suggesting ways of reducing the risks of
both, through prevention and personal
counseling.
EUROCARE Survival of cancer patients in
Europe
The Registry is a full member of the
WHO’s International Clearinghouse for
Birth Defects Surveillance and Research,
and of the Coordinamento dei Registri
Italiani delle Malformazioni Congenite
(ISS, Rome).
IARC - International Agency
for Research on Cancer
(WHO)
ICBDSR - International Clearinghouse for
Birth Defects, Surveillance and Research
(WHO)
ENCR- European Network of Cancer
Registries
ECCO- European Cancer Organisation
CONCORD program for global
surveillance of cancer survival - London
School of Hygiene & Tropical Medicine
EPIC The European Prospective
Investigation into Cancer and Nutrition
RARECARE Surveillance of rare cancer in
Europe
Department of Physics and Atmospheric
Science of the Dalhousie University
(Canada)
Harvard-Smithsonian Center for
Astrophysics of Cambridge (USA)
UTAH Pediatrics, University of Utah
School of Medicine
AIRTUM Associazione Italiana Registri
tumori
Istituto Superiore di Sanita’ – Centro
Malattie Rare
CNR, Unità di ricerca in epidemiologia
ambientale, Istituto di fisiologia clinica,
Pisa
IRFMN - Istituto di Ricerche
Farmacologiche Mario Negri
Rete Open Registry
CANCER REGI
188
Keywords
cancer,
registry,
birth defects,
population based studies
Allemani C., Weir H.K., Carreira H., Harewood R., Spika D., Wang X.S.,
Bannon F., Ahn J.V., Johnson C.J., Bonaventure A., Marcos Gragera R.,
Stiller C., Azevedo E Silva G., Chen W.Q., Ogunbiyi O.J., Rachet B., Soeberg
M.J., You H., Matsuda T., Bielska Lasota M., Storm H., Tucker T.C., Coleman
M.P., Concord Working Group {TAGLIABUE G.} Global surveillance of cancer survival
1995-2009: analysis of individual data for 25,676,887 patients from 279 populationbased registries in 67 countries (CONCORD-2). Lancet. 2015 Mar 14;385(9972):9771010
Buzzoni C., Crocetti E., De Angelis R., Dal Maso L., Airtum Working Group. {Tagliabue G.}
Cancer survival in Italy in 2000-2007 is better than in Europe. 2015; 39:270 Epidemiol
Prev. 2015 Jul-Aug;39(4):270. Epidemiol Prev. 2015 May-Jun;39(3):208. ICBDSR Annual
Report on Birth Defects 2014, (WHO 2015, http://icbdsr.org/)
Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasotta M, Clavel J, Dimitrova N, Jakab Z,
Kaatsch P, Lacour B, Mallone S, Marcos-Gragera R, Minicozzi P, Sanchez-Perez MJ,
Sant M, Santaquilani M, Stiller C, Tavilla A, Trama A, Visser O, Peris-Bonet, and the
EUROCARE Working Group {Tagliabue G.}: Childhood cancer survival in Europe 19992007: results of EUROCARE-5-a population-based study. The Lancet. 2014 Jannuary;
Vol. 15 35-47
Contiero P, Berrino F, Tagliabue G, Mastroianni A, Di Mauro MG, Fabiano S, Annulli M,
Muti P. Fasting blood glucose and long-term prognosis of non-metastatic breast
cancer: a cohort study. Breast Cancer Res Treat. 2013 Apr;138(3):951-9
OF THE UNIT
Staff
HEAD
Giovanna Tagliabue, MD, PhD
RESEARCH ASSOCIATES
Laura Di Grazia, B Sci
Emanuela Frassoldi, B Sci
Daniela Gada, B Sci
ISTRY
TECHNICIANS
Sabrina Fabiano, PhD
Andrea Tittarelli, Statistics
DATA MANAGER
Tiziana Rita Codazzi
22
PUBLICATIONS
127.554
IMPACT FACTOR
1
3-24, 5
Anna Maghini
189
MEDICAL GENETICS
SIRANOUSH MANOUKIAN, Head of the Unit
Clinical activity
Research activity
Networking
The Medical Genetics Unit
provides genetic counseling for
hereditary cancer syndromes.
Hereditary tumors represent
only a minority of all cancers and not all
causative genes have been identified.
Although genetic evaluation is now part
of the good clinical practice for some
type of cancer, genetic counseling and
testing should actually be offered only
to patients/families suspected to have
increased risk and only when a benefit
from a thorough assessment of their
genetic risk of cancer is expected.
The diagnostic activity is
integrated with several research
programs, taking advantage of the
continuous recruitment through genetic
counseling of selected individuals
and families with suspected cancer
predisposing syndrome.
The Unit participates in the
following consortia/study
groups:
The Unit main clinical focus is the
Hereditary Breast and Ovarian
Cancer syndrome (HBOC). During
2015, about 850 new families asked
for a risk evaluation. To rationalize
access to genetic counseling/testing
and to guarantee a high level of
appropriateness and effectiveness,
all requests underwent a first clinical
evaluation in order to better select
patients who might really benefit from
risk assessment. Only patients fulfilling
INT eligibility criteria underwent genetic
counseling/testing. Since the beginning
of the activity more than 6,130 genetic
counseling for HBOC were performed,
over 330 in the last year. About 1,000
at risk women (healthy/affected) are
followed for clinical surveillance at INT
and preventive/therapeutic options
are discussed together with other
specialists.
Other rare inherited predispositions to
cancer are also investigated although
representing only a small fraction (10%)
of the Unit activity.
The consolidated and long lasting
clinical activity of the Medical Genetics
Unit has allowed the collection of the
largest Italian cohort of HBOC families
(>4,360, including >9,340 individuals).
All relevant data have been recorded in
the Medical Genetics HBOC database
(>760 families with BRCA1/2 pathogenic
mutations and >150 families with
unknown genetic variants). Tumour
specimens and blood samples are
collected from all patients treated at INT.
All new clinical, familial, pathological
and molecular data are updated for a
large proportion of families which have
been followed throughout the Unit’s
activity. Clinical data and biological
specimens of selected populations have
allowed research studies conducted
with other INT Units, national and
international collaborations and
partecipation to consortia as well:
Breast Cancer Association Consortium
(BCAC)
Consortium of Investigators of Modifiers
of BRCA1/2 (CIMBA)
Evidence-based Network for the
Interpretation of Germline Mutant
Alleles (ENIGMA)
Hereditary Breast Cancer Clinical Study
Group (Coordinated by Women’s College
Research Institute, Toronto)
The IMPACT study (Identification of
Men with a genetic predisposition to
ProstAte Cancer: Targeted Screening in
men at higher genetic risk and controls
– Coordinated by Royal Marsden NHS
Trust)
Moreover, in the last years, the Unit set
up several collaborations with local/
regional Departments of Oncology and
Surgery in order to enable external
centres to effectively identify patients
to be referred to INT for a genetic
evaluation/testing
genetic characterization of HBOC
(penetrance, tumour features, as well
as genetic and environmental risk
modifiers, and new predisposing genes)
clinical and psychological impact of
surveillance, risk reducing measures in
HBOC individuals
biological and clinical significance of
BRCA gene mutations with unknown
significance
strategies for an effective
identification/referral of women at
increased risk to genetic counseling/
testing
MEDICAL GEN
190
Keywords
Hereditary breast/
ovarian cancer, genetic
predisposition,
genetic counseling/testing,
risk assessment
Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkas K, Roberts J,
Lee A, Subramanian D, De Leeneer K, Fostira F, Tomiak E, Neuhausen SL,
Teo ZL, Khan S, Aittomaki K, Moilanen JS, Turnbull C, Seal S, Mannermaa
A, Kallioniemi A, et al. [Radice P, Manoukian S, Peterlongo P]. Breastcancer risk in families with mutations in PALB2. New England Journal Of Medicine
2014;371:497-506
Borreani C, Manoukian S, Bianchi E, Brunelli C, Peissel B, Caruso A, Morasso G, Pierotti
MA. The psychological impact of breast and ovarian cancer preventive options in
BRCA1 and BRCA2 mutation carriers. Clinical Genetics 2014;85:7-15
Berrino J, Berrino F, Francisci S, Peissel B, Azzollini J, Pensotti V, Radice P, Pasanisi P,
Manoukian S. Estimate of the penetrance of BRCA mutation and the COS software for
the assessment of BRCA mutation probability. Familial Cancer 2015;14:117-128
Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, Mcguffog L, Mazoyer S,
Chenevix Trench G, Easton DF, Antoniou AC, Nathanson KL, Cimba Consortium.
{Peissel B, Zaffaroni D, Scuvera G, Radice P, Manoukian S}. Association of type and
location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. Jamajournal of The American Medical Association 2015;313:1347-1361
Roversi G, Picinelli C, Bestetti I, Crippa M, Perotti D, Ciceri S, Saccheri F, Collini P,
Poliani Pl, Catania S, Peissel B, Pagni F, Russo S, Peterlongo P, Manoukian S, Finelli P.
Constitutional de novo deletion of the FBXW7 gene in a patient with focal segmental
glomerulosclerosis and multiple primitive tumors. Scientific Reports 2015;5:15454
OF THE UNIT
Staff
HEAD
Siranoush Manoukian, MD, PhD
STAFF SCIENTIST
Bernard G. Peissel, MD, PhD
RESEARCH ASSOCIATES
Jacopo V.F. Azzollini, MD
NETICS
Mariarosaria Calvello, MD
Lidia Pezzani, MD
DATA MANAGERS
Daniela Zaffaroni, Biol Sci D, PhD
19
PUBLICATIONS
186.170
IMPACT FACTOR
2
7.555
4-34, 17
Caterina Spina, Alex Sandra Masioli Dos Santos
191
HEREDITARY DIGESTIVE TRACT TUMORS
GIUSEPPE PELOSI, Head of the Unit (interim)
Clinical activity
Research activity
Networking
The Unit of Hereditary Digestive
Tract Tumours, in-between
clinic and research, is devoted
to the counselling, molecular
testing, and clinical management of
individuals with genetic predisposition
to the major hereditary syndromes of
gastrointestinal cancer. Over 4,000
families have been enrolled in an ad
hoc Registry since 1989. These include:
Lynch Syndrome (or 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
cancer susceptibility are counseled and
informed about their own risk and the
one of their “at-risk relatives”. Depending
on the fulfillment of pre-defined
criteria, individuals who receive genetic
counseling are offered 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 tumour
characteristics. During 2015, about 500
individuals were screened for germline
mutations in cancer predisposing
genes. The genes presently screened
on a routine basis include: MLH1, MSH2,
MSH6 and PMS2 cumulatively referred
to as DNA Mismatch Repair (MMR)
genes (Lynch Syndrome); APC and
MUTYH (FAP, AFAP, MAP); STK11 (PeutzJeghers Syndrome); SMAD4 (Juvenile
Polyposis); PTEN (Cowden Syndrome);
CDH1 (Hereditary Gastric Cancer); TP53
(Li-Fraumeni Syndrome).
During 2015, in collaboration
with Manuela Gariboldi from
the Department of Experimental
Oncology and Molecular Medicine
(DOSMM), plasma samples from
subjects with high risk to develop
colorectal cancer due to hereditary
predisposition have been collected at
routine control colonoscopy. Samples
will be tested for the presence of
tumor-released miRNAs. The aim is
to set-up a miRNA-based blood test
for the detection of cancerous lesions
in intensive surveillance programs of
subjects at high risk for developing
colorectal cancer.
The Unit is the referral
center for Familial
Adenomatous Polyposis
management in Lombardy Region (Rare
Disease Network)
An observational study has also been
designed in collaboration with the
Diagnostic Endoscopy and Endoscopic
Surgery Unit in patients affected by
Familial Adenomatous Polyposis
with the aim to identify the duodenal
adenomas at risk for malignancy using
confocal laser microendoscopy.
HEREDITARY D
TRACT TUMO
192
Keywords
Hereditary digestive tract
tumor,
hereditary colorectal cancer,
Familial Adenomatous Polyposis,
Lynch Syndrome
Sahnane N, Magnoli F, Bernasconi B, Tibiletti MG, Romualdi C, Pedroni
M, Ponz de Leon M, Magnani G, Reggiani-Bonetti L, Bertario L, Signoroni
S, Capella C, Sessa F, Furlan D, Aifeg (2015) Aberrant DNA methylation
profiles of inherited and sporadic colorectal cancer. Clin Epigenetics 7:131
Movahedi M, Bishop DT, Macrae F, Mecklin JP, Moeslein G, Olschwang S, Eccles
D, Evans DG, Maher ER, Bertario L, Bisgaard ML, Dunlop MG, Ho JW, Hodgson SV,
Lindblom A, Lubinski J, Morrison PJ, Murday V, Ramesar RS, Side L, Scott RJ, Thomas
HJ, Vasen HF, Burn J, Mathers JC (2015) Obesity, Aspirin, and Risk of Colorectal Cancer
in Carriers of Hereditary Colorectal Cancer: A Prospective Investigation in the CAPP2
Study. J Clin Oncol 33:3591-3597
Vitellaro M, Sala P, Signoroni S, Radice P, Fortuzzi S, Civelli EM, Ballardini G, Kleiman
DA, Morrissey KP, Bertario L (2014) Risk of desmoid tumours after open and
laparoscopic colectomy in patients with familial adenomatous polyposis. Br J Surg
101:558-565
Molinari F, Signoroni S, Lampis A, Bertan C, Perrone F, Sala P, Mondini P, Crippa S,
Bertario L, Frattini M (2014) BRAF mutation analysis is a valid tool to implement in
Lynch syndrome diagnosis in patients classified according to the Bethesda guidelines.
Tumori 100:315-320
Vasen HF, Blanco I, Aktan-Collan K, Gopie JP, Alonso A, Aretz S, Bernstein I, Bertario
L, Burn J, Capella G, Colas C, Engel C, Frayling IM, Genuardi M, Heinimann K, Hes FJ,
Hodgson SV, Karagiannis JA, Lalloo F, Lindblom A, Mecklin JP, Moller P, Myrhoj T,
Nagengast FM, Parc Y, Ponz de Leon M, Renkonen-Sinisalo L, Sampson JR, Stormorken
A, Sijmons RH, Tejpar S, Thomas HJ, Rahner N, Wijnen JT, Jarvinen HJ, Moslein G,
Mallorca G. (2013) Revised guidelines for the clinical management of Lynch syndrome
(HNPCC): recommendations by a group of European experts. Gut 62:812-823
OF THE UNIT
5
DIGESTIVE
ORS
PUBLICATIONS
33.771
IMPACT FACTOR
Staff
HEAD
Giuseppe Pelosi, MD (interim)
1
STAFF SCIENTIST
Marco Vitellaro, MD
2.449
RESEARCH ASSOCIATES
Lucio Bertario, MD; Maria Teresa Ricci, MD;
Stefano Signoroni, Biol Sci D
7-39, 23
Mariangela Di Ceglie, Ornella Galuppo
193
MOLECULAR BASES OF GENETIC RISK
AND GENETIC TESTING
PAOLO RADICE, Head of the Unit
Research activity
The research activities of
this unit are focused on the
identification and characterization
of the genetic elements associated with
hereditary predisposition to cancer and
with cancer progression. Our studies
are mainly focused on familial breast/
ovarian carcinoma (HBOC) and Wilms’
tumor (WT).
Main achievements of 2015:
The association between breast cancer
and the c.5791C>T nonsense mutation
(p.Arg1931*) in the FANCM gene was
investigated. This variants had been
previously identified in an Italian HBOC
family unlinked to mutations in BRCA
genes. An analysis of genotyping data
from 8,635 familial breast cancer cases
and 6,625 controls from different
countries yielded an association
between the mutation and breast
cancer risk [odds ratio (OR) = 3.93; p =
0.017]. Following information theorybased prediction, we demonstrated
that the mutation caused an out-offrame deletion of exon 22, due to the
creation of a binding site for the premRNA processing protein hnRNP A1.
Furthermore, genetic complementation
analyses showed that the mutation
influenced the DNA repair activity of the
FANCM protein.
involved in the genesis of this
rare neoplasia and provide
useful information for its
treatment.
To provide insight into the high
genetic heterogeneity characterizing
WTs, we had previously performed
a genome-wide SNP array analysis
on 96 WT samples. Eventually, we
focused on a few minimal regions
commonly involved in aberrations
and examined genes with a possible
role in WT development - based on
the prior knowledge of their biological
relevance - therein located. Considered
genomic portions and related genes
were as follows: chromosome 2p24.3
(MYCN gene); 2q37.1 (DIS3L2, miR-562);
9p21.3 (CDKN2A, CDKN2B); 6q21(HACE1);
7p14.1, (GLI3); and 16p12.1 (PALB2);
22q12.1 (CHEK2). These genes were
investigated by DNA direct sequencing
and mRNA expression analysis, and
for promoter methylation, when
appropriate. Altogether, our data provide
a contribution to the definition of the
role of some already reported putative
WT genes, and adds a new gene, CHEK2,
to this genetic heterogeneous scenario.
Networking
During 2015 this research
Unit participated in
collaborative studies of
the following national and international
networks:
Breast Cancer Association Consortium
(BCAC);
The Consortium of Investigators of
Modifiers of BRCA1/2 (CIMBA);
Evidence-based Network for the
Interpretation of Germline Mutant
Alleles (ENIGMA);
Associazione Italiana di Ematologia ed
Oncologia Pediatrica (AIEOP)
Société Internationale d’Oncologie
Pédiatrique (SIOP).
Within the frame of these collaborations,
a few studies were carried out as
project leader. These include: a) the
ascertaiment of an allelic variant of the
FANCM gene as a risk factor for breast
cancer, and b) the identification of
chromosomal and genetic abnormalities
undelying recurrences in Wilms tumour
patients.
In addition, Dr. Radice is a current
member of the international Steering
Committee of ENIGMA (https://
enigmaconsortium.org/)
MOLECULAR B
OF GENETIC R
AND GENETIC
We investigated the link between
gynecological carcinosarcomas and
HBOC. In the INT registry, including 1,854
HBOC affected probands, 11 families with
one documented case of carcinosarcoma
were retrieved. Of these, 8 were tested
positive for a BRCA mutation. Of the
four carcinosarcoma patients that could
be investigated (all in BRCA1-related
families), three were positive for the
family mutation. Fragment analyses
and target sequencing of tumor DNA of
the latter patients assessed the loss of
the wild-type BRCA1 allele in all cases.
Similarly, TP53 alterations, including
p53 immunohistochemical positivity
and somatic mutations, were detected
in all cases. Therefore, these tumors
showed BRCA1-related pathological and
molecular features. Exploring the role
of BRCA genes in a prospective series of
sporadic carcinosarcomas could improve
the knowledge of genetic factors
194
Keywords
HBOC,
Wilms tumor,
genetic variants
Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL,
Schmidt MK, Chang-1. Antoniou AC, Casadei S, Heikkinen T, Barrowdale D,
Pylkas K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F, Tomiak
E, Neuhausen SL, Teo ZL, Khan S, Aittomaki K, Moilanen JS, Turnbull C, Seal
S, Mannermaa A, Kallioniemi A, et al. [Radice P, Manoukian S, Peterlongo P]. Breastcancer risk in families with mutations in PALB2. New England Journal Of Medicine
2014;371:497-506
Colombo M, Blok Mj, Whiley P, Santamarina M, Gutiérrez Enríquez S, Romero A,
Garre P, Becker A, Smith LD, De Vecchi G, Brandao Rd, Tserpelis D, Brown M, Blanco A,
Bonache S, Menéndez M, Houdayer C, Foglia C, Fackenthal JD, Baralle D, et al. [Radice P].
Comprehensive annotation of splice junctions supports pervasive alternative splicing
at the BRCA1 locus: A report from the ENIGMA consortium. Human Molecular Genetics
2014;23:3666-3680
Mavaddat N, Pharoah PD, Michailidou K, Tyrer J, Brook MN, Bolla MK, Wang Q, Dennis J,
Dunning AM, Shah M, Luben R, Brown J, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger
H, Czene K, Darabi H, Eriksson M, Peto J, et al. [Radice P, Manoukian S]. Prediction of
breast cancer risk based on profiling with common genetic variants. Jnci-journal Of The
National Cancer Institute 2015;107:djv036
Michailidou K, Hall P, Gonzalez Neira A, Ghoussaini M, Dennis J, Milne RL, Schmidt MK,
Chang Claude J, Bojesen SE, Bolla MK, 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, et al. [Radice P, Peterlongo P, Manoukian S]. Large-scale genotyping
identifies 41 new loci associated with breast cancer risk. Nature Genetics 2013;45:353361
Peterlongo P, Catucci I, Colombo M, Caleca L, Mucaki E, Bogliolo M, Marin M, Damiola
F, Bernard L, Pensotti V, Volorio S, Dall’Olio V, Meindl A, Bartram C, Sutter C, Surowy H,
Sornin V, Dondon MG, Eon Marchais S, Stoppa Lyonnet D, et al. [Peissel B, Manoukian
S, Pierotti MA, Pizzamiglio S, Verderio P, Radice P]. FANCM c.5791C>T nonsense
mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a
familial breast cancer risk factor. Human Molecular Genetics 2015;24:5345-5355
BASES
RISK
C TESTING
Staff
HEAD
Paolo Radice, Biol Sci D
STAFF SCIENTIST
Daniela Perotti, Biol Sci D, PhD
RESEARCH ASSOCIATES
Carla B. Ripamonti, MD, PhD;
Laura Caleca, Biol Sci D, PhD;
Mara Colombo, Biol Sci D, PhD;
Antonio Fiorino, Food Tech Sci D;
Claudia Foglia, Biol Sci D
POST DOCTORAL FELLOW
Sara Ciceri, Med Biotech, PhD
TECHNICIAN
Patrizia Mondini
OF THE UNIT
24
PUBLICATIONS
256.036
IMPACT FACTOR
1
6.393
1-45, 7
ADMINISTRATIVE
Silvia Grassi
195
GENETIC EPIDEMIOLOGY
AND PHARMACOGENOMICS
TOMMASO DRAGANI, Head of the Unit
Research activity
During 2015, our study on
a novel genetic profile of four
SNPs associated with survival of
lung adenocarcinoma patients was
published. The result may be of clinical
interest since the identification of
the reasons underlying individual’s
predisposition to poor prognosis
are important for improvements in
follow-up and therapeutic strategy of
these cancer patients. We have also
investigated the possible influence
of single nucleotide polymorphisms
(SNPs), known to associate with the risk
of colorectal cancer (CRC), on overall
survival in Italian CRC patients. We
found that the risk of death significantly
increased by rare allele count for
rs1801133 (MTHFR), rs4939827 (SMAD7),
rs2306283 (SLCO1B1), and rs12898159
(BMP4), while for rs736775 (GPX3) the
opposite was observed. Our findings
show that some genetic variants
previously found to associate with CRC
risk are also associated with survival
after treatment. The identification
of alleles defining subgroups of
patients with worse clinical outcome
may have application in developing
pharmacogenetic strategies aimed at
personalizing CRC treatment.
We have submitted the results of our
study which was aimed to identify
sex- and age-related transcriptional
differences in lung. We identified
transcriptional profiles significantly
associated with sex (215 genes; FDR
<0.05) and age at surgery (217 genes) in
non-involved lung tissue resected from
284 lung adenocarcinoma patients.
When these profiles were tested in
three independent series of non-tumor
lung tissue from an additional 1,111
patients, we validated the association
with sex and age for 25 and 22 genes,
respectively. Therefore, gene expression
in non-tumor lung tissue is modulated
by both sex and age. These findings
represent a validated starting point for
research on the molecular mechanisms
underlying the observed differences in
the course of lung diseases among men
and women of different ages.
Networking
Division of Genetics and
Epidemiology Institute
of Cancer Research, Sutton, United
Kingdom
Laboratório de imunogenética Instituto
Butantan, Sao Paulo,Brazil
Thoracic Surgery Department, Icahn
Medical Institute, Mount Sinai Hospital,
New York, NY, USA
Department of Molecular Medicine,Laval
University, Québec, Canada
GENETIC EPID
AND PHARMA
196
Keywords
Lung cancer,
genetic variations,
pharmacogenomics
Galvan A, Colombo F, Frullanti E, Dassano A, Noci S, Wang Y, Eisen
T, Matakidou A, Tomasello L, Vezzalini M, Sorio C, Dugo M, Ambrogi
F, Iacobucci I, Martinelli G, Incarbone M, Alloisio M, Nosotti M, Tosi D,
Santambrogio L, Pelosi G, Pastorino U, Houlston RS, Dragani TA. Germline
polymorphisms and survival of lung adenocarcinoma patients: a genome-wide study
in two European patient series. Int J Cancer. 2015;136:E262-71
Dassano A, Colombo F, Trincucci G, Frullanti E, Galvan A, Pettinicchio A, De Cecco L,
Borrego A, Martinez Ibañez OC, Dragani TA, Manenti G. Mouse pulmonary adenoma
susceptibility 1 locus is an expression QTL modulating Kras-4A. PLoS Genet.
2014;10:e1004307
Renieri A, Mencarelli MA, Cetta F, Baldassarri M, Mari F, Furini S, Piu P, Ariani F, Dragani
TA, Frullanti E. Oligogenic germline mutations identified in early non-smokers lung
adenocarcinoma patients. Lung Cancer. 2014;85:168-74
Galvan A, Frullanti E, Anderlini M, Manenti G, Noci S, Dugo M, Ambrogi F, De Cecco L,
Spinelli R, Piazza R, Pirola A, Gambacorti-Passerini C, Incarbone M, Alloisio M, Tosi D,
Nosotti M, Santambrogio L, Pastorino U, Dragani TA. Gene expression signature of
non-involved lung tissue associated with survival in lung adenocarcinoma patients.
Carcinogenesis. 2013;34:2767-73
alvella FS, Alberio T, Noci S, Santambrogio L, Nosotti M, Incarbone M, Pastorino U,
F
Fasano M, Dragani TA. Multiple isoforms and differential allelic expression of CHRNA5
in lung tissue and lung adenocarcinoma. Carcinogenesis. 2013;34:1281-5
OF THE UNIT
2
DEMIOLOGY
ACOGENOMICS
PUBLICATIONS
Staff
HEAD
Tommaso Dragani, Pharm Sci D, PhD
9.890
IMPACT FACTOR
STAFF SCIENTIST
Giacomo Manenti, Pharm Sci D, PhD
1
RESEARCH ASSOCIATES
Francesca Colombo, PhD; Chiara E. Cotroneo,
Biotech D; Sara Noci, PhD
5.085
Alice Dassano, PhD Student, Giulia Pintarelli, Biol
Sci D
1-33, 7
TECHNICIANS
Angela Pettinicchio
197
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 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
As an Affiliated Research Center of the Open University, Milton Keynes, UK, INT offers
a PhD Program in Life and Biomolecular Sciences. The program 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 fellowships/grants to European Community postgraduate
students holding a degree in Medicine, Biological Sciences or Pharmacy. Students are
involved in several activities, including courses, generic skills training, journal club
meetings, and seminars.
2015 list of Open University PhD students
and their research topics
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
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
199
Andrea Tomirotti
Identification of early biomarkers of neoplastic transformation in mouse models of
breast and prostate carcinogenesis
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
Dissecting melanoma heterogeneity by integrative genomic analysis for tailored anticancer therapy
Lorenzo Castagnoli
Role of ∆16HER2 splice variant in breast cancer stem cells
Nadia Castioni
Role of SPARC and mast cells in non-hodgkin B cell lymphomas
Elena Cetti
Identification and Characterization of Potential novel targets in thyroid carcinoma:
evidence of non-oncogene addiction unveiling tumor cell vulnerabilities
Roberta Nicoletti
The role of mi RNAs in regulating drugs sensitivity and cellular plasticity in
ovarian cancer: mechanisms evaluation and cellular delivery through retargeted
nanoparticles
Tiziana Triulzi
Identification of markers to predict benefit from trastuzumab treatment
Rihan El Bezawi
The role of MicroRNAs in the radiation response of human prostate cancer
Maria Teresa Majorini
Investigating the role of the inhibitor of apoptosis proteins (IAPs) in metastasis
formation
Alessandra Tuccitto
Tumour microenvironment-driven mechanisms regulating cancer cell plasticity and
cancer stem cell expansion: role of hypoxia/acidity and inflammatory/suppressive
cells in human Hepatocellular Carcinoma (HCC)
Noemi Arrighetti
New therapeutic approaches for pediatric sarcomas based onheparanase/heparan
sulfate inhibition
Claudia Enriquez
SPARC molds tumor microenvironment protecting from neuroendocrine prostate
cancer
Eriomina Shahaj
Modulation of Immune Checkpoints by Tumour Exosomes
Martina Di Modica
Gut microbiota and Trastuzumab response in HER2-positive breast cancer
In 2015, the following OU students obtained their PhD Diploma:
Davide Bernareggi, Daniele Lecis, Olga Kuchuk, Valentina Profumo, Alice Rigoni,
Marianna Sasso.
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: Chiara Maura
Ciniselli, Claudia Barberi, Maria Filomeno , Matteo Di Maso, Cristina Galli, Maria Gori,
Teresa Greco, Alessandra Lugo, Elisabetta Marzo, Roberta Mercorio, Monica Pandolfi,
Delphine Praud, Tiziana Rosso, Maria Giovanna Scarale, Monica Solbiati.
The Surgery Department hosts PhD Students from the UNIMI PhD Program in
Physiopathological Sciences: Andrea Billé (fellowship granted by the Fondazione
200
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:
Alessandro Satta, (all registered with the UNIMI PhD School in Biological and
Molecular Sciences), Annalisa Conti (School of Clinical and Experimental Biomedical
Sciences, UNIMI). In 2015 the following students obtained their Doctoral Diploma:
Katia Rea, Giulia Grazia.
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. The Master Rectal Surgery for medical doctors offered by INT and ARECO
(Association for the European Research in Surgical Oncology).
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.
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.
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 Care, Cardiology, Nutritional Support (University of Milan
and Milano-Bicocca) work within all the Units of the Department. 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,
chosen for clinical fellowships by many visiting clinicians and surgeons every year, is
a training center for the University of Milan and has been for over 10 years a training
centre for the School for Italian Surgeons ”ACOI”, where various of the surgeons
from this Unit are involved as teachers. 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 Otolaryngology Surgery Unit
has close links with the University of Milan, and is involved in postgraduate teaching
and supervision of junior medical staff. Thanks to a collaboration with the Human
Morphology Department of the University of Milan (where a surgeon from the Unit is
engaged as a teacher) every year a live surgery session is organized for postgraduate
students. A renewed collaboration with the Otorhinolaryngoiatric School of
Specialization of the University of Milan have been discussed in 2014. 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.
Several postgraduate students attend the Melanoma and Sarcoma Unit that actively
collaborates with several Medical Universities in Italy and Europe. 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.
201
PUBLICATIONS
PUBLICATIONS
AUTHORS
TITLE
JOURNAL
I.F.
1
AGNOLI C, GRIONI S, SIERI S, Sacerdote C, Ricceri F, Tumino
R, Frasca G, PALA V, Mattiello A, Chiodini P, Iacoviello L, De
Curtis A, Panico S, KROGH V.
Metabolic syndrome and breast cancer risk: A casecohort study nested in a multicentre Italian cohort.
Plos One
2015;10:e0128891
3,234
2
Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn
Cedermark G, Fizazi K, Horwich A, Laguna MP, NICOLAI N,
Oldenburg J.
Guidelines on Testicular Cancer: 2015 Update.
European Urology
2015;68:1054-1068
13,938
3
Aleksandrova K, Chuang SC, Boeing H, Zuo H, Tell GS, Pischon
T, Jenab M, Bueno De Mesquita B, Vollset SE, Midttun O,
Ueland PM, Fedirko V, Johansson M, Weiderpass E, Severi G,
Racine A, Boutron Ruault MC, Kaaks R, Kuhn T, Tjonneland A,
et al. [Sieri S].
A prospective study of the immune system activation
biomarker neopterin and colorectal cancer risk.
Jnci-journal of The
National Cancer Institute
2015;107:djv010
12,583
4
Aleksandrova K, Bamia C, Drogan D, Lagiou P, Trichopoulou A,
Jenab M, Fedirko V, Romieu I, Bueno De Mesquita HB, Pischon
T, Tsilidis K, Overvad K, Tjonneland A, Bouton Ruault MC,
Dossus L, Racine A, Kaaks R, Kuhn T, Tsironis C, Papatesta
EM, et al. [Grioni S].
The association of coffee intake with liver cancer
risk is mediated by biomarkers of inflammation
and hepatocellular injury: Data from the European
Prospective Investigation into Cancer and Nutrition.
American Journal
of Clinical Nutrition
2015;102:1498-1508
6,77
5
Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang
XS, Bannon F, Ahn JV, Johnson CJ, Bonaventure A, Marcos
Gragera R, Stiller C, Azevedo E Silva G, Chen WQ, Ogunbiyi
OJ, Rachet B, Soeberg MJ, You H, Matsuda T, Bielska Lasota
M, et al. {Contiero P, Tagliabue G, Baili P, Berrino F, Gatta G,
Sant M}.
Global surveillance of cancer survival 1995-2009:
analysis of individual data for 25,676,887 patients
from 279 population-based registries in 67 countries
(CONCORD-2).
Lancet
2015;385:977-1010
45,217
6
Amant F, LORUSSO D, Mustea A, Duffaud F, Pautier P.
Management strategies in advanced uterine
leiomyosarcoma: Focus on trabectedin.
Sarcoma
2015;2015:704124
0
7
Amoroso V, Generali D, Buchholz T, Cristofanilli M, Pedersini R,
Curigliano G, DAIDONE MG, DI COSIMO S, Dowsett M, Fox S,
Harris AL, Makris A, Vassalli L, Ravelli A, Cappelletti MR, Hatzis
C, Hudis CA, Pedrazzoli P, Sapino A, Semiglazov V, et al.
International expert consensus on primary systemic
therapy in the management of early breast cancer:
Highlights of the Fifth Symposium on Primary
Systemic Therapy in the Management of Operable
Breast Cancer, Cremona, Italy (2013).
Journal of The
National Cancer
Institute Monographs
2015;2015:90-96
0
8
ANANIA M, Gasparri F, CETTI E, Fraietta I, Todoerti K, MIRANDA
C, MAZZONI M, Re C, Colombo R, Ukmar G, Camisasca S,
PAGLIARDINI S, PIEROTTI M, Neri A, Galvani A, GRECO A.
Identification of thyroid tumor cell vulnerabilities
through a siRNA-based functional screening.
Oncotarget
2015;6:34629-34648
6,359
9
Anderson AS, Key TJ, Norat T, Scoccianti C, Cecchini M,
BERRINO F, Boutron Ruault MC, Espina C, Leitzmann M,
Powers H, Wiseman M, Romieu I.
European Code against Cancer 4th Edition: Obesity,
body fatness and cancer.
Cancer Epidemiology
2015;39 Suppl 1:S34-S45
2,711
10
Anderson LA, Tavilla A, Brenner H, Luttmann S, Navarro C,
Gavin AT, Holleczek B, Johnston BT, Cook MB, Bannon F, SANT
M, EUROCARE-5 Working Group.
Survival for oesophageal, stomach and small
intestine cancers in Europe 1999-2007: Results from
EUROCARE-5.
European Journal
Of Cancer
2015;51:2144-2157
5,417
11
Angelini S, Ravegnini G, Nannini M, Bermejo JL, Musti M,
Pantaleo MA, FUMAGALLI E, Venturoli N, PALASSINI E,
Consolini N, CASALI PG, Biasco G, Hrelia P.
Folate-related polymorphisms in gastrointestinal
stromal tumours: susceptibility and correlation with
tumour characteristics and clinical outcome.
European Journal
Of Human Genetics
2015;23:817-823
4,349
12
ANGELONI V, TIBERIO P, APPIERTO V, DAIDONE MG.
Implications of stemness-related signaling pathways
in breast cancer response to therapy.
Seminars in Cancer
Biology 2015;31:43-51
9,33
13
Antonelli M, Badiali M, Moi L, Buttarelli FR, Baldi C,
MASSIMINO M, Sanson M, Giangaspero F.
KIAA1549: BRAF fusion gene in pediatric brain tumors
of various histogenesis.
Pediatric Blood & Cancer
2015;62:724-727
2,386
14
Apetoh L, Smyth MJ, Drake CG, Abastado JP, Apte RN,
Ayyoub M, Blay JY, Bonneville M, Butterfield LH, Caignard A,
CASTELLI C, Cavallo F, Celis E, Chen L, COLOMBO MP, Comin
Anduix B, Coukos G, Dhodapkar MV, Dranoff G, Frazer IH, et al.
Consensus nomenclature for CD8+ T cell phenotypes
in cancer.
Oncoimmunology
2015;4:e998538
6,266
15
Arena M, Virdis M, Morandi E, Viaggi P, Pisani A, Opocher E,
MASCI E.
Blue rubber bleb nevus syndrome: Combined surgical
and endoscopic treatment.
Endoscopy 2015;47
Suppl 1 UCTN:E372-E373
5,053
16
ARRIGHETTI N, CORNO C, GATTI L.
Drug combinations with HDAC inhibitors in antitumor
therapy.
Critical Reviews
in Oncogenesis
2015;20:83-117
0
17
Astolfi A, Melchionda F, PEROTTI D, Fois M, Indio V, Urbini
M, Genovese CG, COLLINI P, Salfi N, Nantron M, D'Angelo P,
SPREAFICO F, Pession A.
Whole transcriptome sequencing identifies BCOR
internal tandem duplication as a common feature of
clear cell sarcoma of the kidney.
Oncotarget
2015;6:40934-40939
6,359
203
AUTHORS
JOURNAL
Biology of Blood and
Marrow Transplantation
2015;21:1605-1611
I.F.
Impact of Pretransplantation 18F-fluorodeoxy
Glucose-Positron Emission Tomography Status
on Outcomes after Allogeneic Hematopoietic Cell
Transplantation for Non-Hodgkin Lymphoma.
Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V,
Scotti L, Jenab M, TURATI F, Pasquali E, Pelucchi C, Galeone C,
Bellocco R, Negri E, Corrao G, Boffetta P, La Vecchia C.
Alcohol consumption and site-specific cancer risk: A
comprehensive dose-response meta-analysis.
British Journal of Cancer
2015;112:580-593
4,836
20
BAILI P, TORRESANI M, AGRESTI R, ROSITO G, DAIDONE MG,
VENERONI S, CAVALLO I, FUNARO F, GIUNCO M, TURCO A,
AMASH H, SCAVO A, MINICOZZI P, BELLA F, MENEGHINI E,
SANT M.
A breast cancer clinical registry in an Italian
comprehensive cancer center: An instrument for
descriptive, clinical, and experimental research.
Tumori 2015;101:440-446
1,269
21
BAILI P, DI SALVO F, Marcos Gragera R, Siesling S, Mallone S,
Santaquilani M, MICHELI A, Lillini R, Francisci S, EUROCARE-5
Working Group.
Age and case mix-standardised survival for all
cancer patients in Europe 1999-2007: Results of
EUROCARE-5, a population-based study.
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11TH INTERNATIONAL
MEETING ON
COMPUTATIONAL
INTELLIGENCE METHODS
FOR BIOINFORMATICS
AND BIOSTATISTICS, CIBB
2014 Eds: C DI Serio, P
Liò, A Nonis, R Tagliaferri
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Brentuximab vedotin as consolidation therapy after
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Factors predictive of pelvic lymph node involvement
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Bendamustine in relapsed/refractory multiple
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421 NICOLAI N, NECCHI A, RAGGI D, BIASONI D, CATANZARO
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422 NICOLAI N, BIANCHI E, DONATI I, L'ACQUA C, BRUNELLI C,
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414 NECCHI A, GIANNATEMPO P, LO VULLO S, FARÈ E, RAGGI D,
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415
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416 NECCHI A, GIANNATEMPO P, LO VULLO S, FARÈ E, RAGGI
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425 Ni M, Esposito E, Raj VP, Muzi L, ZUNINO F, ZUCO V,
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New macrocyclic analogs of the natural histone
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426 Nimptsch K, Aleksandrova K, Boeing H, Janke J, Lee YA,
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427 Nimptsch K, Aleksandrova K, Boeing H, Janke J, Lee YA, Jenab
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428 Norat T, Scoccianti C, Boutron Ruault MC, Anderson A,
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European Code against Cancer 4th Edition: Diet and
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Cancer Epidemiology
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429 Obón Santacana M, Peeters PH, Freisling H, Dossus L, Clavel
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430 Okiror L, Jiang L, Oswald N, BILLÈ A, Rajesh P, Bishay E, Steyn
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Annals Of
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BRAF in metastatic colorectal cancer: The future
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Pharmacogenomics
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432 Orr N, Dudbridge F, Dryden N, Maguire S, Novo D, Perrakis E,
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433 Ose J, Fortner RT, Schock H, Peeters PH, Onland Moret NC,
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Cancer Epidemiology
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435 Ose J, Fortner RT, Rinaldi S, Schock H, Overvad K, Tjonneland
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436 Osman AA, Neskey DM, Katsonis P, Patel AA, Ward AM,
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437 Ostergaard SD, Mukherjee S, Sharp SJ, Proitsi P, Lotta LA,
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438 Ottolina J, Ferrandina G, Gadducci A, Scollo P, LORUSSO D,
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424 NICOLETTI R, Lopez S, Bellone S, Cocco E, Schwab CL,
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440 PALASSINI E, Ferrari S, VERDERIO P, De Paoli A, Martin Broto J,
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Feasibility of preoperative chemotherapy with or
without radiation therapy in localized soft tissue
sarcomas of limbs and superficial trunk in the Italian
sarcoma group/grupo español de investigación en
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441 Palmerini E, Staals EL, Maki RG, PENGO S, Cioffi A, Gambarotti
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Tenosynovial giant cell tumour/pigmented
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5,417
442 Palumbo A, Gay F, Cavallo F, Di Raimondo F, Larocca
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443 Panagiotou OA, Travis RC, Campa D, Berndt SI, Lindstrom S,
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A genome-wide pleiotropy scan for prostate cancer
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European Urology
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13,938
444 Pantano F, Santoni M, PROCOPIO G, Rizzo M, Iacovelli R, Porta
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The changes of lipid metabolism in advanced renal
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445 PAPADIA A, BELLATI F, BOGANI G, DITTO A, MARTINELLI F,
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When Does Neoadjuvant Chemotherapy Really
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446 PAPADIA A, BELLATI F, DITTO A, BOGANI G, Gasparri ML, Di
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Surgical Treatment of Recurrent Endometrial Cancer:
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447 Pappo AS, Furman WL, Schultz KA, FERRARI A, Helman L,
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448 Parrino B, Carbone A, Ciancimino C, Spanò V, Montalbano A,
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Water-soluble isoindolo[2,1-a]quinoxalin-6-imines:
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European Journal Of
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3,447
449 Pasquali S, MAURICHI A, Mozzillo N, Mocellin S, Macripò G,
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Lymph-Node Ratio in Patients with Cutaneous
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The legacy of a pioneer.
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452 Patriarca F, Carobolante F, Zamagni E, MONTEFUSCO V, Bruno
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The Role of Positron Emission Tomography with
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Biology Of Blood And
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453 Paz Ares L, Mezger J, Ciuleanu TE, Fischer JR, Von Pawel
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Necitumumab plus pemetrexed and cisplatin as firstline therapy in patients with stage IV non-squamous
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randomised, controlled phase 3 study.
Lancet Oncology
2015;16:328-337
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454 Pedrazzoli P, CARACENI A, Beano A, Adamo V, Testore F, PIGNI
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Results From a Time and Motion Study of Denosumab
Subcutaneous Injection and Zoledronic Acid
Intravenous Infusion in Patients with Metastatic Bone
Disease From Italian Sites.
Value In Health
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439 Pacella E, Ricci F, COLECCHIA M, Boccardo F, Lopez Beltran A,
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2015;32:469-479
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What clinicians are asking pathologists when dealing
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456 PELOSI G, Barbareschi M, Cavazza A, Graziano P, Rossi G,
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Large cell carcinoma of the lung: A tumor in search of
an author. A clinically oriented critical reappraisal.
Lung Cancer
2015;87:226-231
3,958
457 PELOSI G, FABBRI A, Papotti M, Rossi G, Cavazza A, Righi L,
TAMBORINI E, PERRONE F, SETTANNI G, BUSICO A, TESTI
MA, Maisonneuve P, DE BRAUD F, GARASSINO M, VALERI B,
SONZOGNI A, PASTORINO U.
Dissecting pulmonary large-cell carcinoma by
targeted next generation sequencing of several
cancer genes pushes genotypic-phenotypic
correlations to emerge.
Journal Of
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2015;10:1560-1569
5,282
458 PELOSI G, FABBRI A, TAMBORINI E, PERRONE F, TESTI AM,
SETTANNI G, BUSICO A, CENTONZE G, Braidotti P, Bulfamante
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Challenging lung carcinoma with coexistent δnp63/
p40 and thyroid transcription factor-1 labeling within
the same individual tumor cells.
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2015;10:1500-1502
5,282
459 Penders YW, Albers G, Deliens L, Vander Stichele R, Van Den
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Awareness of dementia by family carers of nursing
home residents dying with dementia: a post-death
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Palliative Medicine
2015;29:38-47
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460 PENNATI M, SBARRA S, DE CESARE M, LOPERGOLO A, Locatelli
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YM155 sensitizes triple-negative breast cancer to
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Cancer 2015;136:299-309
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461 PEREGO P.
Preface: Histone deacetylases as therapeutic targets.
Critical Reviews In
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462 Peris K, LICITRA L, Ascierto PA, Corvò R, Simonacci M, Picciotto
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Identifying locally advanced basal cell carcinoma
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Future Oncology
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463 PESSI MA, NECCHI A, BOSSI P, RESTEGHINI C, GIANNATEMPO
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Nausea and vomiting during the first 3 intercycle
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464 Peterlongo P, Catucci I, COLOMBO M, CALECA L, Mucaki E,
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FANCM c.5791C>T nonsense mutation (rs144567652)
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465 PETERLONGO P, Chang Claude J, Moysich KB, Rudolph
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466 Peterson EJ, Menon VR, GATTI L, Kipping R, Dewasinghe D,
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Nucleolar targeting by platinum: P53-independent
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Molecular Pharmaceutics
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467 Petrelli A, Carollo R, Cargnelutti M, Iovino F, CALLARI M,
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By promoting cell differentiation, miR-100 sensitizes
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Early tumour shrinkage as a prognostic factor and
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469 Piccinelli C, CLERICI CA, VENERONI L, FERRARI A, PROSERPIO T.
Hope in severe disease: a review of the literature on
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470 PICCIONI F, Casiraghi C, Pisciotta V, LANGER M.
Weight and BMI are the most important predictors
influencing the needle insertion distance to the
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European Journal
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2015;32:820-822
2,942
Extraluminal EZ-blocker Placement for One-lung
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2015;29:e71-e73
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with peritonectomy and heated intraperitoneal
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Minor complications during thoracic epidural catheter
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European Journal
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2,942
474 PICCIONI F, MARIANI L, Negri M, Casiraghi C, BELLI F, LEO E,
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Epidural analgesia does not influence anastomotic
leakage incidence after open colorectal surgery for
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Journal Of
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2015;112:225-230
3,244
475 PICCIONI F, KUSAMURA S, LANGER M.
Goal-Directed Therapy for Cytoreductive Surgery with
Hyperthermic Intraperitoneal Chemotherapy: the
Right Approach in the Right Place.
Journal Of
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2015;19:1196-1197
2,798
476 PIETRANTONIO F, Petrelli F, Coinu A, DI BARTOLOMEO M,
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Predictive role of BRAF mutations in patients with
advanced colorectal cancer receiving cetuximab and
panitumumab: A meta-analysis.
European Journal Of
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FGFR as potential target in the treatment of
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Cancer Treatment
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591
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HB, May AM, Siersema PD, Kaaks R, Neamat Allah J, PALA
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Clinical Lung Cancer
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3,104
608 Tiseo M, Bersanelli M, PERRONE F, TAMBORINI E, SETTANNI G,
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Different clinical effects upon separate inhibition
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Lung Cancer
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609 Torrisi A, Castaing M, Giacomin A, Luminari S, Mangone L,
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AIRTUM and SIE for a shared definition of
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Epidemiologia &
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EGFR mutations and EGFR tyrosine kinase inhibitors.
Lancet Oncology
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607 Tiseo M, Boni L, Ambrosio F, Camerini A, Vitale MG, Baldini E,
Cinieri S, Zanelli F, Defraia E, Passalacqua R, Crino L, Dazzi C,
Tibaldi C, Turolla GM, D'Alessandro V, ZILEMBO N, Riccardi F,
Ardizzoni A, Gruppo Oncologico Italiano Di Ricerca Clinica
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611
Tralongo P, Dal Maso L, Surbone A, Santoro A, Tirelli U,
Sacchini V, Pinto C, Crispino S, Ferraù F, Mandoliti G, Tonini
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Use of the word “cured” for cancer patients—
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Current Oncology
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612
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Serraino D, Tavilla A, Van Eycken L, NICOLAI N, EUROCARE-5
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Survival of male genital cancers (prostate, testis
and penis) in Europe 1999-2007: Results from the
EUROCARE-5 study.
European Journal
Of Cancer
2015;51:2206-2216
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613
Trans Atlantic Rps Working Group. {Gronchi A}.
Management of primary retroperitoneal sarcoma
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Annals Of Surgical
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Antibiotic treatment strategies for communityacquired pneumonia in adults.
Internal And
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2,624
614 TRAPANI D, Bonzi M.
615
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin
JH, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB,
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The 2015 World Health Organization Classification
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616
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617
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Procalcitonin for detecting medullary thyroid
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Endocrine-related Cancer
2015;22:R157-R164
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Whole-transcriptome analysis links trastuzumab
sensitivity of breast tumors to both HER2 dependence
and immune cell infiltration.
Oncotarget
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6,359
Diabetes mellitus and risk of prostate cancer in the
Nutrition.
Cancer 2015;136:372-381
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Population-based method for investigating adherence
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reporting of primary cutaneous melanoma: Results of
a EUROCARE-5 high resolution study.
Cancer Epidemiology
2015;39:424-429
2,711
FOXP3 expression in tumor cells and its role in cancer
progression.
Atlas Of Genetics
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Haematology
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620 Tumino R, MINICOZZI P, Frasca G, ALLEMANI C, Crocetti
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621
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622 VALDAGNI R, Van Poppel H, Aitchison M, Albers P, Berthold
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Embracing Phenomenological Approaches to Normal
Tissue Complication Probability Modeling: A Question
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624 Van Saene HKF, Ramos B, LANGER M.
Surveillance samples and selective digestive
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Minerva Anestesiologica
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625 Vansteenkiste JF, Canon JL, BRAUD FD, Grossi F, De Pas
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Safety and Efficacy of Buparlisib (BKM120) in Patients
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2015;10:1319-1327
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626 Van Veldhoven K, Polidoro S, Baglietto L, Severi G, Sacerdote
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Proteomics and lymphomas.
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628 VARINELLI L, CACCIA D, VOLPI CC, Caccia C, DE BORTOLI M,
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4-IPP, a selective MIF inhibitor, causes mitotic
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Endocrine-related Cancer
2015;22:759-775
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2015;33:1735-1740
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630 Vece MM, AGNOLI C, GRIONI S, SIERI S, PALA V, Pellegrini N,
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G, Ricceri F, Sacerdote C, KROGH V.
Dietary Total Antioxidant Capacity and Colorectal
Cancer in the Italian EPIC Cohort.
Plos One
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Dying after cure: A case of suicide in an adolescent
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Facebook in oncology. Review of the literature.
Recenti Progressi In
Medicina 2015;106:46-51
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633 VENERONI L, FERRARI A, Acerra S, MASSIMINO M, CLERICI CA.
Considerations on the use of WhatsApp in physicianpatient communication and relationship.
Recenti Progressi
In Medicina
2015;106:331-336
0
634 VENERONI L, CLERICI CA, PROSERPIO T, MAGNI C, SIRONI
G, CHIARAVALLI S, RONCARI L, CASANOVA M, GANDOLA L,
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Creating beauty: The experience of a fashion
collection prepared by adolescent patients at a
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Tumori 2015;101:626-630
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635 VERDERIO P, BOTTELLI S, CINISELLI CM, PIEROTTI MA,
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636 VERZONI E, GRASSI P, MONTONE R, GALLI G, NECCHI A,
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TOKIO rationale and protocol: A phase II study to
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637 Vetro M, Costa B, Donvito G, ARRIGHETTI N, Cipolla L, PEREGO
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Anionic glycolipids related to
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Chemistry
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Glioblastoma multiforme in a child with tuberous
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641 VILLARINI A, Villarini M, GARGANO G, Moretti M, Berrino F.
DianaWeb: a demonstration project to improve breast
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Epidemiologia
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642 Villarini M, Lanari C, Barchiesi L, Casciari E, Tabascio A,
Castellini M, Levorato S, Vannini S, FORNACIARI G, Moretti M,
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Annali Di Igiene :
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2015;27:595-606
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643 Vinceti M, GRIONI S, Alber D, Consonni D, Malagoli C, AGNOLI
C, Malavolti M, PALA V, KROGH V, SIERI S.
Toenail selenium and risk of type 2 diabetes: The
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Journal Of Trace
Elements In Medicine
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2015;29:145-150
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644 Virgone C, Alaggio R, Dall'Igna P, Buffa P, Tonegatti L, FERRARI
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Epithelial Tumors of the Ovary in Children and
Teenagers: A Prospective Study from the Italian TREP
Project.
Journal Of Pediatric And
Adolescent Gynecology
2015;28:441-446
1,683
645 Virgone C, Cecchetto G, Besutti V, FERRARI A, Buffa P, Alaggio
R, Alessandrini L, Dall'Igna P.
Bowel parasitosis and neuroendocrine tumours of the
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Epidemiology
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2,535
646 Visser O, Ardanaz E, BOTTA L, SANT M, Tavilla A, MINICOZZI P,
Survival of adults with primary malignant brain
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European Journal
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2015;51:2231-2241
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647 Vitale A, Spolverato G, Burra P, De Feo TM, Belli L, Donato
F, Baroni GS, Marianelli T, Picciotto A, Toniutto P, BHOORI
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Transplantation Nitp Working Group.
Cost-effectiveness of pretransplant sofosbuvir for
preventing recurrent hepatitis C virus infection after
liver transplantation.
Transplant International
2015;28:1055-1065
2,599
648 VITALI C, TRIPODO C, COLOMBO MP.
MEF2C and SOCS2 in stemness regulation.
Oncoscience
2015;2:936-937
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649 VITALI C, BASSANI C, CHIODONI C, Fellini E, Guarnotta C,
MIOTTI S, SANGALETTI S, Fuligni F, DE CECCO L, Piccaluga PP,
COLOMBO MP, Tripodo C.
SOCS2 controls proliferation and stemness of
hematopoietic cells under stress conditions and its
deregulation marks unfavorable acute leukemias.
Cancer Research
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650 Von Karstedt S, CONTI A, Nobis M, Montinaro A, Hartwig T,
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L, Grosse Wilde A, Coy JF, El Bahrawy MA, Bergmann F,
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K, Kenessey I, et al.
Cancer cell-autonomous TRAIL-R signaling promotes
KRAS-Driven cancer progression, invasion, and
metastasis.
Cancer Cell
2015;27:561-573
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Low-frequency and rare exome chip variants
associate with fasting glucose and type 2 diabetes
susceptibility.
2015;6:5897
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652 Wolters M, Schlenz H, Bornhorst C, Risé P, Galli C, Moreno LA,
PALA V, Siani A, Veidebaum T, Tornaritis M, Fraterman A, De
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Desaturase activity is associated with weight status
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Journal Of Clinical
Endocrinology
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2015;100:3760-3769
6,209
653 Wozniak MB, Brennan P, Brenner DR, Overvad K, Olsen
A, Tjonneland A, Boutron Ruault MC, Clavel Chapelon F,
Fagherazzi G, Katzke V, Kuhn T, Boeing H, Bergmann MM,
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International
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654 Zamora Ros R, Rinaldi S, Biessy C, Tjonneland A, Halkjaer J,
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655 ZANARDI E, Bregni G, DE BRAUD F, DI COSIMO S.
Better Together: Targeted Combination Therapies in
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of advanced renal cell carcinoma.
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A, Bonizzoni S, Bonetti A, Monarca S, Villarini M, Levorato S,
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658 ZAPPASODI R, RUGGIERO G, Guarnotta C, TORTORETO M,
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Blood
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659 Zappasodi R, DE BRAUD F, DI NICOLA M.
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Establishing criteria for bilateral pelvic lymph node
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Lessons learned from an international multicenter
collaboration.
Journal Of Urology
2015;194:696-701
4,36
Pharmacokinetic study between a bilayer matrix
fentalyl patch and a monolayer matrix fentanyl patch:
single dose administration in healthy volunteers.
British Journal Of
2015;80:110-115
3,878
662 Zhang B, Shu XO, Delahanty RJ, Zeng C, Michailidou K,
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Height and Breast Cancer Risk: Evidence From
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Lenalidomide monotherapy in heavily pretreated
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664 Zinzani PL, CORRADINI P, GIANNI AM, Federico M, Santoro A,
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Brentuximab Vedotin in CD30-Positive Lymphomas: A
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Clinical Lymphoma
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665 Zinzani PL, Vitolo U, VIVIANI S, CORRADINI P, Motta G, Tani M,
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Safety and efficacy of single-agent bendamustine
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Experience with 27 patients.
Clinical Lymphoma
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2015;15:404-408
2,02
666 ZUCO V, CASSINELLI G, COSSA G, GATTI L, FAVINI E,
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667 ZUCO V, DE CESARE M, ZAFFARONI N, LANZI C, CASSINELLI G.
PLK1 is a critical determinant of tumor cell sensitivity
to CPT11 and its inhibition enhances the drug
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661
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243
ONGOING PROJECTS
SUPPORTED
BY CHARITIES,
INTERNATIONAL
AND NATIONAL
ORGANIZATIONS
Association for Italian Cancer Research (AIRC)
213Bi-DOTATATE as agent for peptide receptor alpha therapy: preclinical and clinical evaluation
Adipocytes as the key stromal cells for breast cancer development
Cadherin-associated signalling Pathways in Ovarian Cancer
Cancer therapy trough TLR-induced local innate immunity activation and block of immune checkpoints or suppressive cells
Cell therapy with TRAIL-armed, genetically engineered or phenotypically redirected, effectors (AIRC 5x1000)
Changes in weight and inflammation markers in relation to breast cancer risk: a nested case-control Study
Circulating miRNAs to predict outcome and to guide treatment of breast cancer patients on preoperative systemic therapy
Contribution of fibroblasts to stem cell niche in lung cancer
Diagnostic and therapeutic potential of microRNAs in Lung Cancer
Drug resistence in sarcoma targeted treatments
Dissecting the role of microRNAs in the radiation response of human prostate cancer
Effects of high Intra-abdominal pressure on tissue diffusion and pharmacokinectics of cisplatin during HIPEC
Efficacy of thermal treatment for respiratory airways in heavy smokers
Epistasis in lung tumorigenesis: an experimental approach to discover interacting gene networks relevant to human cancer
Expanding the repertoire of genetic factors associated with hereditary susceptibility to breast cancer
Extracellular matrix-mast cells interplay molds nascent tumor microenvironment
From regional node to systemic immunity suppression in melanoma metastatic progression
Genetic profile and patient-derived xenografts (PDX) for innovative management of screening-detected lung cancer
Hepcidin: clinical utility as a diagnostic tool and potential therapeutic target in breast cancer
Hypercoagulation screening as an innovative tool for risk assessment, early diagnosis and prognosis in cancer (AIRC
5x1000) Identification of expression networks as effectors of genetic susceptibility to lung cancer in mice
Identification of regulators of the alternative lengthening of telomeres in human cancer cells
Identification of a molecular predictor of response to Cetuximab based on a phase II trial in recurrent/metastatic HNSCC
Identifying new molecular pathways and predictor biomarkers of GVHD after allogeneic-HSCT
Innovative approach for discovery and development of promising targeted agents in head & neck cancer
Involvement of microRNAs in breast cancer driving pathways: from biology to possible therapies
Interaction between clinical and genetic factors in modulation of opioid analgesia and side effects in cancer pain
Interference with Akt-mediated drug-resistance mechanisms to target aggressive ovarian carcinoma
Interfering with PH regulators as a immunomodulating therapeutic strategy
Is the protective effect of mediterranean diet on cancer mediated by a methylation pattern?
Lifestyle and breast cancer recurrences: The DIANA-5 Trial
Mesothelioma survivors in Italy: what is contributing to long term survival?
Modelling toxicity after high dose RT for prostate cancer: validating clinical, dosimetric and molecular factors
Overcoming anti-angiogenic therapy resistance in selected sarcomas
Pediatric malignant glioma: progress starting from the worst case scenario of diffuse intrinsic pontine glioma
Regulation of myeloid cells homeostasis by ECM proteins: implication for autoimmunity and myeloid malignancies
245
Retrospective and prospective study of late radiation damages after focal radiotherapy for childhood brain tumors
Role of acidity in tumor immunity
Role of chemotherapy in trastuzumab cytotoxic activity
Role of germline and somatic DNA change in modulating the survival of patients with lung adenocarcinoma
Role of oncogene Induced Senescence and non oncogene addition in thyroid carcinogenesis
Statistical tools for prognosis and prediction in cancer: Assessments and application to a sarcoma case series
Study of HER2 addiction-related features implicated in trastuzumab benefit
Targeted therapy with or without nephrectomy in metastatic renal cell carcinoma: liquid biopsy for biomarkers discovery
Targeting KRAS mutations in NSCLC trough LKB1 co-vulnerability
Targeting melanoma dedifferentiation and EMT to promote immunogenicity
The ovarian cancer cholinic phenotype: exploring possible theragnostic windows
Translational research to a practice changing global prospective study of androgen deprivation in salivary gland cancers
Toremifene in desmoid Tumor: prospective clinical trial and identification of potential molecular targets
Tumor-microenvironment related changes as new tools for early detection and assessment of high-risk \disease (AIRC
5x1000)
Understanding the biological basis of chemorefractoriness in peripheral T-cell Lymphoma to develop novel treatments
Validation of HSP105 as novel biotarget in human non-Hodgkin lymphomas
Targeting acquired and compensatory drug resistance mechanisms of ovarian carcinoma cells, Fellowship
Bianca Garavaglia Association
Bio-molecular characterization of Wilms cancer
Clinical study on renal cancer in pediatric ages
Endocrinology of CNS cancers
Histopathology of renal cancers Identification of potential targets for targeted cell therapy, and expression of immune-inhibitory molecules in the tumor
microenvironment of patients with neuroblastoma
Integration of nursing activity
Liquoral diagnostic of CNS cancers
Molecular study of child and adolescent sarcomas for the identification of new drugs
New drugs in pediatric cancer treatment
Outsourcing projects
Pediatric malignant glioma: progress starting from the worst case scenario of diffuse intrinsic pontine glioma
Physical and psychological rehabilitation of patients with bone tumors Psychodynamic and neuropsychiatric activity
Radiological diagnostic of CNS cancers
Secondcancers/fertility/cardiological sequelae
Serum biomarkers in the brain bridge intrinsic glioma
Strategies of heparanase / heparan sulfate system inhibition, a new molecular target for therapy of pediatric sarcomas
246
Study of the role of breast cancer predisposition genes in the development of pediatric cancers
The youth project
The sport project: in-hospital physical activity with training staff to encourage children and adolescents with cancer in sports
Therapeutical trials
BIOVITAS CAPITAL - USA
Process and apparatus for identifying individuals with lung cancer risk
CARIPLO Foundation
Contribution of T memory stem cells to successful Immune recovery in humans following bone marrow transplantation
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
Role of tumor microenvironment in thyroid carcinogenesis onset and progression: thyroid cell cross-talk with macrophages
Cariverona Foundation Continuation of scFv validation of concentrated D2 / B to radioimmuno Imaging murine models
Compagnia di San Paolo and CARIPLO Foundation
Eurocare 6 - High Resolution- clinical data collection and statistical analysis for the interpretation of prognosis inequalities
detected in Italy
Desmoid Tumor Research Foundation
High throughput genome study to identify predictors of aggressiveness in patients with sporadic desmoid tumor who undergo
a wait and see approach
European Union
BENCH-CAN - Benchmarking comprehensive cancer care that provides interdisciplinary treatment for patients, and yield
examples of best practice in comprehensive cancer care
BIO RARE - K-RAS mutations and DNA repair function in non-small cell lung cancer
CANCON - European guide on quality improvement in comprehensive cancer control
DietINT - A randomized phase II study for tertiary prevention of squamocellular cancer of head and neck (SCCHN) with a dietary
intervention EPIC-CVD - Individualised CVD risk assessment: tailoring targeted and cost-effective approaches to Europe’s diverse
populations EurocanPlatform - A european platform for translational cancer research
EUROSARC - European clinical trials in rare sarcomas within an integrated translational trial network
ExPo-r-NeT - European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment
IACT - Immunostimolatory Agonist Antibodies for Cancer Therapy
I.Family - Determinants of eating behavoiur in european children, adolescents and their parents
IMMUNOCAN - Toward enhancing activities of european institutions in the FDUSCC-IM cancer research joint institute in China
MEMEME - Randomized controlled trial of metformin and dietary restriction to prevent age-related morbid events in people
with metabolic syndrome
RARECARENet - Rare cancers information network
REQUITE - Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality-oflife in cancer survivors TackSHS. Tackling secondhand tobacco smoke and e-cigarette emissions: exposure assessment, novel interventions, impact
247
on lung diseases and economic burden in diverse European populations
Foundation for Italian Cancer Research (FIRC)
DELTA16HER2 involvement in tumor-initiating cells of HER2-positive breast carcinomas, Fellowship
The role of matricellular proteins on Osteosarcoma development and progression, Fellowship
Co-targeting of stress response pathways and oncogenic pathways to identify new therapeutic targets in melanoma,
Fellowship
Biological and Clinical Significance of Circulating Tumor Cells in Breast Cancer, Fellowship
Comparative analysis of human and mouse mutations involved in lung tumorigenesis and study of their genetic control,
Fellowship
Cross-influence between extracellular matrix and differentiated versus undifferentiated breast carcinoma cells, Fellowship
Guido Berlucchi Foundation
Identification of combinations for integrated treatment of pulmonary carcinoma in preclinical models
Search for new predictors of response to erlotinib in patients with non-small cell lung cancer without EGFR mutations
Mechanisms of response and resistance to PD-1 pathway blockade therapy in melanoma, Fellowship
Harry J. Lloyd Charitable Trust - USA
Study of microRNA related to myeloid derived suppressor cells in early melanoma patients
Health Ministry - ITALY
A multicenter randomised trial of contrast-enhanced MR imaging as a breast cancer screening tool in addition to
mammography and ultrasonography in women at intermediate risk. Feasibility, and short term result
A randomized controlled trial of diet and physical activity in BRCA mutation carriers
Activity of Imatinib and Everolimus in advanced chordoma patients progressing on Imatinib
Allergic components in experimental multiple sclerosis: novel targets for immune intervention
Cerebrospinal fluid proteome from Central Nervous System pediatric tumours: patient related pattern
Comparisons of Population- based cancer indicators
Deleted in Breast Cancer 1, a new player in the DNA damage response
Early detection and treatment of recurrent, chemotherapy-resistant ovarian cancer stem cells by CPE peptide complexed
superparamagnetic iron oxide nanoparticles (CPE-SPIONs)
Extending comprehensive cancer centers expertise in patient education: the power of partnership with patient representatives
Exploitation of human NK cell-derived exosomes as cell-free support in tumor immunotherapy
Generating stem cell-like T cells to improve immune reconstitution and anti-tumor immunity
HPV positive oropharyngeal cancer: characterization of immunological and viral profiles, and their role in the response to
treatment
Identification and functional validation of microRNA biomarkers in lung cancer
IGF-I isoforms and Breast Cancer
IL-6-related inflammation signatures as a predictive marker of recurrence in liver cancer patients
Imatinib for the treatment of plexiform neurofibromas in NFI patients
Interaction framework between patient advocacy groups and cancer centers on sarcomas, as a model for rare cancers
Involvement of microRNAs in triple negative breast cancer: from biology to possible therapeutic applications
Neoadjuvant targeted agents followed by surgery in squamous cell carcinoma of head and neck: detection of promising agents
248
through identification of molecular and imaging parameters to predict treatment activity and/or resistance
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
Plasma microRNA profiling as first line screening test for lung cancer detection: a prospective study
Potentiating clinical and immunological effects of chemotherapy by neutralizing acidic pH at tumor site: a phase II randomized
study in melanoma patients
Preoperative TPF chemotherapy in locally advanced resectable oral cavity squamous cell cancer in order to improve
pathological complete response rate: a phase II study
Role of delta16HER2 splice variant in tumor progression and in response to biodrugs targeting HER2 receptor
Role of nutrients involved in one-carbon metabolism in the development of different molecular subtypes of breast cancer in
the ORDET cohort
Tailored accreditation model for comprehensive cancer centers: validation through the applicability of the experimental OECIbased model to the Network of Cancer IRCCS of Alleanza Contro il Cancro (ACC)
Tailored Beta-catenin mutational approach in extraabdominal sporadic desmoid tumor patients
The role of early systematic best palliative care versus on request palliative care consultation during standard oncologic
treatment for patients with advanced gastric or pancreatic cancer: a randomized, controlled, multicenter trial
Italian Citizens “5x1000” to Fondazione IRCCS Istituto Nazionale dei Tumori
Adaptive Brachytherapy guided by MRI images in the exclusive treatment of locally advanced carcinoma of the cervix
according to European standards of excellence: study of quality of treatment in terms of applicability and clinical and
dosimetric outcome
Calory restriction: metabolism and cancer Coordinate the planning and management of clinical trials and optimize the use of dedicated resources through the Clinical
Trials Center Development of the institutional breast cancer clinical registry Evaluation of reproductive risk in national priority contaminated sites (RISCRIPRO_SENTIERI) CCM 2012 External stereotactic high dose-fraction radiotherapy for prostate cancer EPIC Study- Italy
Hereditary predisposition: estimating the risk of being affected by cancer Hereditary breast and ovarian cancer: clinical and molecular characterization Identification of a molecular marker that can help identify patients with breast cancer who benefit from targeted treatment for
HER2 Innovative approaches in tumour diagnostic and therapy
Innovative and interdisciplinary projects through funding of genomics and transcriptomics analysis Institutional Clinical Registry
Long term cancer survivors in childhood and adolescence- agreement 4M05/4
MicroRNA profiling and response to HER2 targeting
Multidisciplinary disease-oriented approach
Multidisciplinary approach to the early detection of colorectal cancer using molecular signature
Multidisciplinary and integrated system for the optimization of INT research activity data management
New frontiers of technology for molecular diagnostics and preclinical research
National network for the understanding of molecular phenomena, for the optimization of diagnostic paths and clinical
prototype interventions for malignant pleural mesothelioma
249
Phase I/II no profit study Resource optimization for the management and conduct of institutional clinical studies: towards the translation of research
findings into experimental no profit therapies in view of a rapid transition “from-bench-to-bedside”
Research Projects management optimization
Rare Cancers in Italy and Europe
SINTART 1-2 - Multidisciplinary approach for sinonasal tumors prognosis: a study of phase II of the integration of surgery,
chemotherapy, photons and heavy ions for a more effective and less toxic treatment in unresectable or inoperable patients
Study on the clinical relevance of gene variants BRCA1 / BRCA2 identified in individuals at risk for hereditary breast and ovarian
cancer
The Institutional biobank
The Research Biobank
Italian League Against Cancer (LILT)
Psychological determinants and e impact in preventive strategy choices in two distinct populations: healthy women/women
affected by breast cancer with BRCA 1 and 2 mutation
Contribution to research projects (i.e. CAPP Chemoprevention project; Prevention and D.A.R.E. Project) and clinical activity (i.e.
Day Surgery, Pediatric Oncology, Clinical Psycology Units)
Contribution to three contracts and four fellowships for clinical and pre-clinical investigators
Italian Neuroblastoma Foundation
Treatment of neuroblastoma patients with T lymphocytes genetically modified to express a GD2-specific chimeric antigen
receptor (CAR) and a safety switch
Italo Monzino Foundation
For a shared feeling
Identification and validation of new therapeutic targets and biomarkers in prostate cancer
PRIAS - Hormonal and genetic characterization of active surveillance in patients (second term)
Local health authority of Pavia
Pavia Province Cancer Registry
Lombardy Region
Use of donors with HBSAG positive encephalic lesions, anti- HBCORE positive, or ANTI-HCV positive according to national
guidelines: improvement of liver allocation model by collecting and evaluating patient organ medium short and long term
survival outcomes
Marta Nurizzo Association
Identification of germline mutations associated with lung cancer in non-smokers
National Institute of Health (NIH)
Identifying non-coding RNAs for early detection and prevention of lung cancer
National Research Council (Cnr)
NanoMax
Pezcoller Foundation
Relevance of HER2 addiction in breast tumor immune infiltration and benefit from trastuzumab treatment, Fellowship
250
Telethon
Determinants of neurodegeneration in Ataxia Telangiectasia
Umberto Veronesi Foundation
Validation of tumor cell vulnerabilities identified by a siRNA-based loss of function screening: a tool for the discovery of new
potential therapeutic targets in thyroid carcinoma, Fellowship
Effects of tumor-secreted miR-9 on human fibroblasts, Fellowship
MicroRNAs in lung cancer: from markers to targets, Fellowship
Modelling, interpretation and forecasting of cancer incidence and mortality in Europe, Fellowship
Identification of B cell intrinsic and extrinsic factors controlling lymphomagenesis in a model of Spontaneous Activated B Cell
Diffuse Large B Cell Lymphoma (ABC-DLBCL), Fellowship
University and Research Ministry (MIUR) - ITALY
Circulating microRNA as markers for monitoring the biological effect and clinical efficacy of neoadjuvant treatment in
patients with HER2-positive breast cancer: a retrospective-prospective study in the international multicenter clinical protocol
NEOALLTO Identification and monitoring of breast cancer recurrence, by sequencing of plasma DNA Metabolism and cancer: analysis of the effects of metformin treatment, in combination with standard chemotherapy, on
treatment and prevention of colorectal cancer and breast cancer
Multiparametric molecular characterization of human solid tumors in adults and children (lung, breast, pancreas, prostate,
urothelium and soft tissue) for the identification of prognostic and predictive factors for clinical use
New drugs for targeted cancer therapy - n.RBID082ATK 004 code in the framework of the “IDEAS - FIRB” initiative
NEWTON - Advanced nanosystems for a new molecular oncology
Next generation sequencing to identify new markers and therapeutical targets for papillary radio resistant thyroid
ONCODIET
The genetics of stem cells in breast cancer: common ancestors or progenitors specific clone?
251
ETHICS
COMMITTEE
ETHICS COMMITTEE
CHAIRMAN
VALTER TORRI
MEMBERS
GIOVANNI APOLONE (since September 2015)
GIUSEPPE BAIGUINI
EMILIO BOMBARDIERI
CARLO CELENTANO
EMANUELE CEREDA
VITO CORRAO
STEFANO FEDERICI (until September 2015)
FRANCESCA CRIPPA FLORIANI
EMILIO DI GENOVA
MOMCILO JANKOVIC
ROBERTO LABIANCA
RENATO MANTOVANI
ANTONIO MIADONNA
MONICA R. MIOZZO
EUGENIO A.PARATI
UGO PASTORINO (until August 2015)
ROBERTA E. PAVESI
TULLIO PROSERPIO
ANTONIO G. RAMPOLDI
GABRIELLA SAIBENE
FRANCESCO SCAGLIONE
MARTA SCORSETTI
RITA VETERE
SCIENTIFIC SECRETARIAT
PAOLO G. CASALI
BIANCA M. FRANCUCCI
T
he Institutional Ethics Committee reviews all new clinical studies submitted
by investigators and previously approved by the Scientific Institutional Review
Board. The Committee was established in 1973.
In 2015, 200 new studies were submitted to the Ethics Committee for approval: 112
were interventional trials, of which 70 were sponsored by commercial companies
and 42 were investigator-driven or sponsored by cooperative groups; 88 were
observational, of which 6 were sponsored by commercial companies and 82 were
investigator-driven or sponsored by cooperative groups.
In 2014, 210 new studies had been submitted, as compared to 200 in 2015. Indeed, the
decrease was exclusively related to observational studies (109 in 2014 versus 82 in
2015), while the number of interventional studies increased (101 in 2014 versus 112 in
2015).
The median time from submission to the Ethics Committee discussion was in the
range of one month (27 days), thus paralleling the timelines of previous years.
During 2015, a total of 590 studies were active: 310 studies were enrolling, 176
studies were closed to accrual and 104 ended during the year. A total of 80,572
cases are involved, 25,845 of which were enrolled in 2015, most of them (n=18,698)
in observational studies or registers (n=4,388) and the others (n=2,759) in
interventional studies (756 patients in commercial-sponsored trials and 2,003 in
investigator-driven trials).
The Institutional Ethics Committee serves as the reference Committee for Scientific
Institutes (IRCCS) of the Lombardy Region. In this capacity, it continued to organize
approximately one meeting a month to discuss and share common issues. The
Investigator-driven studies, the informed consent process and compassionate use of
drugs were the major topics discussed.
ADMINISTRATIVES
MICHAELA DE PALO
RAFFAELLA DIDONÉ
PATRIZIA POLO
EMILIANO STENDARDO
ETHICS
COMMITTEE
253
ONGOING
CLINICAL
STUDIES
Study
Code
Title
Coordinator
Activated
Closed
Patients
enrolled
in 2015
Phase
Total
patients
Observational
2.467
Closed
accrual
BREAST CARCINOMA
32/03
Prognostic significance of blood concentrations of testosterone and
insulin in women with early breast cancer
F. Berrino
2003
06/04
Immunization of patients with locally advanced/metastatic breast
and ovarian cancer with autologous monocyte-derived dendritic cells
loaded with apoptotic/necrotic autologous tumor cells exposed to
heat shock
A. M. Gianni
2004
31/12/15
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
01/09/15
II
7
Closed
accrual
37/07
Randomized trial of diet, physical activity and breast cancer
recurrences: the DIANA-5 study
F. Berrino
2007
-
1.667
Closed
accrual
76/08
Tevere project: primary prevention of breast cancer by diet, physical
activity or Metformin assumption
F. Berrino
2009
III
499
46
16/09
A randomized, multicenter, phase III open-label study of the efficacy
and safety of trastuzumab-MCC-DM1 vs capecitabine+lapatinib in
patients with HER2-positive locally advanced or metastatic breast
cancer who have received prior trastuzumab-based therapy
G. Bianchi
2009
19/01/15
III
6
Closed
accrual
63/09
A randomized phase III, double-blind, placebo-controlled multicenter
trial of daily everolimus in combination with trastuzumab and
vinorelbine, in pretreated women with HER2/neu over-expressing
locally advanced or metastatic breast cancer
G. Bianchi
2010
27/03/15
III
8
Closed
accrual
15/11
The SERISCAFFOLD Use in reconstruction post-market study for tissue
support and repair in direct-to-implant breast reconstruction surgery
M. Nava
2011
18/06/15
-
4
Closed
accrual
93/11
An open-label, multicenter extension study of trastuzumab- MCCDM1 (T-DM1) administered as a single agent or in combination with
other anti-cancer 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
G. V. Bianchi
2011
08/04/15
II
1
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
88
Closed
accrual
102/11
A randomized, two-arm, open label, multicenter 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
G. V. Bianchi
2011
II
2
Closed
accrual
29/12
A phase III prospective, two-cohort non-randomized, multi-centre,
multinational, open label study to assess the safety of asisted-and
self-admnistered subcutaneous trastuzumab as adjuvant therapy in
patients with operable HER-2-positive early breast cancer
G. Mariani
2013
III
5
Closed
accrual
51/12
Identification of genes associated with toxicity from radiation in breast
cancer patients
L. Lozza
2012
Observational
141
15
78/12
A phase III randomized, double blind placebo controlled study of
BKM120 with fulvestrant, in postmenopausal women with hormone
receptor-positive HER2-negative locally advanced or metastatic
breast cancer which progressed on or after aromatase inhibitor
treatment
F. De Braud
2013
III
4
Closed
accrual
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
2070
583
92/12
A randomized trial comparing sentinel lymph node biopsy vs no
axillary surgical staging in patients with small breast cancer and a
negative preoperative axillary assessment
R. Agresti
2013
-
116
30
109/12
SHARE - Cyberknife Partial Breast Irradiation for Early Stage Breast
Cancer. A phase I prospective study
L. Lozza
2013
-
30
5
111/12
Metabolic disorders and breast cancer
R. Agresti
2012
Observational
3116
1043
01/12/15
255
Study
Code
Patients
enrolled
in 2015
Phase
Total
patients
2013
III
5
Closed
accrual
M. Nava
2013
-
35
0
Pre-operative evaluation of distress thermometer in breast cancer
patients
R. Agresti
2013
Observational
1800
400
148/12
Screening of women at high family-genetic risk of breast cancer with
only MRI: prospective randomized study with cost-effectiveness
analysis (ISS-HIBCRIT3 – ISS High Breast Cancer Risk Italian Study n. 3)
P. Panizza
2013
-
56
Closed
accrual
01/13
A phase II, open label, single arm trial of neoadjuvant 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
S. Di Cosimo
2013
II
8
3
15/13
Ex-vivo evaluation of the surgical specimen by MRI in breast cancer
and randomized study comparing MRI and conventional radiography
in non-palpable lesions
R. Agresti
2015
-
1
1
24/13
A multicenter, open-label, dose escalation, Phase I study of LJM716
administered intravenously in combination with trastuzumab in
patients with HER2 overexpressing metastatic breast cancer or gastric
cancer
S. Cresta
2013
I
6
Closed
accrual
26/13
Neoadjuvant chemotherapy with nab-paclitaxel in women with HER2negative high-risk breast cancer ETNA (Evaluating Treatment with
naoadjuvant Abraxane)
A. Moliterni
2013
III
18
0
49/13
Postmastectomy radiotherapy in reconstructed breast: evaluation of
dose distribution in partially and completed inflated tissue expanders
L. Lozza
2013
-
9
1
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
2013
III
6
2
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
71/13
A multicenter randomised trial of contrast-enhanced MR imaging
as a breast cancer screening tool alternative to mammography and
ultrasonography in women at intermediate risk. Feasibility, and short
term results. (MRIB Trial)
P. Panizza
2014
-
72
12
106/13
Randomized controlled trial of diet and physical activity in carriers of
BRCA mutation
P. Pasanisi
2013
-
234
92
111/13
Assessment of breast cancer progression risk based on extracellular
matrix characteristics
E. Tagliabue
2013
Observational
230
30
136/13
FINESSE – An open, 3-cohort, phase II trial testing oral administration
of lucitanib in patients with FGFR1-amplified or non-amplIfied
oestrogeN rEceptor poSitive metaStatic breast cancEr
F. De Braud
2014
II
4
0
145/13
Biomarkers and breast cancer risk prediction in younger women
V. Krogh
2014
Observational
260
0
161/13
Modulation of the Immune System and Adjuvant Chemotherapy in
Breast Cancer
S. Cresta
2014
-
12
10
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
45
7
174/13
Multicenter, randomized, double-blind, placebo-controlled, phase
3 trial of Fulvestrant (FASLODEX) with or without PD-0332991
(Palbociclib) Goserelin in women with hormone receptor-positive,
HER2-negative metastatic breast cancer whose disease progressed
after prior endocrine therapy
G. V. Bianchi
2014
III
5
Closed
accrual
186/13
Circulating miRNAs to predict outcome and to guide treatment of
breast cancer patients on preoperative systemic therapy
S. Di Cosimo
2014
Observational
60
31
Title
Coordinator
Activated
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 chemotherapy-based
treatment
G. V. Bianchi
127/12
Impact of a cellular dermal matrix in reduction of surgical complexity
of breast reconstructions with implants
146/12
256
Closed
31/12/15
31/12/15
Phase
Total
patients
Patients
enrolled
in 2015
2014
II
5
3
A. Balzarini
2014
-
146
106
A randomized, multicenter, open-label, phase III trial comparing
trastuzumab plus pertuzumab plus a taxane following anthracyclines
versus trastuzumab emtansine plus pertuzumab following
anthracyclines as adiuvant therapy in patients with operable HER2positive primary breast cancer
G. V. Bianchi
2014
III
16
9
51/14
Selective axillary dissection vs complete axillary dissection.
Randomized controlled clinical trial to evaluate the prevention of
lymphedema in breast cancer treatment
M. Gennaro
2014
-
61
47
66/14
An international field study of the Reliability and Validity of an EORTC
breast reconstruction questionnaire to assess quality of life in all
types of breast reconstruction
M. Nava
2014
Observational
5
0
80/14
Preoperative Breast MRI in Clinical Practice: Multicenter International
Prospective Meta-Analysis (MIPA) of Individual Woman Data. An EIBIREuroAIM/EUSOBI Study
P. Panizza
2015
Observational
83
83
90/14
A randomized double-blind, placebo-controlled study of LEE011 in
combination with letrozole for the treatment of postmenopausal
women with hormone receptor positive, HER2-negative, advanced
breast cancer who received no prior therapy for advanced disease
G. V. Bianchi
2014
III
4
3
100/14
Assessment of the performance of tomosynthesis in women eligible
for or subjected to Breast Conserving Treatment for invasive breast
cancer
C. Ferranti
2014
Observational
528
453
109/14
Prediagnostic Concentrations of RANKL and Osteoprotegerin and Risk
of Breast Cancer
V. Krogh
2014
Observational
437
0
116/14
A randomized, phase II, multicenter, placebo-controlled study of
ipatasertib (GDC-0068), an inhibitor of AKT, in combination with
paclitaxel as front-line treatment for patients with metastatic triplenegative breast cancer
F. De Braud
2015
II
3
3
128/14
Cardiac Oncology Toxicity in Breast Cancer (ESC-COT) EACVIC-HFA Pilot
Registry
P. Piotti
2015
Observational
1
1
144/14
Role of extracellular matrix components in progression of breast
cancer
E. Tagliabue
2015
Observational
100
100
153/14
A randomized trial comparing maintenance Aromatase Inhibitors (AIs)
+ everolimus (Afinitor) vs. AIs in patients with HR+ metastatic breast
cancer with disease control after first line chemotherapy
G. Mariani
2015
III
4
4
173/14
A phase II randomized, double-blind study of neoadjuvant letrozole
plus GDC-0032 versus letrozole plus placebo in postmenopausal
women with er-positive/her2-negative, early stage breast cancer
S. Di Cosimo
2015
II
3
3
196/14
Institutional clinical registry for breast cancer
M. Sant
2015
Observational
1.291
1.291
201/14
Identification of molecular markers predictive for trastuzumab benefit
E. Tagliabue
2015
Observational
50
50
203/14
Study of the role of adipocytes in the development and progression of
breast cancer
T. Triulzi
2015
Observational
10
10
25/15
Meaning of local recurrence after conservative treatment for breast
cancer
M. Gennaro
2015
Observational
4.543
4.543
30/15
A phase II, randomized, open-label, two-arm study to assess the
efficacy and safety of the epigenetic modifying effects of CC-486
(oral azacitidine) in combination with fulvestrant in postmenopausal
women with ER+, HER2- metastatic breast cancer who have
progressed on an aromatase inhibitor
G. V. Bianchi
2015
II
3
3
52/15
Prognostic and predictive role of tumor-infiltrating lymphocytes in
luminal B subtype breast cancer patients treated with neoadjuvant
chemotherapy
G. V. Bianchi
2015
Observational
39
39
Study
Code
Title
Coordinator
Activated
29/14
PERtuzumab-trastuzumab plus lEtrozoLe In endocrine Sensitive
breast cancer: a phase II neoAdjuvant study – PER ELISA
G. V. Bianchi
30/14
Use of laser scanner volumeter in breast cancer upper arm
lymphedema
43/14
Closed
31/12/15
31/12/15
31/12/15
257
Study
Code
Phase
Total
patients
Patients
enrolled
in 2015
2015
II
5
5
E. Tagliabue
2015
Observational
55
55
1-stage implant-based versus 2-stage expander-based reconstruction
of the breast
E. Riggio
2015
Observational
249
249
A randomized double-blind, placebo-controlled study of Ribociclib in
combination with Fulvestrant for the treatment of postmenopausal
women with hormone receptor positive, her2-negative, advanced
breast cancer who have received no or only one line of prior endocrine
treatment
G. V. Bianchi
2015
III
5
5
Title
Coordinator
Activated
61/15
A randomized, multicenter, open-label, phase II trial to evaluate the
efficacy and safety of palbociclib in combination with fulvestrant or
letrozole in patients with HER2 negative, ER+ metastatic breast cancer
(PARSIFAL 1)
S. Di Cosimo
66/15
Identification of circulating markers for early diagnosis of breast
carcinoma
67/15
108/15
Closed
GASTROINTESTINAL CANCERS
17/04
A phase II, open label study of PTK787/ZK222584 in the treatment
of metastatic Gastrointestinal Stromal Tumors (GISTs) resistant to
imatinib mesylate
P. Casali
2005
II
9
Closed
accrual
11/05
Localized, completely resected, gastointestinal stromal tumors (GIST)
expressing KIT receptor: a controlled randomized trial on adjuvant
Imatini mesylate (Glivec) versus no further therapy after complete
surgery
P. G. Casali
2005
III
36
Closed
accrual
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
22/07/15
II
34
Closed
accrual
01/09
Open label extension study of lanreotide autogel 120 mg in patients
with non functioning entero-pancreatic endocrine tumour
R. Buzzoni
2009
04/12/15
III
1
Closed
accrual
79/09
Observational study of plasma levels of Imatinib in patients with
gastrointestinal stromal tumor
P. Casali
2010
Observational
85
0
80/09
Controlled extension of conventional criteria for liver tranplantation in
hepatocellular carcinoma (HCC): a prospective validation study
V. Mazzaferro
2009
II
35
0
80/10
A randomized, double-blind, placebo-controlled phase III of
regorafenib plus best supportive care versus placebo plus best
supportive care for subjects with metastatic and/or unresectable
gastrointestinal stromal tumors (GIST) whose disease has progressed
despite prior treatment with at least imatinib and sunitinib
P. Casali
2011
III
10
Closed
accrual
100/11
A randomized, open-label, multicenter phase IIIb study comparing two
trastuzumab dosing regimens, each in combination with cisplatin/
capecitabine chemotherapy, as first-line therapy in patients with
HER 2-positive metastatic gastric or gastro-esophageal junction
adenocarcinoma who have not received prior treatment for metastatic
disease
III
8
1
06/12
Efficacy of tandem treatment with [90Y-DOTA, Tyr(3)] Octreotate and
[177LuDOTA, Tyr(3)] Octreotate in patients with neuroendocrine tumour
overexpressing somatostatin receptors and refractory to conventional
therapy
E. Seregni
2012
II
102
25
15/12
Pseudomixoma peritonei: prognostic analysis of micro-RNA and other
factors using tissue
M. Deraco
2012
Observational
63
17
16/12
Multicenter Italian study on the CEUS assessment of Response of
colorectal cancer metastasis Treated with Avastin
R. Lanocita
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
38
8
258
25/08/15
Study
Code
Patients
enrolled
in 2015
Title
Coordinator
Activated
Closed
Phase
Total
patients
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
29/09/15
III
15
Closed
Accrual
77/12
A Non-Interventional Follow-Up to the VELOUR study (multicentre
international study of aflibercept versus placebo in combination with
FOLFIRI for metastatic colorectal cancer) – Translational Research
Observational
13
0
97/12
A randomized, phase III, multicenter, double-blid, placebo-controlled
study evaluating the efficacy and safety of onartuzumab (MetMab)
in combination with metastatic HER2 negative, MET-Positive
Gastriesophageal cancer
Maria Di
Bartolomeo
2012
27/02/15
III
18
Closed
accrual
102/12
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
26/06/15
II
6
Closed
accrual
107/12
Randomized, couble-blind, phase 3 study of TAS-102 plus best
supportive care (BSC) versus placebo plus BSC in patients with
metastatic colorectal cancer refractory to standard chemotherapies
14/05/15
III
7
Closed
accrual
117/12
Identification of circulating biomarkers of resistance to antiangiogenic
treatment in patients with advanced colorectal cancer and
assessment of their modification during therapy with antiangiogenic
drugs (bevacizumab, aflibercept and regorafenib)
F. de Braud
Observational
103
19
129/12
A randomized phase III study of low-docetaxel oxaliplatin,
capecitabine (low-tox) vs epirubicin, oxaliplatin and capecitabine
(EOX) in patients with locally advanced unresectable or metastatic
gastric cancer
III
5
0
03/13
Identification of Genetic Circulating Biomarkers for the Early Diagnosis
of Colorectal Cancer
M. A. Pierotti
2013
Observational
612
374
07/13
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
28
15
20/13
Retrospective observational study on the use of off-label
temozolomide in patients with metastatic colorectal cancer with
methylation of the MGMT gene
Observational
53
0
35/13
Prospective randomized phase II trial comparing mandatory secondlook 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
-
9
4
36/13
Identification of Genetic Circulating Biomarkers for monitoring and
early detection of recurrence in surgically treated colorectal Cancer
patients
M. Gariboldi
2013
Observational
233
99
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
29
9
79/13
A multicenter, stratified, open, randomized, comparator-controlled,
parallelgroup phase III study comparing treatment with 177LuDOTA0-Tyr3-Octreotate to Octreotide LAR in patients with inoperable,
progressive, somatostatin receptor positive midgut carcinoid tumours
E. Seregni
2013
III
7
0
87/13
Retrospective-prospective observational study on the natural history
of brain metastases from colorectal cancer
F. De Braud
2013
Observational
39
Closed
accrual
105/13
Cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy (HIPEC) versus systemic chemotherapy in the
treatment of peritoneal carcinomatosis of colorectal origin. An open
multicentric randomized clinical trial
D. Baratti
2014
II
6
4
110/13
IL-6-related inflammation signatures as a predictive marker of
recurrence in liver cancer patients
V. Mazzaferro
2013
Observational
210
158
116/13
A prospective randomized clinical trial on 90Yttrium trans-arterial
radio-Embolization (TheraSphere®) vs. Standard of care (sorafenib)
for the Thrombosis (PVT)
V. Mazzaferro
2014
III
16
7
2012
02/11/15
259
Phase
Total
patients
Patients
enrolled
in 2015
2014
II
5
1
2013
Observational
52
15
23/03/15
I-II
2
Closed
accrual
15/04/15
III
7
1
2013
Observational
43
Closed
accrual
2014
Observational
8
5
II
38
1
Observational
20
0
2014
Observational
25
12
F. De Braud
2014
II
15
8
The role of early systematic best palliative care versus on request
palliative care consultation during standard oncologic treatment for
patients with advanced gastric or pancreatic cancers: a randomized,
controlled, multicenter trial
A. T. Caraceni
2014
-
4
1
82/14
"BIOGIST” Study: genomic analysis in gastrointestinal stromal tumors
(GIST)
P. Casali
2014
Observational
10
0
101/14
The role of the natural fluorescence spectroscopy of human blood
plasma for colorectal cancer management: study of the correlation
between fluorescence intensity and disease clinical evolution and
qualitative identification of fluorescence responsible agents
E. Leo
2014
Observational
52
32
102/14
Observational study on perioperative management with COI regimen
(Capecitabine plus Oxaliplatin and Irinotecan) in patients with gastric
or gastroesophageal locally advanced and technically resectable
cancer
Observational
7
0
112/14
An open-label, randomized, multicenter, phase II trial designed to
compare the efficacy of CAPTEM combination versus FOLFIRI as
second line treatment in patients who have progressed on or after
first-line oxaliplatin-containing chemotherapy for advanced, MGMT
methylated, RAS mutated colorectal cancer
F. De Braud
II
17
16
118/14
Identification and Characterization of Molecular and Clinical Profiles,
and Outcomes in Subjects With MET-Amplified Cancers
Observational
12
11
123/14
Activation of the druggable pathways in gastric carcinomas and
clinical outcomes of metastatic patients treated with trastuzumab
Observational
1
0
134/14
A prospective, single-arm, multicenter, uncontrolled, open-label Phase
II trial of refametinib (BAY 86-9766) in combination with sorafenib
as first line treatment in patients with RAS mutant Hepatocellular
Carcinoma (HCC)
V. Mazzaferro
II
9
8
Study
Code
Title
Coordinator
Activated
122/13
A Phase II study on Trabectedin in advanced retroperitoneal
leiomyosarcoma and well differentiated/dedifferentiated liposarcoma
– TRAVELL Study
P. Casali
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
137/13
A Single-Arm, Open Label Study of Aflibercept as Maintenance Therapy
Following Induction with Aflibercept in Combination with XELOX, as
First-Line Treatment for Metastatic Colorectal Cancer Patient
155/13
A Randomized, Double-blind, Placebo-controlled Phase-III Study
of Adjuvant Regorafenib Versus Placebo for Patients with Stage IV
Colorectal Cancer After Curative Treatment of Liver Metastases
V. Mazzaferro
2014
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
184/13
Colorectal Cancer Control : Embracing the complexity, going back to
basics
M. Gariboldi
02/14
A multicenter, phase II, single arm, two cohort study evaluating
the efficacy, safety, and pharmacokinetics of AMG 337 in subjects
with MET amplified gastric/gastroesophageal junction/esophageal
adenocarcinoma or other MET amplified solid tumors
14/14
Retrospective/Prospective observational study on the use of off-label
FOLFOX-4 in patients with peritoneal pseudomyxoma relapsed and/
or inoperable
F. De Braud
2014
37/14
Use of donors with encephalic lesions and positive for hepatitis B
surface antigen or hepatitis B core antibodies or anti-HCV antibodies
according to national guidelines: improvement of organ sharing
policies through a collection and analysis of organs’ and patients’
survival results in the short, medium and long term period –
transplant research program according to the provisions of the
Regional Committee Resolution n IX/1301 dated 9.02.2011
V. Mazzaferro
45/14
Activity and safety of Everolimus in combination with Octreotide
LAR and Metformin in patients with advanced pancreatic welldifferentiated Neuroendocrine Tumors (pWDNETs): a Phase II, open,
monocentric, prospective study
50/14
260
Closed
31/12/15
2014
2014
27/04/15
27/04/15
Phase
Total
patients
Patients
enrolled
in 2015
2014
Observational
156
56
V. Krogh
2015
Observational
37
37
A phase Ib/II multi-center, open label, dose escalation study of
WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant
KRAS wild-type metastatic colorectal cancer harboring Wnt pathway
mutations
F. De Braud
2015
I-II
2
2
176/14
Probe-based Confocal Laser Endomicroscopy (pCLE) in the
clinical management of ampullary lesion of patients with Familial
Adenomatous Polyposis
E. Masci
2015
Observational
6
6
177/14
Detection of circulating tumor cells and ct DNA blood levels in patients
with advanced intra- and extra-hepatic cholangiocarcinoma and
evaluation of their changes during treatment
L. Celio
2014
Observational
16
15
192/14
Optimized Response Assessment of Gastrointestinal Stromal Tumors
Using Dual-Energy CT: Prospective Multicenter-Multinational Trial in
Patients Undergoing Targeted Therapy with a TKI Inhibitor
P. G. Casali
2015
-
1
1
198/14
Identification and characterization of circulating DNA in the blood
of patients with advanced colorectal cancer and assessment of
its changes during treatment with cetuximab or panitumumab,
associated or not with chemotherapy
F. De Braud
2015
Observational
11
11
02/15
A Single-Arm Phase II Study of Tivantinib (ARQ 197) plus Cetuximab in
EGFR inhibitor-Resistant MET High Subjects with Locally Advanced or
Metastatic Colorectal Cancer with Wild-Type KRAS
F. De Braud
2015
II
6
6
20/15
Incidence and risk factors of venous thromboembolism in patients
with hepatocellular carcinoma (HCC) before and after liver
transplantation
V. Mazzaferro
2015
Observational
345
345
26/15
Follow-up to the AVANT study up to 8 and 10 years (median follow-up)
in patients with colon carcinoma
R. Buzzoni
2015
Observational
34
34
51/15
Italian Registry of minimally invasive liver resections within the
IGoMILS Association (Italian Group of Minimally Invasive Liver Surgery)
V. Mazzaferro
2015
Observational
19
19
54/15
A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre
Study of Maintenance Olaparib Monotherapy in Patients with gBRCA
Mutated Metastatic Pancreatic Cancer whose Disease Has Not
Progressed on First Line Platinum Based Chemotherapy
L. Celio
2015
III
2
2
59/15
Randomized, multi-center, open-label trial of pembrolizumab
(MK-3475) versus paclitaxel in subjects with advanced gastric
or gastroesophageal junction (GEJ) adenocarcinoma who have
progressed after failure of any combination chemotherapy containing
a platinum and a fluoropyrimidine agent
III
12
12
70/15
First-line FOLFOX-4 plus panitumumab folowed by 5-FU/LV plus
panitumumab or single-agent panitumumab as maintenance therapy
in patients with RAS wild-type, metastatic colorectal cancer: the
VALENTINO study
F. De Braud
2015
II
10
10
74/15
First-line FOLFOXIRI plus bevacizumab followed by reintroduction
of FOLFOXIRI plus bevacizumab at progression versus FOLFOX plus
bevacizumab followed by FOLFIRI plus bevacizumab at progression in
first- and second-line treatment of unresectable metastatic colorectal
cancer . The tribe-2 phase III study
F. De Braud
2015
III
7
7
85/15
Evaluation of glycaemic status and hypoglycemic drugs such as
metformin, insulin and incretin impact on clinical outcome of advanced
pancreatic neuroendocrine tumors patients treated with everolimus
and / or somatostatin analogues. A retrospective, observational,
multicenter, Italian study
F. De Braud
2015
31/12/15
Observational
124
124
104/15
Differential expression of plasma-based microRNAs and pancreatic
cancer risk in EPIC
V. Krogh
2015
31/12/15
Observational
40
40
106/15
A Phase I/II Study of ARQ 087 in Adult Subjects with Advanced
Solid Tumors with FGFR Genetic Alterations, Including Intrahepatic
Cholangiocarcinoma with FGFR2 Gene Fusion
V. Mazzaferro
2015
I-II
1
1
Study
Code
Title
Coordinator
Activated
136/14
Retrospective and prospective observational study on the natural
history of metastatic colorectal cancer, refractory to chemotherapy
F. De Braud
164/14
Blood concentrations of persistent organic pollutants and pancreatic
cancer risk within the European Prospective Investigation into Cancer
and Nutrition (EPIC) cohort
168/14
Closed
31/10/15
261
Study
Code
Phase
Total
patients
Patients
enrolled
in 2015
2014
Observational
175
0
F. De Braud
2015
Observational
62
62
Laser Endomicroscopy Of PAncReatic asymptomatic cyst Disease.
Diagnostic accuracy of confocal endomicroscopy in indeterminate
pancreatic cysts
E. Masci
2015
Observational
1
1
Accuracy of endoscopic resection of 5-20 mm non-polypoid lesions
with and without Narrow-Band Imaging (NBI): a multicenter
prospective study
E. Masci
2015
Observational
1
1
Title
Coordinator
Activated
107/14
Metabolomic profiling and colorectal cancer risk in the European
Prospective Investigation into Cancer and Nutrition (EPIC) study
V. Krogh
117/15
Explorative Evaluation of new potential prognostic factor in patient
with gastrointestinal cancer
154/15
156/15
Closed
GENITAL APPARATUS
46/07
Prostate cancer research international: active surveillance (PRIAS)
R. Valdagni
2007
Observational
480
68
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
Observational
29
7
10/09
Carboplatin and Paclitaxel administered every three weeks vs
Carboplatin and Paclitaxel administered weekly to patients with ovary
carcinoma: multicentric randomized study
F. Raspagliesi
2009
III
39
Closed
accrual
65/09
LION - Lymphadenectomy in ovarian neoplasm. An open randomized
prospective multicenter trial. A project of the AGO Study Group
F. Raspagliesi
2010
-
32
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
38/10
Tandem transplantation of autologous hematopoietic progenitors in
relapsed/refractory patients with metastatic germinal tumors
R. Salvioni
2010
II
62
15
50/10
Multicentric observational study DUE-01: urinary and erectile
dysfunction after radical external beam therapy in localized prostate
cancer
S. Villa
2010
Observational
174
Closed
accrual
03/11
A phase III, randomized, double-blind trial of weekly paclitaxel plus
AMG386 or placebo in women with recurrent partially platinum
sensitive or resistant epithelial ovarian, primary peritoneal or fallopian
tube cancers
F. Raspagliesi
2011
III
12
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
221
10
61/11
Randomized multicentric study comparing the efficacy of additional
cytoreductive surgery vs exclusive chemotherapy in patients with
platinum-sensitive recurrent ovarian cancer
F. Raspagliesi
2011
IV
7
Closed
accrual
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
95/11
Active surveillance “SA INT” in prostate cancer patients with low
progression risk
R. Valdagni
2011
Observational
99
43
105/11
A randomized controlled study on the effectiveness of first-line
chemotherapy (carboplatin and paclitaxel) versus chemoimmunotherapy (carboplatin-paclitaxel-oregovomab) in patients with
advanced epithelial ovarian, adnexal or peritoneal carcinoma
F. Raspagliesi
2011
II
11
Closed
accrual
106/11
A randomized phase II study of carboplatin and paclitaxel +/cetuximab, in advanced and/or recurrent cervical cancer
F. Raspagliesi
2011
II
13
Closed
accrual
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
III
14
1
108/11
Randomized multicentric phase II study with weekly pazopanib plus
taxolo versus weekly taxolo alone in platinum-resistant or refractory
ovarian carcinoma
D. Lorusso
2011
II
16
Closed
accrual
262
02/12/15
Study
Code
Patients
enrolled
in 2015
Phase
Total
patients
2012
III
11
Closed
accrual
F. Raspagliesi
2012
II
26
Closed
accrual
Phase II study of trabectedin (Yondelis) in BRCA1 e BRCA2 mutation
carrier and BRCA ness phenotype advanced ovarian cancer patients
F. Raspagliesi
2012
II
18
Closed
accrual
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
33
Closed
accrual
68/12
Rare tumors in gynecologic oncology: retrospective and prospective
collection data on diagnosis and treatment of rare gynecologic
neoplasia
D. Lorusso
2012
Observational
390
30
70/12
Evaluation of the geriatric care needs and pathways after initial
treatment in elderly patients with urogenital cancer (prostate, kidney,
bladder and penis)
R. Valdagni
2012
Observational
110
Closed
accrual
110/12
Phase II study of the Pan-HER inhibitor Dacomitinib (PF-00299804) for
patients with locally advanced or metastatic squamous cell carcinoma
of the penis
A. Necchi
2013
II
16
5
123/12
Phase II study of single-agent Pazopanib (Votrient®) for patients with
relapsed or refractory germ-cell tumors (GCT)
A. Necchi
2013
II
39
12
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
60
Closed
accrual
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
Brentuximab vedotin (SGN-35) as salvage therapy for males with
advanced and platinum-resistant germ-cell tumors. An open label,
single group, phase II trial
A. Necchi
2013
II
9
3
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
-
9
3
53/13
Non-invasive diagnosis of prostate cancer using urine samples –
Feasibility study
C. Marenghi
2014
Observational
36
14
72/13
Predictive models of genito-urinary toxicity and erectile dysfunction
after external high dose radiotherapy for prostate cancer
R. Valdagni
2015
-
11
11
74/13
A multicenter phase II randomized study with second line
chemotherapy plus or minus bevacizumab in patients with platinum
sensitive epithelial ovarian cancer recurrence after a bevacizumab/
chemotherapy first line
D. Lorusso
2014
III
37
30
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
38
16
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
11
Closed
accrual
125/13
A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre
Study of Olaparib Maintenance Monotherapy in Patients with BRCA
Mutated Advanced (FIGO Stage III-IV) Ovarian Cancer following First
Line Platinum Based Chemotherapy
F. Raspagliesi
2014
III
11
Closed
accrual
Title
Coordinator
Activated
02/12
A phase III randomized, double-blind, placebo-controlled, multicenter 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
F. Raspagliesi
18/12
A randomized phase II trial of carboplatin-paclitaxel compared to
carbplatin-paclitaxel-bevacizumab in advanced (stage III-IV) or
recurrent endometrial cancer
20/12
Closed
31/12/15
03/12/15
263
Phase
Total
patients
Patients
enrolled
in 2015
2014
Observational
26
8
D. Lorusso
2014
III
20
15
A randomized Phase III, factorial design, of cabazitaxel and pelvic
radiotherapy in patients with localized prostate cancer and high-risk
features of relapse
R. Valdagni
2014
III
1
0
03/14
Open label, randomized, pilot study on the activity of olanzapine
with or without delayed dexamenthasone versus dexamenthasone
alone for the prevention of delayed nausea and vomiting in patients
with gynecologic cancers receiving carboplatin and paclitaxel-based
chemotherapy and guidline-directed prophylactic anti-emetics
L. Celio
2014
IV
85
9
05/14
A multinational, phase 3, randomized, double-blind, placebocontrolled, efficacy and safety study of enzalutamide in patients with
nonmetastatic castration-resitant prostate cancer
G. Procopio
2014
III
11
6
10/14
The MILO study (MEK inhibitor in low-grade serous ovarian cancer:
A multinational, randomized, open-label phase 3 study of MEK162
vs. physician's choice chemotherapy in patients with recurrent or
persistent low-grade serous carcinomas of the ovary, fallopian tube
orprimary peritoneum
F. Raspagliesi
2015
III
1
1
12/14
A multicenter, randomized, doubli-blind, placebo-controlled phase 3
study of rucaparib as switch maintenance following platinum-based
chemotherapy in patients with platinum sensitive, high-grade serous
or endometrial ephitelial ovarian, primary peritoneal or fallopian tube
cancer
D. Lorusso
2014
III
31
16
16/14
What do primary and recurrent ovarian caner (OC) patients expect
from maintenance therapy? (EXPRESSION IV OVAR STUDY)
D. Lorusso
2014
Observational
52
16
18/14
Hematopoietic stem cell collection and engraftment results in patients
with germ cell tumours (GCT) who are candidates to myeloablative
chemotherapy: a retrospective analysis from the Solid Tumours
Working Party of the European Blood and Marrow Transplantation
A. Necchi
2014
Observational
106
0
32/14
A Prospective, Longitudinal, Multinational, Observational Study to
Describe Patterns of Care and Outcomes of Men who are at High Risk
for Poor Clinical Outcomes after Experiencing Biochemical Failure
Following Definitive Prostate Cancer Therapy, Men with CastrationResistant Prostate Cancer and Men with Metastatic Prostate Cancer at
Initial Diagnosis Sponsored
G. Procopio
2014
Observational
47
36
56/14
Disease recurrence in epithelial ovarian cancer: deciphering
miRNAdriven regulatory networks related to drug sensitivity/cellular
plasticity and exploring nanomaterial-based targeted delivery of
identified key molecules for therapeutic purposes
D. Mezzanzanica 2015
Observational
43
43
67/14
Multicenter prospective observational study of intestinal,
haematological and urinary toxicity from irradiation of the pelvic
lymph node (IHU WPRT TOX) in prostate cancer
R. Valdagni
2014
Observational
13
11
68/14
A phase III randomized, double-blind, placebo-controlled trial of
radium-223 dichloride in combination with abiraterone acetate and
prednisone/prednisolone in the treatment of asymptomatic or mildly
symptomatic chemotherapy-naïve subjects with bone predominant
metastatic castration-resistant prostate cancer (CRPC)
G. Procopio
2014
III
6
0
73/14
Multicenter, randomized trial of carboplatin +/- paclitaxel in
vulnerable elderly patients with stage III-IV advanced ovarian cancer
D. Lorusso
2015
II
3
3
77/14
A multicentre study to examine the short and long term outcomes of
the conservative management of benign-looking adnexal masses and
the pre-operative characterisation of ovarian tumours
F. Raspagliesi
2014
Observational
245
153
105/14
Chlamydia trachomatis and other infections and risk of ovarian cancer
V. Krogh
2014
Observational
46
0
106/14
Serum amino acids and other metabolites in relation to prostate
cancer risk in a case-control study nested within the EPIC study
V. Krogh
2014
Observational
103
0
108/14
Pilot Study of Metabolomic Profiles and Epithelial Ovarian Cancer Risk
(1355GCC)
V. Krogh
2014
Observational
50
0
138/14
International endometrial tumor analysis (IETA): an observational noninterventional academic multicentre study on the ultrasound features
of the endometrium
F. Raspagliesi
2014
Observational
34
28
Study
Code
Title
Coordinator
Activated
128/13
RUAB2012-11: A retrospective study for the identification of predictive
and prognostic biological factors in penile squamous cell carcinoma
A. Necchi
140/13
A phase 3 randomized double-blind trial of maintenance with niraparib
versus placebo in patients with platinum sensitive ovarian cancer
157/13
264
Closed
21/04/15
01/03/15
Phase
Total
patients
Patients
enrolled
in 2015
Observational
24
24
Observational
275
254
2015
Observational
468
468
G. Procopio
2015
III
26
26
REASSURE - Radium-223 alpha Emitter Agent in Safety Study in
mCRPC popUlation for long-teRm Evaluation
R. Valdagni
2015
Observational
4
4
208/14
Dissecting the role of microRNAs in the radiation response of human
prostate cancer
N. Zaffaroni
2015
Observational
40
40
06/15
Clinical outcome assessment and identification of risk factors for
disease progression of patients with penile squamous cell carcinoma
and ascertained pelvic node metastases
N. Nicolai
2015
Observational
53
53
35/15
"A Phase III, Open Label, Randomised, Controlled, Multi-centre Study
to assess the efficacy and safety of Olaparib Monotherapy versus
Physician's Choice Single Agent Chemotherapy in the Treatment of
Platinum Sensitive Relapsed Ovarian Cancer in Patients carrying
germline BRCA1/2 Mutations”
F. Raspagliesi
2015
III
2
2
48/15
Analysis of the prognostic value of body mass index in patients
diagnosed with hormone refractory prostate cancer receiving
chemotherapy: retrospective observational study
G. Procopio
2015
Observational
28
28
49/15
Correlation between genotype, phenotype and clinical outcome in
BRCA mutated ovarian cancer: retrospective study
D. Lorusso
2015
Observational
72
72
50/15
Observational retrospective study on therapy and clinical outcome in
low grade serous ovarian cancer: MITO 22 trial
D. Lorusso
2015
Observational
48
48
53/15
“GYNADART” Adaptive, MRI- guided brachytherapy in definitive
treatment of locally advanced cervical carcinoma, according to the
international recommendations: feasibility in daily practice, dosimetric
and clinical outcome
A. Cerrotta
2015
Observational
16
16
77/15
A multicentre open-label single-arm phase II study evaluating the
safety and efficacy of bevacizumab in combination with carboplatin
and paclitaxel in patients with metastatic, recurrent or persistent
cervical cancer
D. Lorusso
2015
II
8
8
86/15
A Phase 2, Two-arm Multicenter, Open-Label Study to Determine the
Efficacy and the Safety of Two Different Dose Regimens of a pan-FGFR
Tyrosine Kinase Inhibitor JNJ-42756493 in Subjects with Metastatic
or Surgically Unresectable Urothelial Cancer with FGFR Genomic
Alterations
A. Necchi
2015
II
1
1
95/15
Phase III Randomized Clinical Trial of Lurbinectedin (PM01183) versus
Pegylated Liposomal Doxorubicin or Topotecan in Patients with
Platinumresistant Ovarian Cancer (CORAIL Trial)
D. Lorusso
2015
III
8
8
Study
Code
Title
Coordinator
Activated
161/14
Pros-IT CNR: Progetto per il monitoraggio dei Tumori della Prostata in
Italia
R. Valdagni
2015
178/14
Evaluation of the role of parametrial state in adjuvant treatment of
patients with locally advanced cervical cancer after neoadjuvante
chemotherapy and surgery
F. Raspagliesi
2014
184/14
Project Plan Movember GAP3 Active Surveillance
R. Valdagni
186/14
A Randomized, Double-Blind, Placebo-Controlled, Phase IIIb Study of
the Efficacy and Safety of Continuing Enzalutamide in Chemotherapy
Naïve Metastatic Castration Resistant Prostate Cancer Patients
Treated with Docetaxel plus Prednisolone Who Have Progressed on
Enzalutamide Alone
193/14
Closed
28/02/15
15/05/15
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
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
12
1
65/10
A double-blind, randomized phase III study evalutating the efficacy
and safety of Sorafenib compared to placebo in locally advanced/
metastatic RAI-refractory differentiated thyroid cancer
L. Licitra
2011
III
5
Closed
accrual
14/12/15
265
Phase
Total
patients
Patients
enrolled
in 2015
2012
II
36
15
L. Licitra
2011
II
34
Closed
accrual
A randomised, double-blind, placebo-controlled, phase III study to
evaluate the efficacy and safety 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
L. Licitra
2011
III
3
0
68/11
A randomised, open-label, phase III study to 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
L. Licitra
2011
25/02/15
III
24
Closed
accrual
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
27/01/15
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
10
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
76/12
Neoadjuvant afatinib based treatment strategies followed by surgery
in squamous cell carcinoma of the head and neck: an EORTC NOCIHNCG window study
L. Licitra
2012
II
15
3
28/13
Multidisciplinary approach for poor prognosis sinonasal tumors: phase
II study of chemotherapy, surgery, photon and heavy ion radiotherapy
integration for more effective and less toxic treatment in operable
patients
L. Licitra
2014
II
8
6
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
10
3
69/13
INduction chemoThERapy followed by CEtuximab Plus definiTive
radiOtheRapy versus radiation plus cisplatin
L. Licitra
2013
III
10
6
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
2013
III
10
Closed
accrual
95/13
A phase II study exploring the safety and efficacy of nintedanib
(BIBF1120) as second line therapy for patients with either
differentiated or medullary thyroid cancer progressing after first line
therapy
L. Licitra
2014
II
7
2
121/13
Phase II multicenter randomized, double blind, 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
L. Licitra
2013
II
10
3
178/13
Molecular Profile of metastatic sporadic medullary thyroid cancer
(sMTC) patients and possible correlation with vendetanib therapy
L. Locati
2014
Observational
26
0
187/13
Identification of a molecular predictor of response to Cetuximab based
on a phase II trial in recurrent/metastatic HNSCC
S. Canevari
2014
Observational
98
50
48/14
Health and economic outcomes of two different follow up strategies in
effectively cured advanced head and neck cancer
L. Licitra
2014
-
16
9
52/14
Preventive treatment with MDD001 a medical device to reduce
radiation induced dermatitis in head and neck cancer patients
receiving curative treatment
E. Orlandi
2015
-
41
41
Study
Code
Title
Coordinator
Activated
35/11
Cetuximab and Cisplatin with or without Paclitaxel in recurrent/
metastatic head and neck cancer
L. Licitra
45/11
A single arm, open-label, phase II, multicentre study, to assess the
safety of vismodegib (GDC-0449) in patients with locally advanced or
metastatic basal cell carcinoma
57/11
266
Closed
Phase
Total
patients
Patients
enrolled
in 2015
2015
Observational
25
25
L. Licitra
2014
III
23
15
Phase II trial of abiraterone acetate in patients with relapsed and/or
metastatic, castration resistant, salivary gland cancers
L. Licitra
2015
II
6
6
92/14
Efficacy and safety of single agent pan-HER inhibitor Dacomitinib
in the treatment of locally advanced unresectable or metastatic
squamous cell cancer of the skin or with clinical contraindication to
surgery
P. Bossi
2014
II
34
28
135/14
Phase II study on Inlyta® (axitinib) in recurrent and/or metastatic
salivary gland cancers (SGCs) of the upper aerodigestive tract
L. Licitra
2014
II
18
15
137/14
A retrospective observational study on patients treated with
concurrent cetuximab and radiotherapy for locally advanced
Squamous Cell Carcinoma of the Head&Neck
L. Licitra
2014
Observational
15
0
156/14
A Phase III Randomized Trial of MK-3475 (Pembrolizumab) versus
Standard Treatment in Subjects with Recurrent or Metastatic Head and
Neck Cancer
L. Licitra
2015
III
18
18
157/14
A randomized, double-blind, placebo controlled, mono-centre phase
II study to evaluate the efficacy of treatment with ginseng in reducing
fatigue in patients treated for head and neck cancer
P. Bossi
2015
-
5
5
160/14
Prospective Observational Trial to Assess the Impact of Mucositis in
pazietnts treated with targeted therapy in Oncology
P. Bossi
2014
Observational
63
55
163/14
Obesity, inflammation, endogenous hormones and risk of
differentiated thyroid carcinomas in men and women
V. Krogh
2015
Observational
29
29
167/14
A phase II, multicenter, single arm study to assess the safety and
efficacy of single agent CC-486 (oral Azacitidine) in previously
treated subjects with locally advanced or metastatic nasopharyngeal
carcinoma
L. Licitra
2015
II
7
7
15/15
A randomized phase II study to evaluate the efficacy and safety of
chemotherapy (CT) vs androgen deprivation therapy (ADT) in patients
with recurrent and/or metastatic, androgen receptor (AR) expressing,
salivary gland cancer (SGCs)
L. Locati
2015
II
1
1
38/15
Phase II study on Lenvatinib in recurrent and/or metastatic
adenoid cystic carcinomas (ACC) of the salivary glands of the upper
aerodigestive tract
L. Licitra
2015
II
14
14
45/15
Analysis of patients’ preference in post-treatment clinical follow-up
(FU) for head and neck cancer
P. Bossi
2015
30/12/15
Observational
152
152
46/15
Healthcare-associated infections in patients with head and neck
cancer treated with chemotherapy and/or radiotherapy
L. Licitra
2015
30/05/15
Observational
140
140
69/15
Retrospective observational multicenter study for the assessment of
the incidence and the "pattern of care" of bone metastasis in patients
with squamous carcinoma of the head and neck
L. Licitra
2015
29/09/15
Observational
78
78
122/15
Observational retrospective study on dynamic and predictors of
opioids use in the treatment of concurrent chemoradiotherapy
induced oral mucositis in patients with squamous cell carcinoma of
the oropharynx
L. Licitra
2015
31/08/15
Observational
75
75
133/15
A Phase III Randomized, Open-Label, Multi-Center, Global Study
of MEDI4736 Monotherapy and MEDI4736 in Combination with
Tremelimumab Versus Standard of Care Therapy in Patients with
Recurrent or Metastatic Squamous Cell Carcinoma of the Head and
Neck (SCCHN)
L. Licitra
2015
III
3
3
172/15
Serum inflammation markers in relation to esophageal
adenocarcinoma: a pooled analysis within the Cohort Consortium
V. Krogh
2015
Observational
5
5
Study
Code
Title
Coordinator
Activated
55/14
Role of tumor microenvironment in thyroid carcinogenesis onset and
progression: thyroid cells cross-talk with macrophage
A. Greco
61/14
An Open Label, Randomized Phase 3 Clinical Trial of Nivolumab vs
Therapy of Investigator's Choice in Recurrent or Metastatic Platinumrefractory Squamous Cell Carcinoma of the Head and Neck (SCCHN)
71/14
Closed
31/12/15
267
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2015
31/12/15
Observational
23
0
HEMATOLOGIC MALIGNANCIES
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
02/05
A multicenter, open label study of oral melphalan, and CC-5013
(Revlimid) (MPR) as induction therapy in elderly newly diagnosed
multiple mieloma patients
P. Corradini
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
14/06
A phase III, prospective, randomized clinical study with velcadethalidomide-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
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
38/07
A multicentric randomized trial in adult patients with acute
myelogenous leukemia (AML) to compare: 1) a standard-dose versus
high-dose remission induction regimen, and 2) an autologous blood
stem cell transplantation versus an autologous blood cell-supported
multicycle high-dose chemotherapy program,, within a risk-oriented
postremission strategy reserving allogeneic stem cell transplantation
for high-risk cases
P. Corradini
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
28
3
55/07
Treatment with imatinib mesylate (Glivec) of severe
chronic scleroderma-like GVHD, refractory to conventional
immunosuppressive therapy
P. Corradini
2008
II
8
Closed
accrual
02/08
A phase 3, multicentre, randomized, controlled study to determine the
efficacy and safety of lenalidomide, melphalan and prednisone (MPR)
versus melphalan (200 mg/m2) followed by stem cell transplant in
newly diagnosed multiple myeloma subjects
A.M. Gianni, P.
Corradini
2008
III
16
Closed
accrual
44/08
Comparison of Whole Body Diffusion Weighted Magnetic Resonance
Imaging (DW-MRI) with skeletal X-Ray and MRI of the spine for the
assessment of bone disease in Multiple Myeloma (MM)
P. Corradini
2008
Observational
88
20
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
52
Closed
accrual
09/09
Phase III study comparing rituximab-supplemented ABVD (R-ABVD)
with ABVD followed by involved-field radiotherapy (ABVD-RT) in
limited-stage (stage I-IIA with no areas of bulk) Hodgkin's lymphoma
A. M. Gianni, P.
Corradini
2009
III
16
0
13/09
Safety and efficacy of lenalidomide as main therapy in patients with
newly diagnosed multiple myeloma following a tandem autologousallogeneic transplant
P. Corradini
2009
II
1
Closed
accrual
39/09
A phase III intergroup multicentre, randomized, controlled 3
arm parallel group study to determine the efficacy and safety
of lenalidomide in combination with dexamethasone (Rd9
versus melphalan, prednisone and lenalidomide (MPR) versus
cyclophosphamide, prednisone and lenalidomide (CPR) in newly
diagnosed multiple myeloma subjects
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
25/03/15
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
26/06/15
III
12
Closed
accrual
268
01/07/15
Study
Code
Patients
enrolled
in 2015
Title
Coordinator
Activated
Closed
Phase
Total
patients
76/09
Brief induction chemoimmunotherapy with rituximab + bendamustine
+ mitoxantrone followed by rituximab in elderly patients with
advanced stage previously unrtreated follicular lymphoma
P. Corradini
2010
26/01/15
II
4
Closed
accrual
07/10
Monitoring of human polyomavirus reactivation in patients
with lymphoproliferative disease treated with chemotherapy,
chemotherapy and rituximab, and rituximab alone
P. Corradini
2010
Observational
8
0
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
P. Corradini
2010
I-II
11
Closed
accrual
31/10
A randomized, double-blind, placebo-controlled 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)
A. M. Gianni
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
4
Closed
accrual
56/10
A randomized, open label study of Ofatumumab and Bendamustine
combination therapy compared with Bendamustine monotherapy in
indolent B-cell non-Hodgkin's lymphoma unresponsive to Rituximab
or a Rituximab-containing regimen during or within six months of
treatment
P. Corradini
2013
III
2
0
57/10
A phase III trial comparing bertozomib, cyclofosfamide and
dexamethasone versus lenalidomide cyclofosfamide and
dexamethasone in patients with multiple myeloma at first relapse
P. Corradini
2010
III
20
0
83/10
A phase III, double-blind, randomized, placebo-controlled,
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
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
33/11
A phase III, multicenter, open label randomized 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)
P. Corradini
2011
III
15
Closed
accrual
37/11
A multicenter, open label phase II study of carfilzomib,
cyclophosphamide and dexamethasone in newly diagnosed multiple
myeloma patients
P. Corradini
2011
II
2
Closed
accrual
58/11
A phase III, 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 II study evaluating SAR3419,
an anti-CD19 antobody-maytansine 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, multicenter
study to determine safety and efficacy of Nilotinib in a population with
steroid-refractory/or steroid-dependent cGVHD
P. Corradini
2011
I-II
2
0
89/11
A randomized phase III study to compare Bortezomib, melphalan,
prednisone (VMP) with high dose melphalan followed by Bortezomib,
Lenalidomide, Dexamethasone (VRD) consolidation and Lenalidomide
maintenance in patients with newly diagnosed multiple myeloma
P. Corradini
2011
III
25
Closed
accrual
110/11
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
49
0
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 Int-2/High risk myelodysplastic syndromes (MDS)
P. Corradini
2012
II
4
Closed
accrual
16/07/15
31/10/15
269
Phase
Total
patients
Patients
enrolled
in 2015
2013
III
5
2
P. Corradini
2013
II
1
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)
P. Corradini
2013
Observational
4
Closed
accrual
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
2
0
133/12
Chronic Lymphocytic Leukemia (CLL) Registry: a prospective,
observational study within the Rete Ematologica Lombarda
P. Corradini
2013
Observational
45
9
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
P. Corradini
2013
III
47
Closed
accrual
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
P. Corradini
2013
II
4
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
6
0
31/13
A multicenter, open label, study of weekly carfilzomib,
cyclophosphamide and dexamethasone (wCCyd) in newly diagnosed
multiple myeloma (MM) patients
P. Corradini
2013
I-II
13
2
47/13
Phase II randomized study with R-DHAP +/- Bortezomib as induction
therapy in relapsed/refractory Diffuse Large B-cell Lymphoma
(DLBCL) patients before High-Dose chemotherapy BEAM with
autologous stem cell transplantation (ASCT): BR-DHAP + BEAM + ASCT
versus R-DHAP + BEAM + ASCT
P. Corradini
2014
II
5
3
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
Observational
17
7
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
2013
II
6
3
58/13
Chronic Myeloid Leukemia Register - Lombardy Hematologic Network
P. Corradini
2014
Observational
1
0
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
P. Corradini
2013
II
2
0
83/13
A Randomized, Open-label, Phase 3 Trial of A+AVD Versus ABVD
as Frontline Therapy in Patients With Advanced Classical Hodgkin
Lymphoma
S. Viviani
2014
III
9
5
86/13
Identification of possible genetic causes responsible of a familiar form
of Multiple Myeloma
P. Corradini
2013
Observational
4
0
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
8
4
113/13
Role of T memory stem cell in the process of immune reconstitution
following bone marrow transplantation
P. Corradini
2013
Observational
17
1
118/13
An open-label, single-arm, 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
P. Corradini
2014
I-II
4
0
119/13
Prospective REsearch Assessment in Multiple Myeloma: an
OBservationaL Evaluation (PREAMBLE)
P. Corradini
2014
Observational
42
19
Study
Code
Title
Coordinator
Activated
66/12
A phase III multicenter, randomized study comparing consolidation
with 90YTTRIUM-LABELED IBRITUMOMAB TIUXETAN (ZEVALIN®)
radioimmunotherapy vs autologous stem cell transplantation (ASCT)
in patients with relapsed follicular lymphoma (FL) aged 18-65 years
P. Corradini
80/12
Bendamustine, lenalidomide and rituximab (R2-B) combination
as a second-line therapy for first relapsed-refractory mantle cell
lymphomas: a phase II study
112/12
270
Closed
23/02/15
05/05/15
Phase
Total
patients
Patients
enrolled
in 2015
2014
I
10
4
P. Corradini
2014
III
7
Closed
accrual
Phase IIa study on the role of Gemcitabine plus Romidepsin (GEMRO
regimen) in the treatment of relapsed/refractory peripheral T-cell
lymphoma patients
P. Corradini
2014
II
6
Closed
accrual
154/13
A multicenter, phase III, randomized study to evaluate the efficacy of
a response-adapted strategy to define maintenance after standard
chemoimmunotherapy in patients with advanced-stage Follicular
Lymphoma
P. Corradini
2014
III
21
12
156/13
A multicenter, phase III, randomized study to evaluate the efficacy of
a response-adapted strategy to define maintenance after standard
chemoimmunotherapy in patients with advanced-stage Follicular
Lymphoma
A. M. Gianni
2014
III
1
0
21/14
Ofatumumab-Bendamustine for relapsed/refractory indolent
lymphoma: a multicenter phase 2 trial
P. Corradini
2014
III
5
2
36/14
A prospective, multicenter survey of Severe Infections by Gram
Negative Bacteria in patients submitted to autologous and allogeneic
stem cell transplant
P. Corradini
2014
Observational
56
Closed
accrual
41/14
Risk-adapted, MRD-directed therapy for young adults with newly
diagnosed acute myeloid leukemia
P. Corradini
2014
II
3
1
62/14
Single-Arm, Open-Label Phase 2 Study of Nivolumab (BMS-936558) in
Subjects with Relapsed or Refractory Follicular Lymphoma (FL)
P. Corradini
2014
II
2
0
63/14
Single-Arm, Open-Label, Phase 2 Study of Nivolumab (BMS-936558) in
Subjects with Relapsed or Refractory Diffuse Large B-Cell Lymphoma
(DLBCL) After Failure of Autologous Stem Cell Transplant (ASCT)
or After Failure of At Least Two Prior Multi-Agent Chemotherapy
Regimens in Subjects Who Are Not Candidates for ASCT
P. Corradini
2014
II
2
0
72/14
A phase Ib/II, multi-center, study of oral LGH447 in combination with
oral BYL719 in patients with relapsed and refractory multiple myeloma
P. Corradini
2014
I
8
2
74/14
A phase II study of Chlorambucil in combination with subcutaneous
Rituximab followed by maintenance therapy with subcutaneous
Rituximab in patients with extranodal marginal zone B-cell lymphoma
of mucosa associated lymphoid tissue (MALT LYMPHOMA)
L. Devizzi
2015
II
1
1
87/14
Romidepsin in combination with Choep as first line treatment before
hematopoietic stem cell transplantation in young patients with nodal
peripheral T-cell lymphomas: a phase I-II study
P. Corradini
2014
I-II
7
4
95/14
Identification of biological/clinical prognostic factors in patients with
not-transformed Hodgkin Lymphoma
P. Corradini
2014
Observational
13
9
96/14
Retrospective case-control study evaluating the efficacy of autologous
transplantation as first line therapy in Peripheral T-cell Lymphomas
P. Corradini
2014
Observational
6
1
97/14
Prospective data collection of elderly patients (>= 65 years) with
Diffuse Large B-cell Lymphoma (DLBCL) receiving at the time of
diagnosis Multidimensional Geriatric Assessment (VGM)
P. Corradini
2014
Observational
4
1
117/14
Observational study on the effectiveness of Brentuximab Vedotin (BV)
in patients with relapsed or refractory Hodgkin Lymphoma (R/R HL)
considered ineligible for a transplant procedure
S. Viviani
2014
Observational
26
0
124/14
Prevalence study of eye disorders in patients with symptomatic
multiple myeloma
V. Montefusco
2014
Observational
80
16
129/14
Phase III Study Comparing Daratumumab, Bortezomib and
Dexamethasone (DVd) vs Bortezomib and Dexamethasone (Vd) in
Subjects With Relapsed or Refractory Multiple Myeloma
P. Corradini
2015
III
16
16
147/14
A phase III, multicentre, randomized, controlled study to determine
the efficacy and safety of standard schedule versus a new algorithm
of dose reductions in elderly and unfit newly diagnosed multiple
myeloma patients receiving lenalidomide plus steroids
P. Corradini
2015
III
7
7
Study
Code
Title
Coordinator
Activated
134/13
A Phase 1B, Multi-center, Open-label Study of Novel Combinations
of CC-122, CC-223, CC-292 and Rituximab in Diffuse Large B-cell
Lymphoma
P. Corradini
135/13
A single arm, multicentre, phase IIIb study to evaluate safety,
efficacy and pharmacokinetic (PK) of subcutaneous (SC) rituximab
administered during induction phase or maintenance in previously
untreated patients with CD20+ diffuse large B cell lymphoma (DLBCL)
or follicular lymphoma (FL)
142/13
Closed
28/10/15
30/06/15
271
Phase
Total
patients
Patients
enrolled
in 2015
2015
III
4
4
P. Corradini
2015
I-II
2
2
The role of haploidentical hematopoietic stem cell transplantation in
multiple myeloma
V. Montefusco
2015
Observational
4
4
179/14
A Retrospective, Observational study on the prognostic role of the
histological grade in patients with refractory or relapsed Follicular non
Hodgkin Lymphoma undergoing Allogeneic Hematopoietic Stem Cell
Transplantation
P. Corradini
2015
Observational
2
2
180/14
A pilot phase II study with brentuximab vedotin as pre-ASCT induction
therapy in relapsed/refractory Hodgkin’s lymphoma patients non
responding to IGEV salvage treatment
P. Corradini
2015
II
1
1
09/15
Prognostic role of GATA-3 and T-bet in peripheral T-cell lymphomas
P. Corradini
2015
Observational
37
37
39/15
A phase 3, randomized, double-blind study of PF-05280586 versus
rituximab for the first-line treatment of patients with CD20- positive,
low tumor burden, follicular lymphoma
L. Devizzi
2015
III
3
3
40/15
A multicenter, randomized, open label phase II study of carfilzomib,
cyclophosphamide and dexamethasone (CCyd) as pre transplant
induction and post transplant consolidation or carfilzomib,
lenalidomide and dexamethasone (CRd) as pre transplant induction
and post transplant consolidation or continuous treatment with
carfilzomib, lenalidomide and dexamethasone (12 cycles) without
transplant, all followed by maintenance with lenalidomide (R) versus
lenalidomide and carfilzomib (CR) in newly diagnosed Multiple
Myeloma (MM) patients elegible for autologous transplant
P. Corradini
2015
II
7
7
41/15
Prospective, phase II study to evaluate the efficacy and the safety of
a combination of bendamustine-melphalan as preparative regimen
to autologous transplantation of hematopoietic cells for multiple
myeloma who have relapsed after previous high-dose therapy
P. Corradini
2015
II
1
1
43/15
Observational multicentric retrospective Italian study in Hodgkin’s
Lymphoma and Anaplastic Large Cell Limphoma patients who received
SGN35 according to normal clinical practice
P. Corradini
2015
Observational
6
6
44/15
Retrospective study of the prognostic value of MYC/BCL2
coexpression in relapsed/refractory Diffuse large B-cell lymphoma
patients treated with autologous- and/or allogeneic-hematopoietic
stem cell transplantation
P. Corradini
2015
Observational
5
5
63/15
A phase I/II clinical trial to assess safety and efficacy of a new
treatment for Hodgkin lymphoma's disease combining Adcetris® and
Levact® in Old patients
S. Viviani
2015
I-II
3
3
78/15
A randomized phase III multicenter trial assessing efficacy and toxicity
of a combination of Rituximab and Lenalidomide (R2) vs Rituximab
alone as maintenance after chemoimmunotherapy with RituximabBendamustine for relapsed/refractory FL patients not eligible for
autologous transplantation (ASCT)
P. Corradini
2015
III
1
1
80/15
A Phase II Clinical Trial of MK-3475 (Pembrolizumab) in Subjects with
Relapsed or Refractory (R/R) Classical Hodgkin Lymphoma (cHL)
P. Corradini
2015
II
3
3
81/15
A non interventional observational retrospective post authorization
study of relapsed and refractory Multiple Myeloma patients treated
for at least 24 months with Lenalidomide and Dexametasone
V. Montefusco
2015
Observational
18
18
82/15
Quantification of the Time and Effort Required for Peripheral Blood
Stem Cell Collection-The European Perspective
P. Corradini
2015
Observational
38
38
96/15
Observational study of BVD regimen (Bendamustine, Velcade,
Dexamethasone) after AIFA authorization (Law 648, 13/08/2014)
P. Corradini
2015
Observational
2
2
100/15
A retrospective study comparing allogeneic stem cell transplantation
vs novel therapeutic agents in patients with high-risk chronic
lymphocytic leukemia
L. Farina
2015
Observational
20
20
Study
Code
Title
Coordinator
Activated
149/14
Phase III randomized, double-blind, placebo controlled, multicenter
study to compare the efficacy and safety of lenalidomide (CC-5013)
plus R-CHOP chemotherapy (R2-CHOP) versus placebo plus R-CHOP
chemotherapy in subjects with previously untreated activated b-cell
type diffuse large b-cell lymphoma
P. Corradini
150/14
Carfilzomib in combination with bendamustine and dexamethasone
in refractory or relapsed multiple myeloma – A multicenter phase Ib/II
trial of the European Myeloma Network Trialist Group (EMNTG)
159/14
272
Closed
31/12/15
Study
Code
Phase
Total
patients
Patients
enrolled
in 2015
2015
II
2
2
P. Corradini
2015
II
1
1
-
4.099
Closed
accrual
III
5
Closed
accrual
Title
Coordinator
Activated
132/15
A multiarm, open label, randomized phase II study of MLN9708
plus oral Dexamethasone or plus oral Cyclophosphamide and
Dexamethasone or plus Bendamustine and Dexamethasone or plus
oral Thalidomide and Dexamethasone followed by maintenance with
MLN9708 in newly diagnosed elderly multiple myeloma patients
P. Corradini
138/15
A phase II study with bendamustine plus brentuximab vedotin in
Hodgkin’s lymphoma and CD30+ peripheral T-cell lymphoma in first
salvage setting: the BBV regimen
Closed
LUNG CANCER
53/05
Spiral CAT, biomarkers and proteomic analysis, associated to a
program of primary prevention for the early diagnosis of lung cancer:
randomized study in subjects at high risk: project MILD
U. Pastorino
2006
18/07
START - stimulating Targeted Antigenic Responses To NSCLC
M. Platania
2007
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 and etoposide with
or without bevacizumab as first-line treatment in extensive stage (ED)
small cell lung cancer (SCLC)
N. Zilembo
2013
III
4
0
75/09
A randomized, multicenter, open-label phase 3 study of pemetrexedcisplatin chemotherapy plus IMC-11F8 versus pemetrexed-cisplatin
chemotherapy alone in the first-line treatment of patients with non
squamous stage IIIb or IV non-small cell lung cancer (NSCLC)
N. Zilembo
2010
17/12/15
III
9
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
26/02/15
III
5
Closed
accrual
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
2011
II
13
Closed
accrual
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
F. Leo
2011
-
580
0
21/11
BioMILD: a prospective study of efficacy of plasma microRNA as first
line test for early dignosis of lung cancer
U. Pastorino
2013
Observational
4.045
1.982
92/11
Phase III randomized, open-label study of the 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
F. de Braud
2011
III
2
Closed
accrual
48/12
Be-positive: Beyond progression after tki in EGFR positive NSCLC
patients
M. Garassino
2012
Observational
5
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
2013
II
28
5
63/12
Phase II study of oral PHA-848125AC in patients with thymic
carcinoma previously treated with chemotherapy
M. Garassino
2012
II
32
13
98/12
PASS Pleural mesothelioma Strategies Study
U. Pastorino
2014
-
5
2
100/12
An Open-label Randomized Phase III Trial of BMS-936558 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
2013
II
3
Closed
accrual
137/12
An Open-Label Randomized Phase III Trial of BMS-936558 versus
Docetaxel in Previously Treated Metastatic Non-squamous Non-small
cell Lung Cancer (NSCLC)
M. Garassino
2013
III
11
Closed
accrual
01/07/15
31/12/15
23/02/15
273
Phase
Total
patients
Patients
enrolled
in 2015
2014
I
4
3
M. Garassino
2014
Observational
63
19
Phase II study of oral PHA-848125AC in patients with malignant
thymoma previously treated with multiple lines of chemotherapy
Marina
Garassino
2013
II
16
10
45/13
A Phase II study of the selective BRAF kinase inhibitor GSK2118436
in subjects with advanced non-small cell lung cancer and BRAF
mutations
N. Zilembo
2014
II
27
4
61/13
POST-ALK: observational study of treatment and outcome after
crizotinib in advanced ALK-positive NSCLC patients
M. Garassino
2013
Observational
9
0
78/13
An open label trial of afatinib in treatment-naive (1st line) or
chemotherapy pre-treated patients with locally advanced or
metastatic non-small cell lung cancer (NSCLC) harboring EGFR
mutation(s)
N. Zilembo
2014
III
4
Closed
accrual
91/13
LUME Study - Long survivors in pleural mesothelioma
G. Gatta
2014
Observational
2.534
134
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
16
Closed
accrual
138/13
A Phase 2, Randomized, Double-blind Study Comparing Tremelimumab
to Placebo in Second- or Third-line Treatment of Subjects with
Unresectable Pleural or Peritoneal Malignant Mesothelioma
M. Garassino
2014
II
8
Closed
accrual
169/13
Rationale for the use of anti-PD-L1 in patients with malignant pleural
mesothelioma
M. Garassino
2014
Observational
100
0
172/13
A single arm, open-label, phase II study to assess the efficacy of the
dual VEGFR-FGFR tyrosine kinase inhibitor, lucitanib, given orally as a
single agent to patients with FGFR1-driven lung cancer
M. Garassino
2014
II
11
5
19/14
C4d as a novel risk biomarker in the context of CT-screening for lung
cancer
G. Sozzi
2014
Observational
150
Closed
accrual
40/14
Role of germline and somatic DNA changes in modulating the survival
of patients with lung adenocarcinoma
T. A. Dragani
2014
Observational
32
0
42/14
A phase II, multicenter, single-arm study of MPDL3280A in patients
with PD-L1 positive locally advanced or metastatic non small cell lung
cancer
M. Garassino
2014
II
66
Closed
accrual
64/14
Intratumor heterogeneity of lung adenocarcinoma by using next
generation sequencing analysis: a feasibility study
G. Pelosi
2014
31/05/15
Observational
20
Closed
accrual
79/14
Retrospective observational study in patients with dual neoplasia:
breast cancer and lung cancer
M. Garassino
2014
31/12/15
Observational
61
0
89/14
Protective versus conventional ventilation during thoracic surgery
F. Piccioni
2014
-
60
44
91/14
Decurarization After Thoracic Anesthesia - Studio prospettico
multicentrico randomizzato in doppio cieco per confrontare la
gestione del reversal del blocco neuromuscolare con sugammadex e
neostigmina dopo chirurgia toracica
F. Piccioni
2015
IV
8
8
111/14
A Phase II, Non-comparative, Open label, Multi-centre, International
Study of MEDI4736, in Patients with Locally Advanced or Metastatic
Non-Small Cell Lung Cancer (Stage IIIB-IV) who have received at least
Two Prior Systemic Treatment Regimens Including One Platinumbased Chemotherapy Regimen (ATLANTIC)
M. Garassino
2014
II
62
21
131/14
A phase III, randomised, double-blind, placebo-controlled, multicentre, international study. of MEDI4736 as sequential therapy in
patientes with locally advanced, unresectable non-small cell lung
cancer (stage III) who have not progressed following definitive,
platinum-based, concurrent chemoradiation therapy (PACIFIC)
M. Garassino
2015
III
2
2
Study
Code
Title
Coordinator
Activated
13/13
A Phase IB/II, open label, multicenter study of INC280 administered
orally in combination with gefitinib in adult patients with EGFR
mutated, c-MET-amplified non-small cell lung cancer who have
progressed after EGFR inhibitor treatment
F. De Braud
18/13
K-RAS mutations and DNA Repair Function in NSCLC
34/13
274
Closed
31/12/15
12/03/15
Phase
Total
patients
Patients
enrolled
in 2015
III
21
17
15/02/15
Observational
30
Closed
accrual
30/06/15
Observational
80
Closed
accrual
2014
III
15
14
M. Garassino
2015
Observational
100
100
Cancer therapy through TLR-induced local innate immunity activation
and block of immune checkpoints or suppressive cells
A. Balsari
2015
Observational
30
30
19/15
Randomized, multicenter, phase III, open-label study of alectinib
versus crizotinib in treatment-naïve anaplastic lymphoma kinasepositive advanced non-small cell lung cancer
M. Platania
2015
III
5
5
22/15
Observational study to assess the prognostic impact of factors related
to the immune response in non-small cell lung cancer
M. Garassino
2015
Observational
58
58
56/15
A Phase Ill, Open label, Randomised, Multicentre,International
Study of MEDI4736, given as monotherapy or in combination with
tremelimumab determined by PO-L 1 expression, versus Standard
of Care in Patients with Locally Advanced or Metastatic Non-Small
Cell Lung Cancer (Stage 1118-IV) Who Have Received at Least Two
Prior Systemic Treatment Regimens Including One Platinum-based
Chemotherapy Regimen and Do Not Have Known EGFR TK Activating
Mutations or ALK Rearrangements (ARCTIC)
M. Garassino
2015
III
3
3
58/15
A Randomized, Double-Blind Phase 2 Study of Ruxolitinib or Placebo
in Combination With Pemetrexed/Cisplatin and Pemetrexed
Maintenance for Initial Treatment of Subjects With Nonsquamous
Non–Small Cell Lung Cancer That Is Stage IIIB, Stage IV, or Recurrent
M. Platania
2015
II
2
2
90/15
A multi-center, open-label study to assess the safety and efficacy of
combination ceritinib (LDK378) and nivolumab in adult patients with
anaplastic lymphoma kinase (ALK) - positive non-small cell lung
cancer (NSCLC)
F. De Braud
2015
I
6
6
92/15
A phase III, open-label, randomized study of MPDL3280A (anti-PDL1
antibody) compared with cisplatin or carboplatin+pemetrexed for PDL1-selected chemotherapy naive patients with stage IV non-squamous
non-small cell lung cancer
M. Garassino
2015
III
3
3
93/15
A phase III, open-label, randomized study of mpdl3280a (anti-pdl1
antibody) compared with gemcitabine+ cisplatin or carboplatin for
pd-l1-selected, chemotherapy naive patients with stage IV squamous
non-small cell lung cancer
M. Garassino
2015
III
2
2
107/15
A Phase III open-label, multicenter trial of avelumab (MSB0010718C)
versus docetaxel in subjects with non-small cell lung cancer that has
progressed after a platinum-containing doublet
M. Garassino
2015
III
1
1
114/15
A Phase II, multi-center, open-label, five-arm study to evaluate the
efficacy and safety of oral ceritinib treatment for patients with ALKpositive non-small cell lung cancer (NSCLC) metastatic to the brain
and/or to leptomeninges
M. Platania
2015
II
3
3
147/15
Continuity of cAre in Thoracic Tumor
M. Garassino
2015
Observational
300
300
165/15
A Phase III Randomized, Open-Label, Multi-Center, Global Study of
MEDI4736 in Combination with Tremelimumab Therapy or MEDI4736
Monotherapy Versus Standard of Care Platinum-Based Chemotherapy
in First-Line Treatment of Patients with Advanced or Metastatic NonSmall-Cell Lung Cancer (NSCLC) (MYSTIC)
M. Garassino
2015
III
2
2
Study
Code
Title
Coordinator
Activated
132/14
A Phase III, Open Label, Randomized Study of AZD9291 versus
Platinum-Based Doublet Chemotherapy for Patients with Locally
Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease
has Progressed with Previous Epidermal Growth Factor Receptor
Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a
T790M mutation within the Epidermal Growth Factor Receptor Gene
(AURA3)
M. Garassino
2014
145/14
Analysis of next generation sequencing of large cell carcinoma of the
lung: a retrospective observational study
G. Pelosi
2014
162/14
Molecular characterization of sarcomatoid carcinoma, a lifethreatening subtype of lung cancer
G. Pelosi
2014
166/14
A Randomized Open-Label Phase III Trial of pembrolizumab versus
Platinum based Chemotherapy in 1L Subjects with PD-L1 Strong
Metastatic Non-Small Cell Lung Cancer
M. Garassino
204/14
Targeting KRAS mutations in NSCLC through LKB1 co-vulnerability
206/14
Closed
275
Study
Code
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2015
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
M. Santinami
2009
08/09/15
III
36
Closed
accrual
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
2010
30/06/15
III
10
Closed
accrual
34/10
A phase II single arm study of the combination of Ipilimumab and
fotemustine in patients with non-resectable 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 NYESO-1 positive unresectable and progressive metastatic cutaneous
melanoma
M. Santinami
2010
I
26
0
01/11
A phase III randomized, open-label study comparing GSK1120212 to
chemotherapy in subjects with advanced or metastatic BRAFV600E/K
mutation-positive melanoma
M. Del Vecchio
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
299
31
40/11
A study of immunomodulatory effect of BRAF and MEK inhibitors in
melanoma patients
L. Rivoltini
2011
Observational
90
2
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
2
0
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
28/12
Tracing the melanoma lineage: cancer stem cells and genetic noise
M. Santinami
2012
Observational
26
Closed
accrual
37/12
Malignant skin lesions in patients with cancer: an observational
prospective study
A. T. Caraceni
2012
Observational
103
2
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 the combination
of the BRAF inhibitor, dabrafenib 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
M. Del Vecchio
2013
III
13
Closed
accrual
71/12
A phase II study of intratumoral application of L19IL2/L19TNF in
melanoma patients in clinical stage III or stage IV M1a with presence of
injectable cutaneous and/or subcutaneous lesions
M. Santinami
2012
II
19
Closed
accrual
103/12
A multicentre, open label, randomized Phase II trial of the MEK inhibitor
pimasertib or dacarbazine in previously untreated subjects with
N-Ras mutated locally advanced or metastatic malignant cutaneous
melanoma
Filippo De Braud 2012
II
8
Closed
accrual
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 BMS-936558 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
276
23/03/15
05/08/15
26/05/15
05/11/15
Study
Code
Patients
enrolled
in 2015
Phase
Total
patients
2013
III
39
Closed
accrual
F. De Braud
2013
III
11
Closed
accrual
A phase III, double-blind, placebo-controlled study of vemurafenib
versus vemurafenib plus GDC-0973 in previously untreated
BRAFV600-mutation positive patients with unresectable locally
advanced or metastatic melanoma
F. De Braud
2013
III
11
Closed
accrual
44/13
A randomized, Phase III study of Fotemustine versus the Combination
of Fotemustine and Ipilimumab in Patients with Metastatic Melanoma
with brain metastasis
M. Del Vecchio
2013
III
9
4
64/13
Constitution of a Clinical National Melanoma Registry (CNMR)
M. Del Vecchio
2014
Observational
3
0
94/13
A Phase 3, Randomized, Double-Blind Study of Nivolumab
Monotherapy or Nivolumab Combined with Ipilimumab Versus
Ipilimumab Monotherapy in Subjects with Previously Untreated
Unresectable or Metastatic Melanoma
M. Del Vecchio
2013
III
14
Closed
accrual
117/13
ZeSS: A Prospective Observational Safety Study of Patients with
BRAFV600 Mutation-positive Unresectable or Metastatic Melanoma
Treated with Vemurafenib (Zelboraf®)
M. Del Vecchio
2014
Observational
1
Closed
accrual
124/13
Identification of molecular markers of multiple cutaneous melanoma
- MULTIMELMARKERS
L. Rivoltini
2014
-
61
14
27/14
Immunomodulatory effect of esomeprazole antitumoral and highdose in patients with melanoma in stage III. Multi-stage pilot study
(AdESOM2)
L. Rivoltini
2014
II
67
34
44/14
A Phase II, Open-Label, Multicentre Study of Dabrafenib plus
Trametinib in Subjects with BRAF Mutation-Positive Melanoma that
has Metastasized to the Brain
M. Del Vecchio
2014
II
3
2
60/14
The NEMO trial (NRAS melanoma and MEK inhibitor): A randomized
Phase III, open label, multicenter, two-arm study comparing the
efficacy of MEK162 versus dacarbazine in patients with advanced
unresectable or metastatic NRAS mutation-positive melanoma
M. Del Vecchio
2014
III
12
5
69/14
A phase III randomized, 3-arm, open label, multicenter study of LGX818
plus MEK162 and LGX818 monotherapy compared with Vemurafenib
in patients with unresectable or metastatic BRAF V600 mutant
melanoma
M. Del Vecchio
2014
III
3
0
84/14
Overall survival of braf v600 mutated and non mutated metastatic
melanoma patients: a cohort observational study of braf inhibitors
and current therapies effectiveness
M. Del Vecchio
2015
Observational
13
13
158/14
An observational study to evaluate the effectiveness and safety of
ipilimumab, administered during the European expanded access
programme in pretreated patients with advanced (unresectable or
metastatic) melanoma
M. Del Vecchio
2015
Observational
47
47
170/14
A Single-Arm, Open-Label, Multicenter Clinical Trial with Nivolumab
(BMS-936558) for Subjects with Histologically Confirmed Stage III
(unresectable) or Stage IV Melanoma Progressing Post Prior Treatment
Containing an Anti-CTLA-4 Monoclonal Antibody
M. Del Vecchio
2015
II
23
23
200/14
Pharmacoutilization analysis of Ipilimumab in advanced melanoma of
regional reference center in Italy
G. Saibene
2015
Observational
69
69
207/14
Targeting melanoma dedifferentiation and Epithelial-Mesenchymal
Transition (EMT) to promote immunogenicity
R. Mortarini
2015
Observational
27
27
209/14
Co-targeting of stress response pathways and oncogenic pathways to
identify new therapeutic targets in melanoma
A. Anichini
2015
Observational
30
30
31/15
A Phase III, Randomized, Double-blind Study of Adjuvant
Immunotherapy with Nivolumab versus Ipilimumab after Complete
Resection of Stage IIIb/c or Stage IV Melanoma in Subjects who are at
High Risk for Recurrence
M. Del Vecchio
2015
III
42
42
Title
Coordinator
Activated
143/12
COMBI-AD: A phase III randomized double blind study of dabrafenib
(GSK2118436) in COMBInation with trametinib (GSK1120212) versus two
placebos in the ADjuvant treatment of high-risk BRAF V600 mutationpositive melanoma after surgical resection
M. Santinami
42/13
A Phase 3, Randomized, Double-Blind Study of BMS-936558 vs
Dacarbazine in Subjects with Previously Untreated Unresectable or
Metastatic Melanoma
43/13
Closed
12/03/15
12/11/15
277
Study
Code
Title
Coordinator
Activated
103/15
Sex steroid hormones and cutaneous melanoma risk and survival
V. Krogh
2015
105/15
Melanoma susceptibility genetic variants in the Italian population
M. Rodolfo
2015
Closed
31/12/15
Phase
Total
patients
Patients
enrolled
in 2015
Observational
40
40
Observational
400
400
MISCELLANEA
66/05
Registry of congenital malformations in Lombardy
G. Tagliabue
2006
Observational
23.092
2.760
32/09
Epidemiologic studies on environmental risk factors and their
interactions with genetic factors of bladder cancer and sarcomas
A. Decarli
2009
Observational
1.168
355
35/09
Efficay of thermal treatment for respiratory airways in heavy smokers
U. Pastorino
2009
Observational
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
S. Cresta
2009
I
8
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
04/09/15
II
5
Closed
accrual
27/11
Role of chemotherapy in trastuzumab cytotoxic activity
E. Tagliabue
2011
31/12/15
Observational
15
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
37
11
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
0
104/11
An open label, multicenter, expanded access study of INC424 for
patients with primary myelofibrosis (PMF) or post polycythemia
myelofibrosis (PPV MF) or post-essential thrombocythemia
myelofibrosis (PET-MF)
P. Corradini
2011
III
7
Closed
accrual
112/11
Toremifene in desmoid tumor: prospective clinical trial and
identification of potential molecular targets
C.Colombo
2011
II
23
4
08/12
Hypercoagulation screening as an innovative tool for risk assessment,
early diagnosis and prognosis in cancer
F. de Braud
2012
Observational
539
194
25/12
Identification and validation of microRNAs as novel biomarkers and
therapeutic targets in diffuse malignant peritoneal mesothelioma
N. Zaffaroni
2012
Observational
70
Closed
accrual
39/12
A phase I dose escalation study of NMS-1191372 in adult patients with
advanced/metastatic solid tumors
F. de Braud
2012
I
124
95
59/12
Identification of Polymorphisms Predicting Bevacizumab-Related Side
Effects: SToPtrial
Observational
72
0
61/12
A Phase Ib, multi-center, open label, dose escalation study of oral
LDE225 in combination with BKM120 in patients with advanced solid
tumors
F. de Braud
2012
I
9
Closed
accrual
75/12
A Phase Ia/Ib, Multi-Center, Open-Label, Dose 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
F. De Braud
2013
I
8
1
105/12
The Lombardy Rare Donor Programme
F. Arienti
2012
Observational
63
0
122/12
Phase Ib 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
9
0
278
19/10/15
31/12/15
12/03/15
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2015
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
31/12/15
Observational
29
11
06/13
Cross-tumoral phase 2 clinical trial exploring crizotinib (PF-02341066)
in patients with advanced tumors induced by causal alterations of ALK
and/or MET ("CREATE")
P. G. Casali
2013
II
18
0
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
F. De Braud
2013
I
25
22
21/13
Variation of respiratory function and chest wall mechanics after
resection and rib-like costal reconstruction
F. Piccioni
2013
-
17
2
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 anti-emetogenic therapy
P. Bossi
2013
-
72
1
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
R. Buzzoni
2013
IV
2
Closed
accrual
56/13
Italian Oncologic Pain multiSetting - Multicentric Survey (IOPS-MS)
A. T. Caraceni
2013
Observational
204
14
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
26
11
77/13
Dose escalation, safety, pharmacokinetic and pharmacodynamic,
first in man study, of SAR125844 single agent administered as slow
intravenous infusion in adult patients with advanced malignant solid
tumors
F. De Braud
2013
I
63
27
85/13
Randomized controlled trial of metformin and dietary restriction
to prevent age-related morbid events in people with metabolic
syndrome
F. Berrino
2014
III
338
277
107/13
PreveDi (Prevention Disease) - Prevention of chronic degenerative
diseases
A. Villarini
2013
30/04/15
-
442
20
143/13
Innovative approaches in the treatment of giant congenital nevi
melanocytes
A. Colombetti
2013
31/12/15
-
25
Closed
accrual
148/13
Procedures, complications and follow-up of tracheostomy techniques
in intensive care
L. Persiani
2014
Observational
30
9
166/13
Novel molecular mechanisms of genetic predisposition to early-onset
breast cancer
P. Radice
2014
Observational
1.300
150
170/13
A Phase I/II, Open-label Study of Nivolumab Monotherapy or
Nivolumab combined with Ipilimumab in Subjects with Advanced or
Metastatic Solid Tumors
F. De Braud
2014
I-II
39
18
183/13
Experimental evidence of tollerance to high intra abdominal pressure
(IAP) during HIPEC
S. Kusamura
2014
II
20
19
08/14
Comparison pilot study between complex decongestive therapies
for the treatment of secondary lower limbs lymphedema in cancer
patients
A.T. Caraceni
2014
-
15
0
20/14
Phase IB study of MK-3475 in Subject with select advanced solid
tumors
F. De Braud
2014
I
49
6
23/14
A RandomisEd, double-bLind, placebo-controlled study to evaluate
the Efficacy of two different dose levels of orVEpitant (1 0 and 30 mg)
compared with placebo on EGFRi-induced intense pruritus in oncology
subjects
P. Bossi
2014
II
4
2
24/14
REQUITE Study Protocol Validating predictive models and biomarkers
of radiotherapy toxicity to reduce side-effects and improve quality-oflife in cancer survivors
R. Valdagni
2014
Observational
260
148
57/14
A Phase II, Open-label, Study in Subjects with BRAF V600E Mutated
Rare Cancers with Several Histologies to Investigate the Clinical
Efficacy and Safety of the Combination Therapy of Dabrafenib and
Trametinib
F. De Braud
2015
II
1
1
Study
Code
20/04/15
14/11/15
16/06/15
279
Phase
Total
patients
Patients
enrolled
in 2015
2014
I
5
3
R. Buzzoni
2015
II
5
5
A phase I, open-label, multi-center, dose escalation study of oral
BGJ398, a pan FGF-R kinase inhibitor, in adult patients with advanced
solid malignancies
F. De Braud
2015
I
1
1
194/14
Psychological determinants of preventive choices in BRCA1-2 carriers
C. Borreani
2015
Observational
73
73
195/14
Psychological distress assessment in hospitalized oncological
patients
C. Borreani
2015
30/06/15
Observational
261
261
210/14
Quality of nutritional care and prevalence of malnutrition in the elderly
in hospital wards of the 16 sections of the Degree Course in Nursing at
the University of Milan
M. Magri
2015
26/02/15
Observational
74
74
04/15
Prospective study for the determination of the molecular profile of
resistance to "target therapies" in patients with solid tumors - Protocol
PROFILING
F. De Braud
2015
Observational
6
6
05/15
Longitudinal genotyping or circulating tumor DNA in patients
with metastatic solid tumors responding to targeted therapies to
understand and monitor drug resistance
F. De Braud
2015
Observational
30
30
27/15
Palliative radiotherapy of bone metastasis. Classification,
inflammatory biomarkers, and longitudinal clinical follow-up
L. Lozza
2015
Observational
5
5
33/15
A phase I, multicenter, open-label dose escalation and expansion
study of PCA062, administered intravenously in adult patients with
pCAD-positive tumors
F. De Braud
2015
I
6
6
34/15
A pilot study to test the feasibility of a two-arm, double blind, parallelgroup, randomized controlled trial for the comparison of the duration
of the analgesic efficacy of a single matrix transdermal fentanyl patch
compared vs a double matrix transdermal fentanyl patch
A. T. Caraceni
2015
IV
1
1
36/15
A randomized, blinded, placebo-controlled, phase II trial ofLEE011 in
patients with relapsed, refractory, incurable teratoma with recent
progression
A. Necchi
2015
II
1
1
72/15
An open-label, multicohort, phase II study of MPDL3280A in advanced
solid tumors
F. De Braud
2015
II
27
27
102/15
Is the protective effect of mediterranean diet on cancer mediated by a
methylation pattern?
V. Krogh
2015
Observational
100
100
121/15
International Consumer Quality for Cancer Patients
C. Melani
2015
16/09/15
Observational
56
56
149/15
Retrospective revision of ALK and ROS1 expression in solid tumors
S. Cresta
2015
27/10/15
Observational
987
987
151/15
Observational study designed to evaluate the prognostic and
predictive impact of factors related to immunity in cancer patients
treated with immunotherapy
M. Di Nicola
2015
Observational
35
35
161/15
Experimental tests of probe molecules encapsulation into human red
blood cells aimed at the design of a device to be used on-line with the
patient
A. Mazzocchi
2015
Observational
2
2
IV
113
33
Observational
85
85
Observational
34
14
Study
Code
Title
Coordinator
Activated
114/14
A phase lb open-label, multi-center, dose escalation and expansion
study of orally administered MEK162 plus BYL719 in adult patients with
selected advanced solid tumors
F. Raspagliesi
151/14
A Phase II, open-label, multicenter trial to investigate the clinical
activity and safety of MSB0010718C in subjects with Merkel cell
carcinoma
152/14
Closed
PALLIATIVE CARE
123/13
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
153/13
Interaction between clinical and genetic factors in modulation of
opioid analgesia and side effects in cancer pain
A. T. Caraceni
2015
98/14
A multi-centre, non-interventional investigation of the relationship
between pain intensity numeric rating scale scores and health status,
as assessed with the EQ-5D, in patients with cancer-related chronic
pain
A. T. Caraceni
2014
280
17/08/15
16/02/15
Study
Code
Patients
enrolled
in 2015
Title
Coordinator
Activated
Closed
Phase
Total
patients
99/14
Time and Motion (T&M) Study of Denosumab (XGEVA) Subcutaneous
(SC) Injection and Zoledronic Acid (ZOL) Intravenous (IV) Infusion in
Patients with Metastatic Bone Disease in Europe
A. T. Caraceni
2014
20/04/15
Observational
30
Closed
accrual
120/14
Action - Observation Therapy in young patients with upper limb
neuromotor outcomes from brain tumor
F. Gariboldi
2014
Observational
7
4
79/15
A phase II, multicentre, randomized controlled study evaluating the
quality of life in patients with inoperable malignant bowel obstruction
treated with Lanreotide Autogel 120 mg in combination with standard
care vs. standard care alone (QoL in IMBO study)
A. T. Caraceni
2015
II
2
2
PEDIATRIC TUMORS
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
89
3
40/01
Protocol NB-AR-01: First European Cooperative Study for high-risk
neuroblastoma
R. Luksch
2002
III
64
2
12/03
Second protocol for diagnosis and treatment of ependymoma in a
pediatric age
M. Massimino
2003
Observational
53
1
13/03
Non-controlled clinical study for the treatment of Ewing’s sarcoma in
relapse
R. Luksch
2003
II
24
0
14/03
Wilms’ tumor: diagnostic-therapeutic protocol AIEOP 2003
F. Spreafico
2003
Observational
131
11
16/03
Germ cell tumors: diagnostic-therapeutic protocol AIEOP 2003
M. Terenziani
2003
III
129
13
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
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,
non-rhabdomyosarcoma 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
34
5
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
38
7
25/09
Therapeutic protocol with high-dose chemotherapy, radiotherapy,
maintenance therapy with low-dose Cyclophosphamide and antiCOX2 in metastatic Ewing’s sarcoma: ISG/AIEOP study
P. Casali, R.
Luksch
2009
II
29
1
53/10
Phase 1/2combined dose ranging and randomised, 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
R. Luksch
2012
I-II
2
Closed
accrual
84/10
Evaluation and treatment of bone mass and body composition
alterations in pediatric patients with oncological disease of central
nervous system
E. Seregni
2010
Observational
48
2
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
14
0
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
2
0
62/11
First International Inter-Group Stydu for nodular lymphocytepredominant Hodgkin's Lymphoma in Children and Adolescents
M.Terenziani
2015
IV
1
1
07/12
Nimotuzumab and vinorelbina concomitantly to radiation and as
maintenance for newly diagnosed diffuse pontine glioma in childhood
M. Massimino
2012
Observational
43
21
43/12
European Low an Intermediate Risk Neuroblastoma
R. Luksch
2013
III
10
4
31/12/15
281
Study
Code
Patients
enrolled
in 2015
Phase
Total
patients
2013
Observational
164
Closed
accrual
M. Casanova
2013
III
5
Closed
accrual
Assessment of symptoms in children and adolescents with malignant
disease during treatment
S. Macchi
2013
Observational
62
Closed
accrual
05/13
Re-induction protocol for patients with high-risk neuroblastoma at
first relapse
R. Luksch
2013
II
2
0
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
5
0
16/13
A phase I/II dose schedule finding study of CH14.18/CHO continuous
infusione combined with subcutaneous aldesleukin (IL-2) in patients
with primary refractory or relapsed neuroblastoma. A SIOPEN Study
R. Luksch
2013
I-II
3
2
80/13
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)
M. Casanova
2013
I
12
4
103/13
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
M. Casanova
2014
I
7
5
176/13
Retrospective and prospective study of late radiation damages after
focal radiotherapy for childhood brain tumors
L. Gandola
2014
Observational
59
22
65/14
Complications related to indwelling central venous catheter in
pediatric oncology patients
D. Codazzi
2015
Observational
20
20
103/14
Observational retrospective and prospective study on patients
enrolled in AIEOP and IPINET Centers
M. Massimino
2014
Observational
234
202
126/14
REACT: REsources in Adolescent Cancer Treatment
C. A. Clerici
2014
Observational
45
41
127/14
Quality of life in long-term survivors pediatric patients treated for
metastatic medulloblastoma
M. Massimino
2014
Observational
22
12
139/14
Italian peripheral neuroblastic tumors Registry (RINB) - AIEOP (Italian
Association of Pediatric Hematology Oncology) Registry
R. Luksch
2014
Observational
15
12
142/14
Pathways to diagnosis project in adolescent and young adult tumors
A. Ferrari
2015
Observational
20
20
172/14
Phase I/II Study of Lenvatinib in Children and Adolescents With
Refractory or Relapsed Solid Malignancies
M. Casanova
2015
I-II
3
3
175/14
Identification of potential targets for therapy and expression
of immune inhibitors in the neoplastic stroma in patients with
neuroblastoma
R. Luksch
2015
Observational
5
5
87/15
An early-phase, multicenter, open-label study of the safety and
pharmacokinetics of anti-PD-L1 antibody (MPDL3280A) in pediatric
and young adult patients with previously treated solid tumors
M. Casanova
2015
I
4
4
94/15
Phase II open label randomized study of radiotherapy,
concomitantnimotuzumab and vinorelbine and re-irradiation at
relapse versus radiotherapy and multiple elective radiotherapy
courses with concomitant vinorelbine and nimotuzumab for newly
diagnosed childhood and adolescence diffuse intrinsic pontine glioma
(dipg)
M. Massimino
2015
III
2
2
Title
Coordinator
Activated
93/12
PanCareSurFup: PanCare Childhood and Adolescent Cancer Survivor
Care and Follow-up Studies
M. Terenziani
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 Hh-pathway activated relapsed medulloblastoma
147/12
Closed
07/01/15
SARCOMAS
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
14
Closed
accrual
31/05
EpSSG RMS 2005 - A protocol for non metastatic Rhabdomyosarcoma
A. Ferrari
2005
III
120
8
32/05
EpSSG NRSTS 2005. A protocol for localized non-rhabdomyosarcoma
soft tissue sarcomas
A. Ferrari
2005
III
183
12
62/08
Open label, multi-center, phase 2 study denosumab in subject with
giant cell tumor of bone
P. Casali
2008
II
26
0
282
Phase
Total
patients
Patients
enrolled
in 2015
II
8
1
II
11
Closed
accrual
2011
II
44
Closed
accrual
A. Gronchi
2010
II
58
5
Evaluation of the role of immunosuppressive mechanisms in the
prognosis and response to treatment with targeted therapy drugs in
sarcoma patients
L. Rivoltini
2010
Observational
177
15
05/11
Translational study on modulation of gene transcription induced by
Trabectedin in patients with myxoid/round cell liposarcoma
P. Casali
2011
Observational
2
0
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
2011
III
4
Closed
accrual
28/11
Rabdomiosarcoma of adults. An observational prospective study
R. Bertulli
2011
Observational
11
1
59/11
STARSS: a phase III randomized STudy of preoperative RAdiotherapy
plus Surgery versus surgery alone for patients with Retroperitoneal
Sarcoma (RPS)
A. Gronchi
2011
-
32
9
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
34
11
13/12
Tailore Beta-catenin mutational approach in extra-abdominal sporadic
desmoid tumor patients
A. Gronchi
2013
31/12/15
Observational
38
16
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
05/11/15
Observational
8
Closed
accrual
142/12
Multicentric, prospectic, randomized study for the treatment of
patients with relapsed osteosarcoma
C. Meazza
2014
13/11/15
II
1
0
54/13
Observational study of whole-trascriptome and wholeexome sequencing analysis in tumor samples of extraskeletal
myxoid chondrosarcoma, malignant myoepithelioma, and
dermatofibrosarcoma protuberans with or without fibrosarcomatous
component
S. Stacchiotti
2013
Observational
30
10
114/13
Patients with atipical osteosarcoma and/or are not elegible in other
ISG clinical trials
R. Bertulli
2013
Observational
5
3
182/13
High throughput genome study to identify predictors of
aggressiveness in patients with sporadic desmoid tumor who undergo
a wait and see approach
C. Colombo
2013
Observational
10
4
188/13
Overcoming anti-angiogenetic therapy resistance in selected
sarcomas
S. Pilotti
2014
Observational
35
27
07/14
Phase II study of axitinib in advanced solitary fibrous tumor
S. Stacchiotti
2015
II
7
7
13/14
Long term morbidity and quality of life after multivisceral resection
for primary retroperitoneal soft tissue sarcomas: a prospective
observational study
M. Fiore
2014
Observational
59
41
17/14
Assessment of BoNT/A effects on muscle cells and fibroblasts
C. Colombo
2014
Observational
8
3
93/14
A Phase II Open-Label Trial of Pazopanib Administered as a Single
Agent in Patients with Unresectable or Metastatic Solitary Fibrous
Tumor (SFT) and Extraskeletal Myxoid Chondrosarcoma (EMC)
S. Stacchiotti
2014
II
11
9
Study
Code
Title
Coordinator
Activated
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
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
2010
44/10
Phase II study on imatinib in combination with RAD001 in advanced
chordoma
S. Stacchiotti
66/10
Localized high-risk soft tissue sarcomas of the extremities and
trunk wall in adults: an integrating approach comprising standard vs
histotype-tailored neoadjuvant chemotherapy
85/10
Closed
12/10/15
283
Title
Coordinator
Activated
Closed
Phase
Total
patients
Patients
enrolled
in 2015
03/15
Malignant peripheral nerve sheath tumors in a multi-centre cohort of
patients with NF1
A. Gronchi
2015
15/03/15
Observational
33
33
23/15
Evaluation of MGMT promoter methylation status and clinical benefit
from therapy based on temozolomide for advanced Ewing’s sarcoma
R. Bertulli
2015
Observational
6
6
84/15
Peritoneal Surface Oncology Group International (PSOGI) Registry on
Peritoneal Mesothelioma
S. Kusamura
2015
Observational
202
202
97/15
Sacral chordoma: long-term outcome of a large series of patients
surgically treated at two reference centers
S. Radaelli
2015
15/09/15
Observational
35
35
98/15
Development and external validation of a nomogram to predict overall
and disease-free survival in primary resected extremity soft tissue
sarcoma patients
A. Gronchi
2015
30/07/15
Observational
1.452
1.452
99/15
Rehabilitation and psychological features in paediatric bone sarcomas:
the way from diagnosis to cure
C. Meazza
2015
Observational
4
4
110/15
Phase II study on Regorafenib in advanced Solitary Fibrous Tumor
S. Stacchiotti
2015
III
1
1
III
6
Closed
accrual
II
11
Closed
accrual
Study
Code
URINARY APPARATUS
53/07
Sunitinib treatment of renal adjuvant cancer (S-TRAC): a randomized
double-blind phase 3 study of adjuvant sunitinib vs placebo in subjetcs
with high risk RCC
G. Procopio
2007
11/10
Phase II study of sunitinib in metastatic renal cancer with non-clear
cell histology
G. Procopio
2010
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
44
8
09/11
A randomized, double.blind, placebo-controlled phase III study to
evaluate the efficacy and safety of pazopanib as adjuvant therapy
for subjects with localized or locally advanced RCC following
nephrectomy
G. Procopio
2011
III
18
Closed
accrual
10/11
Biotech of prostate cancer
N. Zaffaroni
2011
Observational
149
17
46/12
Evaluation of microRNA expression in prostate cancer for the
identification of novel diagnostic and prognostic markers
D. Zaffaroni
2012
Observational
17
Closed
accrual
62/12
A randomized, open label, multicenter phase 2 study, to evaluate the
efficacy of Sorafenib in patients with advanced Renal Cell Carcinoma
(RCC) after a radical resection of the metastases
G. Procopio
2012
II
30
9
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
40
Closed
accrual
108/12
A Randomized, Open-Label, Phase 3 Study of BMS-936558 vs.
Everolimus in Subjects with Advanced or Metastatic Clear-Cell Renal
Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy
G. Procopio
2013
III
14
Closed
accrual
48/13
Personalizing antiangiogenic treatment in advanced urothelial cancer
A. Necchi
2014
Observational
5
0
98/13
A phase Ib/II study of GDC-0068 or GDC-0980 with abiraterone
acetate versus abiraterone acetate in patients with castrationresistant prostate cancer previously treated with docetaxel-based
chemotherapy
G. Procopio
2013
I-II
8
Closed
accrual
171/13
A re-treatment safety study of radium-223 dichloride in subjects
with castration-resistant prostate cancer with bone metastases who
received an initial course of six doses of radium-223 dichloride 50
kBq/kg every four weeks
G. Procopio
2014
II
2
Closed
accrual
04/14
A Phase III trial to evaluate the efficacy of orasol plus mouthwash
associated with oral hygiene standard (vs oral hygiene standard) in
the prevention of stomatitis of everolimus in patients with advanced
renal cell carcinoma (everolimus-induced STOmatitis Prevention trial)
G. Procopio
2014
-
15
9
25/14
A Phase II study of Paclitaxel and Ifosfamide plus either Cisplatin
or Carboplatin for patients with metastatic non-transitional cell
carcinoma of the bladder and the urinary tract
A. Necchi
2014
II
2
1
284
28/12/15
31/05/15
Phase
Total
patients
Patients
enrolled
in 2015
2014
II
11
7
A. Necchi
2014
II
22
12
A phase II, multicenter, single-arm study of MPDL3280A in patients
with locally advanced or metastatic urothelial bladder cancer
A. Necchi
2014
II
25
Closed
accrual
94/14
Activity and safety of third line tyrosin kinase inhibitor (TKI) after two
tyrosin kinase inhibitors(TKIs) in patients with metastatic renal cell
carcinoma (mRCC) (Tokio Study)
G. Procopio
2014
II
9
8
115/14
Feasibility of a home-based Pre-habilitation Program for Patients
with Muscle Invasive Bladder Cancer, submitted to Neo-Adjuvant
Chemotherapy and candidates to Radical Cystectomy with Urinary
Reconstruction
M. Maffezzini
2014
-
16
9
133/14
A Phase III Randomized Clinical Trial of Pembrolizumab (MK-3475)
versus Paclitaxel or Vinflunine in Subjects with Recurrent or
Progressive Metastatic Urothelial Cancer
A. Necchi
2014
III
12
8
146/14
Prospecive translational study investigating possible molecular
predictors of resistence to first-line pazopanib in metastatic renal cell
carcinoma for future research
G. Procopio
2015
-
6
6
171/14
A Phase III, Randomized, Open-Label Study of Nivolumab Combined
with Ipilimumab Versus Sunitinib Monotherapy in Subjects with
Previously Untreated, Advanced or Metastatic Renal Cell Carcinoma
G. Procopio
2015
III
10
10
189/14
An open label, randomized, phase II study of Paclitaxel and
Panitumumab compared to Paclitaxel alone in patients with relapsed
or refractory urothelial cancer
A. Necchi
2015
II
5
5
190/14
A phase III, open-label, multicenter, randomized study to investigate
the efficacy and safety of MPDL3280A (anti-PD-L1 antibody) compared
with chemotherapy in patients with locally advanced or metastatic
urothelial bladder cancer after failure with platinum-containing
chemotherapy
A. Necchi
2015
III
14
14
17/15
A phase II single arm clinical trial of nivolumab (BMS-936558) in
subjects with metastatic or unresectable urothelial cancer who have
progressed or recurred following treatment with a platinum agent
A. Necchi
2015
II
19
19
75/15
Targeted Therapy With or Without Nephrectomy in Metastatic Renal
Cell Carcinoma: Liquid Biopsy for Biomarkers Discovery
G. Procopio
2015
III
2
2
Study
Code
Title
Coordinator
Activated
46/14
Activity and safety of second line SOrafenib After Pazopanib in
patients with metastatic renal cell carcinoma (SOAP Study)
G. Procopio
49/14
Advanced urothelial cancer of the bladder, urethra, or the upper
urinary tract who are resistant to platinum-based therapy
59/14
Closed
285
Editor
Giovanni Apolone
Coordinator
Paola Gabaldi
Advisory Board
Barbara Avuzzi, Dario Baratti, Cinzia Brunelli, Giuseppina Calareso, Paola Collini,
Chiara Colombo, Marina Garassino, Patrizia Giannatempo, Domenica Lorusso,
Roberta Mortarini, Carlo Sposito, Elena Tamborini, Marco Vitellaro
Collaborators
Camilla Amati, Anna De Filippo, Daniela Majerna, Claudia Miranda, Rosaria Parentela
Contribution to Graphics realization
Studio Luvié
We thank all the authors for their contribution to this report
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
www.istitutotumori.mi.it
Copyright © 2015 Fondazione IRCCS Istituto Nazionale dei Tumori.
No part of this communication may be cited, reproduced, stored in a retrieval system, or transmitted
by electronic or other means without prior written permission of the Scientific Director and the
appropriate investigator.

scientific report 2015 - Istituto Nazionale dei Tumori

Transcription

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