SCIENTIFIC REPORT 2013 CONTENTS Introduction 5 Scientific Directorate 8 Ethics Committee 13 Education and Training 14 Clinical Activity Data 22 CLINICAL-SCIENTIFIC DEPARTMENTS Surgery Department 27 Medical Oncology Department 32 Hematology and Pediatric Onco-Hematology Department 35 Anesthesia, Intensive Care, Pain Therapy, and Palliative Care Department 38 Diagnostic Imaging and Radiotherapy Department 41 Pathology and Laboratory Medicine Department 45 Experimental Oncology and Molecular Medicine Department 47 Preventive and Predictive Medicine Department 53 SHARED RESEARCH RESOURCES 59 RESEARCH ACTIVITY PREVENTIVE AND PREDICTIVE MEDICINE 65 Prospective observational studies on diet, lifestyle, endocrine/metabolic and genetic factors and cancer risk 66 Rare tumors: creation of an information network and epidemiological surveillance system 68 Clinical interpretation of cancer survival differences in Italy and Europe 70 Study of the molecular determinants of the genetic predisposition to familial-hereditary cancers 72 MOLECULAR CARACTERIZATION OF TUMOR PROGRESSION 75 Involvement of microRNAs in the principal pathways of breast cancer: from biology to possible therapeutic applications 76 Analysis of circulating markers for monitoring disease progression and treatment response in breast cancer 78 Detection and validation of new genetic/ genomic and metabolic markers of prognosis or prediction of treatment response and/or early relapse in ovarian cancer 80 2 contents Thyroid cancer: functional studies for the detection of new molecular mechanisms and therapeutic targets 83 Extracellular matrix protein SPARC regulates primary and secondary lymphoid organs homeostasis and the transition of myeloproliferative or autoimmune spurs toward leukemia and lymphoma 85 INNOVATIVE PROBLEM-ORIENTED APPROACHES TO DIAGNOSIS AND TREATMENT 87 Stroma-derived biomarkers with prognostic value in subjects with polygenic or monogenic inheritance predisposing to cancer 88 Development of a platform for the pre-clinical evaluation of new anti-tumor drugs and therapeutic combinations 90 Study of immunosuppression mechanisms in patients with solid tumors and their influence on prognosis and response to drug treatment and immunotherapy 92 Establishing drug and transplant approaches for effective treatment of hematological malignancies 95 Translational project for the development of drugs for personalized cancer treatment 97 MULTIDISCIPLINARY DISEASE-ORIENTED APPROACH 99 Prostate Cancer Program 100 New methodological approaches to the study and personalized treatment of rare tumors and adult sarcomas 102 Biomolecular characterization of rare histological types of ovarian carcinoma and implications for medical treatment of disease 104 Early diagnosis of lung carcinoma and efficacy of plasma miRNAs as first-line tests 106 PEDIATRIC CANCER 108 Tumors of the central nervous system 109 Adolescents with cancer in Italy: from local projects to a National coordinated program 111 Genetic and biomolecular characterization of Wilms tumor and detection of predictive markers of poor prognosis 113 New drugs in pediatric oncology 115 PATHWAYS OF RESEARCH/INTERVENTION AND ASSESSMENT OF QUALITY OF LIFE IN PATIENTS WITH CANCER 118 Assessment and management of symptoms and quality of life in cancer patients receiving palliative care 119 Research and training for the physical, emotional, social, and spiritual support of patients on active cancer treatment and their caregivers 121 Development of algorithms for nutritional therapy in diseases at high risk of malnutrition 123 PUBLICATIONS125 ONGOING PROJECTS SUPPORTED BY EXTERNAL ORGANIZATIONS 179 ONGOING CLINICAL STUDIES 185 3 SCIENTIFIC REPORT 2013 4 back to contents introduction SCIENTIFIC DIRECTOR Marco A. Pierotti INTRODUCTION In 2013, the 85th year since the Istituto Nazionale dei Tumori (INT) started its activities, we felt obliged to offer those who frequent its premises in Via Venezian 1 the opportunity to learn, or remember, its history. The memorial wall in the entrance hall of the INT is a fitting tribute to the extraordinary doctors and scientists who have made this institution what it is today, and who, through their commitment and competence, have allowed Italian oncology to make an important contribution to the advancement of this science worldwide. This was also the year of another anniversary: we have celebrated that 40 years ago the first Italian ethics committee was established at this very Institute. The conference “The Ethics Committee: Past and Future” was well received, also thanks to the participation of the illustrious researchers, above all Gianni Bonadonna, who first brought clinical trials to Italy. The recollection of our history was not intended as a nostalgic reminder of a brighter past, but rather as the recognition of the origins of a success story that continues today, as the contents of this Scientific Report clearly show. The INT has always been one of the most influential Italian entities in the fight against cancer, and our efforts to improve the efficiency of our work at all levels (clinical, scientific and organizational) prompted us to enter the rigorous accreditation procedure of the Organization of European Cancer Institutes. Even though we still have a long assessment ahead of us, the Institute has obtained the preliminary designation of Comprehensive Cancer Center (CCC), a qualification that, when confirmed at the end of the accreditation procedure, INT will share with world-renowned European institutions such as the Karolinska Institute of Stockholm and the French Institut Gustave Roussy. The nature of a CCC is that of a complex organization aimed at the efficient collaboration of a wide range of specialized professionals, including those who make it possible to carry out clinical and research activities with the increasingly indispensable technological support this entails. This year the Istituto Nazionale dei Tumori of Milan won the innovation award of the ICT Observatory of Health Care of Milan Polytechnic’s School of Management for the project “Clinical Analytics for Oncology Care Appropriateness”, a computer system developed in collaboration with IBM. This innovative technological solution offers doctors a decision-making aid to establish the best treatment for each patient according to the clinical picture. The system is currently used by clinicians in the medical treatment of adult sarcomas and tumors of the head and neck, but studies are ongoing for its extension to other departments of the Institute and other centers of the Lombardy Oncology Network (Rete Oncologica Lombarda, ROL). 5 SCIENTIFIC REPORT 2013 ROL has completed the third phase of the project this year, and INT has acted as an implementing agency recognized by the Lombardy Region. This phase included the creation of a multidisciplinary clinical and research community engaged in the steady production of guidelines to be shared with regional oncologists. In the meantime the scientific collaboration with Nerviano Medical Sciences has continued under the supervision of the Regional Foundation for Biomedical Research. A new collaborative model within ROL that allows the public and private sectors to interact fruitfully in research facilitation has been tested with success. Preparations are under way for the creation of an oncology network aimed at promoting clinical research in multicenter studies, developing personalized medicine in oncology (through the integrated FRBR platform), and establishing a virtual research biobank in Lombardy. INT also contributes in important ways to the knowledge of the numbers that define the cancer problem, providing health policy decision-makers with useful insights. Examples are a study published in 2013 on the correlation between the investment in health care among European countries, the type of health care system in those countries and cancer survival, and the paper that INT researchers published in the prestigious journal The Lancet, establishing a causal relationship between particulate matter and certain types of cancer. Various news items last year have pushed the professionals of the Institute to take a stand on issues that were the subject of debate – not always well-informed – in the media. For example, we have responded to the enormous public interest in the fad of the electronic cigarette with a study (currently in press) on the impact of toxic particles emitted by electronic cigarettes compared to those present in tobacco smoke. When the personal choice of a famous actress sparked a lively debate about possible “extreme” prevention strategies against the risks associated with an inherited predisposition to certain types of cancer, the Institute could intervene with the knowledge and experience accumulated over the years thanks to the medical genetics service, which since 1995 has been identifying and guiding persons who are genetically predisposed to developing cancers of the breast and ovary. In the context of this service more than 3850 families, for a total of more than 7900 individuals, have been screened, and more than 5300 instances of genetic counseling have been provided (the largest number nationally – about a third of the total). Based on this extensive experience we were able to articulate a scientific opinion on this matter, and in a forthcoming publication we make it clear there are no standard choices that are by definition “better” than others, and the most appropriate solution is to let every single person decide, as long as they are thoroughly informed. Over the past years it has become evident that international collaboration is indispensable for cancer research, which is more and more directed towards exploiting the key scientific acquirement of our century by pursuing cancer genome projects that identify the sequences and mutations crucial for the onset and development of cancer. Our Institute is involved in many global initiatives to explore and experiment with new models of collaboration through concrete research projects. We are very pleased to announce that one of the projects approved by the Scientific Advisory Board of the Worldwide Innovative Networking in personalized cancer medicine (WIN Consortium) has as its principal investigator a clinical researcher of the Institute, Andrea Necchi. Lastly, it is worth mentioning that through an internal competition titled “Molecular Signatures for Diagnosis, Prognosis and Targeted Therapies” the Scientific Directorate, based on the judgment of an Expert Committee, has financed 15 of the 20 groups that submitted a project. All groups are multidisciplinary, with projects addressing unsolved issues of major impact on clinical decision-making and with great prognostic and predictive significance. The 15 selected projects cover many cancer types and a wide range of issues. Each is coordinated by a group leader and encompasses different departments of the Institute. 6 back to contents introduction At the time of writing, the crude impact factor (IF) in 2013 had reached a value of 2761.98 for a total of 550 scientific papers published, amounting to an average IF of 4.99. This means that this year we have again surpassed the already considerable IF of previous years. Research owes its significance to the clinic, and where there’s good research there will be clinical excellence; but neither is possible without an effective administration. The practical implementation of this ideal presents extraordinary complexities that can only be addressed with a great sense of collaboration: the unity of purpose of the Scientific Directorate, the Presidency, the General Directorate and the Administration and their constant interaction have been crucial to the Institute’s achievements. As in previous years, this Scientific Report offers the most complete documentation of the many projects designed and conducted at INT Milan. Marco A. Pierotti Impact Factor and published papers 2519.29 Impact Factor 2250 2272.32 2274.62 2761.98 2353.98 Published Papers 1559.97 1686.65 1503.55 1349.13 1390.49 1215.17 1188.21 275 287 320 309 293 366 338 415 465 426 450 518 550 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 7 back to contents SCIENTIFIC REPORT 2013 SCIENTIFIC DIRECTORATE SCIENTIFIC DIRECTOR Marco A. Pierotti, PhD +39 02 2390 2300 [email protected] The responsibilities of the Scientific Directorate traditionally include: • coordination of research and education activities, planning of scientific policy, and evaluation of scientific projects (Committee of the Scientific Directorate); • management of institutional relationships with key health authorities at a regional and national level; support to researchers seeking public and private funding (Grant Office); • giving access to information resources in support of ongoing research programs (Biomedical Library); • enhancement of communication and collaboration among all cancer-related institutions in Lombardy (Lombardy Oncologic Network); • supervision of the Institute’s scientific communication in agreement with the President of the INT Foundation; • management of the Clinical Trial Center, a core office to support clinical studies, especially investigator driven and Phase I and II studies, with the aim of bringing research results and new treatments to the bedside in the shortest time (see page 61); Working in tight cooperation with the Technology Transfer Office (TTO), the Scientific Directorate also facilitates transfer of inventions and knowledge from INT labs to the public. Each year the Scientific Directorate organizes a Research Day: the 2013 edition was held on June 14th at INT. The meeting offers an opportunity to look back to the scientific accomplishments achieved during the year, and to look forward to future research. Staff Members Tiziana Camerini, Maths D; Aurora Costa, Biol Sci D; Cecilia Melani, MD, PhD Secretariat Laura Ballariano Rossi; Eleonora De Palo, MA Mod Lang; Lucia De Zorzi; Antonio Florita, B Litt International Relations and Linguistic Consultant Daniela Majerna, MA Phil Grant Office Valeria Anselmi, MA Lett; Marco Asioli; Costanza Bono, MA Pol Sc; Sabrina Braghieri, MA Mod Lang; Claudia Casoli; Stefania Didonè;Isabella Russo, MA Econ Lombardy Oncology Network (ROL) Rosaria Bufalino; Marco Tricomi, MS Eng Biomedical Library Rossella Ballarini; Marina Calderisi 8 Editorial Office Rosaria Parentela Tumori - Editorial Assistant Elena Morittu Clinical Trial Center Data Manager: Valentina Sinno, BSc (coordinator); Anisa Bermema, BSc; Liana Bevilacqua, BSc; Ilaria Bossi, BSc; Federica Brunero, BSc; Laura Concas, BSc; Debora Deglinnocenti, Biol Sci D ; Federica Favales, BSc; Rosaria Gallucci, BSc ; Elisa Grassi, BSc; Rosanna Montone, BSc; Paola Pistillo, BSc; Iolanda Pulice, BSc; Dominique Ronzulli, BSc; Silvia Sesana, BSc; Eleonora Sparacio, BSc; Irene Vetrano, BSc Statisticians: Luigi Mariani, MD (coordinator); Monica Pacifici, Stat D Scientific and Administrative Secretariat: Paola V. Consonni Research Nurses: Benedetta Bardazza; Alessandra Castano; Ilaria Lo Russo; Giulia Saba; Serena Scrudato; Edoardo Tulli Baldoin Pharmacovigilance: Elena Togliardi, Pharm D scientific directorate COMMITTEE OF THE SCIENTIFIC DIRECTORATE Marco A. Pierotti, Scientific Director Emilio Bombardieri, Director Diagnostic Imaging and Radiotherapy Department (until August 31) Paolo Corradini, Deputy Scientific Director, Director Hematology and Pediatric Onco-Hematology Department Vito Corrao, Chief Medical Officer Maria Grazia Daidone, Director Experimental Oncology and Molecular Medicine Department Filippo de Braud, Director Medical Oncology Department Alessandro M. Gianni, Deputy Scientific Director Martin Langer, Anesthesia, Intensive Care, Pain Therapy, and Palliative Care Department Alfonso Marchianò, Director Diagnostic Imaging and Radiotherapy Department (since September 1st) Vincenzo Mazzaferro, Deputy Scientific Director Ugo Pastorino, Director Surgery Department Giuseppe Pelosi, Director Pathology and Laboratory Medicine Department Mario Santinami, Deputy Scientific Director Gustavo Galmozzi, Medical Director The Committee is the Institutional Reviewer Board and assists the Scientific Director in defining the Strategic Scientific Program and the contents of correlated educational activities. Its main objectives are: • definition of research areas at INT • approval of multidisciplinary research projects • approval of the development of research projects at a scientific and administrative level •evaluation of scientific quality and feasibility of newly-proposed clinical studies prior to submission to the Independent Ethics Committee • evaluation of educational programs for residents and non-residents. In 2013, Emilio Bombardieri, for many years head of the Department of Diagnostic Imaging and Radiotherapy and a member of the Committee, retired after a successful clinical and scientific career. The Committee welcomed Alfonso Marchianò who was appointed as new Director of the Diagnostic Imaging and Radiotherapy Department. GRANT OFFICE The Grant Office (GO) has the mission of supporting research activities within the INT, facilitating access to external financing, both national and international, by looking for relevant information in the appropriate media, making direct contact with public and private funding agencies, and swiftly providing information to potentially interested researchers. Announcements regarding funding possibilities are constantly updated in the “Calls for Application” section of the INT IntraNet website on the Scientific Directorate web page. A section of the website is dedicated to the 7th Framework Program and a new section to Horizon 2020 (the next EU research and innovation program). It is the duty of the GO to help investigators in preparing and submitting grant applications, promote collaborations among researchers at INT and in other public services, and help them to collaborate on research projects. At the Scientific Directorate office, databases are continuously updated according to emerging needs. The database stores information regarding research projects and INT publications to monitor scientific productivity. The GO maintains contact with the officers in charge of research at the Ministry of Health 9 SCIENTIFIC REPORT 2013 and at the Health Management offices of the Lombardy Region. The activities of the GO include management of ongoing Institutional Projects and design of calls aimed at distributing the funding coming from the Italian 5‰ tax donation. In 2013, the GO provided support for INT researchers in: 61 applications for public funding (Ministero della Salute); 135 applications to private national funding agencies (Associazione Italiana per la Ricerca sul Cancro, Fondazione Berlucchi, Fondazione Cariplo, Fondazione Monzino, etc.) and 42 international funding bodies (American Institute for Cancer Research, Chordoma Foundation, European Commission, Mesothelioma Applied Research Foundation, Swiss Bridge, WIN Consortium, etc.). LOMBARDY ONCOLOGIC NETWORK (ROL) The Lombardy Cancer Network (ROL: “Rete Oncologica Lombarda”) provides a network of organizations and professionals connecting all cancer resources in the region, with over 10,000,000 citizens, in an effort to improve the quality of cancer care and sharing patient data. INT has been the implementing body of the ROL and the Scientific Directorate coordinates all activities since its start-up. ROL is based on clinical cooperation, exchange of information, and sharing and integration of existing cancer facilities. The main goal is the assessment of appropriateness of cancer care on a population level to improve the quality of care by focusing on the cost/efficacy ratio in order to reduce healthcare costs. ROL aims to organize clinical governance resorting to an innovative, feasible, measurable model based on networking of services and providing health benefits to the patient; 58 oncology units are included. ROL designed evidence-based clinical practice guidelines for all solid tumors developed through a consensus process among the oncology community to make a comprehensive impact on clinical oncologic practice. A set of common clinical practice guidelines are annually updated. For each solid cancer, guidelines list all main clinical presentations (“disease phases”) along with their “treatment options”. ROL upgraded the existing non-structured electronic clinical discharge report into a field-based resource, with both free-text and codified fields. Two codified fields enlist, respectively, disease phases as per guidelines, and the corresponding treatment options. If they match, the strategic medical decision is considered tentatively “appropriate”. In 2013, more than 61,000 reports were released. Started in 2012, a research project to set up a system that is able to integrate and analyze all available clinical knowledge and guidelines and correlate this with patient data is ongoing in collaboration with IBM-Italian team and IBM Research-Haifa, Israel to detect causes of mistakes and mismatches by automatically analyzing free-text fields. The system, in addition to the analysis of encoded data, has provided key elements, automatically extracted from text, populating a knowledge model on clinical decisions. BIOMEDICAL LIBRARY The INT Library is affiliated with the European Association for Health Information and Libraries. It offers on-site access to a large collection of basic science paper journals and reference books and electronic access to full text journals, bibliographic databases, and electronic books. The mission of the INT Library, specialized in oncology, is to provide access and management services aimed at meeting the needs of physicians, researchers, and students for the efficient retrieval of information needed for best patient care, advanced research, and postgraduate education. Through participation to the SBBL and Bibliosan consortia, the Library’s electronic resources give access to over 9000 titles. Bibliosan also has a “remote access” option enabling Institute staff to access its services from external sites. The library also offers access to specialized data banks of bibliographic references and 10 back to contents scientific directorate electronic documents such as Medline, Toxnet, Embase, Cochrane Database of Systematic Review (specialized in EBM), Springer E-book, and Springer Images. The international nursing literature is covered by CINAHL – The Cumulative Index to Nursing and Allied Health Literature, with the full text for over 770 journals and 275 books/ monographs in this field. The Library’s collection is supplemented by interlibrary loan services with access to the following catalogues: • GIDIF-RBM: a consortium of key Italian biomedical libraries • SBBL: Biomedical Library System of Lombardy • BIBLIOSAN: a network of 50 Italian Research Institutions sponsored by the Italian Ministry of Health. The library is also a member of ACNP, the National Archival Collection of Periodicals, and is thus linked to over 2300 Libraries in Italy and over 110,000 journals and the Italian framework Nilde (Network for Inter-Library Document Exchange). Library customers can access RefWorks, which is a personal bibliographic management software designed to help researchers gather, manage, and store information, as well as generate citations and bibliographies. To disseminating information via the constantly updated Intranet Library web page, various courses are held to help researchers gather information more easily. EDITORIAL BOARD OF TUMORI In 2013, the Editorial Board of Tumori received 717 manuscripts for publication. In the same year, 6 issues containing 183 reviews, original articles, and case reports were published. For each issue, 5,000 copies were printed. EDITORIAL OFFICE The Editorial Office coordinates and manages all activities related to the production of materials that describe the clinical and scientific activities of the INT. In addition, the Editorial Office oversees the publication of the annual Scientific Report and Brochure, and provides support to individual departments for preparation of more specific materials such as brochures and meeting reports. 11 SCIENTIFIC REPORT 2013 back to contents AWARDS AND RECOGNITIONS • The Comitato Ospedale Donna of the Osservatorio Nazionale sulla Salute della Donna (O.N.Da) awarded the Fondazione IRCCS INT with three “Bollino Rosa” prizes for its care in the research and treatment of female diseases and its attention to the specific needs of admitted women. • The School of Management del Politecnico di Milano awarded the INT for innovation in health care. Recognition given in the category “Clinical Governance and decision support” for the project “Clinical Analytics for Oncology Care Appropriateness” computer system developed in collaboration with IBM. This is an innovative technology solution that provides clinicians with decisional support to evaluate the best treatment for each patient according to clinical reference. Starting from the clinical data provided by INT, a first prototype of a platform for data analysis and decision support for clinicians was built. The system also allows retrospective analysis of the effectiveness of treatment programs already carried out, and compare them with guidelines and decisions made in previous similar cases. The future development of this system will allow associating the cost of processing in order to obtain feedback on the appropriateness and sustainability of the care delivered. • Dr. Egidio Riggio of the Plastic and Reconstructive Unit has named Editor in Chief of the Surgical Techiques Development, a new scientific journal with eISSN 2038-9582. All contents published in this journal are considered Open Access. • Drs. Paolo Bossi and Lisa Licitra of the Head & Neck Cancer Medical Oncology Unit won the Swiss Bridge Award 2013 with the project: “Health and economic outcomes of two different follow-up strategies in effectively cured advanced head and neck cancer”. • Dr. Gemma Gatta, Head of the Evaluative Epidemiology Unit, was invited to participate in the selection for the establishment of the European Union Expert Group on Rare Diseases. • Dr. Gabriella Sozzi, Head of the Tumor Genomics Unit, became President Elect of the Italian Cancer Society (SIC). • Dr. Elda Tagliabue, Head of the Molecular Targeting Unit, was named a member of the Scientific Board of the SIC. • Dr. Carlo Sposito of the Gastrointestinal and Hepatopancreatobiliary Surgery and Liver Transplantation Unit was conferred the “Giovani Ricercatori” award of the Fondazione IRCCS INT. • Dr. Veronica Biassoni of the Pediatric Oncology Unit was conferred the “Giovani Ricercatori” award of the Fondazione IRCCS INT. • Dr. Elena Tassi of the Immunobiology of Human Tumors Unit was conferred the “Giovani Ricercatori” award of the Fondazione IRCCS INT. • Dr. Silvia M. Taverna of the Technology Transfer Office was conferred the “Management Support to Research” award of the Fondazione IRCCS INT. 12 ethics committee ETHICS COMMITTEE The institutional Ethics Committee reviews all new clinical studies submitted by investigators and approved by the Scientific Institutional Review Board. The Committee was established in 1973. A public event held on March 18th 2013 marked its 40th anniversary and was an opportunity to appreciate how some issues discussed as from first meetings are still open to public debate. In 2013, 179 new studies received an ethical approval: 96 were prospective interventional trials, of which 50 were sponsored by pharmaceutical companies and 46 were investigatordriven, while 83 were observational. A total of 468 studies were ongoig in 2013, with a total of 15,965 cases involved, including 2,343 patients enrolled in interventional trials. The median time from submission to discussion was in the range of one month (28 days). This was made possible through an optimized pathway for new study processing, which is carried out in close cooperation with all other relevant institutional bodies (General and Legal Affairs Unit, Economic and Financial Resource Management Unit, and the Pharmacy). These tight institutional collaborations resulted in efficient streamlining of all scientific and administrative components of the ethical review process. In September 2013, the Ethics Committee was reshaped and some members substituted, having already spent two terms. Updated national and regional rules on Ethics Committees gave the new Ethics Committee the additional role to link the Ethics Committees of the 12 comprehensive cancer centers of Lombardia Region. Thus, activities were planned in order to harmonize criteria by which they operate and to host public meetings on some of the most critical aspects pertaining to clinical trials in contemporary oncology. A project focusing on the information process of patients enrolled in clinical trials is in place and will provide its first results in 2014. Its aim is to work out practical tools for patient information in clinical trials, to be based on an analysis of ethical and legal requirements on one side and clinical and psychological needs on the other. Chairman Valter Torri Scientific Secretariat Paolo G. Casali, Bianca M. Francucci Members Bruno Andreoni, Giuseppe Baiguini, Emilio Bombardieri, Carlo Celentano, Emanuele Cereda, Vito Corrao, Francesca Crippa Floriani, Emilio Di Genova, Momcilo Jankovic, Roberto Labianca, Renato Mantovani, Monica R. Miozzo, Eugenio Agostino Parati, Roberta E. Pavesi, Marco A. Pierotti, Tullio Proserpio, Antonio G. Rampoldi, Gabriella Saibene, Francesco Scaglione, Marta Scorsetti, Rita Vetere Administratives Michaela De Palo, Raffaella Didoné, Patrizia Polo 13 SCIENTIFIC REPORT 2013 EDUCATION AND TRAINING INT is strongly committed to educating future scientists and clinicians and is directly engaged in quality education and training. INT offers a wide range of educational activities for clinical and experimental researchers at different stages of their professional careers. PhD studentships, postdoctoral research fellowships, graduate student training, medical residency training, psychology, and social work training, as well as continuing medical education are all included in the portfolio of educational opportunities offered to staff and external participants. Invited lectures, seminars and workshops in a variety of research disciplines related to cancer are regularly arranged. Participants in education and training programs are encouraged to attend interdepartmental journal clubs, clinical case discussions, and grand rounds as well as other multidisciplinary activities aimed to create cross-specialty knowledge. ACADEMIC PROGRAMS INT provides education and training at various levels, including undergraduate, graduate as well as postgraduate medical and biotechnology students, physicians, nursing students, and nurses. On the basis of formal agreements with the University of Milan, INT hosts the Chairs of Medical Oncology (Prof Alessandro M. Gianni), Hematology (Prof Paolo Corradini, Coordinator of the Experimental Hematology Doctoral Program at the University of Milan), Medical Statistics and Biometry (Prof Adriano Decarli), Anesthesiology (Prof Martin Langer), and Pathology (Prof Giuseppe Pelosi). A number of staff members have joint appointments as professors at the University of Milan. INT hosts the “Postgraduate School in Oncology”, the “Postgraduate Medical School in Pathology”, and the 3-year degree in “Nursing Sciences” of the University of Milan. Additionally, INT participates in the degree in “Biotechnology and Molecular Medicine in Oncology”, as well as in two PhD programs at the University of Milan (Hematology and Medical Biotechnology). Every year INT offers a range of highly specialized Master Courses. DOCTORAL (PHD) TRAINING PROGRAM AT INT The INT is an Affiliated Research Center of the Open University, Milton Keynes, UK, providing a PhD Program in Life and Biomolecular Sciences. The program run at INT is regularly monitored to ensure that it meets the requirements of the Quality Assurance Agency (QAA) for Higher Education Code of Practice. INT provides direct support for these training positions and offers fellowship/grants to European Community postgraduate students holding a degree in Medicine, Biological Sciences or Pharmacy. Students are involved in several activities, including induction courses, generic skills training, journal club meetings, and seminars. 14 back to contents education and training OPEN UNIVERSITY PHD STUDENTS AND THEIR RESEARCH TOPICS Mattia Boeri Exploring the Role of microRNA in Early Lung Cancer Alessandra Santangelo SPARC, a Matricellular Protein that Protect Tumors from Therapy Marianna Sasso Biomarkers of Aggressive Phenotype in Triple Negative Breast Cancer Alice Rigoni Mast Cells at the Interface between External Challenges and Immune Regulation in Colitis and Colorectal Cancer Davide Bernareggi Conversion of AFRA Fab into a Fully Human Monoclonal Antibody directed against a Folate Receptor: in vitro and in vivo Studies Daniele Lecis Inhibitors of Apoptosis Proteins (IAPs) as Targets for Anti-Cancer Treatment Ilaria Torselli The Influence of Tumor Microenvironment on Osteosarcoma Gaia Ghedini Role of Δ16HER2 Splice Variant in Response to Drug Targeting HER2 Receptor Sara Ciceri Molecular Characterisation of Wilms Tumor Alice Dassano Expression Networks and Effectors of Genetic Susceptibility to Lung Cancer in Mice Elvira D’Ippolito The Role of microRNAs in Triple Negative Breast Cancer Emanuela Fina Biological and Clinical Significance of Circulating Tumor Cells in Breast Cancer Olga Kuchuk Interference of pH Regulators as an Immunomodulating Therapeutic Strategy for Liver Cancer Emanuela Minna miRNA Deregulation in Thyroid Carcinogenesis: in vitro Models to Study Molecular Mechanisms and Functional Effects. Valentina Profumo The Role of microRNAs in Triple Negative Breast Cancer Andrea Tomirotti Identification of Early Biomarkers of Neoplastic Transformation in Mouse Tumor Models of Breast and Prostate Carcinogenesis Emanuela Fina Biological and Clinical Significance of Circulating Tumor Cells in Breast Cancer Valeria Maiorana Analysis of in vitro and in vivo Effects of Metformin Alone or in Combined Treatments in Colorectal Cancer Martina Magni Functional Characterization of the Human Protein Deleted in Breast Cancer 1 (DBC1) Involvement in the DNA Damage Response Matteo Dugo Investigation of Microenvironment Changes in Breast Cancer Patients through Genomic Approaches and Assessment of their Prognostic Value 15 SCIENTIFIC REPORT 2013 In addition to the students enrolled in the Open University Program, INT hosts PhD students from diverse institutional and disciplinary backgrounds, mainly registered in PhD Courses with Italian Universities: The Preventive and Predictive Medicine Department hosts PhD Students enrolled in the School of Biomedical, Clinical and Experimental Sciences, UNIMI: Laura Angelici, Marco Centola, Chiara Ciniselli, Maria Filomeno, Maria Ghazanfar, Teresa Greco, Elena Landoni, Alessandra Lugo, Elisabetta Marzo, Valentina Rosato, Annalisa Orenti, Delphine Praud, Tiziana Rosso, Maria Giovanna Scarale, Antonella Zucchetto. Attending the Hematology and Pediatric Onco-Hematology Department is Sara Rizzitano (Experimental Medicine and Medical Biotechnologies). The Surgery Department hosts PhD Students from the UNIMI PhD Program in Physiopathological Sciences: Leonardo Duranti, Andrea Billè, and Nicola Rocco (fellowship granted by the Fondazione Adele e Bruno Onlus). The Palliative Care, Pain Therapy, and Rehabilitation Unit hosts Cinzia Brunelli, a PhD student registered in a Program in Palliative Care at the Norwegian University of Science and Technology (Trondheim). The Department of Experimental Oncology and Molecular Medicine hosts the following PhD students: Elena Fusar Poli (Dept BICOM and Neuroscience Center, Insubria University of Varese), Chiara Alberti, Barbara Frigerio, Anna Granata, Katia Rea, Alessandro Satta, and Marcella Tazzari (all registered with the UNIMI Ph.D. School in Biological and Molecular Sciences), Annalisa Conti, Giulia Grazia, Valentina Uva (School of Clinical and Experimental Biomedical Sciences, UNIMI), Maurizio Callari, (PhD School in Biomedical Sciences and Oncology, University of Turin), Valeria Musella (School of Clinical and Experimental Biomedical Sciences, UNIMI). MASTERS • Academic Master in Epidemiology. This is a joint appointment with the University of Turin, ISI Foundation, and INT Unit of Epidemiology and Prevention. • Master in Rectal Surgery. INT and ARECO (Association for the European Research in Surgical Oncology) offer a Rectal Surgery Master for medical doctors with a surgery degree. • Academic Course in Oncologic Lymphology. The course is designed for physicians and students graduating in lymphology and oncologic lymphology. The Unit of Palliative Care, Pain Therapy, and Rehabilitation is the scientific coordinator and is in charge of educational activities, referred to the Medical Faculty of the University of Milan. • Master of Palliative Medicine for Nurses. Under the direction of the University of Milan and in collaboration with INT, this academic course trains graduated nurses to provide palliative care to patients with cancer diseases. • Master in Medical Statistics and Statistical Methods for Epidemiological Research. MSSME is aimed for graduate with Medicine, Biological Sciences, Physics or Statistics degree. Postgraduate course in biostatistics are also provided. Postgraduate students are often directly involved in research projects coordinated by MSBB members. OTHER COURSES The Pathology Department is involved in the training programs of the Postgraduate Medical Schools of Pathology, Endocrinology, and Respiratory Medicine (University of Milan) and of the Soft Tissue Pathology, Postgraduate School of Pathology (Insubria University of Varese). The Anesthesia Department is involved in the training program and residency of the Postgraduate School for Anesthesia and Intensive Care, hosting a number of residents/students and organizing part of teaching in the program of the postgraduate course of the Medical School, University of Milan. Residents in Anesthesia and Intensive 16 back to contents education and training Care, Cardiology, Nutritional Support (University of Milan and Milano-Bicocca) work within all the Units of the Department. Many staff members have teaching positions or are tutors in postgraduate medical schools or in national/international master programs. Within the Surgery Department, the Unit of Colorectal Surgery is affiliated with the General Surgery Residency Programs of the Milano-Bicocca and Pavia Universities; the Unit of Gastrointestinal and Hepatopancreatobiliary Surgery and Liver Transplantation is a training center for the University of Milan and the Italian College of Surgeons and is chosen for clinical fellowships by many visiting clinicians and surgeons every year. In the area of clinical and training activities, the Plastic and Reconstructive Surgery Unit holds very sought-after weekly and 3-monthly surgery courses for Italian and foreign surgeons. The Gynecologic Oncology Unit is chosen for clinical fellowships by many visiting surgeons from Italy and abroad every year. It also organizes a biennial international meeting and a gynecologic oncology course with more than 50 participants three times a year. The Otorhinolaryngology Surgery Unit has close links with the University, and is involved in postgraduate teaching and supervision of junior medical staff. In collaboration with the Human Morphology Department of the University of Milan, this Unit activated two research doctoral degrees to develop a new non-invasive method to evaluate the functionality of the mimetic musculature after iatrogenic damage to the facial nerve. The Unit also collaborates with the Otorhinolaryngoiatric School of Specialization of the University of Milan, hosting students for practical training and organizing lessons and courses. The Thoracic Surgery Unit collaborates with the General Surgery and Thoracic Surgery School of Specialization of the University of Milan, hosting students for practical training. Many postdoctoral fellows attend the Melanoma and Sarcoma Unit that collaborates actively with several medical universities. The Senology Unit collaborates with the University of Milan in teaching and research projects. The Medical Staff of the Diagnostic Imaging and Radiotherapy Department is involved in educational activities cooperating with the University of Milan and Milan-Bicocca in the Radiology, Radiotherapy, and Medical Oncology Specialization Schools, in the Clinical Application of Nuclear Medicine of the Nuclear Medicine School of Specialization. The Radiotherapy Unit also provides tutoring of radiography and radiation technician students. CONTINUING MEDICAL EDUCATION PROGRAM The educational and training program promotes professional, cultural and human growth of INT employees. During 2013, the INT ECM Provider has proposed 196 events in the main areas (clinical governance, on the job learning, risks prevention, and emergency management, etc.) of ECM-CPD (174 were accredited), attracting the interest and the participation of resident and visiting health professionals. In particular, the educational initiatives included in the Business Formation Plan (BFP) have achieved a total amount of 37,886 formative credits, involving 4,750 individuals. 17 SCIENTIFIC REPORT 2013 SEMINARS AND CONFERENCES JANUARY Giovanni Capranico Department of Pharmacy and Biotechnology. University of Bologna Topoisomerase I functions at promoters and genome stability Rosanna Piccirillo Laboratory of Cancer Cachexia, AIRC Start-Up. Oncology Department. Istituto di Ricerche Farmacologiche Mario Negri. Milan The p97/VCP ATPase complex is critical in muscle atrophy and for the accelerated degradation of most muscle proteins FEBRUARY CONTRIBUTION OF NEW TOOLS TO “OMICS” ANALYSIS IN CANCER RESEARCH Chair: Silvana Canevari, Molecular Therapies, Istituto Nazionale dei Tumori. Milan Evaluation of a NGS technologic platform with Health Technology Assessment (HTA) tools Cecilia Melani, Scientific Directorate, Istituto Nazionale dei Tumori. Milan BRCA 1-2 genes target re-sequencing: comparison between Sanger methodology and Ion Semiconductor Sequencing Loris Bernard, IFOM-IEO Campus. Milan New software tools for studying the role of miRNAs in complex regulatory circuits Andrea Bisognin, Laboratory of Computational Genomics, Department of Biology. University of Padova Andy Silver Colorectal Cancer Genetics, Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry. London A role for Dual oxygenase 2 in intestinal tumourigenesis Mahvash Tavassoli Molecular Oncology, Guy’s Hospital. Kings College. London Stratification biomarkers for the treatment of head and neck cancers Elia M. Biganzoli Biostatistics, Section of Medical Statistics, Biometry and Bioinformatics « Giulio A. Maccacaro ». Department of Clinical Sciences and Community Health, University of Milan. Campus Cascina Rosa, Istituto Nazionale dei Tumori. Milan The statistical bioinformatics in the era of “big data” Raimo Tanzi NGS Business Development, Lifetechnologies. Europe Solid Widfire INT users meeting: introduction to the technology, the presentation of applications and protocols available on the SOLiD 5500WF, feasibility studies and cost microRNA Workshop Chair: Franco Martinez, EuroClone. Pero. Milan Analysis of circulating microRNA biomarkers for cancer Hazel Pinheiro, Exiqon. Denmark The miRNA workflow Laura Monti, EuroClone. Pero. Milan MARCH Mario Ciocca Unit of Medical Physics. CNAO Foundation, Pavia Hadrontherapy, new infallible weapon: another election promise ? 18 back to contents education and training MAY Evi Lianidou Laboratory of Analytical Chemistry. Analysis of Circulating Tumor Cells (ACTC) Lab. Department of Chemistry – University of Athens. Athens. Greece Circulating Tumor Cells: Recent advances in their detection and molecular characterization Uppugunduri Srinivas Department of Clinical Chemistry, University Hospital, Linköping. Sweden Novel anti-infiammatory drug candidates Robert Clarke Breast Biology Group. Institute of Cancer Sciences. Paterson Building. University of Manchester. Wilmslow Road. Manchester Signalling pathways regulating breast cancer stem cells Peter K. Rogan Canada Research Chair in Genome Bioinformatics, Tier I, Biochemistry & Computer Science. University of Western Ontario Discovery and predicting impact of non-coding sequence variants that affect gene expression on a genome scale and in inherited breast cancer JUNE Michele Visentin Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York Insight the cellular pharmacology of pralatrexate - a new weapon against the Non-Hodgkin lymphomas Stefano Cairo Laboratory of Head R&D Xentech – France Patient-derived xenografts to assist basic research and clinical practice Stephanie Dorman Department of Biochemistry, Schulich School of Medicine and Dentistry Western University, London, Canada Graduate studies in cancer genetics: exchanging experiences between Canadian and Italian Institutions Augusto Pessina Department of Biomedical, Surgical and Dental Sciences. University of Milan Mesenchymal stromal cells for the transportation of paclitaxel: potential applications Workshop: “Mast cells: host defense or offence?” Stephen J. Galli - Department of Pathology, Stanford University, CA Rosetta Pedotti - Neuroimmunology Unit, Istituto Neurologico Besta, Milan Mario P. Colombo - Molecular Immunology Unit, Experimental Oncology and Molecular Medicine Department, Istituto Nazionale dei Tumori, Milan Claudio Tripodo – Department of Human Pathology, University of Palermo Carlo Pucillo - Department of Biomedical Science and Technology, University of Udine JULY Yosef Yarden Department of Biological Regulation - Weizmann Institute of Science - Rehovot, Israel HER2 and EGFR: Signalling mechanisms and next generation cancer therapies Jörg Mages Field Application Scientist at Partek, Inc The Ease of Flow: Intuitive and Sophisticated Analysis of Tumor Cell lines using Partek Software 19 SCIENTIFIC REPORT 2013 Anil K. Sood Ovarian Cancer Research, Department of Gynecologic Oncology, University; Center for RNA Interference and Non-Coding RNA, The University of Texas. MD Anderson Cancer Center, Houston, TX About Trousseau, Platelets and Ovarian Cancer Anna Saran Laboratorio di Biologia delle Radiazioni e Biomedicina, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, Roma New paradigms in radiobiology: Evidence for radiation induced bystander effects Diana Eccles Cancer Genetic Faculty of Medicine Academic Unit of Cancer Sciences. University of Southampton, University of Southampton Clinical Trials Unit, Clinical Genetics University Hospital Southampton Foundation Trust – UK Genetic background determines breast cancer sub-types and prognosis SEPTEMBER GENOMICS IN ONCOLOGY: UNDERSTANDING THE PATHOBIOLOGY AND DEVELOPMENT OF INFORMATIVE ESSAYS FROM THE CLINICAL POINT OF VIEW Chair: Silvana Canevari, Molecular Therapies, Experimental Oncology and Molecular Medicine Department, Istituto Nazionale dei Tumori, Milan Maria Grazia Daidone, Biomarkers, Experimental Oncology and Molecular Medicine Department, Istituto Nazionale dei Tumori, Milan Giampaolo Bianchini, Department of Medical Oncology. Ospedale San Raffaele. Milan Francesca De Michelis, Center for Integrative Biology (CIBIO), University of Trento Antonino Neri, Department of Clinical Sciences and Community, University of Milan, Hematology CTMO, Fondazione Cà Granda IRCCS Ospedale Policlinico. Milan OCTOBER Andrew R. Reynolds Tumor Biology Team. The Breakthrough Breast Cancer Research Centre The Institute of Cancer Research . London Vessel co-option: an under-appreciated phenomenon with profound consequences for the clinical translation of anti – angiogenic therapy and Anti – angiogenic therapy: from bench to bedside and back again Alessandro Santin Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT-USA Homing Devices and Microscopic Shuttles-Iron Oxide Nanoparticles functionalized with Clostridium Perfringens Enterotoxin (CPE) as Novel Agents for Ovarian Cancer Diagnosis and Therapy Dèsirèe Bonci Department of Hematology, Oncology and Molecular Medicine. ISS, Rome Role of microRNA in primary and metastatic prostate cancer NOVEMBER MASS SPECTROMETRY IN THE FIELD OF EXPERIMENTAL AND CLINICAL ONCOLOGY Chairs: Italia Bongarzone, Rosaria Orlandi, Maria Grazia Daidone, Experimental Oncology and Molecular Medicine Department, Istituto Nazionale dei Tumori, Milan Mass spectrometry in the field of proteomics: recent discoveries and projects in progress Italia Bongarzone, Cancer Proteomics Mass spectrometry at low and high resolution to analyze peptide and metabolomic profiles of plasma and breath of patients with breast cancer Rosaria Orlandi, Molecular Targeting The new platforms: potential and applications Giulia Garrone, Samuele Pedraglio e Adalberto Cavalleri, Preventive and Predictive Medicine Department 20 back to contents education and training Metabolomics diagnosis by GCMS and LC-MS/MS Valerio Leoni, Laboratorio di Patologia Clinica e Genetica Medica. Istituto Neurologico “Carlo Besta” Interpretation of metabolomic profiles in experimental models Silvana Canevari, Molecular Therapies, Istituto Nazionale dei Tumori, Milan Matteo Bellone, Cellular Immunology Unit, Istituto Scientifico San Raffaele, Milan & Maria Grazia Daidone, Experimental Oncology and Molecular Medicine Department, Istituto Nazionale dei Tumori, Milan Circulating tumor cells, “not everything that can be counted counts, and not everything that counts can be counted” DECEMBER Massimo Gadina Translational Immunology Section, Office of Science and Technology, National Institute of Arthritis Musculoskeletal and Skin diseases, National Institutes of Health. Bethesda Janus Kinase Inhibitors: from autoimmunity, to inflammation to malignancies 21 CLINICAL ACTIVITY DATA back to contents clinical activity data INpatients by Geographical Area (overall 14,253) northwest 6%% lombardy northeast 65% 4% south 11% center 8% outside Number of normal admissions during 2013 divided according to major geographic areas. The total number of admissions increased (14,253 in 2013 vs. 13,904 in 2012). 1% islands 5% OUTpatients by Geographical Area (overall 7397) northwest 4%% northeast lombardy 4% 78% south 6% center 3% Number of admissions in a Day Hospital (DH) setting during 2013 in each major area. The total number of admission in DH slightly decreased (7397 in 2013 vs. 7727 in 2012) due to the introduction of a new type of assistance, namely complex ambulatory activity. outside 1% islands 3% 23 back to contents SCIENTIFIC REPORT 2013 Inpatients: average length of stay over the years Medical Oncology Medical SurgeryOncology Average duration of admission in days, both medical and surgical, among those lasting more than one day. A further decrease in the mean duration of admission, for both medical and surgical admissions, was observed. Surgery 9.03 8.95 8.91 9.03 8.95 8.91 5.96 5.96 8.34 8.49 8.49 8.53 8.34 8.49 8.49 8.53 5.47 5.66 5.80 5.47 5.66 5.80 5.90 5.90 5.92 5.90 5.90 5.92 7.42 7.14 7.42 7.14 6.83 6.83 4.93 4.93 4.83 4.53 4.83 4.53 2004 2004 2005 2005 2006 2006 2007 2007 2008 2008 2009 2009 2010 2010 2011 2011 2012 2012 2013 2013 Inpatients: over the years (length of stay >1 DAY) Medical Oncology Number of total admissions, medical and surgical, with recovery times exceeding one day. Medical SurgeryOncology Surgery 6925 6945 6945 6347 6347 5347 5347 2004 2004 24 5959 5959 7145 7145 6250 5965 6174 5987 6250 5965 6174 5987 6705 6802 5994 6705 6802 5994 5786 5574 5508 5452 5594 5804 5427 5574 5508 5452 5594 5804 5427 2005 2005 2006 2006 2007 2007 2008 2008 2009 2009 2010 2010 6925 5786 2011 2011 2012 2012 2013 2013 clinical activity data outpatient visits (overall 166,387) Private Patients 18,684 Transfusion Unit 6,188 Anesthesia, Intensive Care, Palliative Care 19,902 Diagnostic Imaging & Radiotherapy 12,691 Surgery 55,500 Medical Oncology 53,422 The graphs are based upon currently used data: on SDO information and on Budget and Management Control’s Data. 25 CLINICAL SCIENTIFIC S T N E M T R A P DE back to contents clinical-scientific departments SURGERY DEPARTMENT DIRECTOR OF DEPARTMENT: Ugo Pastorino +39 02 23902906 [email protected] The Department of Surgery treats oncological diseases that affect all areas of the body except for the brain, providing elective and emergency surgical activity, in ordinary inpatient and day hospital regimens, as well as specialist outpatient activity for diagnosis and follow-up. Routine clinical activity ensures a high standard of care for all surgically-treated patients, providing conservative surgery (organ/function preserving or minimally invasive) for early stage disease and combined treatment modalities for advanced disease. The Department is organized in the following Units: Gastrointestinal, HepatoPancreatobiliary Surgery, and Liver Transplantation. Has the goal to improve the standard of care for primary and secondary tumors affecting the liver, biliary system, pancreas, and gastrointestinal tract. In the field of hepato-oncology, it offers the complete range of the most up-to-date therapeutic options for liver cancer, including liver transplantation, minimally-invasive and computer assisted surgery, transarterial chemo-/radio-embolization, percutaneous and laparoscopic tumor ablation, and targeted molecular therapies. The Unit is a pioneer in computed-assisted liver surgery performed using an ultrasound navigation system that allows localization of tumors deep in the liver that are not visible with conventional ultrasound. Colorectal Surgery. Devotes special attention to tumors of the distal rectum and has established high standards of care for the management of this subset of patients. Conservative, function-preserving surgical techniques to avoid extensive resection an definitive colostomy have been perfected. The Peritoneal Surface Malignancies (PSM) program is responsible for the treatment of pseudomyxoma peritonei, peritoneal mesothelioma, and peritoneal carcinomatosis from colorectal cancers. In 2013, an important study was published on the role of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Breast Surgery. Clinical activity includes all aspects of breast cancer treatment, i.e. diagnosis, primary and adjuvant therapy, and follow-up. Enhanced understanding of the pathogenesis of breast cancer coupled with a growing interest in improved esthetic results led to the investigation of skin- and nipple-sparing mastectomy as a potential improvement over conventional mastectomy. In 2013, the longstanding experience on breast conserving surgical treatment was further strengthened by the publication of the final results of a randomized controlled clinical trial on breast cancer treatment without axillary surgery. 27 SCIENTIFIC REPORT 2013 Melanoma and Sarcoma. Comprises all aspects of melanoma and sarcoma treatment, i.e. diagnosis, primary and adjuvant therapy, and follow-up. The Unit conducts clinical trials in the field of adjuvant therapy for melanoma and pre-operative therapy for sarcoma. The Unit is the referring center for melanoma and sarcoma guidelines. Diagnostic Endoscopy and Endoscopic Surgery. Includes activities of the multidisciplinary endoscopy, i.e., diagnostic and therapeutic procedures of the gastrointestinal, biliopancreatic, respiratory, and urinary tracts. The Unit is particularly committed to cancer prevention and diagnosis and treatment of early cancers. Otolaryngology Surgery and Maxillo-Facial Surgery. Specialized in the treatment of benign and malignant tumors of the head and neck area. State-of-the-art surgical treatment for patients with head and neck tumors is guaranteed by experts from across disciplines: otolaryngologists and maxillofacial surgeons. Gynecologic Oncology. Deals mainly with primary and secondary tumors of the female genital tract. Surgical research was conducted on the following techniques: nerve sparing radical surgery, debulking surgery, mini-invasive surgery, laparoscopic surgery in diagnosis, staging and treatment of early gynecological tumors; sentinel node detection in endometrial cancer. Thoracic Surgery. Covers all aspects of thoracic oncology, focusing on pulmonary, mediastinal, chest wall, and esophageal tumors. In the management of lung cancer, the mainstay of surgical treatment is maximal functional sparing. Innovative techniques for tridimensional chest wall reconstruction have been developed (rib-like technique), permitting appropriate reconstruction even in case of removal of an entire hemithorax. In mediastinal surgery, superior vena cava (SVC) replacement is performed by procedures not requiring SVC cross-clamping, avoiding intraoperative hemodynamic instability. Pleuro-pneumonectomy is proposed in limited malignant mesothelioma, after induction chemotherapy. Plastic and Reconstructive Surgery. Performs reconstructive surgical procedures related to extensive breast and head and neck surgery, soft-tissue tumors, chest-wall surgery, and other types of aggressive oncologic surgery, as well as surgical treatment and repair of skin cancer. Oncoplastic surgery represents a new standard for reconstructive procedures after tumor excision. Urologic Surgery. Strengthens multidisciplinary care and clinical trials in difficult to treat diseases. In particular, a number of phase II clinical trials have been approved in different clinical settings of urothelial, testicular, and penile cancer and are initiating in 2014. Most importantly, a primary objective of the Unit is to develop a modern framework for clinical research, and with this aim the collaboration with EORTC was fulfilled, together with the establishment of an urothelial cancer patient advocacy group. The multicentric international cooperation for next generation sequencing analyses was another endpoint, and collaboration with MSKCC as well as with UAB Comprehensive Cancer Center of Alabama has been established in urothelial and penile cancers, respectively. The objective of these collaborations will be to characterize extreme responders to specific targeted drugs as well as conventional therapy from a molecular standpoint in order to provide information to design informed clinical trials in multiple urological cancers. Pediatric Surgery. Collaborates with pediatric oncologists and provides a high standard of treatment for the most frequent solid – non-CNS – tumors in children and adolescents. The role of surgery is established according to ongoing European treatment protocols. Laser Therapy Unit. Uses high-quality instrumentation including four lasers for a total of 20 wavelengths. It allows conservative and ablative therapies in diseases where laser therapy is the first or only treatment choice. Selective photothermolysis laser treatment is performed for keloids as well as pigmented and vascular lesions, and laser ablation is used for mucosal and skin cancer lesions requiring histological evaluation. Day Surgery Unit. Devoted to surgical procedures performed in ambulatory and day hospital settings. The clinical activity covers many aspects of oncologic surgery, and in 28 back to contents clinical-scientific departments particular includes the treatment of different lesions involving skin, soft tissues, breast, as well lesions in gynecologic, urologic, and head and neck areas. This activity involves the collaboration of physicians from Units within the Surgical Department. HIGHLIGHTS The Liver Transplant Program is mainly focused on establishing oncological guidelines and plays a leading role worldwide in defining consistent indications and prospective lines of research. INT is a referral center for soft-tissue sarcomas of the limbs and trunk, as well as retroperitoneal sarcomas, GIST, and axial bone sarcomas. A special effort is dedicated to the Regional Colorectal Cancer Screening Program as well as to endoscopic surveillance of patients affected by familial adenomatous polyposis (FAP) or Lynch syndrome. Lung cancer early detection program: at INT a large prospective study in heavy smokers volunteers is ongoing, based on plasma miRNA profiling to assess its efficacy as a first line screening test for lung cancer detection (www.biomild.org). INT is certified as a Center of Excellence by the European Society Neuroendocrine Tumors (ENET). KEYWORDS liver transplantation, peritoneal carcinomatosis, locoregional therapy, immunotherapy, cancer prevention, laser therapy, skin cancer, lung cancer, screening GASTROINTESTINAL, HEPATOPANCREATOBILIARY SURGERY, AND LIVER TRANSPLANTATION Head Vincenzo Mazzaferro, MD Clinical Research Staff Carlo Battiston, MD; Sherrie Bhoori, MD (hepatogastroenterologist); Jorgelina C. Coppa, MD; Christian Cotsoglou, MD; Alessandro Germini, MD; Andrea Pulvirenti, MD; Enrico Regalia, MD; Raffaele Romito, MD; Carlo F. Sposito MD COLORECTAL SURGERY Head Ermanno Leo, MD Clinical Research Staff Dario Baratti, MD; Luigi Battaglia, MD; Filiberto Belli, MD; Giuliano Bonfanti, MD; Alessandro Cesa Bianchi, MD; Marcello Deraco, MD; Shigeki Kusamura, MD, PhD; Marco Vitellaro, MD Residents Marcello Guaglio, MD; Mario Moschita, MD; Giovanni Piscitelli, MD; Vincenzo Pruiti, MD; Monica Zisa, MD Research Staff Marco A. Bongini, MD; Maria F. Reyes, MD; Daniela Sia, MD; Elisa Sottotetti, MD Administrative Personnel Roberta Aceto Residents Davide Citterio, MD; Glenda Grossi, MD; Cecilia Muscarà, MD; Marco Nencioni, MD; Matteo Origi, MD Nurses Fabiana Bettoni, Lucia Caracciolo, Rut Cittadin, Angela Colamonaco, Stefania Labori, Magdalena-Alonso Manuel, Marica Melis, Vanessa Neri, Palma, Mirtha Ybazeta Ramos, Riccardo Vacca Administrative Personnel Elisa Giavari and Francesco Roncacci (Unit secretaries); Daniela Guarneri and Nela Zito (scientific secretaries); Simona G. Marchesi (data manager) Healthcare Assistants Monica Anzaghi, Isabella Damasi, Nunzia Di Perna, Fabio Lizzano, Maria Petrosina Nurses Paola Serafin (coordinator), Adriana Blanco, Salvatore Bonafede, Annateresa Bugada, Morena De Santis, Milda Di Giacomo, Angela Mihaela Farcas, Stefania Fici, Francesca Maiorano, Antonella Masiello, Monica Mitarotonda, Nadia Nicoletti, Patrizia Perotto Ghi, Patrizia Rota, Rossina Sitta, Stefania Sperandio, Cristina Stracquadaini, Patrizia Valentini BREAST SURGERY Head Roberto Agresti, MD (until 30 November) Marco Greco, MD (since 1 December) Healthcare Assistants Nicoletta Damiani, Rosa De Felice, Mariangela Lopriore, Annamaria Pancari, Angela Restaini, Enza Spina, Anna Vecchio Clinical Research Staff Silvia Bohm, MD; Alberto Rudy Conti, MD; Cristina Ferraris, MD; Massimiliano Gennaro, MD; Maria Ilaria Grosso, MD; Gabriele Martelli, MD; Cristina Pellitteri MD (until 30 November); Domenico Piromalli, MD, Gianbattista Spatti MD Research Fellows Mario Rampa, MD; Alessandra Moscaroli, MD (until August 30th), Ilaria Maugeri, MD 29 back to contents SCIENTIFIC REPORT 2013 Administrative Personnel Angela Allegri Nurses Irene Alessandrini, Giovanni Cavaliere, Miriam P. Conti, Stefano Licata, Bruna Nuscis, Maria C. Puddu, Michele Rossello, Gelsomina Sasso, Francesco A. Spagnolo, Liliane Venafra Healthcare Assistants Maria C. Fadda, Luigi Magnifico, Caterina Pianu MELANOMA AND SARCOMA Head Mario Santinami, MD Clinical Research Staff Melanoma Francesco Gallino, MD; Andrea Maurichi, MD; Daniele Moglia, MD; Roberto Patuzzo, MD; Roberta Ruggeri, MD Surgery of Sarcoma Alessandro Gronchi, MD (Head); Marco Fiore, MD; Chiara Colombo, MD, Stefano Redaelli, MD Research Staff Valentina Girgenti, MD; Roberto Grillo, MD; Elena Tolomio, MD Residents Consuelo Barbieri, MD; Federica Marazza, MD OTOLARYNGOLOGY SURGERY Head Gabriele Scaramellini, MD Clinical Research Staff Roberto Bianchi, MD; Sarah Colombo, MD; Walter Fontanella, MD; Marco Guzzo, MD; Tullio M. Ibba, MD, PhD; Natalia R. E. Pizzi, MD; Madia Pompilio, MD; Stefano Riccio, MD Nurses Vincenzo Spanò (coordinator), Giovanna V. Bello, Petronilla D’Agostino, Elena Cotellessa, Angelo Di Caro, Giorgio Fumi, Giorgio Inverni, Carmen Minio, Rosita A. Nanna, Laura Ongari, Daniele Pezzera, Francesca Pisano, Federica Prudenzano, Raffaella Repetto, Maura Rimoldi, Maria S. Selva Technicians Pablita Endaya, Vincenzo Marotta, Giuseppe Messana, Laura Somma Administrative Personnel Sabrina Zazzera GYNECOLOGIC ONCOLOGY Head Francesco Raspagliesi, MD Administrative Personnel Antonella Vescera Clinical Research Staff Antonino Ditto, MD; Rosanna Fontanelli, MD; Barbara Grijuela, MD; Domenica Lorusso, MD; Marina Merola, MD; Andrea Papadia, MD; Eugenio Solima, MD; Flavia Zanaboni, MD Data Managers Annabella Di Florio, Adele Di Fazio, Giulia Bonarini Research Fellows Fabio Martinelli, Stefano Ramondino, Maria Mancini, Italo Sarno Research Nurse Gabriella Nicolò Nurses Patricia A. Costa, Alice Casali, Francesco Crugliano, Floriana Dimo, Lorenza Greco, Eva Guitti, Antonio Micello, Marianna Miranda, Claudio Oppido, Rossana Penasa, Ylenia Ponti, Paolo Re, Patrizia Valente Nurses and Healthcare Assistants Giovanna Lomartire (coordinator), Nicola Abatangelo, Roberta Allenza, Annamaria Biondo, Sonia Cappellini, Annarita Carluccio, Alessio Cremonesi, Nello Curatolo, Floarea Dorca, Loridana Marino, Silvana Mirante, Erica Panigada, Giusy Pede, Lucia Preto, Esther Reinoso Crespo, Francesca Ruiu, Claudia Sonzogni, Antonella Tomasicchio, Monica Ullio, Addolorata Volpe DIAGNOSTIC ENDOSCOPY AND ENDOSCOPIC SURGERY Head Emanuele Meroni, MD Clinical Research Staff Giovanni Ballardini, MD; Giuseppe Calarco, MD; Gabriele Delconte, MD; Gianfranco Di Felice, MD; Massimo Falsitta, MD; Andrea Mancini, MD Nurses Vittorio Mauro (coordinator), Francesco Bottani, Raffaele Calò, Roberto Fiocco, Daniele Lo Curcio, Francesca Mannai, Giovanni Sammartino, Raffaele Quagliolo Technicians Silvia Cara, Rosanna Loi, Salvatore Morfeo Administrative Personnel Concetta Di Quattro, Annamaria Mercuri 30 Health Care Assistants Rosa Farro, Alessia Formicola, Natalia Munante, Cecilia Muzzupappa Administrative Personnel Cinzia Marretta, Rosella Zennoni, Stefano Ramondino, Maria Mancini, Italo Sarno THORACIC SURGERY Head Ugo Pastorino, MD Clinical Research Staff Andrea Billè, MD, PhD student; Leonardo Duranti, MD, PhD student; Riccardo Giovannetti, MD; Francesco Leo, MD, (until March 2013); Paolo Scanagatta, MD; Luca D. Tavecchio, MD Fellows Giuseppe Garofalo, MD; Mara Gisabella, MD; Stefano Sestini, MD Resident Lara Girelli, MD Nurses Federica Pirovano (coordinator), Brice Atiomeguim, Francesco Auletta, Marcella Bernardo, Claudia Costa, Yesica Del Rio Mendez, Antonino De Vita, Raffaele Di Nino, Margherita Fersurella, Hilda A. Martinez, Daniele Marino, Maria L. Quitadamo, Anna M. Panareo, Antonio Pantano, Antonella Prete, Antonino Proto clinical-scientific departments Technicians Oss Nekpen Eguavoen, Angela Di Luglio, Diego Risuglia, Svitlana Shulzhenko, Pamela K. Soto Fernandez Administrative Personnel Tiziana Negri (Unit secretary) Research Staff Elena Bertocchi (Research Coordinator) Anna Maria Calanca, Carolina Ninni (Scientific secretaries), Claudio Jacomelli (Informatics); Paola Suatoni (Biol Sci D) External Collaborator Nicola Sverzellati (Radiologist) Testicular Cancer Surgery Nicola Nicolai, MD (Coordinator) Pediatric Surgery Luigi Piva, MD (Coordinator) Nurses Graziella Russo (coordinator), Rosanna Candigliota, Maria L. Cennamo, Anna M. Cercaci, Zino Ferro, Francesca Marelli, Lucia Mesiano, Arturo Monetta, Valentina Musarò, Giuseppa Napoli, Veronica P. Rojas, Annalisa Simone, Raffaella Rossi, Rita Sciancalepore Administrative Personnel Maria G. Bodini PLASTIC AND RECONSTRUCTIVE SURGERY Head Maurizio B. Nava, MD Technicians Elena Cristiani, De La Cruz, Velesmoro Rocio Del Pilar, Olimpia Liberatore, Anna Mastroianni, Isabella Vurchio, Clinical Research Staff Novella Bruno, MD; Pierfrancesco Cadenelli, MD; Umberto Cortinovis, MD; Joseph Ottolenghi, MD; Angela E. Pennati, MD; Egidio Riggio, MD; Andrea Spano, MD LASER THERAPY Head Anna Colombetti, MD Nurses Maria Saracino (coordinator), Samantha F. Castelli, Cinzia Gentilini, Giusppe L’Abbate, Marisa Labò, Giovanna Melia, Caterina Pireddu, Irene Rossi, Raffaella Tupputi Technicians Nadia Casati, Provvidenza Peci, Nomi Ibazeta Ramos, Iolanda Panipucci, Annunziata Rugolo Administrative Personnel Luisa Morandi UROLOGIC SURGERY Head Roberto Salvioni, MD Clinical Research Staff Davide Biasoni, MD; Mario A. Catanzaro, MD; Alessandro Crestani, MD (Fellow, University of Padua School of Urology); MD; Elena Farè, MD (Fellow, University of Milan School of Medicine); Patrizia Giannatempo, MD (Resident, Department of Medical Oncology, Medical Oncology Unit 2); Andrea Guttilla, MD (Fellow, University of Padua School of Urology); Massimo Maffezzini, MD; Andrea Necchi, MD (Faculty, Department of Medical Oncology, Medical Oncology Unit 2); Daniele Raggi, MD (Fellow, University of Milan School of Medicine); Silvia Stagni, MD; Tullio Torelli, MD Clinical Research Staff Silvia Aiello, MD; Mario Z. Raso, MD Nurses Maria Saracino (coordinator), Emilia D’Arrigo Healthcare Assistant Domenica Lo Prete Administrative Personnel M. Rosaria Aceto DAY SURGERY Head Aldo E. Bono, MD Nurses Giovanna R. Colaci, Mariangela Lena, Mara D. Luisoni, Pina P. Mele, Anna Picciallo, Domenica Violi, Marina Zocchi Healthcare Assistants Antonella Bordoni, Silvia Cara, Rosa Selvati Administrative Personnel Maria R. Bignamini, Anna Corella, Loredana Orezzi FOR MORE INFORMATION ABOUT THE UNITS, VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT 31 back to contents SCIENTIFIC REPORT 2013 MEDICAL ONCOLOGY DEPARTMENT DIRECTOR OF DEPARTMENT: Filippo de Braud +39 02 2390 3066 [email protected] The Department carries out comprehensive cancer treatments in adults with solid tumors and performs research focusing on new drug development and treatment strategies. Opportunities are maximized for inter-departmental and inter-institutional collaborations to ensure the forefront of patient care and oncology research. The Medical Oncology Department comprises various clinical medical units and a centralized day hospital; outpatients visits are performed in dedicated rooms. The Department is organized in the following Units: Medical Oncology 1. New drug development (phase I, early phase II), breast cancer, gastrointestinal tumors (gastric, colorectal, neuroendocrine, pancreatic and biliary tract), melanoma, thoracic tumors (lung cancer, mesothelioma, thymoma), urogenital tumors (renal and prostatic cancer). Medical Oncology 2. Preclinical and clinical activities mainly for malignant lymphomas, germ cell tumors and bladder cancer. Medical Day Hospital. Deals with adult patients referred by the clinical Units of the Department, as well as diagnosis, treatment, and follow-up of neuroendocrine tumors. Adult Mesenchymal Tumor Medical Oncology. Clinical research and care in sarcomas and peritoneal mesothelioma. Head and Neck Cancer Medical Oncology. Clinical research and care in cancer, thyroid, and salivary gland cancer. Cardiology. Evaluation of patients subjected to surgery and medical treatments. Followup of cardiovascular toxicities due to antineoplastic treatments (see Shared Research Resources page 59) Respiratory Pathophysiology. Evaluates patients addressed to surgery and medical treatments. Follow-up of pulmonary toxicities due to chemo-radiotherapy. Hospitalbased tobacco control policies as well as outpatient and inpatient smoking cessation clinic activities (see Shared Research Resources page 59). 32 clinical-scientific departments HIGHLIGHTS Overall, 58 studies ranging from Phase I to an antismoking campaign [Phase I (8), Phase II (19), Phase III (15), Observational (16)] were activated in 2013. New drug development (Phase I and Ib studies) and the promotion of translational research projects. An entire unit is fully dedicated to Phase I and early Phase II studies. Translational research on prognostic and/or predictive biomarkers to investigate new therapeutic strategies for all solid tumors (upper and lower gastrointestinal tract cancer, non-small cell lung cancer, malignant pleural mesothelioma, thymoma, breast cancer, and genitourinary tumors). New generation targeted therapy and immunotherapy for malignant melanoma, lung cancer, gastrointestinal tumors, and prostate cancer. Translational research on poor prognosis relapsed/refractory lymphoma with the development of new chemotherapy approaches and combinations of targeted therapeutics. Health organization and networking in rare tumors: coordination of the Italian Network on Rare Cancers (about 800 new sarcoma patients shared clinically within the project; activation of an educational Web site); coordination of the rare cancer area of the Rete Oncologica Lombarda (ROL, the cancer network of Lombardy Region); involvement in the European RareCareNet project (“Information network on rare cancers”). Translational research on predictive biomarkers, new drug development including rare head and neck cancer and thyroid cancer, studies in supportive care. Cardiologic surveillance to assess the cardiotoxicity of new experimental drugs (monoclonal antibodies, receptor tyrosine kinase inhibitors, BRAF inhibitors, MEK inhibitors). Preclinical studies on the pharmacogenetics of smoking cessation drugs as well as the safety of new electronic cigarette devices in terms of second-hand vapor exposure. INT is certified as a Center of Excellence by the European Society Neuroendocrine Tumors (ENET). KEYWORDS new drug development, personalized medicine, high-dose chemotherapy, immunotherapy, rare cancers, pharmacovigilance, neuroendocrine tumors, smoking cessation clinic, cardiotoxicity MEDICAL ONCOLOGY 1 Head Filippo de Braud, MD Clinical Research Staff Giulia V. Bianchi, MD; Giuseppe Capri, MD; Luigi Celio, MD; Sara Cresta, MD; Michele Del Vecchio, MD; Maria Di Bartolomeo, MD; Serena Di Cosimo MD; Marina Garassino, MD; Gabriella Mariani, MD; Angela Moliterni, MD; Marco Platania, MD; Giuseppe Procopio, MD; Elena Verzoni, MD; Nicoletta Zilembo, MD Postdoctoral Fellows Valentina Colonna, MD; Silvia Damian, MD; Elena De Benedictis, MD; Lorenza Di Guardo, MD; K. Fiorella Dotti, MD; Francesco Gelsomino, MD; Paolo Grassi, MD; Eva R. Haspinger, MD; Roberto Iacovelli, MD; Paola Mariani, MD; Filomena Panzone, MD; Filippo Pietrantonio, MD; Lorenzo Pilla, MD; Sara Pusceddu, MD; Danila Serpico, MD; Vitali Milena, MD; Elisa Zanardi, MD Research Staff Benedetta Bardazza and Alessandra Castano (Research Nurses); Antonia Martinetti, Biol Sci D; Elisa Sottotetti, Biol Sci D Residents Francesco Agustoni, MD; Pamela Biondani, MD; Matteo Duca, MD; Arpine Gevorgyan, MD; Alice Indini, MD; Claudia Maggi, MD; Alessia Mennitto, MD; Monica Niger, MD; Francesca Ricchini, MD; Lorenzo Sica, MD; Anna Tessari, MD; Isabella Testa, MD Administrative Personnel Barbara Formisano, Giuseppa Iannaci, Sabrina Lanterna, Susanna Maggi Data Managers Valentina Sinno, DSc (coordinator); Ilaria Bossi, DSc; Rosaria Gallucci, DSc; Silvia Sesana DSc; Alessandra Siliprandi, DSc; Eleonora Sparacio DSc; Irene Vetrano, DSc MEDICAL ONCOLOGY 2 Head Alessandro M. Gianni, MD Clinical Research Staff Liliana F. Devizzi, MD; Massimo A. Di Nicola, MD; Anna Guidetti, MD; Michele Magni, MD; Paola Matteucci, MD; Andrea Necchi, MD; Simonetta Viviani, MD Research Staff Anna Rossini, Fellow; Giusi Ruggero, Fellow; Roberta Zappasodi, PhD Postdoctoral Fellow Patrizia Giannatempo, MD Residents Barbara Bocci, MD; Emanuela Paternò, MD Healthcare Assistants Antonietta M. Maglione, Agnese Lasala, Loredana Costa, Mauro L. Pedretti, Antonella Di Perna Administrative Personnel Maria Luisa Longhi 33 back to contents SCIENTIFIC REPORT 2013 Data Manager Liana Bevilacqua ADULT MESENCHYMAL TUMOR MEDICAL ONCOLOGY Head Paolo G. Casali, MD Clinical Research Staff Rossella M. Bertulli, MD; Elena R. Fumagalli, MD; Michela Libertini, MD; Elena Palassini, MD; Roberta G. Sanfilippo, MD; Silvia Stacchiotti, MD Residents Vittoria Colia, MD; Salvatore Provenzano, MD Administrative Personnel Stefania Cimbari, Anabela Di Giovanni, Paola Esposti, Elisabetta Prati Data Managers Federica Favales, Paola Pistillo HEAD AND NECK CANCER MEDICAL ONCOLOGY Head Lisa Licitra, MD Clinical Research Staff Cristiana Bergamini, MD; Paolo Bossi, MD; Roberta Granata, MD; Laura Locati, MD; Aurora Mirabile, MD Residents Martina Imbimbo MD; Carlo Resteghini, MD Administrative Personnel Stefania Cimbari, Anabela Di Giovanni, Paola Esposti, Elisabetta Prati Data Managers Camilla Cassani (coordinator), Federica Favales MEDICAL DAY HOSPITAL Head Roberto Buzzoni, MD Clinical Research Staff Laura A.M. Ferrari, MD Clinical Fellow Cristina Bregant, MD Administrative Personnel Anna R. Cabiddu, Antonella Bifano Healthcare Assistants Vincenzina Arnone, Fabio Di Bartolo, Lucia A. Di Murro, Maria Rosa Forte, Anna Maria Meloni, Rita Trovato Data Manager Laura Concas CARDIOLOGY Head Patrizia Piotti, MD Clinical Research Staff Patrizia Greco, MD; Costanza Mantovani, MD; Carlo Materazzo, MD Postdoctoral Fellow Iryna Arendar, MD Nurses Sabrina Barrotta, Graziella Borlenghi, Rosella Murru, Luisa Sala Administrative Personnel Maria Grazia Marchetti, Rosanna Villani RESPIRATORY PATHOPHYSIOLOGY Head Roberto Boffi, MD Clinical Research Staff Alessandra Busia, MD Postdoctoral Fellows Paolo Pozzi, MD; Elena Munarini, Psy D; Chiara Marabelli, Psy D Technicians Maria Chiricosta, Simona Montalti, Fabio Valente Healthcare Assistant Sara Santoro Administratives Personnel Maria Grazia Marchetti, Rosanna Villani FOR MORE INFORMATION ABOUT THE UNITS, VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT 34 clinical-scientific departments HEMATOLOGY AND PEDIATRIC ONCO-HEMATOLOGY DEPARTMENT DIRECTOR OF DEPARTMENT: Paolo Corradini Professor of Hematology, University of Milan +39 02 2390 2950 [email protected] The Department of Hematology and Pediatric Onco-Hematology comprises two clinical divisions, the Hematology Unit, a leader in hematological malignancies care and research, and the Pediatric Oncology Unit devoted to the care of children with solid tumors and hematological disorders. The Units participate in national and international clinical research studies, providing patients access to new therapies including new combinations of drugs and monoclonal antibodies and new modalities for autologous or allogeneic stem cell transplantation. The Department has a strong commitment to clinical and basic science research and to advancing the field of stem cell transplants. It maintains an advanced cell processing laboratory that is dedicated to preparing safe and effective hematologic cells for transplantation and a laboratory devoted to translational research to rapidly turn scientific discoveries into more effective and personalized treatment modalities. In 2013, following organizational changes at INT, the Supportive Care In Cancer Unit, responsible for treatment of chronic pain and supportive care in cancer patients, was assigned to this Department. The Unit pursues clinical, educational, and research objectives aimed at the prevention assessment, treatment, and study of side effects or toxicity resulting from cancer therapy, as well as the cure of emotional, social, and spiritual patient needs through global care of patients starting from diagnosis. The treatments offered are compliant with guidelines of the WHO, MASCC, ESMO, and AIOM. The Immunohematology and Transfusion Medicine (SIMT) Unit, responsible for laboratory diagnosis as well as donation, testing, processing, preservation, storage, distribution, and transfusion safety of blood components, was also assigned to the Department. A donor center, apheresis center, and HLA typing laboratory are part of this Unit. 35 back to contents SCIENTIFIC REPORT 2013 HIGHLIGHTS Integrating Next Generation Sequencing in the molecular diagnosis and monitoring of lymphoproliferative disorders Development of new clinical trials integrating Next Generation Sequencing data KEYWORDS hematopoietic stem cell transplantation, hematological malignancies, pediatric tumors, supportive care, international trials, combination of conventional chemotherapy and targeted agents, transfusion medicine. HEMATOLOGY AND ALLOGENEIC BONE MARROW TRANSPLANTATION (ETMO) Head Paolo Corradini, MD Clinical Research Staff Michela Casanova, MD, Andrea Ferrari, MD; Roberto Luksch, MD, Cristina Meazza, MD; Daniela Polastri, MD, Filippo Spreafico, MD; Monica Terenziani, MD Clinical Research Staff Anna Dodero, MD; Lucia Farina, MD; Giulia Perrone, MD; Vittorio Montefusco, MD; Francesco Spina, MD Research Staff Luca Bergamaschi, resident; Veronica Biassoni, MD; Serena Catania, MD; Stefano Chiaravalli, MD; Marco Vajna de Pava, MD; Francesca Favini, resident; Barbara Giacon, Psy D; Giacomo Gotti MD; Carla Moscheo MD; Marta Podda, MD; Nadia Puma, MD; Elisabetta Schiavello, MD; Fabio Simonetti, MD Research Staff Cristiana Carniti, PhD Residents Serena Dalto, MD; Chiara De Philippis, MD; Francesco Maura, MD; Alberto Mussetti, MD; Tommaso Radice, MD; Francesca Rezzonico, MD; Luisa Roncari, MD; Martina Soldarini, MD Postdoctoral Fellow Antonio Vendramin, PhD PhD Students Silvia Gimondi, Med Biotech D; Sara Rizzitano, Med Biotech D Clinical Studies Coordinator Debora Degl’Innocenti, PhD Data Manager Anisa Bermema, Med Biotech D Administrative Personnel Marialuisa Longhi, Elena Maggioni Nurses Giorgia Gobbi (coordinator), Rosa Abate, Sonia Citro, Riccardo De Stefano, David Guiote Pertierra, Donatella Luongo, Elisabetta Martinelli, Simona Mazzella, Francesco Murana, Leonardo Orsini, Alfonso Parisi, Rita Russo, Rita Sciancalepore, Serafina Tomasicchio, Giuseppe Torregrossa, Anna Vernone Research Nurse Ilaria Lo Russo Healthcare Assistants Nunzio Bovello, Carmelo Fedele, Evelina Palella, Jose Noboa Velasco Cell Processing Tecnicians Pietro A. Di Nuzzi, Paolo D. Longoni PEDIATRIC ONCOLOGY Head Maura Massimino, MD 36 Administrative Personnel Elena Barzanò, Liana Bevilacqua, Luna Boschetti, Mattia Bussi, Chiara Secco, Gabriella Vighi Social Worker Giovanna Casiraghi Teachers Stefania Benedetti, Anna Bernasconi, Franca Bertola, Antonia Biasi, Cinzia Cassanelli, Silvia Dragone, Manuela Farina, Andrea Gazzi, Lucia Toniolo, Immacolata Volpe Nurses Mariangela Armiraglio (coordinator), Iris Baranella, Morena Berti, Daniela Bruno, Cristina Comelli, Patrizia Conti, Domenica Costeri, Lucia Curelli, Laura De Porras, Ruggero Fauro, Marta Ferrante, Carmelo Fiorello, Giuseppe Forzini, Marinella Gaidolfi, Rossana Ghezzi, Laura Lottaroli, Simone Macchi, Rossana Marra, Manuela Oriani, Elisa Procopio, Silvana Saverino, Elisa Triglia Healthcare Assistants Annamaria Bilanzuoli, Gisella Cancedda, Rita Carulli, Silvana Celauro, Rita Marina Tamburro, Stella Uzzardi SUPPORTIVE CARE IN CANCER Head Carla I. Ripamonti, MD Clinical Research Staff Maria A. Pessi, MD; Gloria Barone, MD Nurses Pietro Toma , Laura De Taddei, Giuseppina Bottigliero, Technicians Chiarina Pireddu, Fabio Lizzano Healthcare Assistants Anna Aquilini, Adriana Cremagnani, Anna Cremonesi, Renata Nobili, Antonella Puntieri, Fulvia Sangermani, Ivana Zaglio, Silvia Sala, Elisabetta Tandoja clinical-scientific departments SIMT, IMMUNOHEMATOLOGY AND TRANSFUSION MEDICINE Head Fernando Ravagnani, MD Clinical Staff Flavio Arienti, MD; Annalisa Birolini, MD; Paola Coluccia, MD; Carmela Guarino, MD; Laura R. Terranova, MD; Elisabetta Di Giuseppe, Biol Sci D; Claudia Lombardo, Biol Sci D; Arabella Mazzocchi, Biol Sci D Fellow Francesca R. Taverna, Biol Sci D Administrative Personnel Orietta C. Polisena, Elide Spinelli, Maria C. Zanetti, Giovanni Veronese Technicians Mario Avella, Cinzia L. Biasuz, Alvaro Bompadre, Laura M. Bonizzoni, Antonella Falanga, Daniela Ferrari, Marina Galbiati, Annamaria Gorla, Silvia Larghi, Roberto Losa, Antonia Morleo, Ernestina Pigliafreddo, Lara Pusterla, Roberta Serpi, Lorena Sfreddo, Barbara Strada, Tiziano P. Tattanelli, Ornella Zanaboni Nurses Marisa Dentella, Filomena Fedele, Rita Fiorito, Cristina I. Lasala, Monica Pedretti, Pietrina Sanna, Carmela Santolla Healthcare Assistants Antonella Atzeni, Carmela Gizzi, Maria A. Somma, Maria Tamburriello FOR MORE INFORMATION ABOUT THE UNITS, VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT 37 back to contents SCIENTIFIC REPORT 2013 ANESTHESIA, INTENSIVE CARE, PAIN THERAPY, AND PALLIATIVE CARE DEPARTMENT DIRECTOR OF DEPARTMENT: Martin Langer Professor of Anesthesia and Critical Care Medicine University of Milan [email protected] The Department has a key position in the hospital, and is involved in medical and surgical treatment of cancer patients involving very close collaboration between surgeons, medical oncologists, radiologists, and pediatricians for many interventional treatments. The main missions of the Department are peri-operative medicine, palliative care, and terminal support in the hospice and in-home care for patients with advanced cancer after failure of aggressive treatments and safety in the hospital. The provision of palliative care and supportive treatments to cancer patients is recognized as a defining characteristic of a comprehensive cancer center. The Department is organized in the following Units: Clinical Anesthesia. INT runs an intense surgical program supported by the Anesthesia Team, also participating in demanding surgical procedures such as liver transplantation, major liver resection, peritonectomy-HIPEC, and resection of tumors in the thorax and retroperitoneum. INT is a referral center for solid tumors in pediatric patients, and anesthesiologists are also involved in practical techniques such as long-term central venous catheter placement and administration of anesthesia for diagnostics and radiotherapy. Intensive Care Unit (ICU). Mainly functions as a surgical ICU and post-anesthesia care unit, but occasionally treats patients from other medical wards for complications during chemotherapy. Monitoring and surveillance of high-risk surgical patients and intensive treatment of patients with life-threatening postoperative complications and/or organ failure of different origins is the mission of the ICU. Palliative Care, Pain Therapy, and Rehabilitation. Addressed to the needs of patients in all stages of disease with the aim of improving quality of life, and provide a system of care and fully integrated support for the overall program of cancer diagnosis, therapy, and research. Rehabilitative interventions address or reduce acute and chronic complications after 38 clinical-scientific departments cancer surgery, radiation-therapy, and medical treatments as well as manage complications in advanced cases. The Unit has a fully dedicated lymphedema clinic that is open 5 days a week, is linked with the palliative care team service in the hospice, and organizes home care programs. Clinical Nutrition. Prevention and early treatment of malnutrition are the main goals of the Unit. Nutritional intervention should be considered during the different phases of oncologic therapy: diagnosis, surgery, chemo, and radiotherapy. In accordance with the recommendations of the European Society of Clinical Nutrition, nutritional screening is undertaken in all patients with a high risk of malnutrition. Patients affected by any form of malnutrition are included in a comprehensive nutrition program, which consists of nutritional status monitoring and personalized nutrition therapy mainly with artificial nutrition, both enteral and parenteral, nutritional counseling, and diet therapy. HIGHLIGHTS The training program for residents in the Anesthesia and Intensive Care Program at the University of Milan is established and allows 5-7 young doctors/year to specialize in clinical anesthesia and acute postoperative pain therapy. Federico Piccioni is active member of the Working Group in Anesthesia for Thoracic Surgery. Partecipation in Italian multicenter studies in Anesthesia and Postoperative Care: “Gestione delle vie aeree in chirurgia toracica” and “Complicanze postoperatorie polmonari in chirurgia addominale maggiore: studio osservazionale prospettico multicentrico”. In both data collections, our Institution is top contributor. A research project on prevention of surgical site infection in breast cancer surgery started enroling patients in 2013: by April 2014, about 1000 patients were enrolled reaching nearly 50% of the planned enrollment. The “Acute Pain Service” caring for patients after surgery, coordinated by Rossella Brambilla, RN, has nearly completed a dedicated software program to improve clinical support and research opportunities. From August 2013, Daniela Codazzi, MD is the new director of our ICU. Since 2008, the ICU is part of the GiViTI network, part of PROSAFE, a collaborative project aimed at improving the quality of intensive care medicine. The research program “European Palliative Care Research Center” (PRC), founded as a collaboration between the Palliative Care, Pain Therapy, and Rehabilitation Unit and the Cancer Department at the University of Science and Technology in Trondheim (Norway), is active. A noteworthy innovation was the establishment of the Master Course (Master Universitario di II° livello di Alta Formazione e Qualificazione in Cure Palliative) of the University of Milan in Palliative Medicine, one of the first of its kind in Italy, chaired by Prof. Martin Langer. Our specialists in palliative care as well as several INT clinicians are involved. The Hospice at INT provides palliative care to any terminally-ill patient, without regard to the patient’s ability to pay for any services rendered. KEYWORDS anesthesia, postoperative treatment, acute pain service, surgical day hospital, palliative care, rehabilitation, nutritional status, artificial nutrition 39 back to contents SCIENTIFIC REPORT 2013 CLINICAL ANESTHESIA Head Martin Langer, MD Clinical Research Staff Mario Ammatuna, MD; Maria Grazia Bonalumi, MD; Anna Cardani, MD; Roberta Casirani, MD; Pasqualina Costanzo, MD; Ilaria Donati, MD; Luca Fumagalli, MD; Edward A. Haeusler, MD; Antonio Maucione, MD; Silvana Migliavacca, MD; Lucia Miradoli, MD; Marta Negri, MD; Federico Piccioni, MD; Andrea Poli, MD; Paola Previtali, MD; Giacomino Rebuffoni, MD; Giuseppe Rigillo, MD; Mara G. Roberto, MD; Emiliano Tognoli, MD; Alessandro Zanon, MD Residents Jacopo Colombo, MD; Valentina Colosio Lombardi, MD; Valeria Donghi, MD; Giuditta Fallabrino, MD; Silvia Guenzani, MD; Sergio Lassola, MD; Beatrice Motti, MD; Rosalia Paternò, MD; Noemi Sacchi, MD Administrative Personnel Stefania Bettinardi, Fiorina Cantisani Nurses Romano Castellari (coordinator), Elisabetta Anchora, Stefania Soleil Andreoli, Laura E. Anselmi, Marina Balbi, Marco Balconi, Gilda Barletta, Silvana Bertoli, Gabriella Bianchessi, Renata Bordonali, Katia Botrugno, Rossella Brambilla, Debora Buenaventura Boada, Julia D. Burgos Baena, Silvia Cuccaro, Antonella Chiesa, Liviu D. Corbu, Maria B. Corbu, Matrona De Felice, Maria Della Croce, Simonetta Delrio, Andrea Dibiase, Maria A. DiTano, Marina Djokic, Luca G. Falcone, Federica Fiorini, Claudio Gasparro, Angelo Giannuzzi, Rosanna Giumbo, Marcella Gozzo, Elisabetyta Kertez, Mara G. Longo, Ezio Luzzi, Maria P. Maienza, Margherita A. Marzo, Anna R. Mazzotta, Annamaria Morricella, Tatiana M. Monfredini, Antonella Nieddu, Nagore Nieto, Lucia Orru, Hippolito Otani, Barbara Ottonello, Maria R. Pezone, Cecilia Pifarotti, Flavia F. C. Ravasi, Stefania Ronca, Maria A. J. Rosso, Massimo Sanseverino, Renato Santini, Salvatore Santucciu, Sara Sciamanna, Paola Striglia, Adriana Valentini, Filippo Venezia, Silvia Zanotto Healthcare Assistants Rosa M. Benevento, Pierangela Carrino, Denise de Bastiani, Mario Castronovo, Vincenzo Dellaquila, Annuccia Delrio, Antonietta Fantilli, Antonio Labori, Anna Lorenti, Maria Maestri, Francesca Maiorana, Stefania Massella, Monica Mastrogiovanni, Maria C. Pirrotta, Maria C. Pisasale, Elisabetta Saccaggi, Elena Scotti, Carmelo Scrofani, Rosa Selvati, Rosa M. Tirone, Dario Tonelli, Veronica Valentino, Lucia Velotti Technicians Maria I. Cipolletta, Giovanni Di Bari, Gerardo Gizzi, Gianbattista Grazioli, Monica Mastrogiacomo VASCULAR ACCESS TEAM: Maria Chiara Allemano, RN ACUTE PAIN SERVICE: Rossella Brambilla, RN PRE-ANESTHESIA CLINIC: Andrea Dibase, INTENSIVE CARE UNIT (ICU) Head Daniela Codazzi, MD Nurses Katia Masala (coordinator), Salvatore Alcamo, Maria C. Allemano, Maria P. Augello, Marcantonio Boccola, Alice Casali, Armando Cofone, Francesco Filippazzo, Michele Gasparini, Masha Kintaba, Emilia Lonetti, Katia Masala, Flavia Montalto, Laura Morsenti, Andrea Mulas, Sonia Romero Lemos, Achille Simonetti, Salvatore Sirigu, Martina Zoanni Healthcare Assistants J. D. Carmen Garzon, Nadia Duca, Erik Papa, Elisabetta Zedda PALLIATIVE CARE, PAIN THERAPY, AND REHABILITATION Head Augusto T. Caraceni, MD Clinical Research Staff Augusta Balzarini, MD; Paola Bracchi, MD; Cinzia Brunelli, MSc; Tiziana Campa, MD; Laura Campanello, PsyD; Daniela Ermolli, MD; Fulvia Gariboldi, MD; Silvia Grecchi, MD; Andrea Magni, MD; Cecilia Mandelli, PsyD; Cinzia Martini, MD; Alessandra Pigni MD; Luigi Saita, MD; Carmela Sigari, MD; Fabio Simonetti, MD; Ernesto Zecca, MD; Marco Carminati, Shiatsu Master; Gianluigi Cislaghi, Shiatsu Master; Giovanni Sala, Chaplain Physical Therapists Livia Bedodi, Maria G. Blandini, Chiara Bottani, Simona Breggiè, Paola Campanini, Lucia Cavallini, Bruna Cotza, Liviana Craba, Heike Feddersen, Cinzia A. Ficcarelli, Donato Ficchì, Alida Grossi, Chiara Piazza, Patrizia Placucci, Raffaella Sensi, Beatrice Simoncini Nurses Barbara Acquisto, Giuseppe Baiguini, Sara Bianchi, Anna Biondo, Giuseppina Bottigliero, Rosa A. Candigliota, Renato Della Vittoria, Olmina Di Florio, Massimo Di Francesco, Vincenzina Ferraro, Antonella Ferraresi, Anna M. Mazzucchelli, Nives Porta, Edoardo Rossetti, Arianna Rossi, Federica Sara Rusconi, Annunziata Sammarro, Gianluigi Schena, Elisabetta Volpato Healthcare Assistants Marco Andreon, Maria L. Cipolletti, Raffaella Diaferio, Maria R. Lia, Nataliya Maksymova, Roberta B. Martinelli, Anna Mastroianni, Teresa Natali, Teresa Pace, Nicola Paternoster Administrative Personnel Manuela Brusati, Loredana D’Urso, Chiara Vinuzzi CLINICAL NUTRITION Head Cecilia Gavazzi, MD Clinical Research Staff Serena Della Valle, MD; Michela Fiscella, MD Fellow Jessica Lops Nurses Anna Armonti, Franca Filincieri, Carmen Maiorana, Lorena Riva Healthcare Assistant Silvia Colatruglio, RD Clinical Research Staff Fortunato D’Elia, MD; Marco Faustini, MD; Renato Manzi, MD; Laura Persiani, MD; Maurillia Rizzi, MD; Edda Merola, MD, Paola Previtali, MD FOR MORE INFORMATION ABOUT THE UNITS, VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT 40 clinical-scientific departments DIAGNOSTIC IMAGING AND RADIOTHERAPY DEPARTMENT DIRECTOR OF DEPARTMENT: Emilio Bombardieri (until 31 August 2013) – Alfonso Marchianò (since 1 September 2013) +39 02 2390 3144 alfonso.marchianò@istitutotumori.mi.it The Department is a large multidisciplinary structure comprising different areas of clinical activity and research, where many disciplines work together in very close interaction. The Department is equipped with a large number of high-technology facilities and supports the implementation of biologic imaging and image-guided contouring radiotherapy at INT. The development and study of several specific radiopharmaceuticals has led to the improvement of targeted radiotherapy. These achievements are possible thanks to the strong collaboration of many experts from the fields of physics, biotechnology, biology, radiopharmacy, instrumentation, and medical sciences. The Department is organized in the following Units: Radiology and Diagnostic Imaging 1 (Functional Imaging). Carries out conventional radiologic tests (X-rays), magnetic resonance imaging (MRI), and breast cancer diagnosis (mammography, US, radioguided biopsies). Radiology and Diagnostic Imaging 2 (CT and Interventional Imaging). Provides computed tomography (CT), US, angiography, interventional radiology, intralesional treatments, and radiological tests for the gastrointestinal tract. Nuclear Medicine Unit. Provides multidisciplinary clinical and research activities. It is equipped with a 17 MeV cyclotron and radiochemistry labs for the synthesis of radiopharmaceuticals for diagnosis and therapy, a bone densitometry scanner, three gamma-cameras, two PET/CT scanners, and a protective ward for radionuclide therapies. The Unit performs routinely bone densitometry scans, conventional scintigraphic and SPECT studies, PET/CT examinations, and radionuclide treatments. In collaboration with the Experimental Oncology and Molecular Medicine Department, small animal tumor models can be evaluated with a dedicated micro-PET system. Radiation Oncology 1. Carries out external beam radiotherapy [3D conformal radiation therapy, intensity modulated radiotherapy (IMRT), Rapid Arc, image guided radiation therapy (IGRT), volumetric modulated arc therapy (VMAT), Calypso 4D localization system]. Radiation Oncology 2. Provides treatments of external beam radiotherapy for head and neck and gynecologic cancer and high-dose rate brachytherapy (HDR-BT) treatments 41 SCIENTIFIC REPORT 2013 back to contents mainly for gynecologic and prostate cancer. Combination of chemo- and radiotherapy and supportive care are delivered in an inpatient setting. Medical Physics. Supports the Radiation Oncology Units in planning radiotherapy treatments and dosimetric calculations. This Unit also takes care of quality control of instruments for diagnostic imaging. A personal dosimetry laboratory is present in the unit as a part of the radioprotection activity. HIGHLIGHTS DWI (diffusion-weighted imaging) and MRS (MR spectroscopy) have been validated as emerging functional tools to improve information about the vitality or aggressiveness of cancer tissue. Breast MRI and pre-operative staging of cancer are performed as part of a surveillance program of high risk and BRCA mutation carriers. A dosimetric study of digital mammography combined with tomosynthesis exams was performed in order to assess benefits and related harms. In liver cancer, we evaluated the use of radiofrequency hyperthermia therapy combined with the arterial stop flow procedure to achieve maximum effectiveness with minimal invasiveness. This procedure has been formally endorsed by the Italian Society of Interventional Radiology. Original experience of percutaneous cryoblation continued in selected patients with small renal tumors. Intra-arterial treatment of HCC with 90Y loaded glass microspheres (in collaboration with Gastrointestinal, Hepatopancreatobiliary Surgery and Liver Transplantations Unit). PET/CT studies using different PET radiopharmaceuticals (18F-FDG, 11C-Methionine, 68Ga- DOTATOC, 18F-FLT). Preclinical studies in animal tumor models with a micro-PET system (in collaboration with the Experimental Oncology and Molecular Medicine Department). Radionuclide therapy with 90Y-Zevalin in non-Hodgkin’s lymphomas. Novel approaches for the treatment of neuroendocrine tumors with tandem radiolabeled somatostatin analogues (111Lu and 90Y DOTA-TATE). Implementation of partial breast irradiation: “SHARE - Cyberknife Partial Breast Irradiation for Early Stage Breast Cancer”, a study performed in conjunction with the IRCCS Istituto Neurologico Besta of Milan. Prediction of acute and late toxicity (rectal, erectile, bladder, skin toxicity) after high dose radiotherapy, correlation with plasma levels of inflammatory markers and acute and late toxicity after prostate cancer irradiation, quality of life new fractionation schemes, and treatment modalities. High-dose rate brachytherapy (HDR BCT) is given as endocavitary treatment in uterine cancers, as endoluminal BCT in biliary tract cancers, and as interstitial BCT in prostate cancer with HDR equipment (Selectron®). In collaboration with the Centre for Medical Radiation Physics (University of Wollongong, Australia) and the Materials Science Department (University of Milan Bicocca, Italy) new detectors were studied and applied to perform in vivo dosimetry during highly hypo-fractionated prostate HDR BCT treatments. In collaboration with the Politecnico di Milano, software to merge CT and MR imaging was developed. The software is able to deform the images to take into account the growth of children. This work is a part of a research where correlations between white and gray matter changes, evaluated by magnetic resonance diffusion tensor imaging (DTI), RT dose, and neurocognitive damages in children who underwent focal brain RT for malignant brain tumors will be studied. KEYWORDS breast imaging, MRI, radiology, functional imaging, diffusion imaging, radiofrequency, percutaneous thermal ablation, tumor cryoblation ablation, pediatric radiotherapy, external beam radiotherapy, brachytherapy, dosimetry, spectrophotometry 42 clinical-scientific departments RADIOLOGY 1 (FUNCTIONAL IMAGING) Head Pietro Panizza, MD Nurses Piero Ciccarese, Laura Fagnani, Addolorata Mauro, Nadia Nicoletti, Roberta Populin, Marinella Porceddu Clinical Research Staff Claudio Ferranti, MD; Alberto Laffranchi, MD; Monica Marchesini, MD; Antonella Messina, MD; Laura Suman, MD; Giovanna Trecate, MD Administrative Personnel Ornella Venegoni Magnetic Resonance Daniele Vergnaghi, MD (Head) Radiology and Magnetic Resonance GI Tract Davide Scaramuzza, MD (Head), Pediatric Magnetic Resonance Paolo Potepan, MD (Head), Roberta Cherubini (Data Manager) Breast Imaging Unit Gianfranco Scaperrotta, MD (Head) Postdoctoral Fellows Alessandra Casale, MD; Marta Vaiani, MD Residents Emanuela Capalbo, MD; Maria Cosentino, MD; Sara Viganò, MD Technicians Cristina Folini (coordinator), Gaetano Annunziata, Luisa Colombo, Luciana Dedei, Cinzia Fossaceca, Antonella Laturra, Maria Pia Mannella, Tina Mastrostefano, Luca Musumeci, Carmelina Pannone, Nicola Pulerà, Stefania Sala, Anna Tavola, Valeria Tosi, Maurizio Zattoni Nurses Mirella Ferruccio, Loredana Palella Healthcare Assistant Guglielmina Riccio Administrative Personnel Giuseppa Pacicca RADIOLOGY 2 (DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY) Head Alfonso Marchianò, MD Clinical Research Staff Enrico Civelli, MD; Giuseppe Di Tolla, MD; Laura F. Frigerio, MD; Rodolfo Lanocita, MD; Marco Milella, MD; Carlo Morosi, MD; Monica Salvetti, MD; Carlo Spreafico, MD NUCLEAR MEDICINE Head Emilio Bombardieri, MD (until 31 August); Flavio Crippa, MD (since 1 September) Clinical Research Staff Alessandra Alessi, MD; Gianluca Aliberti, MD; Anna Bogni, Biol Sci D; Maria R. Castellani, MD; Carlo Chiesa, Physicist; Alice Lorenzoni, MD Marco Maccauro, MD; Claudio Pascali, Radiochemist; Gianluca Serafini, MD Clinical Pet Flavio Crippa, MD (Head) Nuclear Medicine Therapy and Endocrinology Ettore Seregni, MD (Head) Postdoctoral Fellows Claudio Cucchi, Chemist; Barbara Padovano, MD; Federica Pallotti, MD; Elisa Galli, Chemist Technicians Monica Testoni (coordinator), Grazia Aprigliano, Davide Bassani, Gianenrico Cucchetti, Carlotta Edera, Maria Di Francesco, Martino Faedi, Rita Filieri, Deborah Mansi, Rossana Pavesi, Matteo Ragazzoni, Lidia Spano, Roberto Segreti Nurses Rita Sicari (coordinator), Cristina De Somma, Carmela Fallacara, Dario Longo, Calogero Oliveri, Aurelio Scarabelli Administrative Personnel Rosangela Ghilardi RADIATION ONCOLOGY 1 Head Riccardo Valdagni, MD Clinical Research Staff Nice Bedini, MD; Anna Di Russo, MD; Claudia Sangalli, MD; Fulvia Soncini, MD; Sergio Villa, MD Gastrointestinal Radiotherapy Francesca Valvo, MD (Head) Diagnostic and Interventional Gastroenterology Guido Cozzi, MD (Head) Breast Cancer Radiotherapy Laura Lozza, MD (Head) Intralesional Treatment Unit Francesco Garbagnati, MD (Head) Pediatric Radiotherapy Lorenza Gandola, MD (Head) Postdoctoral Fellows Tommaso Cascella, MD; Giuseppina Calareso, MD Clinical and Research Fellows Barbara Avuzzi, MD; Maria Carmen De Santis, MD; Marzia Franceschini, MD; Sara Morlino, MD; Emilia Pecori, MD; Elisa Ciurlia, MD; Mulugeta Haile Techlemichael, MD Residents Guglielmo Cannella, MD; Tien T.U. Van, MD Technicians Antonio Perchinunno (coordinator), Pietro Basile, Enrico De Pedri, Maria Ferrarello, Roberto Gallo, Giuseppina Gentile, Maria Giovanna Grossi, Luca Lanzillotti, Roberto Nioi, Luciana Tanzini, Vanni Tirella Resident Chiara Chiruzzi, MD Technicians Franca Gaetano (coordinator), Claudio Boccadamo, Giuseppina Bonanno, Alberto Buzzetti, Carmelo Campolo, Federica Caputo, Gabriele Carabelli, Pasquale Contessa, Lucio Donatone, Rosa Fortunato, Sarah Frasca, Emanuela Gatti, 43 back to contents SCIENTIFIC REPORT 2013 Manuela Guerra, Antonio Spartano, Francesca Spartano, Carla Valenti, Luca Zappa Nurses Pasquale Brunacci, Flavia Montalto, Emanuela Visentin Healthcare Assistants Grazia Arpaia, Manuel Cornelli, Paola Fiolo, Luca Pedone, Sebastiano Sicilia, Cristina Terenghi Administrative Personnel Donatella Orlandi, Patrizia Riva Data Manager Laura Andreoli RADIATION ONCOLOGY 2 Head Carlo Fallai, MD Clinical Research Staff Annamaria Cerrotta, MD; Ester Orlandi, MD; Silvia Tana, MD Postdoctoral Fellows Eva Iannacone, MD; Anna Maria Mileo MD, Garcia Monica, MD Resident Pappalardi Brigida, MD Technicians Ciro Pintaudi, (coordinator), Sergio Bavusi, Paolo D’Agnese, Carmelo Di Marco, Dayana Pignata, Piera Fusar Poli Nurses Elena Omati (coordinator), Roberta Albasini, Rosa Attolino, Antonella Causio, Luigia Cerra, Cinzia Cocca, Fabrizio D’Amico, Patrizia Galantin, Carmen R. Garcia Cuesta, Carmen Greco, Yuliya Kovhan, Antonio Lucenti, Filippo Monno, Erminia Nardo, Vincenza Natola, Samanta Palmisano, Michela Saracino, Luigi Tamburrino Healthcare Assistants Angela Abatangelo, Fabrizio D’Amico, Marlene Fuentes Delgado, Giuseppe Gaglio, Virginia Marini, Gianluca Severgnini, Claudia Soave MEDICAL PHYSICS Head Emanuele Pignoli, Med Phys D Clinical Research Staff Marta Borroni, Med Phys D; Mauro Carrara, Med Phys D; Valeria Mongioj, Med Phys D; Claudio G. Stucchi, Med Phys D Fellows Manuela Lualdi, Med Phys D; Claudia Cavatorta Phys D Residents Francesca Bonfantini, Phys D; Anna Cavallo Phys D, Tommaso Giandini, Phys D; Silvia Meroni, Phys D; Chiara Tenconi, Phys D Technicians Vito Cosentino, Luca Marrone, Ester Mazzarella, Dario Posté Healthcare Assistant Giuseppina Esposito FOR MORE INFORMATION ABOUT THE UNITS, VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT 44 clinical-scientific departments PATHOLOGY AND LABORATORY MEDICINE DEPARTMENT DIRECTOR OF DEPARTMENT: Giuseppe Pelosi Professor of Pathology, University of Milan +39 02 2390 3017 [email protected] The mission of the Department is to provide accurate diagnoses and information of prognostic and therapeutic value to clinicians. The activities of Surgical Pathology, Diagnostic Molecular Pathology, Cytopathology, and Autopsy Pathology are carried out in the two Anatomic Pathology Units, while laboratory tests and microbiological investigations are carried out at the Laboratory Medicine Unit, all using state-of-the-art techniques and quality certification (ISO9001; 2000-2015). HIGHLIGHTS The Department is engaged in the Institutional human frozen tumor tissue bank, a project aimed at the creation of an extensive collection of human tissues that is not restricted to a specific organ or disease type, as well as in a telepathology project involving several Italian cancer Institutes. Extensive pheno-genotyping and assessment of predictive and/or prognostic factors are an integral part of diagnosis and research activities aiming at the best clinical management of patients, as well as developing diverse research in several human cancers. KEYWORDS therapeutic pathology, immunohistochemistry, diagnosis, molecular assay, mutation, in situ hybridization, cytofluorimetry, clinical chemistry, hematology, microbiology 45 back to contents SCIENTIFIC REPORT 2013 ANATOMIC PATHOLOGY UNITS 1 AND 2 Heads Maria Luisa Carcangiu, MD: Anatomic Pathology Unit 1 Giuseppe Pelosi, MD: Anatomic Pathology Units 2 Clinical Research Staff Marta Barisella, MD; Antonello D. Cabras, MD; Paola Collini, MD; Maurizio Colecchia, MD; Alessandra Fabbri, MD; Massimo Milione, MD; Biagio Paolini, MD; Alessandro Pellegrinelli, MD; Pasquale Quattrone, MD; Gabrina Tragni, MD; Barbara Valeri, MD; Antonella Aiello, Biol Sci D; Annunziata Gloghini, Biol Sci D; Federica Perrone, Biol Sci D; Carla Riva, Biol Sci D (Coordinator of Cytopathology), Mario Ruggeri, Biol Sci D; Elena Tamborini, Biol Sci D; Adele Testi, Biol Sci D Fellows Manuela Bimbatti, MD; Giorgia Leone, MD; Ester Antelmi, Biol Sci D; Enrica Bovio, Biol Sci D; Adele Busico, Biol Sci D; Elena De Paoli, Biol Sci D; Ambra Gualeni, Biol Sci D; Gabriella Montemurro, Biol Sci D; Giulio Settanni, Biol Sci D; Francesca Testa, Biol Sci D; Chiara Volpi, Biol Sci D Technicians Claudia Alphandery (Cytotechnologist); Maria Grazia Bonora; Renata Borchini; Rita A. Carminati; Giovanni Centonze; Luca Cesana; Alessandra Chinosi; Marilena Colantuono; Silvia Colombo (Cytotechnologist); Daniela De Bari; Francesca Dominoni (Chief Technician); Alessandra Elli; Maria Grazia Facciorusso; Elena Fomiatti; Angelo Gaito; Daniela Galbiati; Morena Gobbo; Rosangela Intorre; Teresa Labella; Matteo Marcuzzo; Alessia Mietta; Marzia Mietta; Loretta Missiato; Maria Luisa Moiraghi; Margherita Mondini; Paola Murè; Marta Orsenigo; Desirè Parimbelli; Katia Ponzoni (Cytotechnologist); Silvia Redaelli; Consiglia Sgura Administrative personnel Patrizia Cangioli; Margherita Cariglia; Maria Teresa Codecasa; Maria Cristina Di Bartolomeo; Mariangela Girotti; Maria Morelli; Alda Tosi; Enrica Colzani (volunteer) Healthcare Assistants Paolo Castioni, Cosima Ciccarese, Massimo Festa, Paola Tonielli, Anna Urbano Personnel involved in specific research activities Silvana Pilotti, MD (responsible for selected research projects) Research Fellows Antonino Belfiore, Biol Sci D; Fabio Bozzi, Biol Sci D; Tiziana Negri, Biol Sci; D; Gian Paolo Dagrada, Biol Sci D; Claudia Bertan, Biol Sci D; Silvia Brich, Biol Sci D; Elena Conca, Biol Sci D; Barbara Cortelazzi, Biol Sci D; Valentina Mauro, Biol Sci D; Rosalin Dolores Spagnuolo, Biol Sci D LABORATORY MEDICINE Head Daniele Morelli, Biol Sci D Clinical Research Staff Mariachiara Bonini, Biol Sci D; Eutilia Conte, Biol Sci D; Antonio Mastroianni, Biol Sci D; Roberta Rossi, Biol Sci D; Loredana Simoni, MD; Giovanna Viola, Biol Sci D Technicians Giuseppina Ballabio, Rosella Bonfanti, Chiara Brusati, Maria R. Carati, Maria R. Cattaneo, Maria V. Corengia, Teresa Fontana, Carlo Maggi, Roberta Marchetti, Valerio Motta, Giuseppa Perrucci, Pia S. M. Picco, Marco Ranzani, Nicola Salvatore, Federica Sozzani Administrative Personnel Santa Zingone FOR MORE INFORMATION ABOUT THE UNITS, VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT 46 clinical-scientific departments EXPERIMENTAL ONCOLOGY AND MOLECULAR MEDICINE DEPARTMENT DIRECTOR OF DEPARTMENT: Maria Grazia Daidone +39 02 2390 2238 [email protected] This Department includes 10 Research Units and one AIRC-awarded start-up Unit dedicated to preclinical investigations. Its primary goal is to serve as an important conduit through which new discoveries are applied to cancer diagnosis, prognosis, and treatment. This is fostered by a collaborative environment and strong interaction among physicians and basic scientists working in different disciplines, as well as by collaborations with research groups in Italy and abroad. The activity of the Research Units is addressed: • to identify and validate biomolecular features associated with tumor development and progression as diagnostic, prognostic, and treatment response/resistance markers, and as molecular targets to develop new treatment approaches; • to investigate the tumor microenvironment and extracellular matrix at a molecular and functional level; • to elucidate the interactions between tumor cells and the immune system; with the final aims of: • developing highly sensitive tests (which utilize a panel of novel biomolecular markers) for a possible clinical application; • preclinical testing of novel drug combinations, and to develop novel therapeutic agents; • identifying novel therapeutic strategies based on immunomodulation, and to develop vaccination strategies, also taking advantage of the acquired competence in developing new generation recombinant antibodies. Such studies involve multidisciplinary approaches, statistical and bioinformatic methodologies, and integration among the different high-throughput and high-resolution methodologies and functional tests. Investigations are carried out using different preclinical experimental models and validated on large series of human biospecimens. 47 SCIENTIFIC REPORT 2013 The Department supports investigators with state-of-the-art core facilities, with shared instrumentation and trained specialists. The Department is organized in the following Units: • Molecular Mechanisms of Cell Cycle Control. Research of the Unit is oriented towards: i) analysis of the ATM-dependent pathway in the cellular DNA damage response to double strand breaks and alterations of this response in tumor cells and in cancer-predisposing neurodegenerative syndrome; ii) development of pro-apoptotic SMAC-mimetic compounds with anticancer activity targeting the BIR3 domain of the inhibitor of apoptosis XIAP, frequently upregulated in tumors. • Molecular Mechanisms. The Unit is involved in studies of the molecular mechanisms of thyroid carcinogenesis. The final goal of ongoing studies is the identification of markers useful for early detection, prognosis, and follow-up, as well as novel therapeutic targets through: i) the generation of in vitro models of thyroid carcinogenesis; ii) analysis of the role of selected pathways and molecules; iii) mRNA and microRNA expression analysis; iv) characterization of a thyroid tumor case collection, used both for discovery and validation studies. • Tumor Genomics. The research activity covers all aspects of lung cancer with the final aim of making an impact on a disease that is a major health-care burden in terms of morbidity and mortality. The Unit uses an integrated approach that combines cellular and molecular biology, biochemistry, and pharmacology to gain new insights in the pathogenesis of lung cancer and to find novel ways to provide early diagnosis and new treatment options. The goal of translational studies is the implementation of highly sensitive molecular tests that can be included in screening programs to improve both detection and clinical management of lung cancers. • Immunobiology of Human Tumors. The research activity focuses mainly on cutaneous melanoma. The main goals are: i) to understand how the adaptive immune response developed by cancer patients or promoted by immunotherapy can contribute to control tumor growth; ii) to identify new molecular targets to overcome melanoma resistance to target-specific therapy; iii) to understand the mechanisms of interaction of the tumor with its microenvironment; iv) to develop a functional classification of melanoma based on RTK expression and intracellular signaling pathway activation. • Molecular Immunology. This Unit investigates the complex interplay between cells of the immune system, the extracellular matrix, and transforming tissues, following the hypothesis that the evolving microenvironment is crucial for the fate of incipient tumors and might therefore offer new therapeutic targets within stroma components. Taking advantage of knock out and transgenic mouse models, the role of immune cells (such as mastocytes, T regulatory cells, neutrophils and myeloid derived suppressor cells) and their cross-talk in the context of the tumor stroma embedded in the ECM are elucidated to understand tumor and metastasis development in different neoplasms (prostate, breast, colitis-associated cancer, osteosarcoma, lymphoma and myeloid malignancies). • Immunotherapy of Human Tumors. The major goal is to investigate the cross-talk between tumor cells and the host immune systems in cancer patients, to understand their impact on disease course and response to treatments, and to identify novel therapeutic strategies based on immune manipulation. Towards this aim, the Unit includes both clinical and experimental expertise, to focus on: i) clinical and immunological effects of immunebased cancer therapies; ii) cancer-related immune regulatory pathways; iii) molecular studies on melanoma progression markers. • Biomarkers. Research in this Unit is aimed at identifying and validating cancer-related and actionable biomarkers relevant for cancer progression, using molecular and cell biology, high-throughput techniques, and bioinformatic tools. Studies are mainly focused on breast cancer to investigate: i) gene expression profiles on “critical” samples (formalin-fixed paraffin-embedded material and/or limited amount of cells, such as circulating tumor cells and tumor-initiating cells); ii) microRNA as blood-derived biomarkers that are potentially 48 back to contents clinical-scientific departments useful for early detection and risk assessment through non-invasive approaches. In order to develop sensitive and specific tests for clinical application, particular efforts have been spent in the last years to understand pre-analytical and analytical confounders for circulating markers. • Molecular Targeting Unit. This Unit is currently focused on identifying new molecular targets against which to design drugs against molecular pathways sustaining breast cancer progression without disrupting normal cell functions. Research activities are directed to investigate: i) the patho-biological role of extracellular matrix components in disease progression and response to therapy; ii) therapeutic targets in triple-negative breast tumors, and mechanisms involved in the early metastatic capability; iii) activity of resistance mechanisms to HER2-targeted therapies. • Molecular Therapies. Through a multidisciplinary approach and the integration of functional and analytical methodologies, the Unit aims: i) to gain insight into the molecular events involved in tumor progression; ii) identify and validate new potential targets and prognostic/predictive markers; iii) develop and validate new diagnostic/therapeutic strategies, mainly based on new generation recombinant antibodies, to target ovarian and prostate cancers. • Molecular Pharmacology. The research activity is focused on: i) identification and validation of novel therapeutic targets, (i.e. G-quadruplex structures and heparanase); ii) dissection of drug resistance mechanisms in tumor cells; iii) rational design of novel anticancer drug combinations; iv) preclinical development of novel therapeutic agents, based on the availability of a large number of preclinical models of human tumors of different histologic type; v) identification and functional validation of microRNAs as novel therapeutic targets/tools. • AIRC Start Up Unit. The goal is the identification and study of microRNAs involved in the most important pathways activated in human breast cancer through investigations on: i) microRNAs involved in molecular pathways associated with the different molecular subtypes; ii) biological effects of the microRNAs of interest identified in the previous task and validation of putative targets; iii) prognostic/predictive significance of selected microRNAs on series of primary breast carcinomas; iv) identification of the mechanisms regulating the expression of candidate microRNAs. HIGHLIGHTS In sentinel nodes of melanoma patients with progressing disease, CD30/TNFRSF8 is upregulated and a higher number of CD30(+) lymphocytes can be detected in nodes and peripheral blood lymphocytes from these patients. These findings reinforce the concept that sentinel nodes act as pivotal sites for determining progression patterns, revealing that the presence of CD30(+) lymphocytes at those sites correlates with melanoma progression. Unsupervised clustering analyses in independent datasets of invasive breast tumors profiled by using different platforms segregated ECM3 tumors as an independent subset in all datasets. ECM3 showed a homogeneous gene pattern, consisting of 58 genes encoding 43 structural ECM proteins. Both stromal and breast carcinoma cells can coordinately express ECM3 genes, contributing to an extracellular matrix gene expression profile defining a molecular subtype that is likely to progress. The diagnostic performance of a noninvasive plasma microRNA signature classifier (MSC) was retrospectively evaluated in samples prospectively collected from smokers within the randomized Multicenter Italian Lung Detection (MILD) trial. The diagnostic performance of MSC for lung cancer detection was 87% for sensitivity and 81% for specificity across both arms, and 88% and 80%, respectively, in the LDCT arm. This large validation study indicates that MSC has predictive, diagnostic, and prognostic value and could reduce the false-positive rate of LDCT. miR-205 showed to be the most down-modulated miRNA in prostate cancer (PCa) cells upon CAF stimulation, due to transcriptional repression by HIF-1, a redox- sensitive transcription factor. miR-215 replacement in PCa cells is able not only to prevent but also to revert the oxidative/pro-inflammatory axis leading to EMT induced by CAFs. Such finding sets the rationale for developing miRNA-based approaches to prevent and treat metastatic disease. Moreover, miR-205 proved to impair the autophagic flux and to enhance cisplatin cytotoxicity in castration-resistant prostate cancer cells. Acidification proved to induce reversible anergy in both human and mouse CD8+ T lymphocytes in vivo and in the tumor microenvironment, and the administration of proton pump inhibitors, which buffer tumor acidity, can revert T-cell anergy and increase the efficacy of immunotherapy. Such findings show that acidification of the tumor microenvironment may represent a novel mechanism of immune escape that can be overcome by drugs targeting pH-regulatory pathways. 49 back to contents SCIENTIFIC REPORT 2013 The anti-tumor activity of CpG oligodeoxynucleotides (CpG-ODN) aerosol was demonstrated in mouse lung metastases. In particular, aerosolized CpG-ODN activated a local immune response, while tumor immunogenicity and tumor-induced immunosuppressive environment represent critical factors for the success of CpG therapy in the lung. Combination of CpG-ODN, cetuximab, and cisplatin displayed high efficacy for advanced ovarian xenograft tumors. CpG-ODN combination therapies that enhance the immune response in the tumor microenvironment and concomitantly target tumor cells are highly active even in experimental advanced malignancies. Using mouse tumor and cellular models, trabectedin, a recently approved chemotherapeutic agent, proved to induce rapid apoptosis exclusively in mononuclear phagocytes. SM83, a newly synthesized dimeric SMAC mimetic, modulates in vivo the immune system within the tumor microenvironment and, through its pro-inflammatory action, induces cancer cells to die by necrosis. Our work provides evidence that SMAC mimetics could be more therapeutically active than expected by stimulating the immune system. The heparanase inhibitor SST0001, alone and in combination with antiangiogenic agents, showed antitumor efficacy in human pediatric sarcoma models. Cisplatin or oxaliplatin, in combination with the MEK1/2 inhibitor CI-1040, resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). KEYWORDS antibody-based therapy, apoptosis, blood-derived biomarkers, cancer vaccines, circulating tumor cells, drug resistance, exosomes, extracellular matrix, microRNA, preclinical drug development, regulatory T cells, solid tumors, target-specific therapy, translational medicine, tumor genetics, tumor microenvironment. MOLECULAR MECHANISMS OF CELL CYCLE CONTROL Head Domenico Delia, Biol Sci D Postdoctoral Fellows Benjamin Nachimuthu, Biol Sci D, PhD; Clara Ricci, Med Biotech, PhD; Laura Zannini, Biol Sci D, PhD Research Fellows Luigi Carlessi, Biol Sci D; Federico Lorenzetti, Med Biotech D; Vincenzo Ruscica, Mol Biol Sci D PhD Students Daniele Lecis, Biol Sci D; Annalisa Conti, Biol Sci D; Elena FusarPoli, Biol Sci D, Martina Magni, Biol Sci D Technician Enrico Fontanella MOLECULAR MECHANISMS Head Maria Angela Greco, Biol Sci D Research Staff Maria Grazia Borrello, Biol Sci D; Italia Bongarzone, Biol Sci D Postdoctoral Fellows Maria Grazia Vizioli, Med Biotech D; Maria Chiara Anania, Biol Sci D; Mara Mazzoni, Biol Sci D; Paola Romeo, Med Biotech D; Cetti Elena Med Biotech D, Dario Caccia, Med Biotech D, Luca Varinelli, Med Biotech D. PhD Student Emanuela Minna, Biol Sci D Technicians Maida De Bortoli, Sonia Pagliardini, Maria Grazia Rizzetti, Elena Taverna 50 TUMOR GENOMICS Head Gabriella Sozzi, PhD Research Staff Luca Roz, Pharm Sci D Postdoctoral Fellows Francesca Andriani, Pharm Sci D; Giulia Bertolini, Med Biotech D, PhD; Patrizia Gasparini, Biol Sci D; Massimo Moro, Biol Sci D, PhD; Carla Verri, Biol Sci D PhD Students Mattia Boeri, Biotech D, Tiziana Caputo, Pharm Biotech D Technicians Roberto Caserini, Davide Conte; Federica Facchinetti, Mavis Mensah IMMUNOBIOLOGY OF HUMAN TUMORS Head Andrea Anichini, Biol Sci D Research Staff Roberta Mortarini, Biol Sci D; Marialuisa Sensi, Biol Sci D Fellows Giulia Grazia, Biotechnol Sci D; Ilaria Penna, Biol Sci D; Valentina Perotti, Biol Sci D; Elena Tassi, Biotechnol Sci D Technicians Paola L. Baldassari, Ilaria Bersani, Alessandra Molla, Gabriella Nicolini, Claudia Vegetti MOLECULAR IMMUNOLOGY Head Mario P. Colombo, Biol Sci D clinical-scientific departments Research Staff Silvia Miotti, Biol Sci D; Claudia Chiodoni, Biol Sci D Postdoctoral Fellows Agniezka Chronowska, Biol Sci D, PhD; Giorgio Mauri, Med Biotech D;Sabina Sangaletti, Biol Sci D, PhD; Caterina Vitali, Pharm Biotech D, PhD; Alessia Burocchi, Biol Sci D PhD Students Alice Rigoni, Biol Sci D; Andrea Tomirotti, Med Biotech D, Ilaria Torselli, Biol Sci D Technicians Ivano Arioli, Barbara Cappetti, Ileana Facetti, Renata Ferri, Mariella Parenza, Claudia Bassani, Laura Botti, Biol Sci D; Chiara Ratti IMMUNOTHERAPY OF HUMAN TUMORS Head Licia Rivoltini, MD Research Staff Chiara Castelli, Biol Sci D; Monica Rodolfo, Biol Sci D Postdoctoral Fellows Maja Burdek, PhD (Fellowship from DFG, German Research Association); Chiara Camisaschi, Biol Sci D, PhD; Annamaria De Filippo, Biol Sci D, PhD; Paola Filipazzi, Biol Sci D; Veronica Huber MD, PhD; Viviana Vallacchi, Biotechnol Sci D, PhD; Elisabetta Vergani, Biol Sci D, PhD PhD Students Olga Kuchuk Biol Sci D; Marcella Tazzari, Pharm Sci D Fellows Sara Rigoletto, Biol Sci D; Alessandra Tuccitto, Biol Sci D Technicians Valeria Beretta, Agata Cova, Paola Deho, Simona Frigerio, Francesca Rini, Paola Squarcina Research Nurses Felicetta Giardino, Gianluigi Rigamonti Data Manager Paola Frati BIOMARKERS Head Maria Grazia Daidone, Biol Sci D, PhD Research Staff Vera Cappelletti, Biol Sci D; Silvia Veneroni, Biol Sci D; Raffaella Villa, Biol Sci D Postdoctoral Fellows Valentina Appierto, Biol Sci D, PhD; Valentina Angeloni, Biol Sci D, PhD PhD Students Maurizio Callari, Med Biotech D; Emanuela Fina, Biol Sci D; Valeria Musella, Med Biotech D Research Fellows Eleonora Di Buduo, Med Biotech D; Giuseppe Merlino, Med Biotech D; Paola Tiberio, Biol Sci D Technicians Cinzia De Marco, Chiara Iacona, Patrizia Miodini, Biol Sci D; Gloria Morandi, Rosita Motta MOLECULAR TARGETING UNIT Head Elda Tagliabue, Biol Sci D Research Staff Rosaria Orlandi, Biol Sci D; Serenella Pupa, Biol Sci D Postdoctoral Fellow Manuela Campiglio, Biol Sci D PhD Students Gaia C. Ghedini, Biotech Sci D; Marta Giussani, Biotech Sci D; Alessandra Meini, Biol Sci D; Marianna Sasso, Biol Sci D; Tiziana Triulzi, Biotech Sci D Fellows Lorenzo Castagnoli, Biotech Sci D; Valentina Ciravolo, Biotech Sci D; Viola Regondi, Biotech Sci D; Anna Rossini, Biol Sci D; Federica Turdo, Biol Sci D Consultants Sylvie Ménard, Biol Sci D; Marco Sandri, Stat Sci D Technicians Pierangela Aiello, Patrizia Casalini, Cristina Ghirelli MOLECULAR THERAPIES Head Silvana Canevari, Biol Sci D Research Staff Mariangela Figini, Biol Sci D; Delia Mezzanzanica, Biol Sci D; Antonella Tomassetti, Pharmacol Sci D Postdoctoral Fellows Fabio Benigni, Biol Sci D; Marina Bagnoli, Biol Sci D Fellows Chiara Alberti, Biol Sci D; Davide Bernareggi, Biol Sci D; Barbara Frigerio, Biol Sci D; Anna Granata, Biol Sci D; Roberta Nicoletti, Med Biotech D; Patrizia Pinciroli, Biol Sci D; Katia Rea, Med Biotech D; Alessandro Satta, Vet Biotech D; Valentina Tinaglia, Sci Biotech D Technicians Paola Alberti, Francesco Caroli, Anna Maria Invernizzi, Elena Luison, Cristina Luna MOLECULAR PHARMACOLOGY Head Nadia Zaffaroni, Biol Sci D, PhD Research Staff Marco Folini, Biol Sci D, PhD; Cinzia Lanzi, Biol Sci D; Paola Perego, Biol Sci D, PhD Postdoctoral Fellows Giovanni l. Beretta, Biol Sci D, PhD; Joanna Bidzinska, Biotech Sci D, PhD; Giuliana Cassinelli, Pharm D, PhD; Graziella Cimino Reale, Biol Sci D, PhD; Michelandrea De Cesare, Vet D; Paolo Gandellini, Biotech Sci D, PhD; Laura Gatti, Biol Sci D, PhD; Alessia Lopergolo, Biotech Sci D, PhD; Marzia Pennati, Biol Sci D, PhD; Valentina Zuco, Biol Sci D PhD Student Valentina Profumo, Biol Sci D Fellows Denis Cominetti, Biol Sci D; Nicola Fenderico, Biotech Sci D; Francesca Santambrogio, Biol Sci D; Stefania Sbarra, Biol Sci D 51 back to contents SCIENTIFIC REPORT 2013 Technicians Elisa Campi, Nives Carenini, Elena Cavadini, Elisabetta Corna, Laura Delbo, Enrica Favini, Maria Stella Tinelli, Monica Tortoreto AIRC START UP UNIT Head Marilena V. Iorio, Biotech Sci D The following core facilities are available. Immunohistochemistry (Technical Specialists: Lorena Ventura and Lucia Gioiosa): histological and cytological processing, including tissue microarrays, a wide range of histological techniques, immunohistochemistry, in situ hybridization, and autoradiography. Cell imaging facility (Technical Specialist: Patrizia Casalini, Biol Sci D): provides access to BioRad Radiance 2000 and Leica SP8 AFC AOBS WLL HyD laser confocal microscopes allowing for a wide range of fluorescent dye use, sequential, and simultaneous 3 channel bright field image collection, and live cell imaging. Flow cytometry and cell sorting (Technical Specialist: Gabriella Abolafio; Research Fellow: Andrea Vecchi, Biol Sci D): state-of-the-art flow cytometric and cell sorting instrumentations, and software analysis. Microbiology (Technical Specialist: Maria Teresa Radice): core services include media preparation; bacterial transformation; purification of plasmid DNA, BAC, YAC; freezing and storage of recombinant plasmids and bacterial strains. Cytogenetics and molecular cytogenetics (Specialist: Patrizia Gasparini, Biol Sci D): with state-of-the-art instruments, approaches of classic and molecular cytogenetics (fluorescent in situ hybridization and karyotype analysis using spectral karyotyping) and dedicated software allows identification of specific chromosomal alterations that are potentially useful for cancer diagnosis and as targets for novel treatments and/or associated with drug resistance in several solid tumor types (in particular, lung, colon and breast cancers, and soft tissue sarcomas). Functional genomics and Bioinformatics (Marina Bagnoli, Biol Sci D; Vera Cappelletti, Biol Sci D; Loris De Cecco, Biol Sci D; Rosaria Orlandi, Biol Sci D; Marialuisa Sensi, Biol Sci D; Maurizio Callari, Biotech D, Bioinformatician; Postdoctoral Fellows Ilaria Plantamura, Biol Sci D, PhD; Claudia Piovan, Pharm Biotech D, PhD Phd Student Elvira D’Ippolito, Biotech Sci D Gaetano De Feo, Biol Sci D; Matteo Dugo, Biotech D, Bioinformatician; Patrizia Pinciroli, Biol Sci D and Technical Specialists: Edoardo Marchesi, Donata Penso): see Shared Research Resources, page 62. Proteomics/mass spectrometry laboratory (Dario Caccia, Biotech Med D, PhD; Ruben Magni, Biotech Med D, PhD and Technical Specialist: Maida De Bortoli): see Shared Research Resources, page 63. Tissue and cell repository (Silvia Veneroni, Biol Sci D and Technical Specialists: Antonio Scavo, Francesco Pastore, Gloria Morandi): see Shared Research Resources, page 62. Laboratory animal facility Administrative Personnel: Claudia Miranda Biol Sci D, and Grazia Convertino, Simona Galluzzi, Ester Grande, Silvia Grassi, Laura Mameli, Silvia Portincasa, Luisa Rivetta, Daniela Silva, Laura Zanesi, Cristina Zanini. This team facilitates the activity of the Department by providing administrative support to research unit leaders and core facilities, coordinating the activities of graduate students and fellows, handling purchasing requests for laboratory consumables, and finance administration. Laboratory Management Team: Enrico Ronchi, Domenico Di Fazio, Angelo Labori, Salvatore Venturino. This team plays an essential role in supporting the research units in the Department for maintenance of instrumentation, and management and supervision of areas for cryopreservation of stored tissues/cells/cell extracts and reagents. In addition, the team – in association with the administrative team – also oversees a cost-effective and efficient centralized system of ordering and stock control for the most widely used items. Supporting Personnel: Antonietta Calcagno, Linda Cimaglia, Antonio Illuminato, Giuseppina Liguori, Agata Mancuso, Luisa Mona, David Penni, Gisella Rivadossi, Pasquale Russo, Claudio Santagostini. FOR MORE INFORMATION ABOUT THE UNITS, VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT 52 clinical-scientific departments PREVENTIVE AND PREDICTIVE MEDICINE DEPARTMENT DIRECTOR OF DEPARTMENT: Marco A. Pierotti (interim) +39 02 23902300 [email protected] The department focuses primarily on epidemiological and translational research. This comprises knowledge of lifestyle and genetic risk factors in order to take preventive action (i.e. from prediction to prevention), and knowledge of inequalities in cancer prevention and treatment in order to take corrective actions. The research relies on extensive interaction between researchers in the fields of basic experimental science, epidemiology, genetics, and clinical medicine. The priorities of the Department are: •promotion of healthy diet and lifestyle: to proceed from large cohort studies, in which the INT has been actively involved for more than 20 years, to dietary intervention studies targeting the general population, high-risk subgroups, and cancer patients to minimize the risk of recurrence (facilities include a hormonal laboratory and a teaching kitchen); •inequalities in survival and cure rates of cancer patients: from the systematic description of cancer incidence, prevalence, and survival to research on the interpretation of survival differences between and within countries, and promote actions to minimize such inequalities; •environmental and occupational risk factors: this research ranges from standard epidemiological designs to the systematic monitoring of occupational risk through linkage of cancer registry data and occupational history files; •hereditary cancer prevention in high-risk families: to go beyond clinical surveillance and prophylactic surgery, and promote research on environmental and lifestyle factors as well as genetic characteristics that may affect the penetrance of hereditary cancer genes; •in the field of low penetrance cancer genes and polygenic inheritance: to classify the complex genetics of risk and prognosis of lung and breast cancer. The Department is organized in the following Units: Epidemiology and Prevention. The Unit is involved in large prospective and intervention 53 SCIENTIFIC REPORT 2013 back to contents studies on the association between diet, hormones, nutrition, lifestyle, genetic factors, and cancer risk. Analytical Epidemiology and Health Impact. The Unit investigates patterns of care and cancer patient survival, promotes research in the field of public health, and conducts studies for planning cancer control. Scientific activities are carried out in collaboration with the Istituto Superiore di Sanità. Evaluative Epidemiology. The Unit is mainly involved in assessing the burden of cancer in populations. Several projects are focused on rare cancers and tumors diagnosed in children, adolescents, and young adults (AYA). However, major cancers like prostate, breast, colorectal, lung, cervix, and skin melanoma are considered for estimations of mortality, incidence and prevalence. Cancer Registry and Environmental Epidemiology. The Unit activity focuses on information systems and disease registries for epidemiological research and on the evaluation of the environmental, territorial, and prognostic risks. In July 2013, Dr Paolo Crosignani, for many years head of this Unit, retired after a successful scientific career. Since 1st October following organizational changes, two Units were derived. Medical Genetics. This Unit offers genetic counseling for several hereditary predispositions to cancer syndromes. The main focus is the study of hereditary breast and ovarian cancer syndrome (HBOC), but other inherited predispositions to cancer such as Li-Fraumeni Syndrome and familial melanoma are investigated. The principal goal is to identify individuals with an increased genetic risk of cancer in order to offer a targeted clinical management strategy including integrated and multidisciplinary healthcare service for prevention and treatment. Hereditary Digestive Tract Tumors. The Unit is devoted to the counseling, molecular testing, and clinical management of individuals with genetic predisposition to the major hereditary gastrointestinal cancer syndromes. These include Lynch syndrome (or hereditary non-polyposis colorectal cancer, HNPCC), familial adenomatous polyposis (FAP) and its phenotypic variant, attenuated-FAP, Peutz-Jeghers syndrome, juvenile polyposis, and hereditary gastric cancer. Individuals with evidence of hereditary susceptibility to cancer are counseled and informed about personal risk and that of their relatives. Depending on the fulfillment of defined criteria, individuals who receive genetic counseling are offered the possibility to undergo molecular testing for identification of specific genetic alteration(s) that may be associated with the increased risk of cancer in their families. These criteria include personal and family history of cancer, presence of specific clinical phenotypes, and tumor characteristics. Molecular Basis of Genetic Risk and Genetic Testing. This research Unit is devoted to the identification and characterization of genetic elements associated with predisposition to cancer and cancer progression. Studies are mainly focused on breast carcinoma and Wilms tumor. Genetic Epidemiology and Pharmacogenomics. The research group conducts studies to identify genetic factors associated with the risk and prognosis of individual cancer. The main study model is lung cancer, a ‘big killer’ characterized by a strong environmental risk factor formed by cigarette smoke. HIGHLIGHTS The European Prospective Investigation into Cancer and Nutrition (EPIC) study (http://epic.iarc.fr) was designed to investigate the relationships between diet, lifestyle, genetic, and environmental factors and the incidence of cancer and other chronic disease in 23 centers across 10 European countries: Denmark, France, Germany, Greece, Italy, The Netherlands, Norway, Spain, Sweden, and the United Kingdom. Over 520,000 healthy volunteers, characterized by large variations in dietary habits and cancer risk, have been recruited. The study centers were chosen in order to increase the power to detect diet and cancer associations by increasing the heterogeneity of exposure levels and the variations in the frequency of the cancers of interest. Clinical interpretation of cancer survival differences in Italy and Europe across regions and groups of patients through the collection and analyses of data in population cancer registries (CR) and hospital based cohorts of patients. Survival time trends and geographic 54 clinical-scientific departments differences in cancer survival are being analyzed using the EUROCARE data base - the largest European data base on survival and care of cancer patients- which presently centralizes data from 116 European CRs in 21 countries, with diagnoses from 1995 to 2007. The results of these analyses provide a measure of the efficacy of European health systems in cancer control, contributing to identify regions with low survival, where actions should be implemented to improve cancer diagnosis and treatment and to reduce inequalities in outcomes. Rare diseases including rare cancers are a priority for action in the European Public Health Program (2008-2013). The importance of providing accurate information on rare diseases to all European citizens is clearly stated in the Communication of the European Commission on Rare Diseases: Europe’s challenges, and in the Recommendations from the Council. Data from INT registry, the oldest still active in Italy, are validated and accepted by the IARC for the publication of Cancer Incidence in Five Continents. The registry participates in collaborative studies such as Epic, Ordet, Eurocare, RareCare, Accis, and Caremore, and supports the evaluation of screening programs in the Province of Varese. For more than 20 years, clinical units dedicated to counseling, genetic testing, and clinical management of individuals with evidence of genetic susceptibility to cancer have been operating at INT, mainly on familial breast, ovarian, and colorectal carcinomas. These activities fuel research projects aimed at increasing our current knowledge on the molecular basis of these diseases and our ability to diagnose individuals who are at higher risk of cancer development due to a genetic predisposition. The process of tumor progression and metastatic dissemination can involve germline polymorphisms and individual gene expression signatures in normal tissue. Our project is aimed to integrate genome and transcriptome data across multiple individuals, thus allowing identification of genetic biomarkers that are predictive of clinical phenotypes of colorectal or lung cancer. KEYWORDS prospective studies, diet, hormones, metformin, breast cancer, intervention studies, cancer epidemiology, health indicators, cancer burden, rare cancers, occupation, environment, familial and hereditary cancer, genetic counseling, cancer genetics, single nucleotide polymorphisms, experimental models, in vitro assays. EPIDEMIOLOGY AND PREVENTION Head Vittorio Krogh, MD, MSc Research Staff Claudia Agnoli, Nutrition Tech D, MSc; Manuela Bellegotti, BSc; Eleonora Bruno, Nutrition Tech D, MSc; Patrizia Cogliati, Biol Sci D; M. Gaetana Di Mauro, MD; Giuliana Gargano, Biol Sci D; Giulia Garrone, Chemist D; Sara Grioni, Nutrition Tech BSc; M. Valeria Pala, Agronomy D; Patrizia Pasanisi, MD, MSc; Samuele Pedraglio, Chemist D; Giuseppina Saragò, Biol Sci D; Sabina Sieri, Biol Sci D; Elisabetta Venturelli, Biol Sci D; Anna Villarini, Biol Sci D Technicians Simone Bonfarnuzzo, Alberto Turco Administrative Personnel Agatina A. Cifalà, Chiara Margutti, Stefania Saltarelli EVALUATIVE EPIDEMIOLOGY Head Gemma Gatta, MD Research Staff Laura Botta, BioStatistics D; Roberto Foschi, Math D, Msc; Annalisa Trama, MD PhD Resident Marilena M. Vece, MD Administrative Personnel Rossana Berruti, Lucia Buratti Technicians Adalberto Cavalleri, Daniela Del Sette Cerulli ENVIRONMENTAL EPIDEMIOLOGY (SINCE 1ST OCTOBER) Head Paolo Contiero, DSc, PhD Aministrative Personnel Alberto Evangelista, Paola Consorti, Patrizia Curtosi, Fabrizia Genoni, M. Grazia Guerrini, Maria Larossa Consultant Franco Berrino ANALYTICAL EPIDEMIOLOGY AND HEALTH IMPACT Head Milena Sant, MD Research Staff Hade Amash, MD; Camilla Amati, BA; Paolo Baili, Statistician, PhD; Francesca Bella, MD; Paolo Bonaiuti, Mathematics D, PhD; Ilaria Casella, Economist; Ilaria Cavallo, Informatics D; Francesca Di Salvo, Statistics D; Francesco L. Funaro, Informatics D; Elisabetta Meneghini, Physics, PhD; Pamela Minicozzi, Mathematics D, PhD Research Staff Martina Bertoldi, DSc Fellows Alessandro Borgini, DSc; Maria E. Sanoja Gonzalez, DSc Technician Alessandra Scaburri Administrative Personnel Immacolata Favia, Alessandro Cau CANCER REGISTRY (SINCE 1ST OCTOBER) Head Giovanna Tagliabue, MD, PhD 55 back to contents SCIENTIFIC REPORT 2013 Research Staff Laura Di Grazia, DSc; Emanuela Frassoldi, DSc; Daniela Gada, DSc; Mariarosa Ruzza, DSc Fellows Edoardo Bai, MD, PhD; Enrico Oddone, MD, PhD; Milena Calati, DH; Lucia Preto, DSc Technicians Sabrina Fabiano, Andrea Tittarelli Administrative Personnel Tiziana Codazzi, Anna Maghini MEDICAL GENETICS Head Siranoush Manoukian, MD, PhD Clinical Staff Bernard Peissel, MD, PhD Data Manager Daniela Zaffaroni, Biol Sci D, PhD Residents Giulia Melloni, MD; Giulietta Scuvera, MD Administrative Personnel Alex Sandra Masioli Dos Santos, Caterina Spina HEREDITARY DIGESTIVE TRACT TUMORS Head Lucio Bertario, MD Research Staff Paola Sala, Biol Sci D; Stefano Signoroni, Biol Sci D Administrative Personnel Mariangela Di Ceglie, Ornella Galuppo MOLECULAR BASES OF GENETIC RISK AND GENETIC TESTING Head Paolo Radice, Biol Sci D Research Staff Daniela Perotti, PhD Postdoctoral Fellows Laura Caleca, PhD; Mara Colombo, PhD; Giovanna De Vecchi, Biol Sci D; Antonio Fiorino, Biol Sci D; Carla B. Ripamonti, MD PhD Students Sara Ciceri, Med Biotech D Fellow Claudia Foglia, Biol Sci D Technician Patrizia Mondini Administrative Personnel Silvia Grassi GENETIC EPIDEMIOLOGY AND PHARMACOGENOMICS Head Tommaso A. Dragani, PhD Research Staff Giacomo Manenti, PhD; Paola Orsini, PhD Postdoctoral Fellows Francesca Colombo, PhD; Antonella Galvan, PhD; Marco Giannoccaro, MSc; Sara Noci, PhD; Marco Anderlini, MSc PhD Student Alice Dassano, MSc Technician Angela Pettinicchio FOR MORE INFORMATION ABOUT THE UNITS, VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT 56 back to contents shared research resources SHARED RESEARCH RESOURCES Core Facilities at the INT provide clinicians and researchers with centralized centers of expertise and state-of-the-art technologies. The INT core facilities include clinical resources supporting the physical, social, and emotional needs of cancer patients, in addition to research resources to extend the capabilities and accelerate the research progress of our clinical and experimental researchers. The INT supports core facilities, including: Cardiology, Respiratory Pathophysiology, Clinical Psychology, Medical Statistics, Biometry and Bioinformatics, Clinical Epidemiology and Trial Organization, Clinical Trials Center, Human Tissue Bank, Functional Genomics, and Cancer Proteomics. CARDIOLOGY Director: Patrizia Piotti, MD The Cardiology Unit is mainly concerned with the preoperative evaluation of surgical patients. Working in close collaboration with anesthesiologists and thoracic and abdominal surgeons, the Unit aims to reduce preoperative risk and manage complications. The Unit also provides evaluations and consultations for patients from the Fondazione IRCCS Istituto Neurologico C. Besta. Among the main duties of the Cardiology Unit are evaluation of the general cardiac status of all candidates for chemo-radiotherapy treatment to monitor potential cardiovascular toxicity related to antineoplastic treatments from early recognition to diagnosis and therapy. All of the Phase I, II, and III clinical studies carried out at INT require regular cardiologic surveillance to assess the cardiotoxicity of new experimental drugs (monoclonal antibodies, receptor tyrosine kinase inhibitors, BRAF inhibitors, MEK inhibitors). RESPIRATORY PATHOPHYSIOLOGY Director: Roberto Boffi, MD The Unit provides a broad range of respiratory consultations as well as pulmonary function tests. Inpatient activity is mainly focused on: • preoperative evaluation of patients planned for thoracic surgery; •short- and long-term follow-up of pulmonary toxicities due to chemotherapy and/or radiotherapy; 59 SCIENTIFIC REPORT 2013 • pharmacological aid to smoker inpatients; • healthcare associated pneumonia and/or pulmonary graft-versus-host disease. Outpatient activity is focused on: • asthma and COPD patients; • interstitial lung diseases and evaluation of sarcoidosis; • smoker outpatients with a dedicated anti-tobacco clinic. The clinical research activity stems from productive collaborations with: •Department of Predictive and Preventive Medicine (pharmacogenetic of smoking cessation drugs) • Thoracic Surgery (smoking cessation within a lung cancer screening trial) • Clinical Psychology (smoking cessation counseling for inpatient smokers) •Società Italiana di Medicina Generale (indoor and outdoor pollution from cigarette smoke). CLINICAL PSYCHOLOGY Director: Claudia Borreani, Psy D The Unit supports patients with life-threatening illnesses, along with their families, and is aimed to improve the quality of life and well-being, and relieve mental suffering throughout the course of illness and survivorship. Psycho-Oncology covers the whole range of mental and emotional difficulties related to cancer, stimulates research, and develops training so that psychosocial care may be integrated with clinical oncology specialties for holistic patient care. The research activity aims to assess the subjective impact of cancer and cancer treatments on patients’ quality of life and the psychosocial aspects related to the various phases of the oncologic disease. The clinical activity includes: psychological assessment, individual psychological counseling, short psychotherapies, family therapies, and psycho-educational groups. Collaboration with other clinical Units on specific issues includes: •Multidisciplinary clinical project to support cancer patients undergoing liver transplant surgery (Liver Transplantation Unit) •Multidisciplinary clinical project to support decision-making in BRCA1/2 carriers (Medical Genetics Unit) •Clinical decision making counseling, psychological support, and psychosexual counseling for prostate cancer patients (Prostate Program) • Multidisciplinary smoking cessation project for inpatients (Tobacco Control Laboratory). MEDICAL STATISTICS, BIOMETRY, AND BIOINFORMATICS (MSBB) Director: Adriano Decarli, PhD The MSBB provides quantitative support to research activity across various Departments at INT, and maintains collaborative relationships with other national or international research groups. The activity of the INT group is governed by a convention with the University of Milan. Biostatistics for Oriented Basic Research and Quality Control (Paolo Verderio, Biol Sci D, PhD; Sara Pizzamiglio, Msc). The team applies statistical methods to different phases of the biomarker development process in oncology. It provides implementation and statistical analysis of quality control studies for tumor biomarkers and in vitro diagnostic tools, evaluation of inherited diseases in oncology, establishment and validation of biological assays, preclinical pharmacology and testing new molecular detection strategies based on innovative technologies. As partner of the FP7 EU Project SPIDIA, the team is involved in 60 back to contents shared research resources the planning, implementation, and statistical analysis of ring trials, and contributes to the setup and validation of biological assays and testing new molecular detection strategies based on innovative technologies. Biostatistics for Bioinformatics and Translational Research (Elia M. Biganzoli, PhD; Ilaria Ardoino, PhD; Matteo Malvezzi, PhD). In the context of analytical molecular epidemiology, the team supports the transfer of basic preclinical research to clinics using quantitative approaches to assess the impact of new technologies in oncology according to cost-benefit principles and sustainability perspectives. Within the framework of collaborative projects, the team is involved in research concerning the assessment of high-throughput and next generation sequencing (NGS) platforms for DNA and RNA analysis, qRT-PCR, and highthroughput assays in cancer. Statistical bioinformatics research supports the design and analysis of NGS experiments. Studies on follow-up data with reference to the analysis of risk patterns related to metastatic dormancy are conducted in cooperation with clinical Units. CLINICAL EPIDEMIOLOGY AND TRIAL ORGANIZATION Director: Luigi Mariani, MD PhD Research Staff: Rosalba Miceli, PhD; Elena Landoni, PhD The Unit provides statistical support relating to the design, conduct, and analysis of clinical trials, observational and population-based studies, mainly in the areas of surgical, medical or hematological oncology. CLINICAL TRIALS CENTER Coordinators: Valentina Sinno and Luigi Mariani The operative Clinical Trial Center (CTC) has been re-established in January 2012 by the Scientific Director to support clinical studies, especially investigator driven and Phase I and II studies, with the aim of bringing research results and new treatments to the bedside in the shortest time. The CTC supports Clinical Researchers in managing many aspects of investigational clinical studies, such as study design and statistical validation, submission to the Ethics Committee and regulatory authorities (AIFA for Phase I studies), budget and contract related issues, as well as data management and statistical analysis, thanks to 16 data managers, two medical statisticians, and an administrative and legal specialist. The CTC also provides pharmacovigilance through an “ad hoc” trained pharmacist, employs six qualified Research Nurses to improve patient care in the various steps of the study (scheduling of treatments, blood sampling, exams, controls, etc.), and two laboratory biologists to handle tissue and blood samples for pharmacokinetics and molecular studies. CTC works through validated and updated SOP and electronic CRF customized for each specific study; personnel education and training is coordinated by the Scientific Directorate. The CTC is also improving the organization of sponsored clinical trials, speeding up administrative processes, budget definition, patient recruitment and data management, organizing a centralized record of all radio-diagnostic exams, and assisting Clinical Monitors in their visits. Up to the end of 2013, the CTC managed 21 investigator driven monocentric/multicentric clinical trials, and provided statistic support to 44 studies; among the “for-profit” clinical studies activated in 2013 at INT, 50 were administered by the CTC data managers. 61 SCIENTIFIC REPORT 2013 TISSUE AND CELL REPOSITORY Directors: Giuseppe Pelosi, MD and Maria Grazia Daidone, Biol Sci D, PhD Since 2002, the INT Tissue Bank (ITB) has been dedicated to the collection and distribution of neoplastic, preneoplastic, and normal tissues from human subjects for research projects. This resource is a project of INT Scientific Directorate, with day-to-day staff supervision provided by personnel from the Departments of Pathology and Experimental Oncology & Molecular Medicine. The activities are overseen by an interdepartmental advisory committee, which also evaluates and approves research projects depending on the availability of tissue specimens. Adopting TUBAFROST procedures, although slightly modified to comply with local conditions, the ITB stores frozen samples (primary and metastatic lesions, with corresponding normal tissues) and contributes specimens to a large number of specific research projects dealing with almost all tumor types. All patients/subjects sign an informed consent document (approved by the Independent Ethics Committee and filed in the patients’ records) to donate leftover tissue/biological specimens from diagnostic procedures to the ITB for future studies. It is a one-time general consent with a twostep decision process that allows patients to control the use of their samples and foster important research. Guidelines have been proposed to define responsibilities for ITB management, policies and procedures to protect patient confidentiality and privacy, and establish priorities for specimen distribution. FUNCTIONAL GENOMICS AND BIOINFORMATICS CORE FACILITY (FGBCF) Coordinator: Silvana Canevari, Biol Sci D The activities of the FGBCF are conducted using the following instruments: QIAcube for nucleic acid purification; Agilent Bioanalyzer, Nanodrop, Qubit for quantity and quality control of nucleic acids; Illumina and Agilent platforms for microarray analysis of mRNA expression, miRNA and lncRNA expression, ChIP-on-chip, DNA methylation, CGH and CNV, SNPs; Quantstudio 12K for quantitative real-time PCR; automated liquid handling MultiProbe II; Next Generation Sequencing SOLiD™ 5500xl Wildfire and 3130 Sequencer for Sanger Sequencing; dedicated servers, work-stations, and up-to-date software, hardware and web-based databases. The research group comprises full time personnel involved in wet analyses and personnel dedicating part of their institutional activity to computational analysis using wet and in silico data. The FGBCF performs: study design; RNA and DNA extraction and quality controls; all the labeling and hybridization methodologies required for high quality analysis; data processing and statistical analysis. Full computational analyses are performed using open-source software and dedicated licenses. Identification and bio-functional interpretation of promising biomarkers are based on differential expression analysis, pathway analysis with over-representation or gene set enrichment approaches (GO and GSEA), and integration of different kinds of data. The FGBCF also provides certification of identity of cell lines adhering to ATCC guidelines and sample processing on a 3130 capillary genetic analyzer. 62 back to contents shared research resources PROTEOMICS/MASS SPECTROMETRY LABORATORY (PMSL) Coordinator: Italia Bongarzone, Biol Sci D The INT PMSL uses proteomics to analyze cell lines, tissue biopsies, and biofluid samples. A combination of proteomics profiling - aimed to characterize as many proteins as possible from cell line secretomes, body fluids, or extracts - and bioinformatic analyses allow us to reveal critical biological information. The PMSL studies suggest new tumor classification strategies and lines of therapeutic intervention. In addition to cataloging proteins, the PMSL analytical approach and statistical workflow has the potential to improve the accuracy of patient classification with the aim to better understand pathway-related genes and proteins associated with prognosis. FOR MORE INFORMATION VISIT US ONLINE AT WWW.ISTITUTOTUMORI.MI.IT 63 RESEARCH ACTIVITY back to contents research activity PREVENTIVE AND PREDICTIVE MEDICINE COORDINATOR: Marco A. Pierotti The research activity focuses on epidemiology and prevention through prospective epidemiological studies, case-control studies and survival studies. Our Institute is involved in the coordination of national and international multicenter studies including projects on rare tumors coordinated at a European level as well as interventional prevention projects. In our research on families with a high genetic risk, where a series of interventions has been developed aimed at people with a genetic predisposition to cancer, we intend to continue with the clinical and molecular characterization. AIMS: Organization and implementation of interventional prevention projects, and management of the related biobanks. Creation of information networks directed at all stakeholders through the use of data of population-based cancer registries. Identification of the causes of survival differences between populations of different countries and within the same country; production of health indicators; promotion of information on health and healthy lifestyles; distribution of knowledge in the field of cancer epidemiology.In the setting of familial-hereditary cancer: detection of individuals at increased genetic risk; detection of the predisposing gene(s); provision of appropriate surveillance programs and possible options for prevention; provision of adequate treatment in case disease develops. PROJECTS • Prospective observational studies on diet, lifestyle, endocrine/metabolic and genetic factors and cancer risk (Vittorio Krogh) • Rare tumors: creation of an information network and an epidemiological surveillance system (Gemma Gatta) • Clinical interpretation of cancer survival differences in Italy and Europe (Milena Sant) • Study of the molecular determinants of the genetic predisposition to familial-hereditary cancers (Paolo Radice, Siranoush Manoukian and Lucio Bertario) 65 SCIENTIFIC REPORT 2013 back to contents .Vittorio Krogh. PROSPECTIVE OBSERVATIONAL STUDIES ON DIET, LIFESTYLE, ENDOCRINE/METABOLIC AND GENETIC FACTORS AND CANCER RISK OVERVIEW AND SCIENTIFIC GOALS The Epidemiology and Prevention Unit is involved in large prospective and intervention studies on the association between diet, hormones, nutrition, lifestyle, genetic factors, and cancer risk. The European Prospective Investigation into Cancer and Nutrition (EPIC) study (http://epic.iarc.fr) was designed to investigate the relationships between diet, lifestyle, genetic, and environmental factors and the incidence of cancer and other chronic disease in 23 centers across 10 European countries: Denmark, France, Germany, Greece, Italy, The Netherlands, Norway, Spain, Sweden, and the United Kingdom. Over 520,000 healthy volunteers, characterized by large variations in dietary habits and cancer risk, have been recruited. The study centers were chosen in order to increase the power to detect diet and cancer associations by increasing the heterogeneity of exposure levels and the variations in the frequency of the cancers of interest. Data were collected on diet, physical activity, sexual maturation and reproductive history, lifetime consumption of alcohol and tobacco, previous and current illnesses, and current medication. Following a common protocol and using identical equipment, blood samples were collected, separated into plasma, serum, white blood cells and erythrocytes, and stored in liquid nitrogen at –196°C for future laboratory analyses on cancer cases and matched healthy controls. Anthropometric measurements were taken according to a standard protocol. Follow-up is based on linkage with population cancer registries or a combination of methods including health insurance records, cancer and pathology registries, and active follow-up through study participants and their next-of-kin. The ORDET study is one of the first prospective European studies on the role of hORmones and DiET in the etiology of cancer. A total of 10,786 healthy women, ages 35–69 years, residents of the Varese province in northern Italy, were recruited for this prospective study of hormones, diet, and breast cancer risk. Information on lifestyle characteristics, menstrual and reproductive history, dietary habits, and anthropometric measurements were collected at baseline. Moreover, blood samples were collected, after 12 hours fasting, between 7:30 and 9:00 a.m. from all of the participants in the study. For premenopausal women, blood was collected in the luteal phase of the menstrual cycle. All of the blood samples were processed and stored at –80°C. Women are followed through the local cancer registry (Lombardy Cancer Registry, Varese Province) characterized by high completeness and quality. The ORDET study is participating in the “Pooling project”, a collaborative project that involves major European and North American cohort studies coordinated by Harvard University. 66 research activity PROGRAM HIGHLIGHTS The EPIC project represents an ideal natural laboratory thanks to the very heterogeneous dietary habits still found in different European populations, ranging from the Mediterranean diets of Greece, southern Italy, Spain, and the south of France to the central European food patterns of Germany, Netherlands, and north of France, to the Nordic style diet of Norway, Sweden, and Denmark. At the same time, incidence of several major cancer sites varies substantially across countries and even more across regions. In addition to the variations in risk and dietary habits, a crucial element of the statistical power, which was central in the design of EPIC, is study size. The ORDET study was designed to evaluate the association between endogenous hormones with breast cancer risk, therefore at recruitment several sources of hormone variability were controlled for by both inclusion criteria and highly standardized conditions at blood drawing. Women with bilateral ovariectomy, those currently pregnant or breast-feeding, those on oral contraceptives or hormone replacement therapy, or affected by metabolic diseases influencing the endocrine profile (i.e. liver disease) were not eligible for the study. This allowed to control for or eliminate several sources of bias and undesired variability that have probably blurred the results of some previous studies on prediagnostic sex steroids level and breast cancer risk. PROGRAM MEMBERSHIP Vittorio Krogh. Head of Unit, is an experienced chronic disease epidemiologist with an interest in the link between environment and genetic factors in the etiology of Cancer and Cardiovascular Disease. His main and long standing focus of research interest is the role of diet and nutrition, and its interaction with individual and familial factors, in disease etiology and prevention. He has directed a number of epidemiological studies and participated since 1991 in the EPIC Study. Dr. Krogh’s papers have attracted >15,000 citations to date, and his H-Index is 64. Valeria Pala. Dr Pala is a senior epidemiologist, working since 1995 as researcher at the Department of Preventive and Predictive Medicine. Dr. Pala has been working on longitudinal cohorts (ORDET, EPIC) for about 20 years and her main focus has been on diet, genetic susceptibility, and cancer and other chronic disease etiology. Dr. Pala publications have attracted over 3500 citations to date and her H-index is 35. Sabina Sieri. Dr. Sieri is a senior epidemiologist working in the field of cancer and cardiovascular diseases since 1996. Her main focus of research interest is the role of diet, nutrition, endocrinological and metabolic factors in the etiology of chronic diseases. Dr. Sieri’s papers have attracted >5900 citations and her H-Index is 41. Sara Grioni. Dr. Grioni is a young researcher with interest in nutritional and lifestyle related risk factors in the etiology and prevention of cancer and cardiovascular diseases since 2004. Dr. Grioni is also involved in the continuous update of the EPIC and ORDET follow-up databases. Dr. Grioni’s papers have attracted >1300 citations to date and her H-Index is 24. Claudia Agnoli. Dr. Agnoli is a young researcher who works in the field of cancer and cardiovascular disease epidemiology since 2006. Her main research interests include the role of metabolic syndrome in cancer etiology, with special focus on breast cancer, and the association between dietary patterns and risk of chronic disease. Dr. Agnoli’s papers have attracted >1,200 citations to date and her H-Index is 20. SELECTED RECENT PUBLICATIONS Key T.J., Appleby P.N., Reeves G.K., Travis R.C., Alberg A.J., Barricarte A., Berrino F., Krogh V., Sieri S., Brinton L.A., Dorgan J.F., Dossus L., Dowsett M., Eliassen A.H., Fortner R.T., Hankinson S.E., Helzlsouer K.J., Hoffman-Bolton J., Comstock G.W., Kaaks R., Kahle L.L., Muti P., Overvad K., Peeters P.H., Riboli E., Rinaldi S., Rollison D.E., Stanczyk F.Z., Trichopoulos D., Tworoger S.S., Vineis P.: Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol 2013; 14: 1009-1019 Raaschou-Nielsen O., Andersen Z.J., Beelen R., Samoli E., Stafoggia M., Weinmayr G., Hoffmann B., Fischer P., Nieuwenhuijsen M.J., Brunekreef B., Xun W.W., Katsouyanni K., Dimakopoulou K., Sommar J., Forsberg B., Modig L., Oudin A., Oftedal B., Schwarze P.E., Nafstad P., De F.U., Pedersen N.L., Ostenson C.G., Fratiglioni L., Penell J., Korek M., Pershagen G., Eriksen K.T., Sorensen M., Tjonneland A., Ellermann T., Eeftens M., Peeters P.H., Meliefste K., Wang M., Bueno-de-Mesquita B., Key T.J., de Hoogh K., Concin H., Nagel G., Vilier A., Grioni S., Krogh V., Tsai M.Y., Ricceri F., Sacerdote C., Galassi C., Migliore E., Ranzi A., Cesaroni G., Badaloni C., Forastiere F., Tamayo I., Amiano P., Dorronsoro M., Trichopoulou A., Bamia C., Vineis P., Hoek G.: Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE). Lancet Oncol 2013; 14: 813-822 Kreimer A.R., Johansson M., Waterboer T., Kaaks R., Chang-Claude J., Drogen D., Tjonneland A., Overvad K., Quiros J.R., Gonzalez C.A., Sanchez M.J., Larranaga N., Navarro C., Barricarte A., Travis R.C., Khaw K.T., Wareham N., Trichopoulou A., Lagiou P., Trichopoulos D., Peeters P.H., Panico S., Masala G., Grioni S., Tumino R., Vineis P., Bueno-deMesquita H.B., Laurell G., Hallmans G., Manjer J., Ekstrom J., Skeie G., Lund E., Weiderpass E., Ferrari P., Byrnes G., Romieu I., Riboli E., Hildesheim A., Boeing H., Pawlita M., Brennan P.: Evaluation of human papillomavirus antibodies and risk of subsequent head and neck cancer. J Clin Oncol 2013; 31: 2708-2715 Agnoli C., Grioni S., Sieri S., Palli D., Masala G., Sacerdote C., Vineis P., Tumino R., Giurdanella M.C., Pala V., Berrino F., Mattiello A., Panico S., Krogh V.: Italian Mediterranean index and risk of colorectal cancer in the Italian section of the EPIC cohort. Int J Cancer 2013; 132: 1404-1411 Sieri S., Pala V., Brighenti F., Agnoli C., Grioni S., Berrino F., Scazzina F., Palli D., Masala G., Vineis P., Sacerdote C., Tumino R., Giurdanella M.C., Mattiello A., Panico S., Krogh V.: High glycemic diet and breast cancer occurrence in the Italian EPIC cohort. Nutr Metab Cardiovasc Dis 2013; 23: 628-634 SELECTED RECENT MAJOR GRANTS “Role of nutrients involved in one-carbon metabolism in the development of different molecular subtypes of BC in the ORDET cohort”, funded by Ministry of Health in 2011. Local PI: Sabina Sieri. “Changes in weight and inflammation markers in relation to breast cancer risk: a nested case-control study”, funded by Associazione Italiana per la Ricerca sul Cancro (AIRC) in 2012. Local PI: Vittorio Krogh. “Is the protective effect of Mediterranean Diet on cancer mediated by a methylation pattern?”, funded by Associazione Italiana per la Ricerca sul Cancro (AIRC) in 2013. Local PI: Vittorio Krogh. “ENVIROGENOMARKERS – Genomics biomarkers of environmental health”, funded by European Commission, Seventh Framework Program (Grant Agreement n. 226756), in 2009. Local PI: Vittorio Krogh. KEYWORDS prospective studies, diet, hormones, breast cancer 67 SCIENTIFIC REPORT 2013 back to contents .Gemma Gatta. RARE TUMORS: CREATION OF AN INFORMATION NETWORK AND EPIDEMIOLOGICAL SURVEILLANCE SYSTEM OVERVIEW AND SCIENTIFIC GOALS Rare diseases including rare cancers are a priority for action in the European Public Health Program (2008-2013). The importance of providing accurate information on rare diseases to all European citizens is clearly stated in the Communication of the European Commission on Rare Diseases: Europe’s challenges, and in the Recommendations from the Council. The project Surveillance of Rare Cancers in Europe (RARECARE) estimated the burden of rare cancers in Europe by providing the first indication of the size of the public health problem due to these diseases and constitutes a useful basis for implementing public health actions and further research. According to RARECARE, around 4 million individuals in the European Union (EU) are affected by rare cancers. Despite the rarity of each of the 186 identified rare cancers, together they represent about 22% of all cancer cases diagnosed in the EU27 each year. Five-year relative survival is significantly worse for rare cancers (47%) than for common cancers (65%), and differences in survival exist across European regions (Gatta G. Lancet Oncology 2006). There is general agreement that treatment of rare cancers should be concentrated in specialist multidisciplinary centers, and that international collaboration is needed to undertake research in this group of patients. However, there is no evidence on the impact of such initiatives on survival. Due to their low frequency, rare cancers pose particular challenges such as late or incorrect diagnosis, lack of access to appropriate therapies and clinical expertise, limited information about the disease and a scarcity of clinical trials. In responses to these challenges, Rare Cancers Europe (RCE) has launched a Call to Action that urges policymakers and stakeholders to give priority to rare cancers. In particular, it is campaigning to: 1) foster the creation of reference networks for the treatment of patients with rare cancers, 2) spread knowledge and clinical guidelines on rare cancers, 3) promote the establishment of clinical databases and registries, and 4) empower patients. Against the background described, a key goal is to build on a network of organizations collaborating in research, promotion, and implementation of appropriate solutions to address the challenges posed by rare cancers. 68 research activity PROGRAM HIGHLIGHTS The overall goal is to serve as the reference source of information on rare cancers in Europe and contribute to ameliorate diagnosis and treatment of rare cancers, foster research on rare cancers, support the establishment of centers of expertise and empower patients. The list of continuously updated rare cancers promotes better classification. The list complements the EU dynamic inventory of rare diseases developed by Orphanet by providing information on rare cancers and contributing to identify which cancers are rare. Information on health care pathways and estimates of survival differences by European region contribute to identify determinants of variations in survival across Europe and to develop recommendations to improve the situation by reducing health inequalities across Europe. Updated incidence and prevalence data support better healthcare planning and resource allocation for rare cancers. The availability of prevalence data updated to 2007 for rare cancers also facilitate application of the EU orphan drug directive. Monitoring time trends of rare cancers improves information for healthcare planning, from primary prevention to care. The availability of criteria for centers of expertise for rare cancers are essential for their identification, establish networks of such centers in Europe and harmonize practices across EU countries. Networks of reference centers are essential to increase knowledge on rare cancers, define and share best practice, put expert knowledge at disposal of physicians, and improve diagnosis of rare cancers as well as their treatment and research. Knowledge of centers to which rare cancer patients are most frequently referred will help patients and their GPs in finding an appropriate hospital for treatment. Information on diagnosis and treatment of rare cancers support clinical oncologists and physicians in everyday oncology practice. This will contribute to improving the timeliness and appropriateness of diagnoses as well as overall disease management. The clinical database supporting the pooling of cases of very rare cancers leads to the development of new knowledge and to the definition of more homogeneous clinical management of such rare diseases. It also contributes to the development of international collaborative groups to foster research on rare cancers. Empowerment of rare cancer patients requires both information and education. The network contributes to inform, educate, and motivate patients. Information flows, not only towards patients but also from them, are essential so that their needs can be known and enable them to take responsibility, understand their own disease, and know who can manage it. In general, patients can contribute by participating in the definition of a healthcare agenda and becoming empowered patients. The outcomes described contribute to ameliorating survival of patients with rare cancers. PROGRAM MEMBERSHIP The University of Edinburgh (Ian Kunkler) Dissemination of the project Survival of Cancer Patients in Europe (EUROCARE) (Franco Berrino), Milan, Italy Information on epidemiology of rare cancers Institut de CancÈrologie Gustave Roussy (Ellen Benhamou) Evaluation of the project Oncological Societies (ESMO, ESSO, ECCO) Information on centers of expertise for rare cancers and clinical management of rare cancers Istituto Superiore di Sanità (Riccardo Capocaccia) Information on epidemiology of rare cancers SELECTED RECENT PUBLICATIONS Integraal Kankercentrum Nederland (Sabine Siesling) Information on centers of expertise for rare cancers Gatta G., Rossi S., Foschi R., Trama A., Marcos-Gragera R., Pastore G., Peris-Bonet R., Stiller C., Capocaccia R.: Survival and cure trends for European children, adolescents and young adults diagnosed with acute lymphoblastic leukemia from 1982 to 2002. Haematologica 2013; 98: 744-752 Fondazione IRCCS, Istituto Nazionale dei Tumori, Italy (Lisa Licitra) Information on clinical management of rare cancers European Cancer Patient Coalition (Jana Pelouchov· – Francesco De Lorenzo) Information for patients with rare cancers National Oncology Hospital, Bulgaria (Nadya Dimitrova) Contributing to all the above activities National Cancer Registry, Ireland (Harry Comber) Contributing to all the above activities Cancer Society of Finland − Institute for Statistical and Epidemiological Cancer Research, Finland (Eero Pukkala) Contributing to all the above activities Institute of Oncology Ljubljana (Maja Primic Žakelj) Contributing to all the above activities Rare Cancer Europe (Paolo Casali) Information on epidemiology of rare cancers and Information on centers of expertise for rare cancers European Partnership for Action Against Cancer (Josep M Borras), Barcelona, Spain Information on centers of expertise for rare cancers European School of Oncology (Alberto Costa), Milan, Italy Dissemination of the project Mallone S., De Angelis R., van der Zwan J.M., Trama A., Siesling S., Gatta G., Capocaccia R., RARECARE WG.: Methodological aspects of estimating rare cancer prevalence in Europe: The experience of the RARECARE project. Cancer Epidemiol 2013; 37: 850-856 Stiller C.A., Trama A., Serraino D., Rossi S., Navarro C., Chirlaque M.D., Casali P.G.: Descriptive epidemiology of sarcomas in Europe: Report from the RARECARE project. Eur J Cancer 2013; 49: 684-695 Van Der Zwan J.M., Trama A., Otter R., LarraÒaga N., Tavilla A., Marcos-Gragera R., Dei Tos A.P., Baudin E., Poston G., Links T.: Rare neuroendocrine tumours: Results of the surveillance of rare cancers in Europe project. Eur J Cancer 2013; 49: 2565-2578 Gatta G., van der Zwan J.M., Casali P.G., Siesling S., Dei Tos A.P., Kunkler I., Otter R., Licitra L., Mallone S., Tavilla A., Trama A., Capocaccia R.; RARECARE working group. Rare cancers are not so rare: the rare cancer burden in Europe. Eur J Cancer 2011; 47(17): 2493-2511 SELECTED RECENT MAJOR GRANTS Projects supported by the EC DG Sanco and Italian Ministry of Health (for rare diseases) KEYWORDS Europe, rare cancers, network, center of excellence 69 SCIENTIFIC REPORT 2013 back to contents .Milena Sant. CLINICAL INTERPRETATION OF CANCER SURVIVAL DIFFERENCES IN ITALY AND EUROPE OVERVIEW AND SCIENTIFIC GOALS The project investigates differences in cancer outcomes and survival across regions and groups of patients, in Europe and Italy, through the collection and analyses of data in population cancer registries (CR) and hospital based cohorts of patients. Survival time trends and geographic differences in cancer survival are being analyzed using the EUROCARE data base - the largest European data base on survival and care of cancer patients- which presently centralizes data from 116 European CRs in 21 countries, with diagnoses from 1995 to 2007. The results of these analyses provide a measure of the efficacy of European health systems in cancer control, contributing to identify regions with low survival, where actions should be implemented to improve cancer diagnosis and treatment and to reduce inequalities in outcomes. These analyses can also evaluate, in current clinical practice, the impact of innovative treatments validated in controlled clinical studies (i.e. comparing “effectiveness” and “efficacy”). For instance, the large improvement in survival for many hematological malignancies in most European countries, at the population level, is generally attributable to the dissemination of new and effective treatments. However, the EUROCARE analyses show how these improvements are less evident in eastern European countries. Specific studies on patient’s samples are carried out to understand the reasons for these inequalities: “High resolution studies” (HR) are being conducted by collecting data with greater detail than that available for population-based CR, i.e. on diagnostic investigation, stage at diagnosis, treatment, bio-molecular tumor characteristics, and follow-up. The HR studies describe and compare patterns of cancer care across areas between groups of patients and over time; they also study the frequency of adhesion to clinical guidelines and their effect on cancer outcomes. Further insights on mechanisms of tumor progression and metastatic dissemination, as well as differences in clinical outcome, are provided by the INT in-house breast cancer registry, which uses routine administrative files (e.g. hospital discharge records) as well as ad hoc information from clinical records obtained by dedicated personnel. Linkage with INT biological and tissue banks have been established to correlate experimental research results with clinical data. The possibility of extending the adopted clinical registration methodology to other cancers will be tested. Data from the Lombardy Region Oncologic Network (ROL) – covering all oncology departments in the Region – is used to compare patterns of cancer care analyses with adhesion to clinical guidelines between hospitals. 70 research activity PROGRAM HIGHLIGHTS EUROCARE is the largest European population based program monitoring cancer survival in Europe; since its beginning in the late 1980s, it has progressively become a well established program for surveillance of cancer survival in Europe. The latest EUROCARE results show that, over the EUROCARE-5 study period, survival increased steadily in all countries, for practically all cancers, possibly because of improved treatment and probably in relation to earlier diagnosis. However, differences between countries remain large within Europe, with a large gap between eastern Europe and the rest of Europe. Survival in the UK, Ireland and Denmark remains low for many solid cancers. Possible explanations for persistent international differences in survival include use of diagnostic tests and screening, stage at diagnosis, access to high-quality care, and differences in cancer biology. Although distribution of stage at diagnosis remains the main factor affecting between-area survival differences, past HR studies also indicate that adhesion to treatment guidelines affects cancer survival inequalities. The HR studies have therefore contributed to the identification of factors associated with cancer outcome, and provide the basis for future progress and assessing appropriate actions to reduce inequalities and improve cancer outcomes. In addition to the above aspects, which are mainly related to public health services and delivery of healthcare, the collection of biomolecular characteristics allows us to investigate the distribution and prognostic influence of breast cancer molecular subtypes in population-based cohorts of patients. For instance, the HR Italian study on breast cancer has shown that in ER+PR+ patients high blood glucose and high BMI are independently associated with an increased risk of breast cancer death, indicating that detection and correction of these factors patients may improve prognosis. Based on past experiences, we launched a new round of HR studies in the framework of the EC Funded European Action Against cancer (EPAAC) Joint Action on breast, colorectal and lung cancer, melanoma, and non-Hodgkin’s Lymphoma. Beside staging, treatment and recurrences, the new HR studies are collecting data on co-morbidities and undesired effects of treatment, as well as on tumor biomarkers of clinical relevance. Population based studies are supplemented by INT’s clinical registry and related biological repositories, which help investigating the relation of the molecular characteristics of the tumor with clinical outcome and comorbidity. PROGRAM MEMBERSHIP Milena Sant (MD): project leader Pamela Minicozzi (Mathematician, PhD): Statistical analyses on EUROCARE and HR databases. Centralization and management of population based HR data. Paolo Baili (Statistician, MSc): coordination and management of INT inhouse clinical registries and ROL data Hade Amash (MD): collection of HR data in INT, medical advice on technical registration activities Francesca Di Salvo (Statistician, PhD): support for statistical analyses of EUROCARE survival data and HR data) Elisabetta Meneghini (Physicist, MSc): statistical analyses on the INT inhouse clinical breast cancer registry. Camilla Amati (Humanities BA): EUROCARE Secretariat, scientific secretariat in research projects Simone Bonfarnuzzo: IT support for the clinical registry Agata Cifalà: secretarial support for research projects Chiara Margutti: EUROCARE secretariat, administrative secretariat in research projects Stefania Saltarelli (Political Science MSc): dissemination of results and research activities through www.tumori.net Alberto Turco: HR data collection in INT, support to management of INT in-house clinical registry and ROL data Ilaria Cavallo (IT degree): IT activity of the clinical registries Francesco Funaro (IT degree): IT activity of the clinical registry SELECTED RECENT PUBLICATIONS Allemani C., Sant M., Weir HK., Richardson L.C., Baili P., Storm H., Siesling S., Torrella-Ramos A., Voogd A.C., Aareleid T., Ardanaz E., Berrino F., Bielska-Lasota M., Bolick S., Cirilli C., Colonna M., Contiero P., Cress R., Crocetti E., Fulton J.P., Grosclaude P., Hakulinen T., Izarzugaza M.I., Malmström P., Peignaux K., Primic-Žakelj M., Rachtan J., Safaei Diba C., Sánchez M.J., Schymura M.J., Shen T., Traina A., Tryggvadottir L., Tumino R., Velten M., Vercelli M., Wolf H.J., Woronoff A.S., Wu X., Coleman M.P.: Breast cancer survival in the US and Europe: a CONCORD high-resolution study. Int J Cancer 2013; 132(5): 1170-1181 Minicozzi P., Berrino F., Sebastiani F., Falcini F., Vattiato R., Cioccoloni F., Calagreti G., Fusco M., Vitale M.F., Tumino R., Sigona A., Budroni M., Cesaraccio R., Candela G., Scuderi T., Zarcone M., Campisi I., Sant M.: High fasting blood glucose and obesity significantly and independently increase risk of breast cancer death in hormone receptor-positive disease. Eur J Cancer 2013; 49(18): 3881-3888 Bouvier A.M., Minicozzi P., Grosclaude P., Bouvier V., Faivre J., Sant M.: Patterns of adjuvant chemotherapy for stage II and III colon cancer in France and Italy. Dig Liver Dis 2013; 45(8): 687-691 Bella F., Minicozzi P., Giacomin A., Crocetti E., Federico M., Ponz de Leon M., Fusco M., Tumino R., Mangone L., Giuliani O., Budroni M., Sant M.: Impact of diabetes on overall and cancer-specific mortality in colorectal cancer patients. J Cancer Res Clin Oncol 2013; 139(8): 1303-1310 Mangone L., Minicozzi P., Vicentini M., Giacomin A., Caldarella A., Cirilli C., Falcini F., Giorgi Rossi P., Sant M.: Key factors influencing lung cancer survival in northern Italy. Cancer Epidemiol 2013; 37(3): 226-232 SELECTED RECENT MAJOR GRANTS EUROCARE-6 disuguaglianze di sopravvivenza e cure in Europa (financed by Compagnia di San Paolo) (April 2011-October 2014) High resolution Eurocare - clinical data collection and statistical analysis for interpretation of inequalities in prognosis observed in Italy (financed by the Cariplo Foundation) (August 2011-August 2014) European Partnership for Action Against Cancer: WP-9 “Health information and data” (financed by the EU) (March 2011-February 2014) Cancer survival comparisons: a global perspective (financed by the Istituto Superiore di Sanità) (July2013-December 2013) Survival and management of tumors in Italy and Europe (financed by the Ministry of Health for prevention and control of disease (CCM)(September 2011-September 2013) KEYWORDS Tumors, survival and prognosis, care, diagnostic and therapeutic procedures, cancer registry 71 back to contents SCIENTIFIC REPORT 2013 ...Siranoush Manoukian... ............Paolo Radice............ ..........Lucio Bertario........... STUDY OF THE MOLECULAR DETERMINANTS OF THE GENETIC PREDISPOSITION TO FAMILIAL-HEREDITARY CANCERS OVERVIEW AND SCIENTIFIC GOALS In recent years, several genetic factors associated with hereditary susceptibility to cancer have been identified, and genetic testing is routinely applied in clinical practice to search for germline cancer predisposing alleles. This allows for identification of, within cancer prone families, at-risk individuals and to offer them appropriate surveillance programs and/ or other measures of risk reduction, such as chemoprevention or prophylactic surgery. Conversely, family members who are not found to be carriers of the disease-related gene variants observed in their relatives may be advised to follow the same recommendations offered to the general population. However, at present only a fraction of cancer families benefit from genetic testing. In fact, a large fraction of familial cancer risk remains still molecularly unexplained (so-called “missing hereditability”). In addition, molecular analyses in a diagnostic context are limited to only a subset of genes associated with cancer susceptibility, i.e. those whose mutations confer much higher risks than those of the general population (high penetrance alleles). In fact, the clinical relevance of cancer susceptibility genetic markers that are relatively common and individually associated with marginal risk increase (low penetrance alleles) is still debated. The same applies to hereditary cancer associated genes in which only a small number of mutations have been identified, and for which there is still a degree of uncertainty about the clinical consequences of such mutations. Finally, while loss-of-function mutations are generally considered as deleterious, the pathogenicity of a sizable fraction of variants identified in hereditary cancer genes, such as missense mutations and variants in introns and regulatory sequences, still remains undetermined (unclassified variants, UVs). For more than 20 years, clinical units dedicated to counseling, genetic testing, and clinical management of individuals with evidence of genetic susceptibility to cancer have been operating at INT, mainly on familial breast, ovarian, and colorectal carcinomas. These activities fuel research projects aimed at increasing our current knowledge on the molecular basis of these diseases and our ability to diagnose individuals who are at higher risk of cancer development due to a genetic predisposition. The main goals of our research projects are: 1.Definition of the mutational spectra of known cancer associated genes, with particular reference to those occurring in non-coding regions that are usually not investigated in diagnostic laboratories, and the identification of pathogenic variants that are recurrent in high-risk Italian families. 72 research activity 2.Development of experimental assays for functional characterization of allelic variants of cancer predisposing genes, and their employment for the clinical classification of UVs. 3.Identification of novel genetic markers of cancer susceptibility. These objectives are also pursued through the participation of national and international collaborative consortia. PROGRAM HIGHLIGHTS This research program takes advantage of the continuous recruitment of individuals and families with evidence of genetic predisposition to cancer who are counseled at the involved clinical units. In particular, the consolidated and long-lasting clinical activity of the Medical Genetics unit has assembled the largest Italian collection of HBOC patients and their relatives, including more than 8150 individuals from 3950 different families, of whom approximately 1200, from some 650 families, are BRCA1/BRCA2 gene carriers. As for the unit of Hereditary Digestive Tract Tumors, in the course of 2013 approximately 600 individuals were screened for germline mutations in genes associated with hereditary susceptibility to gastrointestinal cancers. Main achievements of 2013 include the following. 1.The effect on mRNA of 24 variants ascertained in HBOC families at splicing regions of the BRCA1 and BRCA2 genes has been investigated. Overall, 19 were found to lead to aberrant mRNA splicing. The results of experimental assays were compared with the outcomes of bioinformatic analyses using algorithms developed to predict the consequences of genetic variants at the transcript level, demonstrating that in silico tools can be used for prioritizing variants that are more likely to be pathogenic (Colombo et al., PLoS One. 2013;8:e57173). 2.A case of acinic cell carcinoma of the breast, a rare malignancy diagnosed in a woman carrying a BRCA1 mutation, has been characterized molecularly and immunohistochemically. The observed tumor features suggest involvement of the patient’s germline mutation in the disease. This broadens the spectrum of BRCA1-associated breast malignancies (Ripamonti et al., BMC Cancer. 2013;13:46). 3.A study carried out in collaboration with the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan on 450 women with mutations in BRCA genes did not confirm a previously reported association of preferential X chromosome inactivation (XCI) with BRCA status and breast/ovarian cancer risk. However, an increase in the frequency of XCI with ageing and in cancer patients submitted to chemotherapy was observed (Manoukian et al., Eur J Cancer. 2013;49:1136-41). 4. The units involved in the present project have actively contributed to studies of collaborative national groups and international consortia. Among the most relevant, it is worth mentioning: a) genome-wide analysis carried out on 10,052 breast cancer cases and 12,575 controls that led to the discovery of 41 new loci associated with breast cancer risk (Michailidou et al., Nat Genet. 2013;45:35361); b) an integrative analyses on 132 patients affected with hereditary non-polyposis colorectal cancer, demonstrating the wide genetic and allelic heterogeneity associated with this disease and enlightening the role of allelic-specific gene expression (De Lellis et al., Plos One 2013; 8:e81194); c) an Italian multicenter survey on cancer risk in carries of STK11/LKB1 germline mutations (Resta et al., Dig Liver Dis. 2013; 45:606-11). PROGRAM MEMBERSHIP Paolo Radice, PhD Head of Molecular basis of genetic risk and genetic testing research unit. Principal investigator of research projects on the identification and characterization of genetic factors responsible for hereditary predisposition to cancer. Siranoush Manoukian, MD Head of Medical Genetics clinical and research unit. Identification of hereditary breast and ovarian cancer (HBOC) families, genetic counseling, and collection of blood withdrawal for genetic testing and research purposes. Collection of genetic, clinical, and pathological data of high-risk individuals. Lucio Bertario, MD Head of Hereditary Digestive Tract Tumors unit. Counseling, molecular testing, and clinical management of individuals with predisposition to major hereditary gastrointestinal cancer syndromes: Lynch syndrome, familial adenomatous polyposis (FAP) and its phenotypic variant attenuated-FAP, Peutz-Jeghers syndrome, juvenile polyposis and hereditary gastric cancer. Data collection on high-risk individuals. Maria Luisa Carcangiu, MD Head of Anatomic Pathology Unit 1 and Reference pathologist. Paolo Verderio, PhD and Sara Pizzamiglio, Msc Research staff scientists at the Medical statistics, biometry, and bioinformatics unit. Reference statisticians. SELECTED RECENT PUBLICATIONS Colombo M., De Vecchi G., Caleca L., Foglia C., Ripamonti C.B., Ficarazzi F., Barile M., Varesco L., Peissel B., Manoukian S., Radice P.: Comparative in vitro and in Silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. PLoS One 2013; 8(2): e57173 Manoukian S., Verderio P., Tabano S., Colapietro P., Pizzamiglio S., Grati F.R., Calvello M., Peissel B., Burn J., Pensotti V., Allemani C., Sirchia S.M., Radice P., Miozzo M.: X chromosome inactivation pattern in BRCA gene mutation carriers. Eur J Cancer 2013; 49(5): 1136-1141 De Lellis L., Aceto G.M., Curia M.C., Catalano T., Mammarella S., Veschi S., Fantini F., Battista P., Stigliano V., Messerini L., Mareni C., Sala P., Bertario L., Radice P., Cama A.: Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms. Plos One 2013; 8(11): e81194 73 back to contents SCIENTIFIC REPORT 2013 Resta N., Pierannunzio D., Lenato G.M., Stella A., Capocaccia R., Bagnulo R., Lastella P., Susca F.C., Bozzao C., Loconte D.C., Sabbà C., Urso E., Sala P., Fornasarig M., Grammatico P., Piepoli A., Host C., Turchetti D., Viel A., Memo L., Giunti L., Stigliano V., Varesco L., Bertario L., Genuardi M., Lucci Cordisco E., Tibiletti M.G., Di Gregorio C., Andriulli A., Ponz de Leon M.; AIFEG. Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study. Dig Liver Dis 2013; 45(7): 606-611 Michailidou K., Hall P., Gonzalez-Neira A., Ghoussaini M., Dennis J., Milne R.L., Schmidt M.K., Chang-Claude J., Bojesen S.E., Bolla M.K., Wang Q., Dicks E., Lee A., Turnbull C., Rahman N.; Breast and Ovarian Cancer Susceptibility Collaboration, Fletcher O., Peto J., Gibson L., Dos Santos Silva I., Nevanlinna H., Muranen T.A., Aittomäki K., Blomqvist C., Czene K., Irwanto A., Liu J., Waisfisz Q., Meijers-Heijboer H., Adank M.; Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), van der Luijt R.B., Hein R., Dahmen N., Beckman L., Meindl A., Schmutzler R.K., Müller-Myhsok B., Lichtner P., Hopper J.L., Southey M.C., Makalic E., Schmidt D.F., Uitterlinden A.G., Hofman A., Hunter D.J., Chanock S.J., Vincent D., Bacot F., Tessier D.C., Canisius S., Wessels L.F., Haiman C.A., Shah M., Luben R., Brown J., Luccarini C., Schoof N., Humphreys K., Li J., Nordestgaard B.G., Nielsen S.F., Flyger H., Couch F.J., Wang X., Vachon C., Stevens K.N., Lambrechts D., Moisse M., Paridaens R., Christiaens M.R., Rudolph A., Nickels S., Flesch-Janys D., Johnson N., Aitken Z., Aaltonen K., Heikkinen T., Broeks A., Veer L.J., van der Schoot C.E., Guénel P., Truong T., Laurent-Puig P., Menegaux F., Marme F., Schneeweiss A., Sohn C., Burwinkel B., Zamora M.P., Perez J.I., Pita G., Alonso M.R., Cox A., Brock I.W., Cross S.S., Reed M.W., Sawyer E.J., Tomlinson I., Kerin M.J., Miller N., Henderson B.E., Schumacher F., Le Marchand L., Andrulis I.L., Knight J.A., Glendon G., Mulligan A.M.; kConFab Investigators; Australian Ovarian Cancer Study Group, Lindblom A., Margolin S., Hooning M.J., Hollestelle A., van den Ouweland A.M., Jager A., Bui Q.M., Stone J., Dite G.S., Apicella C., Tsimiklis H., Giles G.G., Severi G., Baglietto L., Fasching P.A., Haeberle L., Ekici A.B., Beckmann M.W., Brenner H., Müller H., Arndt V., Stegmaier C., Swerdlow A., Ashworth A., Orr N., Jones M., Figueroa J., Lissowska J., Brinton L., Goldberg M.S., Labrèche F., Dumont M., Winqvist R., Pylkäs K., Jukkola-Vuorinen A., Grip M., Brauch H., Hamann U., Brüning T.; GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, Radice P., Peterlongo P., Manoukian S., et al.: Largescale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 2013; 45(4): 353-361 SELECTED RECENT MAJOR GRANTS Associazione Italiana per la Ricerca sul Cancro Novel approaches for the assessment of the functional effects of unclassified variants in BRCA genes (Jan 2012 – Dec 2014) Principal investigator: Paolo Radice INT- Institutional strategic projects “5x1000” of the Scientific Directorate. Novel molecular mechanisms of genetic predisposition to early-onset breast cancer (Jun 2013 – May 2014) Principal investigator: Paolo Radice KEYWORDS hereditary cancer, risk alleles, mutation testing, functional assays Figure: RT-PCR analyses of BRCA1 and BRCA2 variants affecting mRNA splicing. For each variant, the RTPCR products were characterized by agarose gel electrophoresis and sequencing. Gel images: lane 1, no template; lane 2, genomic DNA used as negative control of the RT-PCR reaction; lane 3, cDNA from the BRCA1/BRCA2 wild-type LCL used as positive control; lane 4, cDNA from LCL carrying the UV. M, molecular marker (ΦX-174 HaeIII digest). The size of the full-length (FL) and aberrant transcripts are reported. Sequencing electropherogram data: (B-G) the RTPCR products were directly sequenced; (A, H) the sequencing was performed after band excision or cloning step. (H) An additional band due to improper annealing of full-length and aberrant transcripts is shown by the asterisk. The Ex5del, visible in both sample and control is a naturally occurring isoform lacking exon 5. (A) In addition to the full-length and the Ex14del aberrant transcript, the naturally occurring isoform lacking the first 3 bp of exon 14 (Ex14_3bp del) was observed. Ex, exon; I, intron. (reproduced from Colombo et al., PLoS One. 2013;8:e57173). 74 research activity MOLECULAR CARACTERIZATION OF TUMOR PROGRESSION COORDINATOR: Maria Grazia Daidone Study of molecular mechanisms (and their alterations) responsible for the origin, growth and progression of solid tumors to develop treatment approaches selectively targeting those mechanisms; study of tumor interactions with the surrounding stroma, the cells of the immune system, and the extracellular matrix in order to elucidate biological events (such as tolerance of and resistance against tumor development) and investigate the link between inflammation and cancer. Definition of new therapeutic targets, diagnostic and prognostic biomarkers, and markers predictive of the response to conventional treatments. AIMS: Identification of molecular defects associated with cell transformation and tumor progression, to be used as markers for diagnosis, prognosis and disease monitoring. Creation of highly sensitive molecular tests for possible clinical application. Detection and assessment of molecular targets against which to develop innovative treatments. Development of new drug combinations in models and experimental systems. Identification of mechanisms of interaction with the microenvironment during cancer progression. PROJECTS • Involvement of microRNAs in the principal pathways of breast cancer: from biology to possible therapeutic applications (Marilena Iorio) • Analysis of circulating markers for prognosis and treatment response monitoring in breast cancer (Maria Grazia Daidone) • Detection and validation of new genetic/genomic and metabolic markers of prognosis or prediction of treatment response and/or early relapse in ovarian cancer (Delia Mezzanzanica) • Thyroid cancer: functional studies for the detection of new molecular mechanisms and therapeutic targets (Angela Greco) • Extracellular matrix protein SPARC regulates primary and secondary lymphoid organs homeostasis and the transition of myeloproliferative or autoimmune spurs toward leukemia and lymphoma (Mario P. Colombo) 75 SCIENTIFIC REPORT 2013 back to contents .Marilena V. Iorio. INVOLVEMENT OF microRNAs IN THE PRINCIPAL PATHWAYS OF BREAST CANCER: FROM BIOLOGY TO POSSIBLE THERAPEUTIC APPLICATIONS OVERVIEW AND SCIENTIFIC GOALS In the last years new players have been revealed in cancer biology, namely microRNAs, a class of small non-coding RNAs that are able to regulate gene expression at the post-transcriptional level. Several studies have demonstrated that microRNAs, highly specific for tissue and developmental stages, and playing important roles in essential processes, are involved in several human diseases, including cancer. Our group (Iorio MV et al., 2005) described the first breast cancer-specific microRNA signature obtained by genome wide microRNA expression analysis in a large set of normal and tumor breast tissues, identifying a list of microRNAs able to classify tumors and normal tissues with an accuracy of 100% and signatures associated to specific biopathological features. Breast cancer is a complex and heterogeneous disease, where survival and proliferation of a cancerous cell might depend on the activation of different pathways. In addition to breast tumors depending on ER activation or HER2 overexpression, the third major subgroup of breast cancer includes the so-called Triple Negative Tumors (TNBC), which are negative for ER, PgR, and HER2 expression. Very aggressive from a clinical point of view, they are characterized by an undifferentiated phenotype and lack specific markers for an effective targeted therapy. These tumors still represent a relatively unknown area in breast cancer biology. microRNAs could both provide the missing information to explain the behavior of this class of breast carcinoma, and represent possible tools or targets for a specific therapy. The goal of our project is the identification and the study of microRNAs involved in the most important pathways activated in human breast cancer, with the aim to better define the role of these small but powerful molecules in this neoplasia, and to provide the experimental bases for their possible use as targets or tools of specific therapies. The most recent results of this study include the description of the oncosuppressive role of miR-205 in TNBC (Piovan C et al., 2012); a regulatory loop involving miR-191 and ER in collaboration with Dr Di Leva (Di Leva et al., 2013); a recently accepted manuscript in collaboration with Dr. Tagliabue on PDGFRbeta involvement in vascular mimicry properties of TNBC (Plantamura I et al., 2014), in addition to preliminary data on two microRNAs involved in this phenomenon; the production of two KO mouse models for miR-205; preliminary data on miR-205 and responsiveness to trastuzumab in HER2+ breast cancer. 76 research activity PROGRAM HIGHLIGHTS This is a translational project with the overall goal to increase knowledge about the involvement of miRNAs in breast cancer, and to evaluate their possible use as markers of diagnosis and prognosis, and eventually as new targets or tools of a specific, future therapy. Even though different groups are investigating miRNAs in different subtypes of breast cancer, instead of starting from the expression profile of different subgroups of breast cancer to find the relevant miRNAs, we are dissecting the main pathways driving proliferation/ survival in different breast cancer models to discover microRNAs that may be crucial for the biology of this neoplasm. Moreover, the availability at INT of a series of specimens from breast cancer patients make this project a combination of discovery, validation, and clinical applications. Finally, during last year we generated ubiquitous, conditional, miR-205 KO mice (through a Cre-LoxP system). Even though the technique is not innovative per se, just a few experimental models have been developed to date concerning microRNAs. A KO mouse certainly represents a valuable genetic model that will allow not only more accurate demonstration of the causal role of miR-205 in the occurrence of breast cancer, but also investigation of the function of this microRNA in development of the normal breast gland and other tissues. The PI has reached the expertise to carry out the proposed experiments working both at the INT and in Dr. Croce’s laboratories, where she participated in pioneering studies in the miRNA field. Moreover, collaboration with different experts and scientists at the INT guarantees fruitful and reciprocal interaction. PROGRAM MEMBERSHIP Marilena V. Iorio, PI. Coordinates the project. Ilaria Plantamura, Fellow. Mainly focused on the study of miRNAs involved in vascular mimicry properties of TNBC. Sara Baroni, Post-doc fellow. Focused on miRNAs involved in HER2mediated pathway. Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med. 2012 Mar;4(3):143-59. Piovan C, Palmieri D, Di Leva G, Braccioli L, Casalini P, Nuovo G, Tortoreto M, Sasso M, Plantamura I, Triulzi T, Taccioli C, Tagliabue E, Iorio MV, Croce CM. Oncosuppressive role of p53-induced miR-205 in triple negative breast cancer. Mol Oncol. 2012;6(4):458-72. Claudia Piovan, Post-doc, collaborator. In charge of the miR-205/ trastuzumab study and miR-205 KO mice. SELECTED RECENT MAJOR GRANTS AND AWARDS Elvira D’Ippolito, PhD student. Mainly focused in the study of miRNAs involved in vascular mimicry properties of TNBC. AIRC Start Up Grant (2011); Annalisa Elefante, Graduate student. Her thesis is on miRNAs in TNBC. SELECTED RECENT PUBLICATIONS Di Leva G, Piovan C, Gasparini P, Ngankeu A, Taccioli C, Briskin D, Cheung DG, Bolon B, Anderlucci L, Alder H, Nuovo G, Li M, Iorio MV, Galasso M, Santhanam R, Marcucci G, Perrotti D, Powell KA, Bratasz A, Garofalo M, Nephew KP, Croce CM. Estrogen mediated-activation of miR-191/425 cluster modulates tumorigenicity of breast cancer cells depending on estrogen receptor status. PLoS Genet. 2013;9(3). Young Researcher Grant from the Italian Ministry of Health (2012) Young Researcher Award at INT (2008) KEYWORDS Breast Cancer, microRNA, therapeutics 77 SCIENTIFIC REPORT 2013 back to contents .Maria Grazia Daidone. ANALYSIS OF CIRCULATING MARKERS FOR MONITORING DISEASE PROGRESSION AND TREATMENT RESPONSE IN BREAST CANCER OVERVIEW AND SCIENTIFIC GOALS The identification of reliable circulating biomarkers tracking tumor behaviour and allowing to discover novel alterations in cancer cells represents a paradigm shift in the personalized clinical care of different solid tumors, including breast cancer (BC). Blood-based biomarkers as circulating tumor cells (CTCs) and free nucleic acids (circulating tumor DNA, ct-DNA, and circulating microRNAs, miRNAs) represent ideal non-invasive tools since they may allow: 1) multiple “liquid biopsies” over time, when primary tumor and metastatic lesions are not available; 2) longitudinal analyses of the molecular features of cancer cells to understand in real time changes occurring within the tumor; 3) monitoring response to systemic treatments in neoadjuvant, adjuvant and advanced settings, and detecting minimal residual disease in the early disease. Overall, information obtained by liquid biopsies could represent means to address the challenges raised by phenotypic and functional heterogeneity and may provide insights into some of the fundamental processes that led to an aggressive and treatment-refractory phenotype. During the last decade, studies carried out in BC on CTCs, miRNAs and ct-DNA showed promising results. However, despite encouraging results and the development of novel and sensitive technologies to detect molecular changes at the single-cell-level, some weaknesses of the new generation of biomarkers still outperform their strengths. In addition, notwithstanding the growing interest on a molecular characterization of liquid biopsies, ct-DNA, miRNA and CTC molecular features have been mostly investigated singly, on relatively limited case series and convenience samples, without integrative approaches to comparatively analyse the informative contribution provided by each of them to BC biology and clinical outcome. We are performing an extensive molecular characterization of liquid biopsies, in terms of evaluation of ct-DNA, circulating miRNA and CTC profiles (transcriptome, DNA mutations and miRNAs), in blood samples prospectively collected from a consecutive series of BC patients undergoing surgery to assess the clinical implications of biomarkers derived from liquid biopsies and of their dynamic changes as tumor trackers in different clinical scenarios. This step could allow us to monitor the different aspects of tumor heterogeneity, in terms of emergence of new somatic alterations within a patient and occurrence of treatment-related plasticity of cancer cells. In parallel with these translational steps, also pre-clinical in vivo and in vitro studies will be carried out to identify molecular profiles of metastasis-initiating cells and features associated with resistance to targeted therapies. We base our work on biospecimens collected from clinical tumors, established BC cell lines in vitro cultured or injected in the mammary fat pad of NOD/SCID mice, and on highly sensitive technologies able to detect molecular alterations at the single-cell-level. 78 research activity PROGRAM HIGHLIGHTS In this study we plan to define a molecular portrait of liquid biopsies from women with BC, taking also in consideration the molecular subtype of the primary tumor and the clinical setting of the patients with the aim to monitor the different aspects of tumor heterogeneity, in terms of emergence of new somatic alterations within a patient and occurrence of alterations in cancer cell plasticity following specific systemic treatments. Since the molecular characterization will become part of chemotherapy protocols of systemic therapy for resectable and advanced tumors, it might provide insights into some of the fundamental processes that led to metastasis and treatment resistance. During 2013 our group addressed some critical points (such as presence of hemolysis, choice of the most appropriate technique for discovery, lack of established miRNA reference) related to evaluation and analysis of circulating miRNAs from blood specimens. Specifically, we: •by using experiments of controlled hemolysis and lipemia in plasma from cancer patients, developed and validated a simple, robust, sensitive, cost-effective, reproducible, lipemia-independent spectrophotometrically-based system to identify hemolyzed plasma/ serum specimens, which is suitable for limited serum/plasma aliquots (and thus useful for studies on archival material); •critically evaluated strengths and weaknesses of the available analytical tools for circulating miRNA profiling and, once assessed the adequate intra- and inter-array reproducibility of miRNA profiling and the feasibility of using archival plasma samples stored for an extended period of time and available in limited amounts, demonstrated the feasibility of using archival plasma samples with high-throughput microarray-based strategies; •routinely analyzed experimental results using different approaches (raw data, normalization approaches ratio-based or using housekeeping miRNAs). Taking into consideration all these warnings, we profiled long-term stored plasma samples from node-negative BC patients entering from 1987 to 1993 a randomized clinical study of chemoprevention and identified a signature of circulating miRNAs associated with the development of distant metastasis. Candidate miRNAs, proved to be associated with distant metastasis even when evaluated on tumor tissue (Fig.1) and, when added to culture medium, increase BC cell migration. As regards to CTC profiling, we set up a technical protocol to measure by the WG-DASL HT assay the expression of more than 29,000 genes in CTCs captured from whole blood with immune beads linked with antibodies against EpCAM and MUC1, designed to be used for clinical samples. Our approach allows obtaining technically reliable gene expression profiles (GEPs) from isolated CTCs and distinguishing unique features thus providing biologically useful information. It is reproducible and suitable to be challenged in prospective studies, provided that at least 25 CTCs can be isolated. PROGRAM MEMBERSHIP Biomarkers Unit, DOSMM Maria Grazia Daidone, Biol Sci D PhD (PI of the project) Valentina Appierto, Biol Sci D, PhD, and Paola Tiberio, Biol Sci D (Fellows involved in miRNA and ct-DNA studies) Vera Cappelletti, Staff, Biol Sci D, Emanuela Fina, Biol Sci D, PhD student (involved in CTC isolation and molecular characterization) Silvia Veneroni, Staff, Biol Sci D (coordinating the collection of biospecimens) Elena Cavadini, Staff technician involved in miRNA studies Maurizio Callari, Med Biotech D, PhD (Fellow involved in bioinformatic analyses) DOSMM core facilities Loredana Cleris, Staff technician involved in in vivo studies Senology Unit Roberto Agresti, MD (clinical partnership and patient follow-up) Medical Oncology 1 Unit Giulia Bianchi, MD, Serena di Cosimo, MD (clinical partnership and treatment of patients) Medical Statistics Unit Rosalba Miceli, MSc Stats, PhD and Elena Landoni, MSc Stats, PhD (statistical support) SELECTED RECENT PUBLICATIONS Callari M, Tiberio P, De Cecco L, Cavadini E, Dugo M, Ghimenti C, Daidone MG, Canevari S, Appierto V. Feasibility of circulating miRNA microarray analysis from archival plasma samples. Anal Biochem. 2013 Jun 15;437(2):123-5. doi:10.1016/j.ab.2013.03.002 Tiberio P, De Cecco L, Callari M, Cavadini E, Daidone MG, Appierto V. MicroRNA detection in plasma samples: how to treat heparinized plasma. J Mol Diagn. 2013 Jan;15(1):138-9. doi: 10.1016/j. jmoldx.2012.08.009 Bisso A, Faleschini M, Zampa F, Capaci V, De Santa J, Santarpia L, Piazza S, Cappelletti V, Daidone M, Agami R, Del Sal G. Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer. Cell Cycle. 2013 June 1; 12(11): 1679–1687. doi: 10.4161/cc.24757 De Cecco L, Dugo M, Canevari S, Daidone MG, Callari M. Measuring microRNA expression levels in oncology: from samples to data analysis. Crit Rev Oncog. 2013;18(4):273-87. Review. PubMed PMID: 23614615 Daidone MG, Zaffaroni N, Cappelletti V. Strategies to translate preclinical information to breast cancer patient benefit. J Natl Cancer Inst Monogr. 2011;2011(43):55-9. doi: 10.1093/jncimonographs/ lgr033. PubMed PMID: 22043041 ASSOCIATED CLINICAL TRIALS 4-HPR INT study: chemoprevention of stage I breast cancer patients with fenretinide; Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) SELECTED RECENT MAJOR GRANTS Associazione Italiana per la Ricerca sul Cancro (AIRC, Special program “Innovative tools for cancer risk assessment and early diagnosis, 5x1000, PI M.A. Pierotti, and MFAG to SdC), EurocanPlatform, FIRBNewton, Nanomax-MIUR and other MIUR-supported grants. KEYWORDS Liquid biopsy, circulating biomarkers, circulating tumor cells, circulating mutant ct-DNA, circulating miRNAs 79 SCIENTIFIC REPORT 2013 back to contents .Delia Mezzanzanica. DETECTION AND VALIDATION OF NEW GENETIC/ GENOMIC AND METABOLIC MARKERS OF PROGNOSIS OR PREDICTION OF TREATMENT RESPONSE AND/ OR EARLY RELAPSE IN OVARIAN CANCER OVERVIEW AND SCIENTIFIC GOALS Although the incidence is quite low, ovarian cancer (OC) is a highly lethal malignancy and is the leading cause of gynecological cancer death. Factors contributing to its unfavourable prognosis include late diagnosis, frequent relapse after front-line treatment, and development of chemoresistance. In spite of many efforts, to date no reliable clinical measures for prediction of response to treatment are available and survival rates have changed little in the last 30 years, with an overall 5-year survival rate for advanced stage patients of approximately 30%. The analysis of differential gene expression, and more recently of non-coding RNAs, while having contributed to identify diagnostic and prognostic markers in different pathologies, have not yet been sufficiently developed and validated in the case of OC. Our research group has significantly contributed in this area with the identification and characterization of a cluster of microRNAs (miRNAs) that are down-modulated in patients with early relapsing OC and involved in regulation of cellular plasticity and drug sensitivity. Indeed, we demonstrated that one of these miRNAs, when re-expressed, sensitizes OC cells to treatment with platinum compounds. Resistance to apoptotic stimuli is only one of the tumor “hallmarks”, a series of biological properties acquired by tumor cells during transformation and disease progression that also includes the ability to modify/reprogram cellular metabolism. Abnormal choline (Cho) metabolism is an emerging hallmark associated with oncogenesis and tumor progression. We recently reported alterations of the Cho-metabolite magnetic resonance spectral (MRS) profile in OC, characterized by an increased content of phosphocholine (PCho). We showed that choline kinase (ChoK) has a primary role in sustaining the aberrant PCho content of OC as its activity and expression is significantly increased in cancer cells compared to normal counterparts. The overall aim of this project is the definition of new prognostic and predictive markers that take into account tumor biology and its heterogeneity, and will eventually help in identifying patients with an increased risk of disease recurrence. The specific aims are: •Mapping chemoresistance using an integrated transcriptomic approach on clinically homogeneous OC patients with different prognoses and identification of miRNAs driving disease recurrence by matched analyses on primary tumor, omental secondary localization, and tumor at relapse. 80 research activity •Assessment of clinical and biological relevance of increased ChoK expression and activity in OC and to focus attention on a possible prognostic role and druggability, as ChoK has a primary role in sustaining the EOC cholinic phenotype. The effect of ChoK-targeted treatments either alone or combined with conventional therapy will be followed by quantitative MRS and MRI characterization of EOC xenotransplant models. The potential prognostic impact of ChoK will also be explored. PROGRAM HIGHLIGHTS It is well known that resistance to chemotherapeutic treatments is the result of multiple molecular aberrations. We hypothesize that an integrated transcriptomic and metabolomic approach, by considering at the same time genetic, epigenetic and metabolic alterations, could be more informative than single-transcriptome analysis for identification of patients with poor prognosis. We expect that integration of these distinct but complementary levels of information might resemble more precisely the complexity of tumor aberrations that drive recurrence of disease and drug resistance, and improve the effectiveness of outcome prediction procedures, possibly allowing the development of ‘’clinically-useful measures’’. Indeed, the use of metabolic markers as a diagnostic tool has the potential to influence clinical oncology affecting patient care with significant benefit. Metabolic and molecular imaging techniques, in fact, offer the possibility to monitor and discriminate metabolic markers in a non-invasive manner in vivo. The overall expected outcome is to identify prognostic factors tailored to the molecular/metabolic features of patients. This should allow a more accurate identification of patients experiencing early relapse and/or chemoresistance, and significantly help to select the best therapeutic and follow-up modalities. PROGRAM MEMBERSHIP Internal collaborators Unit of Molecular Therapies: Dr. Marina Bagnoli (signaling pathways and statistical/bioinformatic analyses); Dr. Anna Granata (in vitro and in vivo characterization of ChoK silenced cells); Dr. Roberta Nicoletti (biological characterization of miRNAs/genes identified by OC samples profiling). Technical support by Mrs. Paola Alberti. Unit of Functional Genomics: Dr. Loris De Cecco and Dr. Silvana Canevari (genetic/genomic profiling and bioinformatic analysis). Unit of Gynecological Oncology: Dr. Francesco Raspagliesi and Dr. Domenica Lorusso (clinical samples collection and pathological and follow-up data). Anatomic Pathology Unit 1: Dr. Maria Luisa Carcangiu (pathological revision of selected tumor specimens). External collaborators Istituto Superiore Sanità Rome: Dr. Egidio Iorio and Dr. Rossella Canese (characterization of NMR-detectable metabolites and MRI/MRS profiles for early detection of treatment response in preclinical EOC models). Istituto Italiano di Tecnologia, Genoa: (development of nanomaterial and their functionalization with antibodies for specific tumor targeting). Fondazione G. Pascale Naples: Dr. Sandro Pignata, Dr. Daniela Califano, Dr. Stefano Greggi, Dr. Simona Losito (samples and clinical data collection at Pascale, nucleic acid extraction and quality control). Johns Hopkins University - Baltimore, USA: Dr. Zaver M. Bhujwalla (expert in choline metabolism and MRS/MRI imaging). MD Anderson Cancer Center, Houston, USA: Dr. Anil K. Sood and Dr. Wei Zhang (miRNAs functional characterization). SELECTED RECENT PUBLICATIONS Sonego M., Schiappacassi M., Lovisa S., Dall’Acqua A., Bagnoli M., Lovat F., Libra M., D’Andrea S., Canzonieri V., Militello L., Napoli M., Giorda G., Pivetta B., Mezzanzanica D., Barbareschi M., Valeri B., Canevari S., Colombatti A., Belletti B., Del Sal G., Baldassarre G.: Stathmin regulates mutant p53 stability and transcriptional activity in ovarian cancer. EMBO Mol Med 2013; 5: 707-722 De Cecco L., Berardi M., Sommariva M., Cataldo A., Canevari S., Mezzanzanica D., Iorio M.V., Tagliabue E., Balsari A.: Increased sensitivity to chemotherapy induced by CpG-ODN treatment is mediated by microRNA modulation. PLoS One 2013; 8: e58849 Bagnoli M., De Cecco L., Granata A., Nicoletti R., Marchesi E., Alberti P., Valeri B., Libra M., Barbareschi M., Raspagliesi F., Mezzanzanica D., Canevari S.: Identification of a chrXq27.3 microRNA cluster associated with early relapse in advanced stage ovarian cancer patients. Oncotarget 2011; 2: 1265-1278 SELECTED RECENT MAJOR GRANTS AND AWARDS AIRC IG-grant 12976 (2013-2016; PI Delia Mezzanzanica): The ovarian cancer cholinic phenotype: exploring possible theragnostic windows. Fondazione CARIPLO grant 2013-0865 (2014-2017; PI Delia Mezzanzanica): Disease recurrence in epithelial ovarian cancer: deciphering miRNA-driven regulatory networks related to drug sensitivity/cellular plasticity and exploring nanomaterial-based targeted delivery of identified key molecules for therapeutic purposes. Winner of the ROL/REL call for pre-clinical research (2012-2013 PI Delia Mezzanzanica/Marina Bagnoli): Selection and functional characterization of Choline kinase-alpha inhibitors for a new targeted therapy approach. KEYWORDS Ovarian cancer, resistance to chemotherapy, genomic/metabolic alterations 81 SCIENTIFIC REPORT 2013 back to contents Figure: The virtuous circle of OC characterization: potential translational applications for a personalized approach to disease treatment. 82 research activity .Angela Greco. THYROID CANCER: FUNCTIONAL STUDIES FOR THE DETECTION OF NEW MOLECULAR MECHANISMS AND THERAPEUTIC TARGETS OVERVIEW AND SCIENTIFIC GOALS Thyroid carcinoma is the most frequent endocrine cancer with an incidence that is rapidly increasing. The majority of thyroid tumors arise from follicular cells and consist of well differentiated papillary (PTC), the most frequent histotype, in addition to follicular (FTC) carcinomas, and poorly differentiated (PDTC) and undifferentiated anaplastic carcinomas (ATC). Generally, PTC and FTC have a good prognosis. Standard therapy, based on total thyroidectomy, ablation with radioiodine and suppressive therapy, is generally successful. Nevertheless, in about 20% of patients with well-differentiated thyroid cancer, the tumor develops resistance to therapy, or tends to dedifferentiate, leading to recurrent disease and death. Furthermore, patients with ATC have a very poor prognosis. Therefore, a better understanding of thyroid carcinogenesis and novel therapeutic opportunities are needed. This need is being approached by different functional approaches. 1) The identification of molecules governing oncogene-induced senescence (OIS) in thyrocytes, a mechanism demonstrated to be involved in thyroid tumor progression. We have recently proposed that OIS may restrain the evolution of early to late tumor stages, as well as the transition of well differentiated to more aggressive variants. We are interested in the characterization of secreted molecules, in particular inflammatory cytokines, produced by senescent thyrocytes, which model in vitro thyroid tumor in the early phase. 2) Dissection of the role, in the process of thyroid carcinogenesis, of genes differentially expressed in PTC, by investigating the effect of their modulation on different aspects of the transformed phenotype of PTC-derived cell lines. 3) Identification of genes whose inactivation selectively promotes lethality of tumor cells but do not affect normal thyroid cells (non-oncogene addiction, NOA). Through the screening of a synthetic small interfering RNA (siRNA) library targeting the human druggable genome a panel of 13 genes whose inhibition interferes with tumor, but not normal thyroid, cell viability has been identified. The effect of their inhibition in several thyroid tumor cell lines, as well as the identification of the affected pathways, will unveil their possible use as therapeutic targets. 4) Characterization of the interaction between tumor microenvironment components, in particular macrophages, and thyroid tumor cells representative of early (senescent thyrocytes) and late (tumor-derived cell lines) thyroid tumor stages. 5) Investigation through functional studies of the biological relevance and possible use as therapeutic tool of selected, under-estimated miRNA, which are under-expressed in PTC. These miRNAs have been identified through our integrated analysis of in vitro PTC models and clinical case list expression profiles. 83 back to contents SCIENTIFIC REPORT 2013 PROGRAM HIGHLIGHTS •The proposed studies allow the identification of novel players in PTC carcinogenesis. Targeting identified genes, miRNAs, and molecules, as well as thyroid associated oncogenes, may represent novel therapeutic options for patients who are not curable by standard therapy. •OIS is a mechanism proposed as a barrier to cancer. Notably, we have demonstrated that it occurs in thyroid tumor early phase, for which senescent thyrocytes represent an in vitro model. Moreover, we have produced an in vitro inducible model of thyrocytes OIS. •Integrated expression profiles of genes and miRNA, combining clinical tumors with in vitro cell models, may lead to identification of novel players in PTC cancerogenesis. This approach allowed us to identify miR-199a-3p as a novel oncosuppressor miRNA in PTC. •The ability of miRNAs to target multiple genes, frequently in the context of a network, makes these molecules very efficient in regulating whole cell functions, more than the single genes they target. •The tumorigenic state, besides the activity of oncogenic pathways, also depends on the activity of various genes and pathways that are not oncogenic themselves, but which are essential to support the oncogenic phenotype of cancer cells and not required to the same degree for viability of normal cells. This phenomenon is referred to as ‘Non-Oncogene Addiction’ (NOA). NOA genes may be identified by loss of function, RNA interference-based genetic approaches, which have not yet been applied to thyroid tumor cells. •The role of tumor microenvironment, and particularly macrophages, is a major issue in cancer. Macrophage infiltration has been reported in thyroid tumors; however, no functional studies dissecting the interplay between macrophages and thyroid tumor cells (representative of different tumor stages) are available. PROGRAM MEMBERSHIP SELECTED RECENT MAJOR GRANTS A Greco: Coordinator of the project Cariplo 2013-0893: “Role of tumor microenvironment in thyroid carcinogenesis onset and progression: thyroid cells cross-talk with macrophages” (2014- 2016; PI: A Greco) MG Borrello: Coordinator of studies involving miRNA MCA Anania, E Cetti: studies related to NOA M Mazzoni: studies related to OIS and senescent thyrocytes and macrophage interaction P Romeo: studies related to thyroid tumor cells and macrophage interaction; collaboration in miRNA studies E Minna: miRNA studies S Pagliardini, MG Rizzetti: technical collaboration SELECTED RECENT PUBLICATIONS Vizioli M.G., Possik P.A., Tarantino E., Meissl K., Borrello M.G., Miranda C., Anania M.C., Pagliardini S., Seregni E., Pierotti M.A., Pilotti S., Peeper D.S., and Greco A.: Evidence of oncogene-induced senescence in thyroid carcinogenesis. Endocr Relat Cancer 2011; 18(6): 743-757 Anania M.C., Miranda C., Vizioli M.G., Mazzoni M., Cleris L., Pagliardini S., Manenti G., Borrello M.G., Pierotti M.A., Greco A.: S100A11 overexpression contributes to the malignant phenotype of papillary thyroid carcinoma. J Clin Endocrinol Metab 2013; 98 (10) E1591-E1600 Degl’innocenti D., Romeo P., Tarantino E., Sensi M., Cassinelli G., Catalano V., Lanzi C., Perrone F., Pilotti S., Seregni E., Pierotti M.A., Greco A., Borrello MG.: DUSP6/MKP3 is over-expressed in papillary and poorly-differentiated thyroid carcinoma and contributes to the neoplastic properties of thyroid cancer cells. Endocr Relat Cancer. 2013; 20(1): 23-37 84 AIRC IG 11347 “Role of ‘oncogene-induced senescence’ and ‘nononcogene addiction’ in thyroid carcinogenesis” (2012-2014; PI: A Greco) AIRC IG 10366: ìMicroRNAs in papillary thyroid carcinoma: pathways involved and possible therapeutic targetsî (2010-2013; PI: MG Borrello) 2013 AIRC annual fellowship ‘Giavanna Ciani’ to MG Vizioli 2013 Fondazione Umberto Veronesi Fellowship to MC Anania KEY WORDS Thyroid tumors, miRNA, oncogene-induced senescence, non-oncogene addiction research activity .Mario P. Colombo. EXTRACELLULAR MATRIX PROTEIN SPARC REGULATES PRIMARY AND SECONDARY LYMPHOID ORGANS HOMEOSTASIS AND THE TRANSITION OF MYELOPROLIFERATIVE OR AUTOIMMUNE SPURS TOWARD LEUKEMIA AND LYMPHOMA OVERVIEW AND SCIENTIFIC GOALS Upon induction of immune responses (either physiological or autoimmune), lymphoid tissues undergo dynamic changes in number, distribution, and phenotype of immune cell populations, which require substantial and concomitant remodeling of tissue architecture (e.g. secondary follicle formation, marginal zone expansion). These modifications normally occur within the fringes of the functionally compartmentalized stroma of secondary lymphoid organs, which is composed by cellular elements (e.g. follicular dendritic cells, reticular cells) and an extracellular matrix that contributes to the regulation of trafficking and activation of immune cells. Our project is challenging the hypothesis that biasing the stromal microenvironment through defective expression of a matricellular protein could be sufficient to drive malignant transformation in the presence of a lymphoproliferative spur such as that occurring under autoimmune conditions. To demonstrate this hypothesis, we have focused on SPARC, a non-structural pleiotropic matricellular protein involved as key regulator of tissue remodeling in physiological conditions such as embryogenesis-associated epithelial mesenchymal transition, lymph-node swelling, and germinal center formation during adaptive immune responses. SPARC also plays a role in the profound changes occurring in the tissue architecture of solid and hematological neoplasms. The SPARC produced by innate immune cells influences the crosstalk between cancer cells and extracellular matrix at the invasive edge of primary tumors and regulates pro-inflammatory TNF production in response to tissue damage. Moreover, bone marrow stroma-derived SPARC has been reported to regulate the expansion of myeloid cell populations under myeloproliferative stress. Experimentally, cell death receptor mutant Fas deficient mice that have unrested lymphoproliferation were crossed with Sparc deficient mice to obtain double mutants. The human validation of mouse findings was obtained by screening SPARC expression in a series of human non-Hodgkin’s B cell lymphomas (NHL) by gene expression profiling and immunohistochemistry. 85 back to contents SCIENTIFIC REPORT 2013 PROGRAM HIGHLIGHTS The working hypothesis is that aberrant changes in ECM organization might participate in the pathogenic events leading to malignancies of lymphoid tissues other than affecting development and function of immune cells. Among the relevant modifications occurring in the stromal compartment of BM and SLO, we have uncovered the relevance of the matricellular protein SPARC in the homeostatic and pathogenic modifications of hematopoietic and immunological settings. Specifically, the high expression of SPARC in stroma leads to the aberrant osteoblastic niche expansion towards myelofibrosis under the pressure of a myeloproliferative spur (Tripodo, 2012). On the contrary, the absence of stromal SPARC alters the hematopoietic niche favoring myeloid precursor expansion in the BM (Tripodo, 2012). In SLO, SPARC deficiency alters the mesenchymal follicular dendritic cells (FDC) networking (Piconese, 2011) and impairs humoral immunity while promoting lymphomagenesis in the case of persistent perturbation of lymphoid tissue homeostasis. In this latter case, the absence of SPARC results in defective collagen assembly and lack of inhibitory signals through the collagen receptor LAIR-1 on myeloid cells, particularly neutrophils. Hyper-activated neutrophils acquire an IFN-related signature and eventually die through NETosis that promotes CD5+ B cell transformation via NF-kB. The emerging scenario indicates that stromal SPARC expression has an effect on lymphomagenesis by controlling the behavior of bystander immune cells rather than influencing CD5+ B cells directly. These data correlate with human B-CLL, which shows reduced microenvironmental SPARC expression and ECM deposition as well as signs of NETotic neutrophil among the activated infiltrating myeloid cells. Overall, these data allow the hypothesis that stromal SPARC may represent a common regulatory trait linking hematopoietic and lymphopoietic homeostasis in both BM and SLO niches. This also lends support to the idea of targeting matricellular proteins to impinge on the efficacy of other agents in combination therapies. PROGRAM MEMBERSHIP Mario P. Colombo, PI and program coordinator. Sabina Sangaletti, Project leader, responsible for experiments and data collection. Caterina Vitali, Post-doctoral fellow, responsible for FACS analysis. Silvia Miotti, Senior scientist, responsible for biochemistry. Paola Portararo and Barbara Cappetti, Lab. Technicians. Collaborators: Claudio Tripodo, University of Palermo, Lead Pathologist; PierPaolo Piccaluga, University of Bologna, Lead for bioinformatics. MP.: Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood 2012; 120: 3007-3018 Sangaletti S., Tripodo C., Cappetti B., Casalini P., Chiodoni C., Piconese P., Santangelo A:, Parenza M., Arioli I., Miotti S., Colombo MP. SPARC oppositely regulates inflammation and fibrosis in bleomycin-induced lung damage. Am J Pathol 2011; 179: 3000-3010 Tripodo C., Sangaletti S., Piccaluga P.P., Prakash S., Franco G., Borrello I., Orazi A., Colombo M.P., Pileri S.A.: The bone marrow stroma in hematological neoplasms-a guilty bystander. Nature Review Clin Oncol 2011; 8: 456-466 SELECTED RECENT PUBLICATIONS SELECTED RECENT MAJOR GRANTS Tripodo C., Sangaletti S., Guarnotta C., Piccaluga P.P., Cacciatore M., Giuliano M., Franco G., Chiodoni C., Sciandra M., Miotti S., Calvaruso G., Carè A., Florena A.M., Scotlandi K., Orazi A., Pileri S.A., Colombo M.P.: Stromal SPARC contributes to the detrimental fibrotic changes associated with myeloproliferation whereas its deficiency favors myeloid cell expansion. Blood 2012; 120: 3541-3554 Supported by grants from the Association for International Cancer Research (AICR UK, grant n° 11-0595), Associazione Italiana per la Ricerca sul Cancro (AIRC: Investigator Grants n° 10137 to MPC and My First Grant n° 12810 to SS) and the Italian Ministry of Health. Sangaletti S., Tripodo C., Chiodoni C., Guarnotta C., Cappetti B., Casalini P., Piconese S., Parenza M., Guiducci C., Vitali C., Colombo 86 KEYWORDS Leukemia/lymphoma, extracellular matrix, autoimmunity, neutrophil extracellular traps research activity INNOVATIVE PROBLEM-ORIENTED APPROACHES TO DIAGNOSIS AND TREATMENT COORDINATOR: Paolo Corradini Research into the interaction between a tumor and its microenvironment and identification of molecular and genetic characteristics that can be translated into biomarkers for diagnosis of cancer at its earliest stages. Studies relative to the development of: i) radiopharmaceuticals for tumor characterization in molecular imaging and treatment; ii) new drugs and/or treatment approaches for solid tumors, including clinical-translational studies prompted by the need for a) the prognostic characterization of rare tumors, which resemble the “big killers” and constitute an as yet unsolved problem both from a diagnostic and therapeutic point of view; b) knowledge of the mechanisms responsible for the different degrees of toxicity of radiotherapy in different tumor types; c) anticancer vaccines, genetic and biological therapies in certain tumors for the clinical testing of new substances. AIMS: Selection of biomarkers for early diagnosis or cancer risk assessment; development of radiopharmaceuticals for biological characterization and use in imaging and treatment; detection of biomarkers that can be used as indicators of treatment response; testing and development of targeted molecular therapies; stratification of radiotoxicity by degree of severity and assessment of its potential indicators. PROJECTS • Stroma-derived biomarkers with prognostic value in subjects with polygenic or monogenic inheritance predisposing to cancer (Tommaso Dragani) • Development of a platform for the pre-clinic evaluation of new anti-tumor drugs and new therapeutic combinations (Nadia Zaffaroni) • Study of immunosuppression mechanisms in patients with solid tumors and their influence on prognosis and response to drug treatment and immunotherapy (Licia Rivoltini) • Establishing drug and transplant approaches for effective treatment of hematological malignancies (Paolo Corradini) • Translational project for the development of drugs for personalized cancer treatment (Filippo de Braud) 87 SCIENTIFIC REPORT 2013 back to contents .Tommaso A. Dragani. STROMA-DERIVED BIOMARKERS WITH PROGNOSTIC VALUE IN SUBJECTS WITH POLYGENIC OR MONOGENIC INHERITANCE PREDISPOSING TO CANCER OVERVIEW AND SCIENTIFIC GOALS The process of tumor progression and metastatic dissemination can involve germline polymorphisms and individual gene expression signatures in normal tissue. Our project is aimed to integrate genome and transcriptome data across multiple individuals, thus allowing identification of genetic biomarkers that are predictive of clinical phenotypes of colorectal (CRC) or lung cancer (LC). Importantly, the availability of RNA levels and genotype data on the same subjects will allow to define cis- and trans-controls of genes expressed in normal tissues, thus revealing the architecture of gene regulation in the microenvironment of CRC and LC. We have carried out a transcriptome study of non-involved lung tissue, excised from a discovery series of 204 lung adenocarcinoma patients, evaluated using whole-genome expression microarrays. Genes associated with survival status at 60 months were identified by Cox regression analysis (adjusted for gender, age and clinical stage) and re-tested in a validation series of 78 additional cases. RNA-Seq analysis from non-involved lung tissue of 12 patients was performed to characterize the different isoforms of candidate genes. Gene expression signatures associated with survival comprised 10 genes: CNTNAP1, PKNOX1, FAM156A, FRMD8, GALNTL1, TXNDC12, SNTB1, PPP3R1, SNX10, and SERPINH1. In CRC patients, we have carried out a study to test the possible role of known SNPs that have been reported to affect risk or other aspects of disease in the modulation of clinical parameters. We have investigated the possible influence of 86 informative SNPs on overall survival and time to recurrence (TTR) in a series of 770 colorectal adenocarcinoma patients with follow-up to 84 months. In Cox multivariate analysis, adjusted for gender, age at surgery, pathological stage, and adjuvant chemotherapy, SNPs rs1801133 (MTHFR), rs4939827 (SMAD7) and rs2306283 (SLCO1B1), showed the highest statistically significant association with overall survival. The highest association with TTR was observed for rs16892766, which maps downstream of the EIF3H gene. By crossing mouse strains that are resistant or susceptible to lung tumorigenesis, it has been observed that mice susceptible to lung tumors express, in normal lung tissue, higher levels of the Kras-4A transcript isoform, compared to mice resistant. This difference is modulated by genetic polymorphisms located near or within this same locus Pas1 where the K-ras gene maps and which modulates susceptibility to lung tumorigenesis in mice. 88 research activity PROGRAM HIGHLIGHTS Our findings support the hypothesis that individual genetic characteristics, as shown by the expression pattern of non-involved tissue, can influence the outcome of lung adenocarcinoma patients. We have also found that a set of genetic variants (SNPs) previously found associated with risk of CRC was also associated with overall survival and TTR. The identification of alleles affecting subgroups of cancer patients with worse clinical outcome may have clinical application in future pharmacogenetic strategies to personalize treatment. PROGRAM MEMBERSHIP Tommaso A. Dragani, principal investigator. Giacomo Manenti, researcher, staff. Antonella Galvan, researcher. Francesca Colombo, researcher. Sara Noci, researcher. Alice Dassano, PhD student. Angela Pettinicchio, laboratory technician. SELECTED RECENT PUBLICATIONS Galvan A., Cabrera W., Vorraro F., Jensen J.R., Borrego A., Starobinas N., Ribeiro O.G., De Franco M., Knott S., Dragani T.A., Manenti G., Ibañez OC.: Genetic linkage analysis identifies Pas1 as the common locus modulating lung tumorigenesis and acute inflammatory response in mice. Genes Immun 2013; 14(8): 512-517 Galvan A., Frullanti E., Anderlini M., Manenti G., Noci S., Dugo M., Ambrogi F., De Cecco L., Spinelli R., Piazza R., Pirola A., GambacortiPasserini C., Incarbone M., Alloisio M., Tosi D., Nosotti M., Santambrogio L., Pastorino U., Dragani T.A.: Gene expression signature of noninvolved lung tissue associated with survival in lung adenocarcinoma patients. Carcinogenesis 2013; 34(12): 2767-2773 Falvella F.S., Alberio T., Noci S., Santambrogio L., Nosotti M., Incarbone M., Pastorino U., Fasano M., Dragani T.A.: Multiple isoforms and differential allelic expression of CHRNA5 in lung tissue and lung adenocarcinoma. Carcinogenesis 2013; 34(6): 1281-1285 Frullanti E., Colombo F., Falvella F.S., Galvan A., Noci S., De Cecco L., Incarbone M., Alloisio M., Santambrogio L., Nosotti M., Tosi D., Pastorino U., Dragani T.A.: Association of lung adenocarcinoma clinical stage with gene expression pattern in noninvolved lung tissue. Int J Cancer 2012; 131(5): E643-8 Dassano A., Noci S., Galbiati F., Colombo F., Trincucci G., Pettinicchio A., Dragani T.A., Manenti G.: Multigenic nature of the mouse pulmonary adenoma progression 1 locus. BMC Genomics 2013; 14: 152 SELECTED RECENT MAJOR GRANTS AIRC-2014, PI Dr. Tommaso A. Dragani AIRC 5x1000, PI Dr. Marco A. Pierotti KEYWORDS Single nucleotide polymorphisms, transcriptome, lung cancer, expression quantitative trait locus. 89 SCIENTIFIC REPORT 2013 back to contents .Nadia Zaffaroni. DEVELOPMENT OF A PLATFORM FOR THE PRE-CLINICAL EVALUATION OF NEW ANTI-TUMOR DRUGS AND THERAPEUTIC COMBINATIONS OVERVIEW AND SCIENTIFIC GOALS The possibility to evaluate the preclinical effectiveness of new anticancer drugs, as well as novel therapeutic combinations, is strongly associated with the availability of appropriate preclinical models, which are representative of clinically relevant phenotypes. In this context, over the years, we generated a large panel of human tumor xenografts of different histological origin in immunodeficient mice. These models have been extensively characterized in terms of: i) frequency of mutations in genes involved in master pathways; ii) constitutive activation of the main mitogenic and cell survival signaling pathways; iii) gene and microRNA expression profiles. In addition, for models with spontaneous or experimentally induced resistance to specific drugs, the molecular determinants of drug resistance have been identified. These models constitute the platform for the study of new therapeutic agents, including newly designed analogues of cytotoxic drugs, targeted drugs, and therapeutic nucleic acids (i.e. siRNA, miRNA mimics). Specifically, our research is focused on: 1) evaluation of effectiveness of new compounds as a function of histological type, genetic background and, more generally, molecular profile of tumor models; 2) the identification of new therapeutic combinations designed to target specific molecular alterations in tumor models. In addition, the availability of specific preclinical models will allow us to investigate new possible therapeutic indications for drugs already used in a clinical setting. Overall, the results of these studies should allow us to define new therapies for clinical development, as well as identify potential predictors of response (such as specific molecular alterations in tumors) that should be useful for patient selection. At the beginning of the study, both optimal route and schedule of administration will be determined. The antitumor efficacy of drugs, administered alone or in combination (i.e. contemporary or sequentially) will be evaluated in terms of tumor volume percentage reduction, induction of complete responses, and increased survival of animals. The modulation of putative molecular targets and specific pathways will be determined on tumor samples obtained after treatment. For promising drugs and/or combinations, the changes induced by treatment in the different signaling networks will be evaluated to obtain more accurate characterization of the mechanism of action. Finally, the histopathological evaluation of material, combined with morphometric and immunohistochemical techniques, will allow us to quantify the effects of treatment on angiogenesis, as well as to determine the infiltration of inflammatory and/or immune system cells and quantify the presence of apoptosis/necrosis. 90 research activity PROGRAM HIGHLIGHTS The project is making progress towards the improvement of therapeutic options for treatment of different tumor types, including rare diseases poorly responsive to conventional therapies, such as diffuse malignant peritoneal mesothelioma (DMPM) and solitary fibrous tumors (SFT). Specifically, concerning the preclinical development of new drugs, we evaluated the activities of: 1) new nortopsentin analogues (1H-pyrrolo[2,3-b]pyridine derivatives) in experimental models of diffuse DMPM. We demonstrated that the three most active compounds (shown to act as cyclin-dependent kinase 1 inhibitors) consistently reduced DMPM cell proliferation and induced a caspase-dependent apoptotic response, with concomitant reduction of the activation of the antiapoptotic protein survivin. In the mouse model, i.p. administration of these derivatives was effective, resulting in a significant tumor volume inhibition of DMPM xenografts at well-tolerated doses, and two complete responses were observed in each treatment group, suggesting a possible clinical relevance of these drugs for the treatment of DMPM; 2) hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex. The compounds (which produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with a cleavage pattern and persistence similar to SN38, the active principle of irinotecan) showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The most active compound also exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, in the absence of toxicity, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support these conjugates as a new class of anticancer agents of potential clinical interest. As far as the identification of new therapeutic combinations is concerned, through collaboration with other research groups at INT, we reported the antitumor activity of CpG oligonucleotides (synthetic DNA sequences recognized by Toll-like receptor 9 and able to induce innate/adaptive immune responses) administered alone or in combination with chemotherapy in preclinical models of human cancer. Considering preclinical experiments performed on xenografts generated from biopsies of patients with rare tumors, we explored the activity of conventional and targeted agents on a human high-grade dedifferentiated SFT characterized by overexpression and activation of PDGFRB and VEGFR1. In a xenograft model, dacarbazine and temozolomide were found to have a high and superimposable antitumor activity and to induce almost complete tumor volume inhibition, which was maintained after treatment interruption and confirmed pathologically. In contrast, sunitinib, pazopanib, and bevacizumab were found to be less active, with appreciable tumor relapse immediately after drug withdrawal. PROGRAM MEMBERSHIP Nadia Zaffaroni (PI), planning and coordination of experiments. Andrea De Cesare (Veterinarian), Denis Cominetti (junior researcher) and Monica Tortoreto (technician) will be involved in: i) subcutaneous and orthotopic xenotransplantation of cancer cells into nude, SCID, and NOD/SCID mice; ii) treatment with new therapeutic agents (alone or in combination); iii) assessment of tumorigenic potential and chemosensitivity profiles of different models; iv) tumor tissue collection and storage; and v) general animal care. Giovanni Beretta (senior researcher), Marzia Pennati (senior researcher), Valentina Zuco (senior researcher), Alessia Lopergolo (junior researcher) will be involved in: i) cell culture maintenance for xenotransplants; ii) molecular and biochemical assays in tumor specimens; and iii) immunohistochemical assessment of proliferation, apoptosis/necrosis, and microvessel density-related markers in explanted tumor xenografts. SELECTED RECENT PUBLICATIONS Carbone A., Pennati M., Parrino B., Lopergolo A., Barraja P., Montalbano A., SpanÚ V., Sbarra S., Doldi V., De Cesare M., Cirrincione G., Diana P., Zaffaroni N.: Novel 1H-pyrrolo[2,3-b]pyridine derivatives nortopsentin analogues: synthesis and antitumor activity in peritoneal mesothelioma experimental models. J Med Chem 2013; 56: 7060-7072 Sfondrini L., Sommariva M., Tortoreto M., Meini A., Piconese S., Calvaruso M., Van Rooijen N., Bonecchi R., Zaffaroni N., Colombo M.P., Tagliabue E., Balsari A.: Anti-tumor activity of CpG-ODN aerosol in mouse lung metastases. Int. J. Cancer 2013; 133: 383-93 Sommariva M., De Cesare M., Meini A., Cataldo A., Zaffaroni N., Tagliabue E., Balsari A. High efficacy of CpG-ODN, cetuximab and cisplatin combination for very advanced ovarian xenograft tumors. J Transl Med 2013; 11: 25 Stacchiotti S., Tortoreto M., Bozzi F., Morosi A., Messina A., Libertini M., Palassini E., Cominetti D., Negri T., Gronchi A., Pilotti S., Zaffaroni N., Casali P.G.: Dacarbazine in solitary fibrous tumor: a case series retrospective analysis and preclinical evidence vis-a-vis temozolomide and antiangiogenics. Clin Cancer Res 2013; 19: 5192-5201 SELECTED RECENT MAJOR GRANTS AIRC Ministero dello Sviluppo Economico Mesothelioma Applied Research Foundation KEYWORDS Experimental models of human tumors, new drugs, new therapeutic combinations Cincinelli R., Musso L., Dallavalle S., Artali R., Tinelli S., Colangelo D., Zunino F., De Cesare M., Beretta GL, Zaffaroni N.: Design, modeling, synthesis and biological activity evaluation of camptothecin-linked platinum anticancer agents. Eur J Med Chem 2013; 63C: 387-400 91 SCIENTIFIC REPORT 2013 back to contents .Licia Rivoltini. STUDY OF IMMUNOSUPPRESSION MECHANISMS IN PATIENTS WITH SOLID TUMORS AND THEIR INFLUENCE ON PROGNOSIS AND RESPONSE TO DRUG TREATMENT AND IMMUNOTHERAPY OVERVIEW AND SCIENTIFIC GOALS This project is aimed at characterizing interactions between tumor cells and the immune system to search for novel predicting/prognostic factors or therapeutic targets. Immunological studies are performed on peripheral blood, saliva, draining lymph nodes, and tumor lesions from patients with different stages of disease and undergoing specific drug treatments. A major focus is devoted to melanoma, sarcoma, liver carcinoma, and head and neck (H&N) cancer. The goal is to perform comprehensive and standardized immune profiling based on multiparametric assays for the visualization of immune cells and circulating factors. Gene-expression and miRNA profiling is also performed to identify immune-related signatures. Specific attention is paid to regulatory cell subsets (including myeloid-derived suppressor cells – MDSC -, regulatory T cells, and plasmocytoid dendritic cells) and plasma content of cyto- and chemokines. We also investigate tumor or immune exosomes to understand their impact on tumor immunity and the potential as source of biomarkers. Applying these strategies, we found that: 1.Multiparametric cytofluorimetry allows the simultaneous visualization of different immune cell subsets present in peripheral blood and lymph nodes, providing a reliable “immune profile” that differs substantially from that detected in age and sex-matched healthy donors. 2.MDSC frequency and activation state are associated with disease progression in melanoma and sarcoma patients, and with insensitivity to different therapeutic strategies including target therapies. 3.Drugs such as ipilimumab and BRAF-inhibitors have an impact on the frequency and function of MDSC, Treg and effector/helper T cells. The role of immune profile in the sensitivity or resistance to treatment is under investigation. 4.MDSC accrual involves the conditioning activity of tumor exosomes on myeloid cells through the delivery of selected chemokines and miRNA affecting HLA-DR, IL-6, HIF1-alpha, and TGF-beta pathways. The presence of exosomes bearing a myeloid-modulating signature is under evaluation in plasma samples from melanoma patients with different disease stage. 5.Salivary cytokines, detected by cytokine-bead array assay, accumulate in H&N cancer patients upon chemoradiotherapy and predict the severity of treatment-induced mucosites. 6.Gene expression profiling of sentinel nodes provides information about immune pathways that are associated with recurrence and poor prognosis. 92 research activity 7.Acidity is a powerful tool for tumor microenviroment to anergize immune responses in melanoma. A clinical trial investigating the ability of anti-acid drugs to improve tumor immunity and control tumor growth is ongoing in melanoma patients. Altogether, these data strongly confirm the potentiality of immune-related pathways as novel source of biomarkers for patient selection and management in cancer PROGRAM HIGHLIGHTS The recent success of novel cancer therapeutics based on immunomodulation has finally shown the key role of the immune system in controlling tumor growth. Evidence is also emerging regarding the influence that immunity exerts on disease progression and on the response to cancer treatment including targeted therapies. Hence, the study of immune-tumor interactions aimed at characterizing the “immune profile” at the single patient level represents a promising tool for the identification of novel predicting/prognostic factors and new therapeutic targets. Thanks to our long-standing experience in tumor immunology, continuously updated at the scientific and technological levels through collaboration with several national and international groups and networks, we are collecting a broad and comprehensive picture of immune-cancer cross-talk and its outcome in patients. Immunomonitoring is performed according to standardized protocols and SOPs, including sample collection and immunological testing. The active and productive collaboration with several clinical units allows the design of studies that meet specific and relevant clinical needs as well as timely patient selection and accrual. Based on these features, we are dissecting the mechanisms of cancer-mediated immunosuppression, possibly finding common features and patterns across different tumor histologies. Focusing on patients and defined questions, we are committed to verify whether investigating the immune system can provide relevant information about patient prognosis and response to treatment. Understanding the pathways regulating tumor immunity may also contribute to the identification of novel therapeutic strategies for cancer patients. PROGRAM MEMBERSHIP Unit of Immunotherapy of Human Tumors Study design and management, immunological and genetic analyses, data interpretation. Melanoma Unit Patient selection, collaboration in study design. Liver Unit Collaboration in study design, patient selection, result discussion and data interpretation. Sarcoma Unit Patient selection, collaboration in study design. Head and Neck Oncology Patient selection, collaboration in study design, result discussion and data interpretation. Unit of Functional Genomics Genetic profiling, data analysis MIA consortium Imaging studies Unit of Statistics and Epidemiology Collaboration in study design, data analysis SELECTED RECENT PUBLICATIONS Camisaschi C., Filipazzi P., Tazzari M., Casati C., Beretta V., Pilla L., Patuzzo R., Maurichi A., Cova A., Maio M., Chiarion-Sileni V., Tragni G., Santinami M., Vergani B., Villa A., Berti E., Umansky L., Beckhove P., Umansky V., Parmiani G., Rivoltini L., Castelli C.: Effects of cyclophosphamide and IL-2 on regulatory CD4+ T cell frequency and function in melanoma patients vaccinated with HLA-class I peptides: impact on the antigen-specific T cell response. Cancer Immunol Immunother 2013; 62(5): 897-908 Castelli C., Tazzari M., Negri T., Vergani B., Rivoltini L., Stacchiotti S., Pilotti S.: Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcoma. J Transl Med 2013; 11:237 Filipazzi P., Pilla L., Mariani L., Patuzzo R., Castelli C., Camisaschi C., Maurichi A., Cova A., Rigamonti G., Giardino F., Di Florio A., Asioli M., Frati P., Sovena G., Squarcina P., Maio M., Danielli R., Chiarion-Sileni V., Villa A., Lombardo C., Tragni G., Santinami M., Parmiani G., Rivoltini L.: Limited induction of tumor cross-reactive T cells without a measurable clinical benefit in early melanoma patients vaccinated with human leukocyte antigen class I-modified peptides. Clin Cancer Res 2012; 18(23): 6485-6496 Calcinotto A., Filipazzi P., Grioni M., Iero M., De Milito A., Ricupito A., Cova A., Canese R., Jachetti E., Rossetti M., Huber V., Parmiani G., Generoso L., Santinami M., Borghi M., Fais S., Bellone M., Rivoltini L.: Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res 2012; 72(11): 2746-2756 ASSOCIATED CLINICAL TRIALS Experimental Clinical Study no Profit AdESOM: Effetto immunomodulatorio e antitumorale dell’ esomeprazolo ad alte dosi in regime neoadiuvante e adiuvante in pazienti con melanoma in stadio III. Studio pilota randomizzato trattamento vs controllo PROVAX: Studio di vaccinazione, in aperto, di fase II con peptidi di survivina emulsionati in Montanide® ISA 51VG dopo somministrazione di IMP321TM, in pazienti con carcinoma prostatico in recidiva biochimica MULTIMELMARKERS: Identificazione di marcatori molecolari del melanoma multiplo NIBIT-001: A Phase II Study of the Combination of Ipilimumab and Fotemustine in Patients with Unresectable Locally Advanced or Metastatic Malignant Melanoma Experimental Clinical Study Profit GINGER: Studio multicentrico, randomizzato, in doppio cieco, controllato verso placebo per valutare l’attività di un integratore alimentare a base di Ginger (Zingiber officinalis) nella gestione della nausea in pazienti che ricevono trattamenti altamente emetizzanti e la terapia antiemetica standard 93 back to contents SCIENTIFIC REPORT 2013 METRIC/MEK114267: Studio di Fase III randomizzato, in aperto, per confrontare GSK1120212 verso chemioterapia in soggetti con melanoma avanzato o metastatico positivo alle mutazioni di BRAF V600E/K NYESO-1: An open Phase I study of immunization with the recNY ESO 1 + AS15 Antigen-Specific Cancer Immunotherapeutic in patients with NY-ESO-1 positive unresectable and progressive metastatic cutaneous melanoma PRAME: An open, dose-escalation Phase I/II study to assess the safety, immunogenicity and clinical activity of recPRAME + AS15 AntigenSpecific Cancer Immunotherapeutic as first-line treatment of patients with PRAME-positive metastatic melanoma Observational Clinical Studies (Non-profit) EPApHIL-6: Analisi dell’infiltrato infiammatorio come fattore prognostico e target terapeutico in pazienti con carcinoma epatico. Ruolo della componente mieloide e dei pathway coinvolti nella regolazione del pH miRNA: Identificazione di microRNA circolanti quali potenziali indicatori di progressione nel melanoma metastatico BRAF-MEK: Studio dell’effetto immunomodulatorio degli inibitori di BRAF e MEK in pazienti con melanoma Target Therapy: Valutazione del ruolo dei meccanismi immunosoppressivi nella prognosi e nella risposta al trattamento con farmaci ‘targeted therapy’ in pazienti affetti da sarcoma SELECTED RECENT MAJOR GRANTS Project MCO-9998 Special Program Molecular Clinical Oncology, AIRC 5 per Mille “Cell therapy with TRAIL-armed, genetically engineered or phenotypically redirected, effectors” Duration: 01/07/2010 - 30/06/2015 Project n. 12162 - AIRC 5 per Mille “Tumor-Microenvironment related changes as new tools for early detection and assessment of high-risk disease” Duration: 31/12/2011 - 30/12/2016 Project AIRC IG-14285 “Modulation of melanoma immunosuppressive microenvironment by proton pump inhibitors”. Duration: 02/01/2014 - 01/01/2015 Project AIRC IG-13335 “From regional node to systemic immunity suppression in melanoma metastatic progression” Duration: 02.01.2014 - 01.01.2015 MINISTERO della SALUTE convenzione n. 52/RF-2010-2312620 “IL-6-related inflammation signatures as a predictive marker of recurrence in liver cancer patients” Duration: 03/12/2012 - 02/12/2015 Harry J Lloyd Charitable Trust “Study of microRNA related to myeloid derived suppressor cells in early melanoma patients” Duration: 14/06/2013 - 30/06/2015 KEYWORDS Immune suppression, myeloid-derived suppressor cells, exosomes, miRNA Figure: Immunosuppressive and exhausted lymphocytes in metastatic sentinel node from melanoma patients with unfavorable disease course at 5 years follow-up. Double staining for CD30 and CD147, Foxp3, and PD1 in a representative PP sample showing cells expressing one or both markers (magnification, ×100). Confocal images of sections stained for CD30 in green and for CD147 or PD1 in red are shown (merge). In the CD30-Foxp3 double staining, CD30+ cells are indicated by red, and nuclear staining for Foxp3 is indicated by brown. From Vallacchi V et al. Cancer Res 2014;74:130-140 94 research activity .Paolo Corradini. ESTABLISHING DRUG AND TRANSPLANT APPROACHES FOR EFFECTIVE TREATMENT OF HEMATOLOGICAL MALIGNANCIES OVERVIEW AND SCIENTIFIC GOALS Treatment options for patients with hematological malignancies include chemotherapy, radiotherapy, immunotherapy, and high-dose chemotherapy followed by autologous and allogeneic stem cell transplantation (auto- and allo-SCT). These therapeutic strategies have an established role in the management of patients at diagnosis, with cure rates ranging between 30% and 90% depending on histology. However, a significant proportion of patients affected by aggressive lymphomas display primary chemo-refractoriness or early relapse and have dismal long-term disease control, and thus represent an unmet medical need. In addition, the mechanisms driving chemo-refractoriness still remain largely unclear. Also, new biomarkers for upfront identification of refractory patients or those requiring intensified approaches (auto- or allo-SCT) as first-line treatment are mandatory. New treatments tailored to overcome aggressiveness and refractorinessdriving lesions are required. Ongoing clinical and biological studies in the field of multiple myeloma (MM), indolent and aggressive non-Hodgkin’s lymphoma (NHL), acute myeloid leukemia (AML), myelodysplastic and myeloproliferative disorders, and graft-versus-host disease (GVHD) are aimed at: •Evaluating the efficacy of new, targeted therapies alone or in combination with standard chemotherapy to allow individualized treatment options designed to target each patient’s specific genetic lesions, thereby reducing toxicity and increasing effectiveness. Massive sequencing technologies will help in identifying genetic lesions/mechanism(s) driving lymphoma aggressiveness and/or chemo-refractoriness and to define new targets for treatment. •Exploiting the role of potential genes/proteins as diagnostic tools and novel biomarkers for the early recognition/ stratification of patients requiring intensified treatment options or those unlikely to respond to standard chemoimmunotherapies. The discovery of biological and/or molecular biomarker(s) of aggressiveness or chemo-refractoriness will lead to the development of innovative clinical programs with substantial impact in clinical practice •Introducing new molecular methods for diagnosis of hematological malignancies. In B cell malignancies, several methods have been developed for the detection of minimal residual disease (MRD). We are now applying a new, next generation sequencing technology strategy based on the use of Ion Torrent Personal Genome Machine (PGM, Life Technologies) to monitor MRD in B cell malignancies and clonal evolution in MM patients. We have also introduced and developed molecular tests for the detection of mutation with diagnostic impact (BRAF V600E in hairy cell leukemia, MYD88 L265P in Waldenstrom macroglobulinemia, TET2 and IDH mutations in peripheral T cell lymphomas, and JAK2 V617F in myeloproliferative disorders). 95 back to contents SCIENTIFIC REPORT 2013 PROGRAM HIGHLIGHTS This project will address currently unmet clinical needs in the management of hematological malignancies. New biomarkers for the upfront identification of patients with aggressive disease, refractory and/or relapsing and new treatments tailored to target cancer-driving lesions are mandatory. Although a variety of genetic and epigenetic lesions as well as microenvironmental features have been mechanistically implicated in the pathogenesis and progression of hematological malignancies, the pathogenesis of chemo-refractoriness remains unclear. Major improvements in sequencing technologies could provide the opportunity to discover genomic alterations and therapeutic targets accounting for chemo-refractoriness and early relapse. This project will also define preclinical models mainly for PTCLs that reliably predict the clinical activity of novel compounds specifically targeting the key genetic lesions identified. The potential role of genes/proteins as diagnostic tools and novel biomarkers with prognostic and predictive value will be assessed. Our research project has the clear goal of a rapid translation in the clinical setting by: i) improving the early identification of chemo-refractory/relapsing patients and patients requiring auto- or allo-SCT as first line treatment with novel biomarkers; ii) designing phase 1/2 clinical studies aimed at exploring the clinical activity of rationale combinations of targeted drugs that have been previously tested in in-vitro models. PROGRAM MEMBERSHIP ASSOCIATED CLINICAL TRIALS The goals of this project will be achieved by integrating the complementary and synergistic skills and facilities of members (clinicians, researchers and data managers) of the Hematology Unit. The clinical staff (Prof Paolo Corradini, Dr. Anna Dodero, Dr. Vittorio Montefusco, Dr. Lucia Farina, Dr. Francesco Spina) has been working in the field of hematological malignancies and stem cell transplantation for many years and will be instrumental in designing clinical studies and selecting patients for biological analysis. All clinical information necessary to correlate the biological results with outcome will be collected by or data managers (Dr. Debora Degli Innocenti, Dr. Anisa Bermema). Well-characterized bio-repositories of biospecimens (blood, plasma, biopsies) from patients enrolled in several clinical trials are available to the research team as a biobanking system, which is ongoing within the Unit and coordinated by Dr. Cristiana Carniti. The biobank will provide a sufficient number of samples for analysis and validation of results. The expertise for the use of new sequencing technologies is increasing in our Unit. Specifically Dr. Silvia Gimondi of the Hematology Branch has recently attended the Ion PGM teaching course at Life Technologies laboratories, Darmstadt, Germany to learn the use of this technology and complement her existing bioinformatic skills. Other members of the team include researchers (Dr. Antonio Vendramin, Dr. Alessandra Cavanè, Dr. Sara Rizzitano) with different but synergistic expertise that have been selected according to their proven welldefined scientific and technical skills. INT 118/13 - Protocol COEB071X2103: An open-label, singlearm, Phase Ib/II study of AEB071 (a protein kinase C inhibitor) and everolimus (mTOR inhibitor) in patients with CD79-mutant or ABC subtype diffuse large B-cell lymphoma SELECTED RECENT PUBLICATIONS Perrone G., Farina L., Corradini P.: Current state of art for transplantation paradigms in peripheral T-cell lymphomas. Expert Rev Hematol 2013; 6(4): 465-474 Larocca A., Montefusco V., Bringhen S., Rossi D., Crippa C., Mina R., Galli M., Marcatti M., La Verde G., Giuliani N., Magarotto V., Guglielmelli T., Rota-Scalabrini D., Omedé P., Santagostino A., Baldi I., Carella A.M., Boccadoro M., Corradini P., Palumbo A.: Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study. Blood 2013; 122(16): 2799-2806 Gay F., Magarotto V., Crippa C., Pescosta N., Guglielmelli T., Cavallo F., Pezzatti S., Ferrari S., Liberati A.M., Oliva S., Patriarca F., Offidani M., Omedé P., Montefusco V., Petrucci M.T., Giuliani N., Passera R., Pietrantuono G., Boccadoro M., Corradini P., Palumbo A.: Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood 2013; 122(8): 1376-1383 Montefusco V., Spina F., Patriarca F., Offidani M., Bruno B., Montanari M., Mussetti A., Sperotto A., Scortechini I., Dodero A., Fanin R., Valagussa P., Corradini P.: Bortezomib plus dexamethasone followed by escalating donor lymphocyte infusions for patients with multiple myeloma relapsing or progressing after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19(3): 424-428 96 INT 134/13 - Protocol CC-122-DLBCL-001: A PHASE 1B, MULTICENTER, OPEN-LABEL STUDY OF NOVEL COMBINATIONS OF CC-122, CC-223, CC-292, AND RITUXIMAB IN DIFFUSE LARGE B-CELL LYMPHOMA INT 31/13 – IST-CAR-561: A MULTICENTER, OPEN LABEL STUDY OF WEEKLY CARFILZOMIB, CYCLOPHOSPHAMIDE AND DEXAMETHASONE (wCCyd) IN NEWLY DIAGNOSED MULTIPLE MYELOMA (MM) PATIENTS INT 19/13: Studio dei meccanismi molecolari di chemio-resistenza nei linfomi a cellule T periferiche (PTCL) mediante sequenziamento massivo del genoma INT 86/13: Identificazione delle cause genetiche responsabili di una forma famigliare di mieloma INT 149/13: Studio retrospettivo osservazionale sul monitoraggio dei livelli sierici di TARC e i risultati PET dei pazienti con linfoma di Hodgkin sottoposti a trapianto allogenico di cellule staminali emopoietiche GRANTS AIRC IG 2013 Prof Paolo Corradini UNDERSTANDING THE BIOLOGICAL BASIS OF CHEMOREFRACTORINESS IN PERIPHERAL T-CELL LYMPHOMA TO DEVELOP NOVEL TREATMENTS MFAG Mariotti Identifying new molecular pathways and predictor biomarkers of GVHD after allogeneic-HSCT FP7 PEOPLE 2010 RG Role and Modulation of Jak and STAT signaling in Graft Rejection and Graft versus KEYWORDS Hematological malignancies; Drug response and/or resistance; Targeted therapy; Next Generation Sequencing research activity .Filippo de Braud. TRANSLATIONAL PROJECT FOR THE DEVELOPMENT OF DRUGS FOR PERSONALIZED CANCER TREATMENT OVERVIEW AND SCIENTIFIC GOALS The Division of Medical Oncology 1 has the mission to develop methodology and evidences to bring personalized medicine and the most active drugs to treat cancer into clinical practice. Therefore, it is involved in several phase I and II studies with solid rationales and preclinical background. In the very early phase of new drug development, information about patients screened, but not included in studies, as well as evidence of efficacy for small subgroups of patients are frequently missing. Nevertheless, much data becomes available because of the availability of systematic blood sample collections, used for pharmacodynamics and pharmacokinetics, and tumor samples for biomarker screening. The Pathology Department has implemented diagnostic procedures with the most up to date approaches using immunohistochemistry, molecular diagnostics with PCR, and next generation sequencing (Ion Torrent) to screen tumor specimens from patients who may be candidates for clinical trials. Together we have designed molecular panels that are being investigated within subgroups of solid tumors to study the individual steps of several pathways, gene mutations, signal transduction, and response to TKIs, cell cycle checkpoints, and expression of single genes expression. The Experimental Department applies high-throughput technologies of transcriptomics (microarrays for gene expression, exome sequencing) to understand molecular pathways within cancer tissues on paraffin embedded samples. Through collection of clinical data, clinical observations, medical history, acute and chronic adverse events , drug interaction data, and sharing of personal views, clinicians can bring researchers together to correlate clinical behavior with pathological, pathophysiological, molecular, and genetic information. Through astute clinical observation, we are posing key questions to collaborating scientists to help answer the clinical unmet needs, and gathering information on pharmacological targets and histological, molecular or/and mutational characteristics of tumors. Our methodology is simple and consists in systematic collection of all data available on outpatient first access lists, considering the pathology and inclusion or not into a clinical trial. Whenever possible, patients also receive a molecular diagnosis by identifying targets for available phase I/ first in human drugs. Thanks to the support of the data management, several database have been implemented that can be consulted according to disease, molecular target, mutational status, and clinical response to therapy. Collections are also planned on retrospective material. 97 back to contents SCIENTIFIC REPORT 2013 PROGRAM HIGHLIGHTS The strength of this project is represented by systematic data collection organized since the first visit of a patient to our Outpatient Department. This collection enables identification of possible target populations for further phase I studies, but also collects information about the distributions of molecular targets and their expression in a specific population. This implies that first access of patients becomes a resource for future research. Analyzing past treatments, we can rapidly obtain information on toxicities or responses to specific drugs, that, when collected in a database, can be retreived by seeking for molecular target or drug (e.g. data are available on TKI treatments, gathering cross sectional experience from clinical trials). Furthermore, through clinical experience on specific target inhibitors we can compare classes of drugs on different solid tumors and address our efforts to new research programs based on a solid clinical background, optimizing the investments of time, patients, and researchers. The different role of detected mutations, classified as “driver”, “passenger”, or “addictive” with regards to tumor development may guide the use of a wide spectrum of available targeted therapies in phase I, Ib, and early phase II clinical trials, as well as provide a solid rationale to plan single or double targeted treatment from the onset of therapy or forecast a multiple step sequential treatment at disease progression. PROGRAM MEMBERSHIP Filippo de Braud, Project Coordinator Clinical researchers: Sara Cresta, MD, Silvia Damian, MD, Anna Tessari, MD, Lorenzo Pilla, MD, Luigi Celio, MD, Filippo Pietrantonio, MD Pietrantonio F., Biondani P., Ciurlia E., Fanetti G., Tessari A., Bertarelli G., Bossi I., Musella V., Melotti F., Di Bartolomeo M., Valvo F., Pellegrinelli A., Milione M., Perrone F., de Braud F.: Role of BAX for outcome prediction in gastrointestinal malignancies. Med Oncol 2013; 30: 610 Clinical data management: Valentina Sinno Pietrantonio F., Biondani P., Milione M., Melotti F., Bertarelli G., Perrone F., De Braud F., Mariani L., Fanetti G., Cortinovis D., Di Bartolomeo M.: Lack of Bax expression is associated with irinotecan-based treatment activity in advanced colorectal cancer patients. Clin Transl Oncol 2013; 15: 582-586 SELECTED RECENT PUBLICATIONS ASSOCIATED CLINICAL TRIALS Tessari A., Palmieri D., Di Cosimo S.: Overview of diagnostic/targeted treatment combinations in personalized medicine for breast cancer patients. Pharmgenomics Pers Med 2013; 7: 1-19 Prospective observational study of the genetic polymorphisms role in the development of chemotherapy related toxicity in gastroenteric tumors. INT126/13 PI: F. de Braud 29/11/2013 Translational researchers: Manuela Iorio, PhD, Antonia Martinetti, Biologist Tessari A., Pilla L., Paolini B., Carcangiu M.L., Mariani L., Moliterni A:, de Braud F., Cresta S.: Expression of NY-ESO-1, MAGE-A3, PRAME and WT1 in different subgroups of breast cancer. AACR Annual Meeting 2013, Abstract number LB-320 Plantamura I., D’Ippolito E., Tessari A., Cresta S., Orlandi R., Moliterni A., Carcangiu M.L., De Braud F., Tagliabue E., Iorio M.V.: PDGFR-betainduced miR-9 is up-regulated in triple negative breast cancer. SABCS 2013; P4-07-18 Pilot study to identify miRNA predictive for response to gemcitabine treatment in metastatic breast cancer. INT115/13 PI: S. Cresta 09/08/2013 Retrospective multicentric analysis of the prognostic role of cMet mutations in GE tumors. INT163/13 PI: L: Celio 23/12/2013 KEYWORDS Personalized medicine, biomarkers, target therapy, solid tumors Figure: Molecular target database outpatient visit screening for target mutations amplification “positive” molecular screening target therapy “negative” Molecular screening standard therapy (eg. trial screening failure) analysis prognostic predictive factors “driver” vs “passenger” mutation, etc 98 standard therapy research activity MULTIDISCIPLINARY DISEASE-ORIENTED APPROACH COORDINATOR: Vincenzo Mazzaferro Organ disease-focused interdisciplinary studies including lung carcinoma, hepatocellular carcinoma, soft tissue sarcomas, tumors of the adult lymphohematopoietic system, and possibly other tumor types. To create added value between preclinical and clinical research based on novel molecular characterization, for new treatment approaches and a wider use of targeted molecular therapies. Translational project development in the context of single diseases with operational support for the design and conduct of non-profit institutional clinical trials. To promote the development of a multidisciplinary disease-oriented approach across different types of cancer. AIMS: Focal areas of study will be chemoprevention and the treatment of preinvasive disease; early diagnosis; molecular characterization and staging; conservative and minimally invasive treatment; targeted, biologically based therapies. Additional areas will include assessing the potential of therapies tailored to the individual patient (personalized medicine) using both conventional cytotoxic drugs and new molecular compounds to minimize toxicity. PROJECTS • Prostate cancer program (Riccardo Valdagni) • New methodological approaches to the study and personalized treatment of rare tumors and adult sarcomas (Paolo Casali) • Biomolecular characterization of rare histological types of ovarian carcinoma and implications for the medical treatment of the disease (Francesco Raspagliesi) • Early diagnosis of lung carcinoma and efficacy of plasma miRNAs as first-line tests (Ugo Pastorino) 99 SCIENTIFIC REPORT 2013 back to contents .Riccardo Valdagni. PROSTATE CANCER PROGRAM OVERVIEW AND SCIENTIFIC GOALS The Prostate Cancer (PC) Program is a translational multidisciplinary (MD) and multi-professional (MP) program started in September 2004. Endorsed by the Scientific Director, the PC Program has expertise in epidemiology, experimental oncology, molecular pharmacology, pathology, imaging, urologic surgery, radiotherapy, medical oncology, palliative care, and psychology. Its goals are to outline and implement research strategies in PC, including the study of mechanisms of PC development and progression; to promote clinical and experimental studies, also in collaboration with national and international partners; to offer PC patients a MD management of their disease; to run MD clinical activities; to organize educational activities (i.e. Grand Rounds, Multidisciplinary Team Meetings, conferences for clinicians, general practitioners, patients); and to optimize the human and technological resources within a disease-focused translational MD framework. More than 20 research projects are currently on-going. The rationale at the basis of the PC clinical program is that, depending on the state of disease, there are several therapeutic options. Although the therapies show no clear differences in cancer control rates in the same state, they can induce adverse effects and affect patients’ quality of life. In addition, selected patients can be addressed to observational strategies, namely active surveillance (AS) and watchful waiting. For this reason, patients should receive objective, comprehensive information about the disease, therapeutic and observational options, therapy-induced side effects, and be accompanied in the decision-making process. Within this framework, several MD clinical activities are organized: •First Consultations (350 MD visits in 2013) with the synchronous participation of the urologist, radiation oncologist, and psychologist; the medical oncologist is on call for patients with locally advanced, hormone-refractory and metastatic PC; supportive care, rehabilitation, and specialist palliative care interventions are available on demand; PC patients are offered psychological support (decision-making support, counseling for individuals, couples, families, and self-help groups); •Follow-up visits for patients on AS or watchful waiting (600 visits in 2013): the urologist or the radiation oncologist meet patients continuing in the observation in a mono-disciplinary setting; a psychologist is on demand; if patients have to discontinue the observational setting and be addressed to treatment, a MD setting is undertaken; •Multidisciplinary Team Meetings, a CME activity aimed to share decisions and paths of care on PC patients, tailor therapeutic and observational strategies, enroll patients in trials, and verify adherence to guidelines and quality assurance. In this process, great attention is paid to quality of life and psychological issues. The PC Program is acknowledged worldwide as an important experience in managing AS protocols. This observational option is being offered to patients with low and very low risk PC as an alternative to radical treatment since March 2005. The PC Program is the top recruiting center in the PRIAS (Prostate cancer Research International: Active Surveillance) consortium (327 patients) and is the coordinator of the Italian institutions participating in PRIAS under the name of SIUrO PRIAS ITA. The PC Program has been running a biobank and collects blood, urine, and tissue from different categories of patients to obtain biological material for research. 100 research activity PROGRAM HIGHLIGHTS Research is focused in multiple areas, such as interpretation of survival differences and improvement over time in Italy, development of novel approaches for the inhibition of cell survival factors in preclinical models, identification of epithelial and stromal/microenvironmental microRNAs regulating PC progression and metastasis, identification of long non-coding RNAs governing prostate epithelial biology and tumor development, molecular characterization of indolent PCs, quality of life of patients on AS, toxicity and quality of life in patients treated with radiotherapy. An urgent need is related to the improvement of selection criteria for AS, which is currently suboptimal and relies exclusively on clinical and pathological parameters, with the addition of novel biological markers for early identification of occult high-risk PC. We plan to evaluate microRNA profiles in plasma from patients on AS and correlate these with patient outcomes to assess whether specific microRNAs are able to better predict disease behavior and/or earlier compared to conventional markers. Upon confirmation of results in an independent patient cohort, the final aim of this study will be the integration of selected microRNAs in an updated and improved model for the prediction of indolent PC. More generally, the current understanding of low-risk, potentially indolent tumors is very limited, due to a number of technical hurdles inherent in the analysis of these lesions. Because of their very favorable prognosis, a matter of debate is the possibility that they could be regarded as non-malignant. In this regard, it can be hypothesized that molecular alterations characteristic of indolent PC may be different from those previously detected in clinically-significant tumors. We will use Whole Exome Sequencing (WES) technology to detect DNA alterations in positive core biopsies from a subset of AS patients (60), with the aim: 1. Compare such genomic alterations with those characteristic of clinically significant PC; 2.Shed light on the nature of such tumors (clinically insignificant disease, early lesions preceding the development of aggressive cancer - versus indolent cancer - which do not progress during the patient’s lifetime); 3. Identify specific DNA alterations associated to disease progression during AS. In the same subset of AS patients, the presence of TMPRSS2-ERG gene fusion transcripts will be assessed in urine. Information derived from these analyses will be integrated with miRNA expression and WES data to generate a more complete molecular profile for each individual patient. We have initiated research aimed to develop a non-invasive innovating diagnostic method to detect PC on urine samples measuring urinary volatiles. This will enable to identify and distinguish emission spectra in urine from patients with PC from healthy specimens. If this preliminary evaluation is positive, substances contained in PC patients urine will be more specifically identified in a larger group in order to implement the technique and produce low cost and non-invasive diagnostic kits. PROGRAM MEMBERSHIP Riccardo Valdagni, Group Leader Nadia Zaffaroni, Preclinical activities and protocols Group Leader Participating Departments and Units Scientific Director’s Office Diagnostic Imaging and Radiotherapy Experimental Oncology and Molecular Medicine Medical Oncology Medical Statistics and Biometry Palliative Care, Pain Therapy, and Rehabilitation Pathology and Laboratory Medicine Preventive and Predictive Medicine Psychology Supportive Care in Cancer Urologic Surgery SELECTED RECENT PUBLICATIONS Mauri G., Chiodoni C., Parenza M., Arioli I., Tripodo C., Colombo M.P.: Ultrasound-guided intra-tumor injection of combined immunotherapy cures mice from orthotopic prostate cancer. Cancer Immunol Immunother 2013; 62(12): 1811-1819 Valdagni R., Procopio G., Nicolai N., Gruppo Multidisciplinare del Programma Prostata. Neoplasie della Prostata. In: Labianca R., Cascinu S., La Medicina Oncologica - Diagnosi Terapia e gestione clinica, Edra – Masson Ed., 2013 ASSOCIATED CLINICAL TRIALS Non-invasive diagnosis of PC based on urine samples test. PI: Cristina Marenghi Predictive models of genitourinary toxicity and erectile dysfunction after external high dose radiotherapy in PC. PI: Riccardo Valdagni PC Patient’s choice after the MD First Consultation. PI: Riccardo Valdagni Quality of life of men on Active Surveillance. PI: Riccardo Valdagni Bellardita L., Rancati T., Alvisi M.F., Villani D., Magnani T., Marenghi C., Nicolai N., Procopio G., Villa S., Salvioni R., Valdagni R.: Predictors of health-related quality of life and adjustment to prostate cancer during active surveillance. Eur Urol 2013; 64(1): 30-36 Phase Ib/II study comparing GDC-0068 or GDC-0980 associated with abiraterone acetate versus abiraterone acetate in patients with castration resistant PC already treated with docetaxel based chemotherapy. PI: Giuseppe Procopio Bul M., Zhu X., Valdagni R., Pickles T., Kakehi Y., Rannikko A., Bjartell A., van der Schoot D.K., Cornel E.B., Conti G.N., Boevé E.R., Staerman F., Vis-Maters J.J., Vergunst H., Jaspars J.J., Strölin P., van Muilekom E., Schröder F.H., Bangma C.H., Roobol M.J.: Active surveillance for low-risk prostate cancer worldwide: The PRIAS study. Eur Urol 2013; 64(4): 597-603 SELECTED RECENT MAJOR GRANTS Fenderico N., Casamichele A., Profumo V., Zaffaroni N., Gandellini P.: MicroRNA-mediated control of prostate cancer metastasis: implications for the identification of novel biomarkers and therapeutic targets. Curr Med Chem 2013; 20(12): 1566-1584 AIRC (My First AIRC Grant) Fondazione Italo Monzino Fondazione ProADAMO KEYWORDS Translational research, multidisciplinary approach, experimental therapeutics 101 SCIENTIFIC REPORT 2013 back to contents .Paolo G. Casali. NEW METHODOLOGICAL APPROACHES TO THE STUDY AND PERSONALIZED TREATMENT OF RARE TUMORS AND ADULT SARCOMAS OVERVIEW AND SCIENTIFIC GOALS Soft tissue and bone sarcomas, including GISTs, are rare and highly heterogeneous tumors, which related to their ubiquitous anatomic origin. In this regard, it is well known that application of good surgical principles to all sarcoma primary sites is not feasible. It is realized that new therapeutic avenues should be explored for these tumors, exploiting all disciplines, from surgery to radiation and medical therapy. Heterogeneity is also related to the pathology of these tumors. It is well-known that the natural history of sarcomas differs substantially depending on the histological subtype. It has also become clear that histologic subtypes possess distinct cytogenetic and molecular profiles that affect sensitivity to medical therapies, including cytotoxic and targeted agents. These latter have mechanisms of action that are more specifically dependent on the molecular profile of the tumor. This poses new challenges to medical therapy of sarcomas, reinforcing the need to personalize medical treatment, mainly by exploiting knowledge of deregulated molecular profiles. In particular, it is clear that the current approach to sarcomas should be highly personalized, on a highly multidisciplinary basis. GISTs constitute an advanced platform, but other sarcomas are catching up rapidly as new targeted agents are becoming available at a steady pace. The aim of this project is to strengthen the institutional research platform aimed at gaining new insights on the antitumor activity of cytotoxics and molecular targeted agents in selected types of sarcoma, including the rarest ones. New insights will also be gained on how to incorporate these medical therapies into multidisciplinary treatment strategies, with insights in the most challenging clinical presentations of sarcoma. New avenues in the methodology of clinical research will be attempted, so that an additional value of the project will be the assessment of new strategies for clinical research, potentially serving as a model for other rare tumors. From a healthcare perspective, new organizational tools are being experimented, which are aimed at diminishing healthcare migration in the field of rare cancers in Italy. Distant “shared” patient care is carried out within the Italian Network for Rare Cancers (RTR). This is a collaborative project aimed to improve quality of care, let institutions share clinical cases, define clinical practice guidelines, and rationalize patient access to health facilities. Finally, clinical observations shared within the RTR project could allow a shared national database, also aimed to encourage clinical research on rare tumors. The patient populations involved in this project include those affected by sarcoma: soft tissue sarcoma, GIST, small blue round cell sarcoma, osteosarcoma, chordoma and chondrosarcoma, and rare histological types. 102 research activity PROGRAM HIGHLIGHTS Within the project, the global international collaboration among sarcoma centers was strengthened. The ESMO International Conference on Sarcoma & GIST was organized by INT and planned for February 2014. The event has important educational intent and is a crucial moment for the sarcoma community, aimed to share new investigational trials and methodologies in sarcomas. Several rare sarcoma subtypes are the target of on-going or just completed clinical trials: •pigmented villonodular tenosynovitis (PVNS); a rare condition in which tumor growth is sustained by CSF1R/CSF1 through an autocrine/paracrine loop. A phase II trial on nilotinib was completed. Role of nilotinib in imatinib resistant-PVNS was published. •imatinib-pretreated chordoma: a phase II trial on the activity of lapatinib, an EGFR inhibitor, was published. A phase II study to test the activity of combined targeted therapy with everolimus (mTOR inhibitor) and imatinib in first line is on-going . •GIST: an effort was made to activate an international phase II trial on sunitinib in first line therapy for advanced disease in a pediatric population. From a clinical point of view, pediatric GISTs have mostly wild-type genotype, an indolent course, and are related to syndromic conditions. •solitary fibrous tumor: activity of dacarbazine was reported in a case series on a preclinical evidence vis-a-vis temozolomide and antiangiogenic. Role of pazopanib was presented at CTOS 2013 and response to chemotherapy was retrospectively analyzed in an INT series. Furthermore, outcomes of late recurrences in a small series was published within the National Rare Cancer Network project. •osteosarcoma: an Italian Sarcoma Group observational trial was activated to assess the natural history of osteosarcoma arising from atypical sites. • myxoid extraskeletal chondrosarcoma: a retrospective study on the activity of anthracycline-based chemotherapy was reported. The role of sunitinib was observed and an international phase II trial was planned. Intriguing patterns of response to trabectedin were observed, especially in myxoid liposarcoma. Tumor shrinkage was seen, but changes in tumor density suggested a type of ‘targeted’ activity of trabectedin in this histotype, which may be related to the drug’s ability to target the FUS-CHOP-mediated transcriptional block. Uterine leiomyosarcoma may show similar patterns of response to trabectedin. The assessment of tumor response is a goal in an on-going trial in patients affected by high-grade limb and superficial soft tissue sarcoma, within a prospective European randomized trial aimed to compare the efficacy of full dose standard chemotherapy vs. histotype-tailored chemotherapy. In 2013, about 800 new cases were shared within the National Rare Cancer Network, confirming the increasing activity of the project. An educational Web site was activated in collaboration with Accademia Nazionale di Medicina: a “Journal Club” section and a “Case Report” section are monthly dedicated to each solid rare tumor. PROGRAM MEMBERSHIP Adult Mesenchymal Tumour Medical Oncology Paolo G. Casali, Coordinator of the project Clinical researchers: Rossella Bertulli, MD, Silvia Stacchiotti, MD, Elena Fumagalli, MD, Michela Libertini, MD, Elena Palassini, MD, Roberta Sanfilippo, MD Surgery Sarcoma Unit Clinical researchers: Alessandro Gronchi, MD, Chiara Colombo, MD, Marco Fiore, MD, Stefano Redaelli, MD Molecular Pathology Laboratory Chief of translational research: Silvana Pilotti, MD Researchers: Elena Tamborini, Biol Sci D, Federica Perrone, Biol Sci D, Tiziana Negri, Biol Sci D, Fabio Bozzi, Biol Sci D., Paolo Dagrada, Biol Sci D, Elena Conca, Biol Sci D Tos A.P., Pilotti S., Casali P.G.: Anthracycline-based chemotherapy in extraskeletal myxoid chondrosarcoma: a retrospective study. Clin Sarcoma Res 2013; 3(1): 16 Sanfilippo R., Casali P.G.: The intriguing patterns of tumor response to trabectedin. Expert Rev Anticancer Ther 2013; 13(6 Suppl 1): 21-24 Casali P.G.: Improving methodology to go beyond histology in rare cancers. Lancet Oncol 2013; 14(4): 276-277 Bozzi F., Manenti G., Conca E., Stacchiotti S., Messina A., Dagrada G., Gronchi A., Panizza P., Pierotti M.A., Tamborini E., Pilotti S.: Development of transplantable human chordoma xenograft for preclinical assessment of novel therapeutic strategies. Neuro Oncol 2013; 16(1):72-80 ASSOCIATED CLINICAL TRIALS Immunotherapy Laboratory Researchers: Marcella Tazzari, Biol Sci D, Chiara Castelli, Biol Sci D Phase II study on imatinib in combination with RAD001 in advanced chordoma. PET Unit. Response assessment: Flavio Crippa, MD A phase I/II study of sunitinib in young patients with advanced gastrointestinal stromal tumor (GISTs) Radiology Unit. Response assessment: Antonella Messina, MD, Carlo Morosi, MD SELECTED RECENT PUBLICATIONS Stacchiotti S., Tortoreto M., Bozzi F., Tamborini E., Morosi C., Messina A., Libertini M., Palassini E., Cominetti D., Negri T., Gronchi A., Pilotti S., Zaffaroni N., Casali P.G.: Dacarbazine in solitary fibrous tumor: a case series analysis and preclinical evidence vis-a-vis temozolomide and antiangiogenics. Clin Cancer Res 2013; 19(18): 5192-5201 Stacchiotti S., Tamborini E., Lo Vullo S., Bozzi F., Messina A., Morosi C., Casale A., Crippa F., Conca E., Negri T., Palassini E., Marrari A., Palmerini E., Mariani L., Gronchi A., Pilotti S., Casali P.G.: Phase II study on lapatinib in advanced EGFR-positive chordoma. Ann Oncol. 2013; 24(7): 1931-1936 Stacchiotti S., Dagrada G.P., Sanfilippo R., Negri T., Vittimberga I., Ferrari S., Grosso F., Apice G., Tricomi M., Colombo C., Gronchi A., Dei A phase II, open label study to evaluate the activity and safety of everolimus in association to imatinib in PDGFRA-D842V unresectable or metastatic gastrointestinal stromal tumors (GISTs) as first-line treatment. Localized high-risk soft tissue sarcomas of the extremities and trunk wall in adults: an integrating approach comprising standard vs. histotype-tailored neoadjuvant chemotherapy. Phase II randomized, non-comparative study on the activity of trabectedin or gemcitabine + docetaxel in metastatic or locally relapsed uterine leyomiosarcoma pre-treated with conventional chemotherapy. Osteosarcoma arising from atypical site: an observational Italian Sarcoma Group study. KEYWORDS Rare tumors, sarcoma, translational research, methodology 103 SCIENTIFIC REPORT 2013 back to contents .Francesco Raspagliesi. BIOMOLECULAR CHARACTERIZATION OF RARE HISTOLOGICAL TYPES OF OVARIAN CARCINOMA AND IMPLICATIONS FOR MEDICAL TREATMENT OF DISEASE OVERVIEW AND SCIENTIFIC GOALS Ovarian cancer is the second most common gynecologic malignancy and by far the most dreadful for its dismal prognosis. In fact, about 5000 women are diagnosed with ovarian cancer every year in Italy alone, and more than 3000 die from disease. The standard treatment for ovarian cancer is surgery followed by adjuvant chemotherapy with carboplatin and paclitaxel. This chemotherapeutic regimen was defined almost 20 years ago, and significantly improved patient survival compared to previous treatments. However, it is now clear that there are at least a few different subtypes of ovarian cancers that have different response rates to the carboplatin and paclitaxel combination. While high grade serous carcinoma, the most prevalent histologic type of ovarian cancer, has approximately 80% response rate to standard chemotherapy, other subtypes show limited to no response: low grade serous carcinoma has a response rate as low as 30%, mucinous and clear cells carcinomas 15%, small cells and Müllerian mixed carcinomas almost no response. These uncommon malignancies account for less than 20% of ovarian epithelial cancers, among which small cell carcinomas and Müllerian mixed carcinomas are extremely infrequent. Interestingly, these rare histotypes have morphologically similar, almost identical, counterparts in cancers arising in different organs, such as small cell carcinomas in the lungs or clear cell carcinomas in the colon, thus suggesting that they are biologically related diseases despite affecting different organs. While the research on biomolecular profiling of high-grade serous ovarian cancer has progressed in recent years, very little has been done towards characterization of more rare subtypes. The purpose of this project is to define the molecular profile of rare ovarian malignancies. Thus, we will analyze all available cases of these diseases treated at our Institution within the past 10 years. They will be examined for gene expression and miRNA expression profiles by microarray technology. We will also compare their profiles to those of identical histotypes affecting other organs, in particular for the most uncommon histotypes. 104 research activity PROGRAM HIGHLIGHTS Rare ovarian carcinoma histotypes are overshadowed by the most prevalent high grade serous ovarian carcinoma. In fact, they account for the majority of standard therapy failures. To date, no effective treatment is available for these diseases. Because these cancer subtypes are characterized by limited to no response to chemotherapy and poor prognosis, this study addresses a compelling area of research. The lack of understanding of their biology constitutes an additional impediment toward the definition of a specific therapy. Our study will shed light on the biomolecular profiles of these diseases. Indeed, it has been shown that gene expression profiles are predictive of response to chemotherapy, particularly to platinum based compounds. The comparison between their profile and those from similar malignant histotypes in other organs will help in identifying effective treatments, as identical cell types may exhibit similar responses to specific chemotherapies regardless of the organ of origin. Any advances in this field, even the simple identification of a more effective chemotherapy among those available, will greatly impact not only survival of patients with specific subtypes, but potentially the overall prognosis of ovarian cancer PROGRAM MEMBERSHIP Raspagliesi Francesco: MD, Principal Investigator of this project. He is the Director of the Gynecologic Oncology Unit. He has internationally recognized leadership in treatment of gynecologic malignancies and application of innovative approaches. He will coordinate the project and oversee the execution of each step of the research. Mezzanzanica Delia: Biologist, Staff Member Head of Molecular Therapies Unit with long-term experience in biochemistry, cellular and molecular biology and translational researches applied to ovarian cancer. She is the Multicenter Italian Trials in Ovarian Cancer (MITO) translational representative at the international level (GCIG, ENGOT). She will contribute in the coordination of laboratory activities related to the project. Agoni Lorenzo: MD, PhD, Gynecologic Oncologist with extensive laboratory experience, particularly in cellular and molecular oncology and translational research. He will be involved in molecular and clinical data integration analysis from bioinformatic and statistical perspectives. Canevari S., Raspagliesi F., Lorusso D.: Bevacizumab treatment and quality of life in advanced ovarian cancer. Future Oncol 2013; 9(7): 951-954 Raspagliesi F., Ditto A., Martinelli F., Haeusler E., Lorusso D.: Advanced ovarian cancer: omental bursa, lesser omentum, celiac, portal and triad nodes spread as cause of inaccurate evaluation of residual tumor. Gynecol Oncol 2013; 129(1): 92-96 Ferrandina G., Salutari V., Vincenzi B., Marinaccio M., Naglieri E., Loizzi V., Carpano S., Amadio G., Tonini G., Scambia G., Lorusso D.: Trabectedin as single agent in the salvage treatment of heavily treated ovarian cancer patients: a retrospective, multicenter study. Gynecol Oncol 2013; 130(3): 505-510 KEYWORDS Ovarian cancer, rare disease, gene expression, chemotherapy. SELECTED RECENT PUBLICATIONS Lorusso D., Cirillo F., Mancini M., Spatti G.B., Grijuela B., Ditto A., Raspagliesi F.: The different impact of BRCA mutations on the survival of epithelial ovarian cancer patients: a retrospective single-center experience. Oncology 2013; 85(2): 122-127 105 SCIENTIFIC REPORT 2013 back to contents .Ugo Pastorino. EARLY DIAGNOSIS OF LUNG CARCINOMA AND EFFICACY OF PLASMA miRNAS AS FIRST-LINE TESTS OVERVIEW AND SCIENTIFIC GOALS Three decades of research have shown that radiological screening of heavy smokers can detect resectable early lung cancers with higher frequency, although the benefits on mortality are still debated. The preliminary results of the first two randomized spiral-CT screening trials appear conflicting, with one study showing no benefit and the other a limited mortality reduction (-7%). In the next 3-4 years, ongoing randomized trials in Europe will provide conclusive data on the efficacy of CT-screening for lung cancer. Nonetheless, no major impact on mortality is to be expected. A possible explanation of these findings is that not all aggressive lung tumors arise from identifiable slow-growing precursors, thus suggesting a possible paradigm shift in our understanding of the natural history of lung cancer. In this respect, the identification of biologic and molecular features of indolent and aggressive disease could be useful to define clinical predictors of high-risk lesions and select suitable cohorts of patients who might benefit from current treatments as well as to identify genetic signatures that might represent novel therapeutic targets. We recently reported that miRNA expression profiles in tumors and in normal lung tissue are indicative of aggressive lung cancer development, and that specific miRNA signatures can be identified in plasma samples of patients up to two years before spiral-CT detection of disease. They are also able to identify the occurrence of early metastatic, but spiral-CT undetectable, lung tumors or small spiral-CT detected lesions with aggressive potential. Our study is divided in different phases: i) analysis of 1000 plasma samples of disease-free smokers already collected in our biological repository during the last two years; ii) enrollment of 4000 smoking volunteers, collection of their blood samples, and enrolment in a program of active surveillance on the basis of their miRNA risk profile; iii) assessment of miRNA expression profile using a custom-made microfluidic card containing the 24 miRNAs previously identified in diagnostic signatures; iv) bioinformatic analyses of miRNA ratios in the cohort to determine which individuals are have or will develop lung cancer, and in particular the aggressive form of the disease; v) assessment of the best diagnostic and treatment algorithm for subjects with suspicious miRNA profiles; vi) functional validation of miRNAs as novel therapeutic targets using novel cellular genetically engineered models of transformation and tumor graft models. The study started recruiting volunteers on January 2013. By the end of 2013, 1016 subjects have been recruited. Overall, the results of this large prospective study will permit establishing the potential of our plasma microRNA assay as a first-line screening test for lung cancer detection in routine clinical practice for high-risk population screening with a low cost, non-toxic, and non-invasive procedure. 106 research activity PROGRAM HIGHLIGHTS For early diagnosis, it is necessary to find non-invasive cancer biomarkers to monitor molecular differences in tumors, which may assist in the selection of the best possible treatment for individual cancer patients. The cancer biomarkers so far identified in clinical use, such as carcinoembryonic antigen (CEA) for colon cancer, alpha-fetoprotein (AFP) associated with HCC and prostate specific antigen (PSA) in prostate cancer, have limitations with respect to their use for screening owing to low sensitivity and specificity in early stages and inability to distinguish aggressive from indolent tumors. Other common cancers, such as lung cancer, lack established biomarkers with demonstrated clinical utility in a screening setting. Thus, there is a need for biomarkers with the required sensitivity and specificity for the detection of lung cancer . Most serum and plasma biomarker studies in lung cancer have so far involved analyses of quite small number of samples, most in retrospective series, and there is a need to prospectively analyze circulating biomarkers in the context of prospective clinical trials. The challenge for the next decade will be to bring biomarkers to the clinic in ways that are efficient and practical. This proposal represents an effort to design and implement a validation study with clear pragmatic outcomes that can be expeditiously translated to clinical use. The prospective spiral-CT screening trials conducted so far did not include biomarkers analyses in their diagnostic algorithm. The innovative aspect of the present proposal is to apply profiling of circulating miRNA in plasma to a large prospective group of heavy smokers of a screening trial. Our study will enroll a large number of smoker volunteers who will undergo baseline chest CT examination, blood collection and plasma miRNA profiling. For the first time, the assessment of the best diagnostic and treatment algorithm will be based on plasma miRNA profile. We will apply a 3 tier classifier based on the accuracy (sensitivity and specificity) observed in an extended validation of our previously published findings. These results suggest that miRNA signatures are robust enough to make potentially impactful clinical decisions in the proposed prospective clinical trial. We believe that plasma miRNA profiling could represent an innovative tool to obtain early diagnosis and have an impact on mortality. Considering the failures of previous several attempts at achieving early diagnosis and any substantial reduction in mortality of lung cancer patients, it may represent a useful tool to screen smokers. Our study will help to address these issues. This project represents a unique attempt to integrate biomarkers in a clinical application such as screening and treatment of lung cancer and exemplifies an effort to bring basic discoveries to the clinic involving collaboration across disciplines. PROGRAM MEMBERSHIP Ugo Pastorino, Principal Investigator, MD, Head of Thoracic Surgery Unit. Coordination of clinical and experimental team and evaluation of results. Design, clinical management and evaluation of diagnostic algorithm for tumors detected on the basis of biomarker profiles. Assessment of sensitivity, specificity, and clinical value of miRNA signatures, impact on cure rates and mortality, frequency of false negative and false positive results, and clinical implications. Gabriella Sozzi, BiolScD, Head of Tumor Genomics Unit. Coordination of research team and evaluation of results. Direct participation in the development and analyses of biomarkers in plasma, thanks to her expertise in biomarkers. Interaction with lung clinicians and statisticians to coordinate biological sampling, planning statistical analyses, and critically discussing the results. Alfonso Marchianò, Radiologist, Director of Radiodiagnostics Department. Responsible for the radiological protocol. Giuseppina Calareso, Mario Silva, Radiologists. CT scan evaluations. Interaction with surgical and experimental team to discuss the results. Mattia Boeri, PhD, Biol ScD. Analyses of miRNA signatures in plasma samples, functional validation of miRNAs as novel therapeutic targets. Bioinformatic analyses of miRNA profiling in plasma, coordination of the miRNA functional studies in vitro and in vivo. Massimo Moro, BiolScD. Tumor graft harvesting from primary tumors, serial maintenance of tumor grafts in vivo, involvement in biological and functional studies and for testing combinations of new therapeutic agents. Paola Suatoni, BiolScD. Collection of blood samples from the enrolled volunteers, separation of plasma samples, harvesting and storage of plasma aliquots. Maintenance of the database. Extraction of RNAs from plasma samples and performing multiplex-RT-PCR reactions. Carla Verri, BiolScD. Collaboration in miRNA expression analyses, using microfluidic cards and q-real time PCR. Davide Conte, Lab tech. Collaboration in the banking of the biological specimen and mRNA extractions, RT-PCR and pre-amplification phases of the miRNA assay, analyses of plasma. Carlo La Vecchia, Epidemiologist. Design of clinical and experimental database. Statistical analyses of experimental and clinical data. Assessment of sensitivity, specificity and clinical value of blood tests. Effect of miRNA analysis on lung cancer survival, and mortality of screened population. Carlotta Galeone, Statistician. Contribution of database design and quality control. Statistical analysis of experimental and clinical data. Claudio Jacomelli, Informatics Consultant. Executive Data management. Annamaria Calanca and Carolina Ninni, Secretary of the Project, enrollment of volunteers and manage of visits, data entry. Elena Bertocchi, Scientific Secretariat. Project coordination and data management. SELECTED RECENT PUBLICATIONS Pastorino U., Sverzellati N.: Lung cancer: CT screening for lung cancerdo we have an answer? Nat Rev Clin Oncol 2013; 10(12): 672-673 Pastorino U.: Current status of lung cancer screening. Thorac Surg Clin 2013; 23(2): 129-140 Silva M., Sverzellati N., Manna C., Negrini G., Marchianò A., Zompatori M., Rossi C., Pastorino U.: Long-term surveillance of ground-glass nodules: evidence from the MILD trial. J Thorac Oncol. 2012; 7(10): 1541-1546 ASSOCIATED CLINICAL TRIALS BIOMILD - Prot INT 11/21 MILD – Prot INT 05/53 SELECTED RECENT MAJOR GRANTS Italian Association for Cancer Research IG UP11991 Italian Ministry of Health – Finalized Research Program KEYWORDS Lung cancer, screening, clinical trials, microRNA, biomarkers 107 back to contents SCIENTIFIC REPORT 2013 PEDIATRIC CANCER COORDINATOR: Maura Massimino Studies of childhood tumors aimed at improving prognosis and reducing adverse treatment effects; studies focused on the prevention, early diagnosis and management of long-term cancer- and treatment-induced effects; when cure is no longer possible, focus on support for patients and family to ensure they are not abandoned but supported (through control of physical and psychological symptoms) and accompanied along the terminal phase of the disease. AIMS: Integrating longer survival and improved quality of life. For the most important childhood tumors (neuroblastoma, Wilms’ tumor, Ewing’s sarcoma), studies will seek to identify new therapeutic targets and thereby new approaches to biological drugs, as well as assessing iatrogenic sequelae with respect to thyroid, cardiac, pulmonary and gonadal function in long-term cancer survivors. PROJECTS • Tumors of the central nervous system (Maura Massimino) • Adolescents with cancer in Italy: from local projects to a National coordinated program (Andrea Ferrari) • Genetic and biomolecular characterization of Wilms’ tumor and detection of predictive markers of poor prognosis (Daniela Perotti) • Introduction of new drugs in the treatment of pediatric cancer (Michela Casanova) 108 research activity .Maura Massimino. TUMORS OF THE CENTRAL NERVOUS SYSTEM OVERVIEW AND SCIENTIFIC GOALS CNS neoplasms are the leading cause of cancer death in children. The incidence is 2.4 cases per 100,000 per year, with approximately 450 new cases in Italy. While high-grade malignant astrocytomas (WHO grade III and IV, WHO) are prevalent in adult histologies, in pediatric patients low-grade gliomas and embryonic tumors (PNET and medulloblastoma) outweigh other histotypes, which represent, respectively, 50% and 20% of brain tumors under the age of 15 years. The signs and symptoms by which a tumor of the CNS occurs should not be underestimated either by the physician, parents or teachers in order to allow a prompt diagnosis and suitable therapy. In fact, at present, more than half of children who are diagnosed with a brain tumor have a chance for cure and become an adult, but the price of healing is often high in terms of sequelae in terms of neuro-cognitive deficits and endocrine, metabolic and somatic growth. Aspects of prevention, rehabilitation and correction of these deficits are thus an integral part of the treatment plan for these children. For some histologies or presentations of disease (i.e. in the first case: the atypical rhabdoid tumor and, in the second case, the intrinsic neoplasms of pons-DIPG) or relapse of the disease, however, the chances of recovery are still an open challenge and treatment with new drugs or combinations of drugs with biological and molecular represent the focus of future therapies. The aims of our activity include to launch new therapeutic clinical protocols for diseases where a treatment standard already exists (medulloblastoma and ependymoma in the European context), experimental strategies in disease with poor prognosis (DIPG, glioblastoma), evaluation of surrogate biochemical markers to understand disease nature and history in those tumors where biopsy is not common or probably not definitely descriptive of tumor heterogeneity as in DIPG, and evaluation of longterm effects in cured patients through novels bio-engineering tools. PROGRAM HIGHLIGHTS Medulloblastoma (MBL) with no residual post-surgery, without metastasis and without biological risk factors (anaplastic / large cell, amplification of myc). The academic protocol for standard risk MBL medulloblastoma for which our center is the national coordinator within the SIOP (International Society of Pediatric Oncology) has already passed the stage of approval AIFA and the Ethics Committee of the INT. Once awarded the contract by the University of Hamburg, we will provide activation in other centers. MBL at relapse. The phase 3 randomized protocol with the inhibitor of the pathway sonic hedgehog - LDE225 was opened. The results of steps 1 and 2 have already been presented in international conference venues. Metastatic MBL. Ongoing debate at the European level in relation to the establishment of the protocol. The basis on which this Protocol is built, however, are the results with the strategy published by us in the Journal of Clinical Oncology in 2009. Ependymoma. Similar stage as for the protocol of medulloblastoma. It obtained the approval of the AIFA and procedures should start at the ethics committees. Our center is also the national coordinator for this protocol. Malignant gliomas. Our center, coordinator for Italy of the Protocol, which includes the randomization of temozolomide and radiotherapy versus radiotherapy, temozolomide + bevacizumab. Eight patients have been enrolled so far and ours is the center with the largest recruitment compared with 81 activated centers around the world including Canada and Australia. A futility report should be made available shortly.) 109 back to contents SCIENTIFIC REPORT 2013 PROGRAM MEMBERSHIP Veronica Biassoni, Clinical researcher, responsible for Italy of the DIPG network Elisabetta Schiavello, Clinical researcher Lorenza Gandola, Senior pediatric radiotherapist Emilia Pecori, Junior pediatric radiotherapist Emanuele Pignoli, Senior physicist Fulvia Gariboldi, Rehabilitation physician Alfonso Marchiano, Senior radiologist and coordinator of pediatric diagnostics Modena P., Buttarelli F.R., Miceli R., Piccinin E., Baldi C., Antonelli M., Morra I., Lauriola L., Di Rocco C., Garrè M.L., Sardi I., Genitori L., Maestro R., Gandola L., Facchinetti F., Collini P., Sozzi G., Giangaspero F., Massimino M.: Predictors of outcome in an AIEOP series of childhood ependymomas: a multifactorial analysis. Neuro Oncol 2012; 14(11): 1346-1356 Sardi I., la Marca G., Cardellicchio S., Giunti L., Malvagia S., Genitori L., Massimino M., de Martino M., Giovannini M.G.: Pharmacological modulation of blood-brain barrier increases permeability of doxorubicin into the rat brain. Am J Cancer Res 2013; 3(4): 424-432 ASSOCIATED CLINICAL TRIALS Randomized trial for pediatric malignant glioma (Herby) SELECTED RECENT PUBLICATIONS Ependymoma 2nd AIEOP trial Massimino M., Antonelli M., Gandola L., Miceli R., Pollo B., Biassoni V., Schiavello E., Buttarelli F.R., Spreafico F., Collini P., Giangaspero F.: Histological variants of medulloblastoma are the most powerful clinical prognostic indicators. Pediatr Blood Cancer 2013; 60(2): 210-216 Nimotuzumab, vinorelbine and radiotherapy for DIPG, Massimino M., Casanova M., Polastri D., Biassoni V., Modena P., Pecori E., Schiavello E., De Pava M.V., Indini A., Rampini P., Bauer D., Catania S., Podda M., Gandola L.: Relapse in medulloblastoma: what can be done after abandoning high-dose chemotherapy? A mono-institutional experience. Childs Nerv Syst 2013 Apr 18 Massimino M., Gandola L., Biassoni V., Spreafico F., Schiavello E., Poggi G., Pecori E., Vajna De Pava M., Modena P., Antonelli M., Giangaspero F.: Evolving of therapeutic strategies for CNS-PNET. Pediatr Blood Cancer 2013; 60(12): 2031-2035 Tensor imaging evaluation of focally irradiated children SELECTED RECENT MAJOR GRANTS AIRC grant 2012-2014 Lombardy Region Grant 2011-2013 for Diffuse Tensor imaging evaluation (co-responsible, PI Geraldina Poggi in IRCCS Eugenio Medea, Bosisio Parini) Grants by patient charities: Associazione Bianca Garavaglia, Fondo di Gio KEYWORDS Childhood brain tumors, prognosis improvement, marker surrogate, late-effects decrease Figure: Images from: Pediatr Blood Cancer, 2013. Histological Variants of Medulloblastoma Are the Most Powerful Clinical Prognostic Indicators. 110 research activity .Andrea Ferrari. ADOLESCENTS WITH CANCER IN ITALY: FROM LOCAL PROJECTS TO A NATIONAL COORDINATED PROGRAM OVERVIEW AND SCIENTIFIC GOALS Adolescents with cancer are a unique group, with special characteristics. Patients in this age group seem to inhabit a “no man’s land”, belonging neither to the pediatric nor to the adult worlds of oncology. Their optimal management (e.g. coping with their complex psychological and social needs, providing age-appropriate facilities, and their inclusion in clinical trials) remains a challenge that requires broad-based processes. In particular, a lack of improvement in survival rates compared to other age groups has been reported, and survival rates of adolescents are poorer than those of children with the same disease, partially due to differences in biology but also to treatment delivered (limited access to optimal cancer services and low accrual to clinical trials). The Youth Project of the Pediatric Oncology Unit at the INT in Milan was launched in 2011, as a dedicated program within the pediatric oncology unit (with no any upper age limit for admitting patients with pediatric cancers to the pediatric unit) focusing on clinical aspects (e.g. inclusion in clinical trials, psycho-social support, fertility preserving facilities), but also with the view of creating dedicated multifunctional spaces and special events. Thereafter, the Youth Project group leaded the Committee on Adolescents of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP), which successively evolved from a pediatric oncology-based Committee to a comprehensive national broad task force dedicated to adolescents and also to young adults, involving various stakeholders and in particular the adult oncology scientific societies: a new society has been created, called SIAMO (Società Italiana Adolescenti con Malattie Onco-ematologiche - Italian Society for Adolescents with Onco-hematological Diseases), which should be the official structure to achieve the support from the National Health Service and other organizations. 111 back to contents SCIENTIFIC REPORT 2013 PROGRAM HIGHLIGHTS Youth Project of the Pediatric Oncology Unit at the INT in Milan (www.ilprogettogiovani.it) •A new model of specific culture, with the challenge to deal not only with disease, but with the life of patients, and their normality, creativity, and strength •Developed within the pediatric oncology unit, as an offshoot of our existing activities, without requiring major changes to organization or new professional staff •Double objective: 1) to improve and standardize clinical aspects (e.g. inclusion in clinical trials, psycho-social support, school and job support, fertility preserving facilities, access to care after cancer therapy), 2) to make the hospital a special place for our teenagers, by creating dedicated multifunctional spaces (including a 30 m2 gym) and special activities, events, and courses (e.g. arts, photography, music, new technologies), involving various professionals working with the patients: in particular, B.LIVE, the stylist collection and the fashion parade (2012 project), the song Clouds of Oxygen (2013 project), sport (hospital & outdoor activities, e.g. sailing). •A project on public information using new technologies easily accessible for teenagers (e.g. YouTube) has been developed with the aim to reduce the delay in diagnosis often observed in adolescents and young adults (www.infoadolescentietumori.it) SIAMO - Società Italiana Adolescenti con Malattie Onco-ematologiche (www.progettosiamo.it) •A comprehensive national program dedicated to adolescents (and young adults) with cancer. For the first time, the pediatric cooperative group Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) and the Federation of Parent Associations for pediatric onco-hematology (Federazione Italiana Associazioni Genitori Oncoematologia Pediatrica - FIAGOP) joins the adult cooperative groups Associazione Italiana di Oncologia Medica (AIOM) and Società Italiana di Ematologia (SIE) •SIAMO moves from a pediatric oncology-based committee on adolescents to a forward-thinking national broad-based task-force dedicated to adolescents and young adults, and wants to represent the official structure to achieve the support from national health service organizations and governments. •SIAMO involves not only physicians (from both the pediatric and the adult medical oncology world), but also various stakeholders such as nurse groups, psychologists, social workers, advocacy organizations, and survivor groups. •SIAMO wants to definitely face up to the strong necessity to bridge the gap in the quality of professional care for adolescents with cancer. This is the major challenge, and requires broad-based schemes able to involve the public and its awareness, healthcare providers, cooperative groups running clinical trials, university, and also the national government. •SIAMO wants to cooperate with the other international specific groups, starting from the European Network for Teenagers and Young Adults with Cancer (ENTYAC). PROGRAM MEMBERSHIP Andrea Ferrari, Responsible of the Youth Project and coordinator of Italian society SIAMO Maura Massimino, Director of the Pediatric Oncology Unit Carlo Alfredo Clerici, Psychologist Laura Veneroni, Psychologist dedicated to adolescents Monica Terenziani, Responsible for the Fertility Program Filippo Spreafico, Responsible for the Sport Project SELECTED RECENT PUBLICATIONS Ferrari A., Bleyer A.: Participation of adolescents with cancer in clinical trials. Cancer Treatement Review 2007; 33(7): 603-608 Ferrari A., Clerici C.A., Casanova M., et al.: The Youth Project at the Istituto Nazionale Tumori in Milan. Tumori 2012; 98(4): 399-407 Ferrari A., Dama E., Pession A., et al.: Adolescents with cancer in Italy: entry into the national cooperative pediatric oncology group AIEOP trials. Eur J Cancer 2009; 45(3): 328-334 112 Ferrari A., Thomas D.M., Franklin A., et al.: Starting an AYA program: some success stories and some obstacles to overcome. J Clin Oncol 2010; 28: 4850-4857 Ferrari A.: The challenge of access to care for adolescents with cancer in Italy: national and local pediatric oncology programs. International Perspectives on AYAO, Part 2. Journal of Adolescent and Young Adult Oncology 2013; 2(3): 112-117 SELECTED RECENT MAJOR GRANTS Financial support is provided by the Associazione Bianca Garavaglia and the Near/Magica Cleme Foundation. KEYWORDS Adolescents, young adults, access to care, national program. research activity .Daniela Perotti.... .Filippo Spreafico. GENETIC AND BIOMOLECULAR CHARACTERIZATION OF WILMS TUMOR AND DETECTION OF PREDICTIVE MARKERS OF POOR PROGNOSIS OVERVIEW AND SCIENTIFIC GOALS Wilms tumor (WT) is a pediatric renal malignancy characterized by a high degree of histological and genetic heterogeneity. While most WTs are sporadic, familial cases have also been described. In addition, approximately 5% of WTs are associated with syndromic conditions. At present, the genetic factors responsible for WT predisposition and development have been elucidated only in part. One of the difficulties in the study of WT is represented by the substantial lack of reliable models of the genesis of this disease. However, a strategy allowing the propagation of primary WTs in vivo has recently been developed (Shakked et al. EMBO Mol Med 2012, 4:1-20) that warrants more comprehensive investigations on WT-derived cells. Overall, WTs display good prognosis and, thanks to a multimodal clinical approach, the 5-year overall survival rate approaches 90%. However, a survival rate <50% is expected in patients who relapse. In addition, a significant proportion of long-term survivors suffer from severe late therapy-related complications. At present, validated risk factors in use for therapeutic stratification are tumor stage and diffuse anaplasia. Studies aimed at identifying genetic factors predictive of adverse prognosis have revealed that loss of heterozygosity (LOH) at chromosomes 1p and 16q occur more frequent in WTs of relapsing cases, although the relative low incidence of 1p/16q losses renders their predictive value relatively low. Gain of chromosome 1q has also been reported as an adverse prognostic factor by several groups, but this finding needs prospective validation. Global gene expression analyses of WTs reported to date have failed to identify a molecular signature related to prognosis. Specific aims of this research program are: 1. Identify genes involved in hereditary susceptibility to WT by massive parallel DNA sequencing. 2. Identify and validate genetic signatures predictive of poor prognosis by genome wide approaches, including single nucleotide polymorphisms (SNPs), gene expression, and miRNA profiling. 3. Verify the accuracy of selected genetic markers in predicting the clinical outcome of WT patients. 4.Obtain WT-derived cell cultures as models recapitulating the disease. Prospective studies and investigations addressing the molecular pathways leading to relapsing disease will be performed by engrafting fresh minced WTs into mice and, following serial passages, by recovering single cell suspensions maintaining both in vivo tumor expansion and in vitro differentiating capabilities. 5.To study functional aspects, relevant to WT, of genes and non-coding RNA misexpressed in tumor specimens. Moreover, as WTs are of embryonic origin, cancer and kidney-derived cell lines will be exploited as read-out models for the study of genes/miRNAs depletion or induction to assess their role on cell morphology and transcriptional regulation of early developmental genes. 113 back to contents SCIENTIFIC REPORT 2013 PROGRAM HIGHLIGHTS 1.Genome-wide gene expression analysis comparing favorable histology WTs from relapsing and non-relapsing patients has been performed in collaboration with the Functional Genomics service. Approximately 700 differentially expressed genes and 20 miRNAs were identified as significantly associated with relapse. Strikingly, mRNA levels of genes expressed in the early stages of kidney development and in the blastemal component of WT tissues were found to be reduced in specimens from relapsing compared to non-relapsing patients. Moreover, the embryonic stem cell (ESC)-like signature, characterizing cancer-initiating cells, appeared to be frequently lost in relapsing WTs. Conversely, in these tumors an increase in the level of transcripts of genes associated with more differentiating steps of kidney organogenesis was observed. The set of genes whose expression was found to be predictive of poor prognosis included SPP1, MAOA, MUC1, CLDN1, and MYC. Further investigations on additional WT samples are necessary to verify the prognostic significance of markers emerging from these studies, and to help stratifying WT patients for risk of relapse thus allowing tailored therapeutic regimens. 2.A total of 125 unilateral favorable histology WTs registered between 2003 and 2008 in the Italian cooperative clinical protocol were examined at microsatellite markers mapping to chromosomes 1p, 7p, 11q, 16q, and 22q. In line with previous findings, loss of heterozygosity (LOH) at 1p was significantly associated with a worse disease-free survival (probability 0.67 for patients with and 0.92 for those without 1p LOH, p = 0.0009), as confirmed by multivariate analysis adjusting for tumor stage and patient age at diagnosis. There was no difference in disease-free survival probability among children with LOH in the other chromosomal regions tested. The worse outlook for children older than 2 years at diagnosis did not seem to be influenced by the LOH patterns considered (Spreafico et al., J Urol. 2013;189:260-266). 3.A family with two cases of WT, the mother and her son, was investigated molecularly. A previously unreported frameshift mutation of the WT1 gene, c.983delC (p.P328QfsX53) causing the loss of the C-terminal of the protein, was detected in both affected family members. This WT pedigree adds to the few already reported in which a role of WT1 mutations has been established (Melchionda et al., Pediatr Blood Cancer. 2013;60:1388-9). 4.A pediatric renal tumor tissue bank has been established with approximately 500 cases from multiple centers throughout Italy to date, with matched clinical and histological data, to support biological studies. PROGRAM MEMBERSHIP Daniela Perotti Research staff scientist - ‘Molecular bases of genetic risk and genetic testing’ Research Unit, Department of Preventive and Predictive Medicine. Molecular biologist, involved in the molecular characterization of WT, coresponsible for biological studies of the National Clinical Protocol on WT. Filippo Spreafico Staff clinician – Pediatric Oncology Unit, Department of Hematology and Pediatric Onco-Hematology. Chair of the National Clinical Protocol on pediatric renal tumors. Antonio Fiorino Associated researcher - ‘Molecular bases of genetic risk and genetic testing’ Research Unit, Department of Preventive and Predictive Medicine. Cellular and molecular biologist, involved in functional studies on WT. Paola Collini Staff clinician - Anatomic Pathology Unit, Department of Pathology and Laboratory Medicine. Pathologist reviewing histological diagnoses within the National Clinical Protocol on WT. Paolo Radice Head of ‘Molecular bases of genetic risk and genetic testing’ Research Unit, Department of Preventive and Predictive Medicine. Expert in cancer genetics. SELECTED RECENT PUBLICATIONS Spreafico F., Gamba B., Mariani L., Collini P., D’Angelo P., Pession A., Di Cataldo A., Indolfi P., Nantron M., Terenziani M., Morosi C., Radice P., Perotti D.; AIEOP Wilms Tumor Working Group: Loss of heterozygosity analysis at different chromosome regions in Wilms 114 tumor confirms 1p allelic loss as a marker of worse prognosis: a study from the Italian Association of Pediatric Hematology and Oncology. J Urol 2013; 189(1): 260-266 Melchionda F., Spreafico F., Ciceri S., Lima M., Collini P., Pession A., Massimino M., Radice P., Perotti D.: A novel WT1 mutation in familial Wilms tumor. Pediatr Blood Cancer 2013; 60(8): 1388-1389 Calvello M., Tabano S., Colapietro P., Maitz S., Pansa A., Augello C., Lalatta F., Gentilin B., Spreafico F., Calzari L., Perotti D., Larizza L., Russo S., Selicorni A., Sirchia S.M., Miozzo M.: Quantitative DNA methylation analysis improves epigenotype-phenotype correlations in BeckwithWiedemann syndrome. Epigenetics 2013; 8(10): 1053-1060 Perotti D., Hohenstein P., Bongarzone I., Maschietto M., Weeks M., Radice P., Pritchard-Jones K.: Is Wilms tumor a candidate neoplasia for treatment with WNT/β-catenin pathway modulators? A report from the renal tumors biology-driven drug development workshop. Mol Cancer Ther 2013; 12(12): 2619-2627 ASSOCIATED CLINICAL TRIALS Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) 2003 WT Diagnostic and Therapeutic Protocol (AIEOP-TW-2003) SELECTED RECENT MAJOR GRANTS Associazione Bianca Garavaglia Project title: Bio-molecular characterization of Wilms tumor Principal investigators: Filippo Spreafico, Paolo Radice Duration: Jan 2012 – Dec 2014 KEYWORDS Wilms tumor, genetic markers, prognostic factors, functional studies research activity .Michela Casanova. NEW DRUGS IN PEDIATRIC ONCOLOGY OVERVIEW AND SCIENTIFIC GOALS Despite major progress in the past 40 years, 20% of children with cancer die from their disease, and 40% of survivors have late adverse effects. Cancer remains the most common fatal disease of childhood. The improvements in cure rates seems to have slowed down during the past decade, probably because we have reached the level where it is difficult to further improve outcomes with currently available treatment. Innovative, safe, and effective medicines are urgently needed. More than 100 drugs are approved by for the treatment of malignancies, and among these about 30 are currently used in pediatric oncology and only 15 have been labeled for use in children. Possible reasons for the disparity between adult and pediatric drug approvals include the relative rarity of childhood malignancies, the histopathologic and biologic differences between many adult and pediatric tumors, and the limited number of pediatric patients eligible for pharmaceutical trials. Although regulatory initiatives in the past 15 years in the USA and Europe have been introduced, new drug development for children with cancer remains insufficient. Many pharmaceutical companies consider the adult population as their key market, and the development of a drug for pediatric use only or primarily is done to comply with regulatory obligations. Most children with cancer are still largely denied access to innovative drugs in Europe. In 2003, a European academic Network (42 academic institutions in 9 European countries) was created to properly address pediatric drug development; ITCC (Innovative Therapies for Children with Cancer) consortium was established through institutional resources, developing partnerships, collaboration, and clinical and biological research projects. This shows the clear commitment of all partners to work together, to combine expertise and strength, and to create a critical mass that is well integrated in the European pediatric oncology research area. Within this European Network (ITCC Consortium), our Institution is the most active center in Italy and recognized internationally. The main objective of the project is to increase preclinical and early clinical evaluation of new drugs in children and adolescents with cancer, with the final aim to increase the number of patients being cured and improve the quality of cure. Pediatric-specific needs include: •Increased knowledge on the pharmacology in pediatric patients (especially in the very young) in order to improve dosing, tolerance and efficacy • Age-appropriate formulations • Evaluation of long-term sequelae in survivors following the use of new drugs. 115 back to contents SCIENTIFIC REPORT 2013 PROGRAM HIGHLIGHTS Thanks to the collaboration with ITCC, the number of clinical trials with innovative drugs was significantly implemented and several phase I – first in children - studies have been opened recently. In most of the ongoing studies, our Institution plays a pivotal role; it is the only Italian center selected for participation, and in others it acts as coordinating center. As an example, in 2011 we started the phase I- first in children - of LDE225, an oral, potent and selective inhibitor of Smo, a key positive regulator of Hedgehog signaling ; it was a dose-escalation study to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug in children with recurrent or refractory medulloblastoma, or other tumors potentially dependent on Hedgehog (Hh) signaling pathway. At that time, our institution was the only Italian center open for accrual. The drug went subsequently entered in phase 2 at is now in phase 3 in patients with recurrent/ refractory medulloblastoma. In the phase 3 study, only patients with activated Hh-pathway are included, who are identified on the basis of a 5-gene signature defined during the phase 1/2 study. Our institution is the coordinating center for Italy, which is currently the country with the highest enrollment. The results of the phase 1/2 studies, already presented in several meetings, will be published soon. Also in the ongoing phase I – first in children – trail on LDK378, a selective inhibitor of ALK, our Institution is the only open center in Italy. Thanks to the positive interaction with the manufacturer, we also received the compound for preclinical evaluation. In vitro and in vivo experiments have been performed and are ongoing. PROGRAM MEMBERSHIP Michela Casanova, Responsible New Drug Project and member of the Clinical Trial Committee of ITCC Maura Massimino, Director of the SC Pediatria Oncologica Elena Barzanò, Trial Coordinator Carla Moscheo, Clinical Researcher Carlo Morosi, Senior Radiologist Paola Collini, Senior Pathologist Patrizia Piotti, Senior Cardiologist Gabriella Saibene, Senior Pharmacist Valentina Sinno, Clinical Trial Office SELECTED RECENT PUBLICATIONS Di Giannatale A., Dias-Gastellier N., Devos A., Mc Hugh K., Boubaker A., Courbon F., Verschuur A., Ducassoul S., Malekzadeh K., Casanova M., Amoroso L., Chastagner P., Zwaan C.M., Munzer C., Aerts I., Landman-Parker J., Riccardi R., Le Deley MC., Geoerger B., Rubie H.: Phase II study of temozolomide in combination with topotecan in relapsed or refractory neuroblastoma: A European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study. Eur J Cancer 2014; 50(1): 170-177 Zsiros J., Brugieres L., Brock P., Roebuck D., Maibach R., Zimmermann A., Childs M., Pariente D., Laithier V., Otte J.B., Branchereau S., Aronson D., Rangaswami A., Ronghe M., Casanova M., Sullivan M., Morland B., Czauderna P., Perilongo G.; International Childhood Liver Tumours Strategy Group (SIOPEL): Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm, feasibility study. Lancet Oncol 2013; 14: 834-842 Semeraro M., Branchereau S., Maibach R., Zsiros J., Casanova M., Brock P., Domerg C., Aronson D.C., Zimmermann A., Laithier V., Childs M., Roebuck D., Perilongo G., Czauderna P., Brugieres L.: Relapses in hepatoblastoma patients: Clinical characteristics and outcome-experience of the International Childhood Liver Tumour Strategy Group (SIOPEL). Eur J Cancer 2013; 49: 915-922 Zsíros J., Brugières L., Brock P., Roebuck D., Maibach R., Child M., Morland B., Casanova M., Pariente D., Paris C., de Camargo B., Ronghe M., Zimmermann A., Plaschkes J., Czauderna P., Perilongo G.: Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma - A phase II trial of the childhood liver tumour strategy group (SIOPEL). Eur J Cancer 2012; 48: 3456-3464 ASSOCIATED CLINICAL TRIALS Phase II open-label, randomized, multi-center comparative study of bevacizumab-based therapy in pediatric patients with newly diagnosed supratentorial high-grade glioma (Herby) Open-label, multi-center, randomized phase II study evaluating the addition of bevacizumab to chemotherapy for childhood and adolescent patients presenting with metastatic rhabdomyosarcoma and nonrhabdomyosarcoma soft tissue sarcoma (the Bernie study) International randomized phase II trial of the combination of vincristine and irinotecan with or without temozolomide (VI or VIT) in children and adults with refractory or relapsed rhabdomyosarcoma An open-label, multicenter, single-arm, phase I dose- escalation with efficacy tail extension study of RO5185426 in pediatric patients with surgically incurable and unresectable stage IIIc or stage IV melanoma harboring BRAFv600 mutations A phase I/II study of sunitinib in young patients with advanced gastrointestinal stromal tumor (GIST) A phase III, multi-center, open-label, randomized, controlled study of the efficacy and safety of oral LDE225 versus temozolomide in patients with HH-pathway activated relapsed medulloblastoma A phase I, open-label, dose escalation study of LDK378 in pediatric patients with malignancies that have a genetic alteration in anaplastic lymphoma kinase (ALK) A phase I/II, multicenter, open-label, dose-finding study to assess the safety, tolerability, and preliminary efficacy of weekly nab®-paclitaxel in pediatric patients with recurrent or refractory solid tumors Relapse in synovial sarcoma: What can be done for poor outcomes? Clinical Practice 2013; 10: 389-391 A phase III, randomized, double-blind, active comparator-controlled clinical trial, conducted under in-house blinding conditions, to examine the efficacy and safety of aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in pediatric patients. Massimino M., Casanova M., Polastri D., Biassoni V., Modena P., Pecori E., Schiavello E., De Pava M.V., Indini A., Rampini P., Bauer D., Catania S., Podda M., Gandola L.: Relapse in medulloblastoma: What can be done after abandoning high-dose chemotherapy? A mono-institutional experience. Childs Nerv System 2013; 29: 1107-1112 A phase I/II combined dose ranging and randomized, open-label comparative study of the efficacy and safety of plerixafor in addition to standard regimens for mobilization of hematopoietic stem cells into peripheral blood, and subsequent collection by apheresis, versus standard mobilization regimens alone in pediatric patients, aged 2 to <18 years, with solid tumors eligible for autologous transplants 116 research activity SELECTED RECENT MAJOR GRANTS Grant from the ROL (Rete Oncologica Lombarda) for the clinical management of the academic trial - International randomized phase II trial of the combination of vincristine and irinotecan with or without temozolomide (VI or VIT) in children and adults with refractory or relapsed rhabdomyosarcoma – as national sponsor and coordinating the activities of Italian centers Grants by patient Charities (Associazione Bianca Garavaglia) KEYWORDS New drugs, Phase I studies, Early phase II studies 117 back to contents SCIENTIFIC REPORT 2013 PATHWAYS OF RESEARCH/ INTERVENTION AND ASSESSMENT OF QUALITY OF LIFE IN PATIENTS WITH CANCER COORDINATOR: Martin Langer Therapeutic and scientific activities have traditionally characterized medical oncology, but concrete operational and human support for cancer patients is equally important at a time when the humanization of cancer treatment is among the main goals of the our Institute (as exemplified by the new hospice facility). Innovation in studies related to palliative care and rehabilitation is therefore fundamental. Palliative care has received increasing emphasis in recent years as a means to improve the treatment and quality of life of cancer patients. To further this goal, evidence from basic knowledge will have to find a place in clinical practice. With regard to oncological rehabilitation, information on the specific needs of patients with debilitating treatment sequelae is still incomplete. AIMS: Assessment of the delivery of analgesic therapy, symptom control and supportive care (infusion of blood products, parenteral nutrition, etc.). Design of questionnaires for comprehensive assessment of symptom and quality of life. Detection of markers potentially associated with the response to compassionate clinical treatment. PROJECTS • Assessment and management of symptoms and quality of life in cancer patients receiving palliative care (Augusto T. Caraceni) • Research and training for the physical, emotional, social and spiritual support of patients on active cancer treatment and their caregivers (Carla Ripamonti) • Development of algorithms for nutritional therapy in diseases at high risk of malnutrition (Cecilia Gavazzi) 118 research activity .Augusto T. Caraceni. ASSESSMENT AND MANAGEMENT OF SYMPTOMS AND QUALITY OF LIFE IN CANCER PATIENTS RECEIVING PALLIATIVE CARE OVERVIEW AND SCIENTIFIC GOALS The project was developed with the main clinical focus on improving clinical guidelines for pain, standardizing the assessment classification and treatment of cancer pain, understanding genetic and clinical determinants of opioid analgesia, and evaluating the impact of interventions on symptoms, quality of life, and quality of care at the end of life. These goals were developed in research performed in close collaboration with the European Palliative Care Research Network [Norwegian University of Science and Technology (NTNU)], the Mario Negri Institute, and a multicenter European project (EUROIMPACT). The European Association for Palliative Care (EAPC) recommendations on the use of opioid analgesics in cancer pain were coordinated by our group on behalf of EAPC, and were published in the Lancet Oncology in 2012.The update of the guidelines is ongoing in collaboration with several international groups, and will be continued during 2014 aiming at a new release by the end of 2015. In this new version, the guidelines will broaden their scope to include recommendations on pain assessment and classification, as well as pharmacological and non-pharmacological treatment strategies. Consistent with the content of these guidelines, different research lines were developed with the aim of improving and standardizing the definition of clinical aspects of cancer pain such as breakthrough pain and neuropathic pain, also using empirical data analysis. A Delphi consensus study has been carried out with the aim of adapting the IASP criteria for neuropathic pain assessment to the cancer pain patients. One PhD student based at our center and NTNU is presently dedicated to this part of the project. Another ongoing project is aimed at developing a software for diagnosis and treatment of cancer pain and other symptoms through an iPad device (EIR). Ongoing analgesic clinical trials include: a randomized, double-blind comparison between sublingual transmucosal fentanyl administration and subcutaneous morphine for the acute treatment of breakthrough pain, single center study, and participation in the CERP randomized open-label, multicenter trial (Mario Negri Institute, Milan) on comparison of four opioids for control of cancer pain. Other national and international collaborative participations include: a) participation in a randomized, multicenter cluster trial on the impact of the Liverpool Care Pathway on overall cancer care, funded by the Italian Ministry of Health; b) clinical trials on other symptoms control; c) epidemiological research on the definition of a palliative care population and end-of-life care (in supervising the EU FP7 project EUROIMPACT). 119 back to contents SCIENTIFIC REPORT 2013 PROGRAM HIGHLIGHTS The project is the result of close collaboration between the European Palliative Care Research Centre (PRC) and the Palliative Care, Pain Therapy, and Rehabilitation Unit. The primary aim of this international collaboration is to extend knowledge and gain new insight in prevalence, assessment, and treatment efficacy of the most frequent cancer-related symptoms, using clinical and basic research methods, and to further develop and consolidate a long-lasting international collaborative in palliative care cancer research. The collaboration will facilitate well defined companion studies and related projects, including the development of cancer pain guidelines and a computer based system to aid cancer pain assessment and treatment. In particular, the most recent achievements include the following: a) A study on the use of measurement tools for evaluation of cancer pain outcomes, emphasizing the use of 0 to 10 Likert scales and identify specific clinically significant endpoints, using data from a longitudinal prospective observational clinical trial on the use of opioids on 1461 patients. The study confirmed that pain ≤4 of 10 is a significant clinical endpoint. b)The importance of standardized definitions for neuropathic and breakthrough pain and their inclusion in guidelines is paramount, as demonstrated by our group in several international case series by applying specific tools such Pain Detect and addressing the concordance of clinicians in applying these clinical diagnoses. The clinical definition of neuropathic pain in cancer and its relationship with the International Association for the Study of Pain criteria was elaborated in an international panel of expert in preparation of a formal evaluation using the Delphi consensus method. c)The recent emphasis on breakthrough cancer pain, which paralleled the development of a number of fentanyl transmucosal preparations for acute pain relief, is reflected by a variable use of this concept in international guidelines, as summarized in a recent review coordinated by our center. d)In a European survey on 1000 patients with breakthrough cancer pain, 44% reported incident pain, and 41.5% spontaneous pain, but only 19% were treated with recently developed fentanyl transmucosal preparations. e)Using the biobank from the European Pharmacogenetic Opioid Study, 759 patients who received chronic morphine for cancer pain were studied, demonstrating that common polymorphisms in the UGT1A8 and UGT1A1 genes, regulating the expression of the UDP-glucuronosyltransferase enzymes, together with clinical factors, contribute to the variability in morphine metabolic ratios and therefore in the production of the metabolytes morphine -3G and morphine-6G in advanced cancer patients. PROGRAM MEMBERSHIP ASSOCIATED CLINICAL TRIALS Augusto Caraceni, Coordinator of the project The European Palliative Care Cancer Symptom study (EPCCS). Sponsored by the European Palliative Care Research Center Cinzia Brunelli, Statistician and PhD Student Alessandra Pigni, Research fellow Ernesto Zecca, Clinical research fellow Cinzia Martini, Clinical research fellow SELECTED RECENT PUBLICATIONS Corli O., Montanari M., Greco M.T., Brunelli C., Kaasa S., Caraceni A., Apolone G.: How to evaluate the effect of pain treatments in cancer patients: results from a longitudinal outcomes and endpoint Italian cohort study. Eur J Pain 2013; 17(6): 858-866 Caraceni A., Davies A., Poulain P., Cortés-Funes H., Panchal S.J., Fanelli G.: Guidelines for the management of breakthrough pain in patients with cancer. J Natl Compr Canc Netw 2013; 11 Suppl 1: S29-36 Davies A., Buchanan A., Zeppetella G., Porta-Sales J., Likar R., Weismayr W., Slama O., Korhonen T., Filbet M., Poulain P., Mystakidou K., Ardavanis A., O’Brien T., Wilkinson P., Caraceni A., Zucco F., Zuurmond W., Andersen S., Damkier A., Vejlgaard T., Nauck F., Radbruch L., Sjolund K.F., Stenberg M.: Breakthrough cancer pain: an observational study of 1000 European oncology patients. J Pain Symptom Manage 2013; 46(5): 619-628 Fladvad T., Klepstad P., Langaas M., Dale O., Kaasa S., Caraceni A., Skorpen F.: Variability in UDP-glucuronosyltransferase genes and morphine metabolism: observations from a cross-sectional multicenter study in advanced cancer patients with pain. Pharmacogenet Genomics 2013; 23(3): 117-126 120 New update of EAPC guidelines, widening the contents from on the use of opioid analgesics in cancer pain to cancer pain management. Sponsored by the European Palliative Care Research Center and the European Association for Palliative Care Research Network CERP Study: Open, randomized clinical study to compare the analgesic efficacy of oxycodone, fentanyl, and buprenorphine to morphine, in patients with moderate to severe cancer-related pain, starting from initiation of treatment with the 3rd step of the analgesic scale of the WHO. KEYWORDS Palliative care, pain, opioids, guidelines, genetics, end-of-life care research activity .Carla Ripamonti. RESEARCH AND TRAINING FOR THE PHYSICAL, EMOTIONAL, SOCIAL, AND SPIRITUAL SUPPORT OF PATIENTS ON ACTIVE CANCER TREATMENT AND THEIR CAREGIVERS OVERVIEW AND SCIENTIFIC GOALS The Departmental Supportive Care in Cancer Unit has clinical, educational, and research objectives aimed at detection, treatment, and study of prevention and treatment of side effects or toxicity resulting from cancer therapy as well as in the cure of emotional, social, and spiritual patient needs through global care of patients starting from diagnosis, and during cure and follow-up. The primary purpose is to support the work of each specialist and to implement supportive medical therapy for the patient during the entire period of cancer treatment to ensure physical well being and improve adherence to treatment protocols in terms of dose-intensity and dosing intervals. Moreover, the Unit provides real-time answers to oncological emergencies by treating patients suffering from iatrogenic toxicity. An additional objective is to give support to family, survivors, and personnel involved in daily care. The treatments carried out are compliant with the guidelines of the WHO, MASCC, ESMO, and AIOM. The well-being of patients is the core of the decision-making process in different settings of care in oncology. While the use of validated assessment tools to measure and treat physical symptoms related to cancer and/or oncological treatments is well known, few data are available regarding spiritual and emotional needs, hope, search of meaning, and dignity of the patient during anticancer therapies. Such poor knowledge and consequent undertreatment may worsen compliance to anticancer therapies and outcomes. We believe that it is important to consider, assess, and treat the existential well-being starting from 1. Diagnosis and staging of the disease, and during all the other moments of “physical and existential crisis” occurring throughout the disease such as: 2. Waiting for surgical/oncological intervention; 3. The impact of chemotherapy and/or radiation for either physical symptoms or the meaning of these oncological therapies for patients and their family (change body images, social situations and working life, fear of death, etc.); 4. Waiting for results of re-staging of disease after treatments; 5. Sense of abandonment after completing oncological therapies; 6. Diagnosis of recurrence or metastasis; 7. Difficulties of survivors and families to integrate the experience of the past illness in the actual personal life. Literature data show a positive correlation between physical and existential well-being in oncological settings. Moreover, patients require the attention of their oncologist considering their emotional and existential needs, also because the decision-making process of the patient is influenced by their attitudes towards life. Therefore, good communication on these aspects between patients and their oncologists is mandatory. 121 back to contents SCIENTIFIC REPORT 2013 PROGRAM HIGHLIGHTS In 2013, Research of the Unit has been oriented to study: 1. Different aspects of cancer-treatment or supportive treatment-related symptoms and complications in patients with solid or hematological malignancies during cure or follow-up (pain, mucositis, nausea, vomiting, diarrhea); 2. Assessment of anxiety and depression in routine clinical practice using a simple tool in comparison with a validated screening tool; 3. The different physical, emotional, and existential needs of patients with solid cancer vs. those with hematological malignancies. All aspects considered represent an innovation in the research. To our knowledge, no comprehensive project has been conducted to date with the intent to recognize all aspects of well-being of patients during cure or follow-up in a Supportive Care Program. This is the first step that will be followed by appropriate training of oncologists, which will allow them to achieve integrated, global care of patients. 1.a) Prospective study on the role of preventive dental measures, after dental screening examination in reducing the incidence of osteonecrosis of the jaw in oncological patients with bone metastasis and/or osteoporosis receiving BPs and RANKL inhibitors such as denosumab. b) Prospective study to collect information on the incidence and intensity of nausea and vomiting during the first three inter-cycle phases (days 14-16) in CT-naïve cancer patients treated with moderate or high emetogenic chemotherapy, and to define the most distressing symptoms between nausea and vomiting as reported by patients, with the goal to optimize personalized therapy. c) Revision of literature on targeted therapy-induced diarrhea. d) Randomized clinical trials to compare morphine mouthwashes vs. placebo in the treatment of painful mucositis in head & neck cancer patients. e) Translation in Italian of The WHO Treatment Guidelines on Persisting Pain in Children with Medical Ilnesses. f) Co-writing of the research protocol and collaboration in data elaboration of a randomized clinical trial on the role of a two-step vs. three-step protocol in 250 cancer patients with pain. g) After the validation in Italian language of the Patient Dignity Inventory (Ripamonti CI, et al. Patient Dignity Inventory (PDI) questionnaire: the validation study in Italian patients with solid and hematological cancers undergoing active oncological treatments. Tumori 2012), coauthor of a research project on Patient Dignity with countries in southern Europe. 2.Prospective study to assess the performance of the Edmonton Symptom Assessment System (ESAS) item on anxiety and depression when detecting Hospital Anxiety Depression Scale (HADS) “cases” in non-advanced patients with solid or hematological malignancies during cure or follow-up. 3.Prospective study to assess physical, spiritual, communication, and social needs, as well as hope, in 300 patients with solid cancer compared to patients with hematological malignancies undergoing oncological therapies cared for at the Supportive Care Unit. PROGRAM MEMBERSHIP Maria Adelaide Pessi, MD and Gloria Barone specialized in oncology, are active in research and clinical activities. External Collaborations Azienda Ospedaliera Universitaria, University of Modena and Reggio Emilia, Italy; Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti); Amadori D., Mercatali L., Nanni O., Aglietta M., Alessi B., Gianni L., Ibrahim T., Farina G., Gaion F., Bertoldo F., Santini D., Rondena R., Bogani R., Ripamonti C., Ibrahim T.: What can we learn from the ZOOM trial? Lancet Oncology 2013; 14: e388-e390 Ramondetta L.M., Sun C., Surbone A., Olver I., Ripamonti C., Konishi T., Baider L., Johnson J.: Surprising results regarding MASCC members’ beliefs about spiritual care. Support Care Cancer 2013; 21: 2991-2998 Psychology Unit, Center for Oncological Rehabilitation-CERION of Florence; Ripamonti C.I., Sichetti D.A., Fanizza C., Romero M.; ECAD_O Working Group: Is pain reporting to health care professionals age-related? A cross sectional multicenter study in a hospital setting. Expert Opin. Pharmacother 2013; 14(15): 2011-2017 Clinical Epidemiology Unit, ISPO-Institute for the Study and Prevention of Cancer, Florence; SELECTED RECENT MAJOR GRANTS World Health Organization for cancer pain relief (WHO); AIFA Sc Pediatria of Fondazione IRCCS, Istituto Nazionale dei Tumori, Milano KEYWORDS SELECTED RECENT PUBLICATIONS supportive care, assessment and treatment of symptoms and complications, bone health, well-being, Santini D., Lanzetta G., Dell’Aquila E., Vincenti B., Venditti O., Russano M., Papapietro N., Denaro V., Tonini G., Ripamonti C.: ‘Old’ and ‘new’ drugs for the treatment of cancer pain. Expert Opin Pharmacother 2013; 14(4): 425-433 Amadori D., Aglietta M., Alessi B., Gianni L., Ibrahim T., Farina G., Gaion F., Bertoldo F., Santini D., Rondena R., Bogani R., Ripamonti C.: Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial. Lancet Oncology 2013; 14: 663-670 122 research activity .Cecilia Gavazzi. DEVELOPMENT OF ALGORITHMS FOR NUTRITIONAL THERAPY IN DISEASES AT HIGH RISK OF MALNUTRITION OVERVIEW AND SCIENTIFIC GOALS Malnutrition is well known to be a negative prognostic factor in the prognosis of cancer patients, as it reduces tolerance to oncological treatment, increases morbidity and mortality, and deteriorates the quality of life; nutrition intervention should be considered throughout all phases of oncologic treatment, from diagnosis, surgery, chemotherapy, and radiotherapy. However, nutrition therapy should be tailored for different cancer types and different oncological treatments. The main goal of the project is the development and implementation of an algorithm for correct nutritional therapy in cancer patients at a high risk of malnutrition starting with head and neck cancer, where we have previously shown that combined treatments have significant impact of weight loss of patients. PROGRAM HIGHLIGHTS International guidelines for nutritional support in cancer patients do not address specific cancer types or oncological treatments. Therefore, this project will aim to provide a specific algorithm for nutritional support in head and neck, upper GI, pancreatic, colorectal, and ovarian cancers. The implementation of the algorithm should distinguish its applicability and efficacy. PROGRAM MEMBERSHIP Cecilia Gavazzi, MD, Supervisor and coordinator Michela Fiscella, MD, Review of literature, development and implementation of algorithm Jessica Lops, Evaluation of nutritional risk and nutritional counseling SELECTED RECENT PUBLICATIONS Palazzi M., Tomatis S., Orlandi E., Guzzo M., Sangalli C., Potepan P., Fantini S., Bergamini C., Gavazzi C., Licitra L., Scaramellini G., Cantù G., Olmi P.: Effects of treatment intensification on acute local toxicity during radiotherapy for head and neck cancer: Prospective observational study validating CTCAE, Version 3.0, Scoring System. Int J Radiat Oncol Biol Phys 2008; 70: 330-337 Gavazzi C., Colatruglio S., Sironi A., Mazzaferro V., Miceli R.: Importance of early nutritional screening in patients with gastric cancer. Br J Nutr 2011;106: 1773-1778 Bozzetti F., Mariani L., Lo Vullo S., The SCRINIO Working Group, Amerio M.L., Biffi R., Caccialanza R., Capuano G., Correja I., Cozzaglio L., Di Leo A., Di Cosmo L., Finocchiaro C., Gavazzi C., Giannoni A., Magnanini P., Mantovani G., Pellegrini M., Rovera G.M., Rovera L., Sandri G., Tinivella M., Vigevani E., Arcovio C., Licitra L.: The nutritional risk in oncology: a study of 1,453 cancer outpatients. Support Care Cancer 2012; 20: 1919-1928 Mariani L., Lo Vullo S., Bozzetti F., Gavazzi C., Arcovio C., Licitra L., on behalf of the SCRINIO Working Group: Weight loss in cancer patients: a plea for a better awareness of the issue. Support Care Cancer 2012; 20: 301-309 KEYWORDS Malnutrition, nutritional support, artificial nutrition 123 back to contents publications PUBLICATIONS N° Authors Title Journal IF 1 Abbas S., Linseisen J., Rohrmann S., Chang-Claude J., Peeters P.H., Engel P., Brustad M., Lund E., Skeie G., Olsen A., Tjønneland A., Overvad K., BoutronRuault M.-C., Clavel-Chapelon F., Fagherazzi G., Kaaks R., Boeing H., Buijsse B., Adarakis G., Ouranos V., Trichopoulou A., Masala G., Krogh V., Mattiello A., Tumino R., Sacerdote C., Buckland G., Suárez M.V.A., Sánchez M.-J., Chirlaque M.-D., Barricarte A., Amiano P., Manjer J., Wirfält E., Lenner P., Sund M., Bueno-De-Mesquita H.B., Van Duijnhoven F.J.B., Khaw K.-T., et al. Dietary intake of vitamin D and calcium Nutr Cancer 2013; and breast cancer risk in the European 65: 178-187 prospective investigation into cancer and nutrition. 2 Adamo M.S., Alessi D., Aletta P., Amodio R., Andreone S., Angelin T., Anghinoni E., Annulli M.L., Antonini S., Artioli M.E., Autelitano M., Balducci C., Balottari P., Baracco M., Battisti W., Bella F., Bellatalla C., Belluardo C., Benatti P., Benedetto G., Benfatto L., Bernazza E., Bianconi F., Biavati P., Bidoli E., Birri S., Bizzoco S., Bonelli L., Bonini A., Borciani E., Bovo E., Bozzani F., Bozzeda A., Braghiroli B., Brucculeri M.A., Brunori V., Bucalo G., Bucchi L., Bugliarello E., et al. Italian cancer figures, report 2013: Multiple tumours. Epidemiol Prev 2013; [IF 0.919] 37: 1-152 3 Agnoli C., Grioni S., Sieri S., Palli D., Masala G., Sacerdote C., Vineis P., Tumino R., Giurdanella M.C., Pala M.V., Berrino F., Mattiello A., Panico S., Krogh V. Italian mediterranean index and risk of colorectal cancer in the Italian section of the EPIC cohort. Int J Cancer 2013; 132: 1404-1411 [IF 6.198] 4 Agresti R., Trecate G., Ferraris C., Valeri B., Maugeri I., Pellitteri C., Martelli G., Migliavacca S., Carcangiu M.L., Bohm S., Maffioli L., Vergnaghi D., Panizza P. Ex vivo MRI evaluation of breast tumors: A novel tool for verifying resection of nonpalpable only MRI detected lesions. Breast J 2013; 19: 659-663 [IF 1.831] 5 Agudo A., Bonet C., Sala N., Muñoz X., Aranda N., Fonseca-Nunes A., Clavel-Chapelon F., BoutronRuault M.C., Vineis P., Panico S., Palli D., Tumino R., Grioni S., Ramón Quirós J., Molina E., Navarro C., Barricarte A., Chamosa S., Allen N.E., Khaw K.-T., Bas Bueno-de-Mesquita H., Siersema P.D., Numans M.E., Trichopoulou A., Lagiou P., Trichopoulos D., Kaaks R., Canzian F., Boeing H., Meidtner K., Johansson M., Sund M., Manjer J., Overvad K., Tjonneland A., Lund E., Weiderpass E., Jenab M., Fedirko V., et al. Carcinogenesis [IF 5.635] Hemochromatosis (HFE) gene 2013; 34: 1244-1250 mutations and risk of gastric cancer in the european prospective investigation into cancer and nutrition (EPIC) study. 6 Aktolun C., Castellani M.R., Bombardieri E. Diagnostic and therapeutic use of MIBG in pheochromocytoma and paraganglioma. Q J Nucl Med Mol Imaging 2013; 57: 109-111 [IF 1.918] 7 Aktolun C., Castellani M.R. Theranostic role of MIBG in neuroblastoma. Q J Nucl Med Mol Imaging 2013; 57: 3-5 [IF 1.918] 8 Alaggio R., Turrini R., Boldrin D., Merlo A., Gambini C., Ferrari A., Dall’igna P., Coffin C.M., Martines A., Bonaldi L., De Salvo G.L., Zanovello P., Rosato A. Survivin expression and prognostic significance in pediatric malignant peripheral nerve sheath tumors (MPNST). PLoS ONE 2013; 8: e80456 [IF 3.73] [IF 2.695] 125 back to contents SCIENTIFIC REPORT 2013 N° Authors Title Journal IF 9 Aleksandrova K., Pischon T., Buijsse B., May A.M., Peeters P.H., Bueno-De-Mesquita H.B., Jenab M., Fedirko V., Dahm C.C., Siersema P.D., Freisling H., Ferrari P., Overvad K., Tjønneland A., Trichopoulou A., Lagiou P., Naska A., Pala M.V., Mattiello A., Ohlsson B., Jirström K., Key T.J., Khaw K.-T., Riboli E., Boeing H. Adult weight change and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition. Eur J Cancer 2013; 49: 3526-3536 [IF 5.061] 10 Al-Jumaily U., Ayyad O., Masarweh M., Ghandour K., Almousa A., Al-Hussaini M., Ferrari A., Sultan I. Improved care of rhabdomyosarcoma in Jordan using less intensive therapy. Pediatr Blood Cancer [IF 2.353] 2013; 60: 53-58 11 Allemani C., Minicozzi P., Berrino F., Bastiaannet E., Gavin A., Galceran J., Ameijide A., Siesling S., Mangone L., Ardanaz E., Hédelin G., Mateos A., Micheli A., Sant M. Predictions of survival up to 10 years after diagnosis for European women with breast cancer in 2000-2002. Int J Cancer 2013; 132: 2404-2412 [IF 6.198] 12 Allemani C., Rachet B., Weir H.K., Richardson L.C., Lepage C., Faivre J., Gatta G., Capocaccia R., Sant M., Baili P., Lombardo C., Aareleid T., Ardanaz E., Bielska-Lasota M., Bolick S., Cress R., Elferink M., Fulton J.P., Galceran J., Gózdz S., Hakulinen T., Primic-Žakelj M., Rachtan J., Diba C.S., Sánchez M.-J., Schymura M.J., Shen T., Tagliabue G., Tumino R., Vercelli M., Wolf H.J., Wu X.-C., Coleman M.P. Colorectal cancer survival in the USA and Europe: A CONCORD highresolution study. BMJ Open 2013; 3: e003055 [IF 1.583] 13 Breast cancer survival in the US and Allemani C., Sant M., Weir H.K., Richardson L.C., Europe: A CONCORD high-resolution Baili P., Storm H., Siesling S., Torrella-Ramos A., study. Voogd A.C., Aareleid T., Ardanaz E., Berrino F., Bielska-Lasota M., Bolick S., Cirilli C., Colonna M., Contiero P., Cress R., Crocetti E., Fulton J.P., Grosclaude P., Hakulinen T., Izarzugaza M.I., Malmström P., Peignaux K., Primic-Žakelj M., Rachtan J., Safaei Diba C., Sánchez M.-J., Schymura M.J., Shen T., Traina A., Tryggvadottir L., Tumino R., Velten M., Vercelli M., Wolf H.J., Woronoff A.-S., Wu X., et al. Int J Cancer 2013; 132: 1170-1181 [IF 6.198] 14 Allen N.E., Appleby P.N., Key T.J., Bueno-DeMesquita H.B., Ros M.M., Kiemeney L.A.L.M., Tjønneland A., Roswall N., Overvad K., Weikert S., Boeing H., Chang-Claude J., Teucher B., Panico S., Sacerdote C., Tumino R., Palli D., Sieri S., Peeters P., Quirós J.R., Jakszyn P., Molina-Montes E., Chirlaque M.-D., Ardanaz E., Dorronsoro M., Khaw K.-T., Wareham N., Ljungberg B., Hallmans G., Ehrnström R., Ericson U., Gram I.T., Parr C.L., Trichopoulou A., Karapetyan T., Dilis V., ClavelChapelon F., Boutron-Ruault M.-C., Fagherrazzi G., et al. Macronutrient intake and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition. Int J Cancer 2013; 132: 635-644 [IF 6.198] 15 Amadori D., Aglietta M., Alessi B., Gianni L., Ibrahim T., Farina G., Gaion F., Bertoldo F., Santini D., Rondena R., Bogani P., Ripamonti C.I. Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): A phase 3, open-label, randomised, non-inferiority trial. Lancet Oncol 2013; 14: 663-670 [IF 25.117] 16 Amadori D., Mercatali L., Nanni O., Aglietta M., Alessi B., Gianni L., Farina G., Gaion F., Bertoldo F., Santini D., Rondena R., Bogani P., Ripamonti C.B., Ibrahim T. What can we learn from the zoom trial? Lancet Oncol 2013; - Authors’ reply. 14: e388-e390 [IF 25.117] 17 Anania M.C., Miranda C., Vizioli M.G., Mazzoni M., Cleris L., Pagliardini S., Manenti G., Borrello M.G., Pierotti M.A., Greco A. S100A11 overexpression contributes to the malignant phenotype of papillary thyroid carcinoma. 126 J Clin Endocrinol Metab 2013; 98: E1591-E1600 [IF 6.43] publications N° Authors Title Journal IF 18 Andriani F., Facchinetti F., Furia S., Roz L., Bursomanno S., Bertolini G., Carniti C., Sozzi G., Pastorino U. J Cell Physiol 2013; Adipose tissue displays trophic 228: 1166-1173 properties on normal lung cellular components without promoting cancer cells growth. [IF 4.218] 19 Angelico M., Nardi A., Marianelli T., Caccamo L., Romagnoli R., Tisone G., Pinna A.D., Avolio A.W., Fagiuoli S., Burra P., Strazzabosco M., Costa A.N., Angelico M., Cillo U., Fagiuoli S., Strazzabosco M., Caraceni P., Toniutto P.L., Costa A., Salizzoni M., Romagnoli R., Bertolotti G., Patrono D., De Carlis L., Slim A., Mangoni J.M., Rossi G., Caccamo L., Antonelli B., Mazzaferro V., Regalia E., Sposito C., Colledan M., Corno V., Tagliabue F., Marin S., Cillo U., Vitale A., Gringeri E., et al. Hepatitis B-core antibody positive donors in liver transplantation and their impact on graft survival: evidence from the Liver Match cohort study. J Hepatol 2013; 58: 715-723 [IF 9.858] 20 Angelini S., Pantaleo M.A., Ravegnini G., Zenesini C., Cavrini G., Nannini M., Fumagalli E., Palassini E., Saponara M., Di Battista M., Casali P.G., Hrelia P., Cantelli-Forti G., Biasco G. Polymorphisms in OCTN1 and OCTN2 transporters genes are associated with prolonged time to progression in unresectable gastrointestinal stromal tumours treated with imatinib therapy. Pharmacol Res 2013; 68: 1-6 [IF 4.346] 21 Antelmi E., Cardone R.A., Greco M.R., Rubino R., Di Sole F., Martino N.A., Casavola V., Carcangiu M.L., Moro L., Reshkin S.J. ß1 Integrin Binding Phosphorylates Ezrin at T567 to Activate a Lipid Raft Signalsome Driving Invadopodia Activity and Invasion. PLoS ONE 2013; 8: e75113 [IF 3.73] 22 Multiple effects of the Na+/H+ Aredia F., Giansanti V., Mazzini G., Savio M., Ortiz L.M.G., Jaadane I., Zaffaroni N., Forlino A., Torriglia antiporter inhibitor HMA on cancer cells. A., Scovassi A.I. Apoptosis 2013; 18: 1586-1598 [IF 3.949] 23 Ascierto P.A., Grimaldi A.M., Acquavella N., Borgognoni L., Calabrò L., Cascinelli N., Cesano A., Del Vecchio M., Eggermont A.M., Faries M., Ferrone S., Fox B.A., Gajewski T.F., Galon J., Gnjatic S., Gogas H., Kashani-Sabet M., Kaufman H.L., Larkin J., Lo R.S., Mantovani A., Margolin K., Melief C., McArthur G., Palmieri G., Puzanov I., Ribas A., Seliger B., Sosman J., Suenaert P., Tarhini A.A., Trinchieri G., Vidal-Vanaclocha F., Wang E., Ciliberto G., Mozzillo N., Marincola F.M., Thurin M. Future perspectives in melanoma research. Meeting report from the Melanoma Bridge. Napoli, December 2nd-4th 2012”. J Transl Med 2013; 11: 137 [IF 3.459] 24 Azim H.A. Jr, Agbor-Tarh D., Bradbury I., Dinh P., Baselga J., Di Cosimo S., Greger J.G. Jr, Smith I., Jackisch C., Kim S.B., Aktas B., Huang C.S., Vuylsteke P., Hsieh R.K., Dreosti L., Eidtmann H., Piccart M., de Azambuja E. Pattern of Rash, Diarrhea, and Hepatic Toxicities Secondary to Lapatinib and Their Association With Age and Response to Neoadjuvant Therapy: Analysis From the NeoALTTO Trial. J Clin Oncol 2013; 31: 4504-4511 [IF 18.038] 25 Azim H.A., Rothé F., Aura C.M., Bavington M., Maetens M., Rouas G., Gebhart G., Gamez C., Eidtmann H., Baselga J., Piccart-Gebhart M., Ellis C., Vuylsteke P., Cure H., Domont J., Ferro A., Toral-Peña J.C., de Azambuja E., Sotiriou C., Di Cosimo S., Ignatiadis M. Breast 2013; 22: Circulating tumor cells and response 1060-1065 to neoadjuvant paclitaxel and HER2targeted therapy: A sub-study from the NeoALTTO phase III trial. 26 Bagnoli M., Beretta G.L., Gatti L., Pilotti S., Alberti P., Tarantino E., Barbareschi M., Canevari S., Mezzanzanica D., Perego P. Clinicopathological impact of ABCC1/ MRP1 and ABCC4/MRP4 in epithelial ovarian carcinoma. Biomed Res Int 2013; 2013: 143202 27 Baili P., Hoekstra-Weebers J., Van Hoof E., Bartsch H.H., Travado L., Garami M., Di Salvo F., Micheli A., Veerus P. Cancer rehabilitation indicators for Europe. Eur J Cancer 2013; 49: 1356-1364 [IF 1.967] [IF 5.061] 127 back to contents SCIENTIFIC REPORT 2013 N° Authors Title Journal IF 28 Baili P., Vicentini M., Tumino R., Vercelli M., Lorenzo M., Foschi R., Guzzinati S., Dal Maso L., Minicozzi P., De Lorenzo F., Micheli A., Di Salvo F., CAREMORE GROUP, Gatta G., Trama A. A method for differentiating cancer prevalence according to health status, exemplified using a population-based sample of Italian colorectal cancer cases. Acta Oncol 2013; 52: 294-302 [IF 2.867] 29 Bakrin N., Gilly F.N., Baratti D., Bereder J.M., Quenet F., Lorimier G., Mohamed F., Elias D., Glehen O. Primary peritoneal serous carcinoma treated by cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. A multiinstitutional study of 36 patients. EJSO-EUR J SURG ONC 2013; 39: 742-747 [IF 2.614] 30 Solitary fibrous tumor of all sites: Baldi G.G., Stacchiotti S., Mauro V., Dei Tos A.P., Gronchi A., Pastorino U., Duranti L., Provenzano S., outcome of late recurrences in 14 patients. Marrari A., Libertini M., Pilotti S., Casali P.G. 31 Baltar V.T., Xun W.W., Johansson M., Ferrari P., Chuang S.-C., Relton C., Ueland P.M., Midttun O., Slimani N., Jenab M., Clavel-Chapelon F., BoutronRuault M.-C., Fagherazzi G., Kaaks R., Rohrmann S., Boeing H., Weikert C., Bueno-De-Mesquita B., Boshuizen H., Van Gils C.H., Onland-Moret N.C., Agudo A., Barricarte A., Navarro C., Rodríguez L., Castaño J.M.H., Larrañaga N., Khaw K.-T., Wareham N., Allen N.E., Crowe F., Gallo V., Norat T., Krogh V., Masala G., Panico S., Sacerdote C., Tumino R., Trichopoulou A., et al. A structural equation modelling approach to explore the role of B vitamins and immune markers in lung cancer risk. Eur J Epidemiol 2013; 28: 677-688 [IF 5.118] 32 Bamia C., Lagiou P., Buckland G., Grioni S., Agnoli C., Taylor A.J., Dahm C.C., Overvad K., Olsen A., Tjønneland A., Cottet V., Boutron-Ruault M.-C., Morois S., Grote V., Teucher B., Boeing H., Buijsse B., Trichopoulos D., Adarakis G., Tumino R., Naccarati A., Panico S., Palli D., Bueno-DeMesquita H.B., Van Duijnhoven F.J.B., Peeters P.H.M., Engeset D., Skeie G., Lund E., Sánchez M.-J., Barricarte A., Huerta J.-M., Quirós J.R., Dorronsoro M., Ljuslinder I., Palmqvist R., Drake I., Key T.J., Khaw K.-T., et al. Mediterranean diet and colorectal cancer risk: Results from a European cohort. Eur J Epidemiol 2013; 28: 317-328 [IF 5.118] 33 Bampo C., Alessi A., Fantini S., Bertarelli G., De Braud F., Bombardieri E., Valvo F., Crippa F., Di Bartolomeo M., Mariani L., Milione M., Biondani P., Avuzzi B., Chiruzzi C., Pietrantonio F. Is the standardized uptake value of FDG-PET/CT predictive of pathological complete response in locally advanced rectal cancer treated with capecitabine-based neoadjuvant chemoradiation?. Oncology 2013; 84: 191-199 [IF 2.165] 34 Bangma C.H., Bul M., van der Kwast T.H., Pickles T., Active surveillance for low-risk Korfage I.J., Hoeks C.M., Steyerberg E.W., Jenster prostate cancer. G., Kattan M.W., Bellardita L., Carroll P.R., Denis L.J., Parker C., Roobol M.J., Emberton M., Klotz L.H., Rannikko A., Kakehi Y., Lane J.A., Schröder F.H., Semjonow A., Trock B.J., Valdagni R. Crit Rev Oncol Hematol 2013; 85: 295-302 [IF 4.637] 35 Baratti D., Kusamura S., Cabras A.D., Bertulli R., Hutanu I., Deraco M. Eur J Cancer 2013; Diffuse malignant peritoneal 49: 3140-3148 mesothelioma: Long-term survival with complete cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). [IF 5.061] 36 Bassoli S., Maurichi A., Rodolfo M., Casari A., Frigerio S., Pupelli G., Farnetani F., Pelosi G., Santinami M., Pellacani G. CDKN2A and MC1R variants influence Exp Dermatol 2013; 22: 411-416 dermoscopic and confocal features of benign melanocytic lesions in multiple melanoma patients. [IF 3.578] 128 Clin Sarcoma Res 2013; 3: 4 publications N° Authors Title Journal IF 37 Belardi V., Fiore E., Giustarini E., Muller I., Sabatini S., Rosellini V., Seregni E., Agresti R., Marcocci C., Vitti P., Giani C. J Endocrinol Invest Is the risk of primary 2013; 36: 321-325 hyperparathyroidismincreased in patients with untreated breast cancer?. 38 Bella F., Minicozzi P., Giacomin A., Crocetti E., Federico M., Ponz De Leon M., Fusco M., Tumino R., Mangone L., Giuliani O., Budroni M., Sant M. Impact of diabetes on overall and cancer-specific mortality in colorectal cancer patients. 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MR-guided stereotactic breast biopsy using a mixed ferromagneticnonmagnetic coaxial system with 12- to 18-gauge needles: Clinical experience and long-term outcome. Radiol Med 2013; 118: 1137-1148 43 Bel-Serrat S., Mouratidou T., Börnhorst C., Peplies J., De Henauw S., Marild S., Molnár D., Siani A., Tornaritis M., Veidebaum T., Krogh V., A. Moreno L. Food consumption and cardiovascular risk factors in European children: The IDEFICS study. Pediatr Obes 2013; 8: 225-236 44 Bel-Serrat S., Mouratidou T., Santaliestra-Pasías A.M., Iacoviello L., Kourides Y.A., Marild S., Molnár D., Reisch L., Siani A., Stomfai S., Vanaelst B., Veidebaum T., Pigeot I., Ahrens W., Krogh V., Moreno L.A. Clustering of multiple lifestyle behaviours and its association to cardiovascular risk factors in children: The IDEFICS study. 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IF 151 back to contents SCIENTIFIC REPORT 2013 N° Authors Title Journal IF 284 Keng V.W., Sia D., Sarver A.L., Tschida B.R., Fan D., Alsinet C., Solé M., Lee W.L., Kuka T.P., Moriarity B.S., Villanueva A., Dupuy A.J., Riordan J.D., Bell J.B., T.Silverstein K.A., Llovet J.M., Largaespada D.A. Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR. Hepatology 2013; 57: 120-130 [IF 12.003] 285 Key T., Endogenous Hormones and Breast Cancer Collaborative Group, Berrino F., Krogh V., Sieri S. Sex hormones and risk of breast cancer in premenopausal women: A collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol 2013; 14: 1009-1019 [IF 25.117] 286 Evaluation of human papillomavirus Kreimer A.R., Johansson M., Waterboer T., Kaaks antibodies and risk of subsequent head R., Chang-Claude J., Drogen D., Tjønneland A., and neck cancer. 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PLoS ONE 2013; 8: e83026 [IF 3.73] 447 Sardi I., la Marca G., Cardellicchio S., Giunti L., Malvagia S., Genitori L., Massimino M., de Martino M., Giovannini M.G. Pharmacological modulation of bloodbrain barrier increases permeability of doxorubicin into the rat brain. Am J Cancer Res 2013; 3: 424-432 448 A very rare cancer in Down syndrome: Satgé D., Stiller C.A., Rutkowski S., Von Bueren A.O., Lacour B., Sommelet D., Nishi M., Massimino Medulloblastoma. Epidemiological data from 13 countries. M., Garré M.L., Moreno F., Hasle H., Jakab Z., Greenberg M., Von Der Weid N., Kuehni C., Zurriaga O., Vicente M.-L., Peris-Bonet R., Benesch M., Vekemans M., Sullivan S.G., Rickert C. 166 Eur J Gastroenterol Hepatol 2013; 25: 1385-1395 J Neurooncol 2013; 112: 107-114 [IF 3.2] [IF 1.915] [IF 3.115] publications N° Authors Title Journal IF 449 Satta A., Mezzanzanica D., Turatti F., Canevari S., Figini M. 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Cosimo S. 505 Travis R.C., Appleby P.N., Siddiq A., Allen N.E., Kaaks R., Canzian F., Feller S., Tjønneland A., Føns Johnsen N., Overvad K., Ramõn Quirõs J., González C.A., Sánchez M.-J., Larrañaga N., Chirlaque M.-D., Barricarte A., Khaw K.-T., Wareham N., Trichopoulou A., Valanou E., Oustoglou E., Palli D., Sieri S., Tumino R., Sacerdote C., Bueno-De-Mesquita H.B., Stattin P., Ferrari P., Johansson M., Norat T., Riboli E., Key T.J. Genetic variation in the lactase gene, dairy product intake and risk for prostate cancer in the European prospective investigation into cancer and nutrition. Int J Cancer 2013; 132: 1901-1910 [IF 6.198] 506 Tripodi S.A., Rocca B.J., Mourmouras V., Barbanti G., Colecchia M., Ambrosio M.R. Benign glomus tumor of the urinary bladder. Arch Pathol Lab Med 2013; 137: 1005-1008 [IF 2.781] 507 Triulzi T., Casalini P., Sandri M., Ratti M., Carcangiu M.L., Colombo M.P., Balsari A., Ménard S., Orlandi R., Tagliabue E. 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Eur J Cancer 2013; 49: 2565-2578 [IF 5.061] 516 Vannelli A., Basilico V., Zanardo M., Caizzone A., Rossi F., Battaglia L., Scaramuzza D. Pelvic lymphedema in rectal cancer: A Eur Rev Med magnetic resonance feasibility study: A Pharmacol Sci 2013; 17: 929-935 preliminary report. 517 Varesco L., Viassolo V., Viel A., Gismondi V., Radice P., Montagna M., Alducci E., Della Puppa L., Oliani C., Tommasi S., Caligo M.A., Vivanet C., Zuradelli M., Mandich P., Tibiletti M.G., Cavalli P., Lucci Cordisco E., Turchetti D., Boggiani D., Bracci R., Bruzzi P., Bonelli L. Performance of BOADICEA and BRCAPRO genetic models and of empirical criteria based on cancer family history for predicting BRCA mutation carrier probabilities: A retrospective study in a sample of Italian cancer genetics clinics. 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Pediatr Blood Cancer [IF 2.353] 2013; 60: 605-610 520 Ventura L., Miccinesi G., Buzzoni C., Crocetti E., Paci E., Foschi R., Rossi S. Estimates of cancer burden in Tuscany. Tumori 2013; 99: 334-341 521 Venturini E., Losio C., Panizza P., Rodighiero M.G., Fedele I., Tacchini S., Schiani E., Ravelli S., Cristel G., Panzeri M.M., De Cobelli F., Maschio A.D. Tailored breast cancer screening program with microdose mammography, us, and mr imaging : Short-term results of a pilot study in 40-49-year-old wome. Radiology 2013; 268: [IF 6.339] 347-355 [IF 1.093] [IF 0.922] 173 back to contents SCIENTIFIC REPORT 2013 N° Authors Title Journal IF 522 Verburg F.A., Luster M., Cupini C., Chiovato L., Duntas L., Elisei R., Feldt-Rasmussen U., Rimmele H., Seregni E., Smit J.W., Theimer C., Giovanella L. Implications of thyroglobulin antibody positivity in patients with differentiated d cancer: a clinical position statement. 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Comment to: Non-invasive assessment Dig Liver Dis 2013; of hepatic fibrosis in a series of patients 45: 265 with Wilson's disease. 526 Vergnaud A.-C., Norat T., Mouw T., Romaguera D., May A.M., Bueno-de-Mesquita H.B., van der A D., Agudo A., Wareham N., Khaw K.-T., Romieu I., Freisling H., Slimani N., Perquier F., BoutronRuault M.-C., Clavel-Chapelon F., Palli D., Berrino F., Mattiello A., Tumino R., Ricceri F., Rodríguez L., Molina-Montes E., Amiano P., Barricarte A., Chirlaque M.-D., Crowe F.L., Orfanos P., Naska A., Trichopoulou A., Teucher B., Kaaks R., Boeing H., Buijsse B., Johansson I., Hallmans G., Drake I., Sonestedt E., Jakobsen M.U., et al. Macronutrient Composition of the Diet and Prospective Weight Change in Participants of the EPIC-PANACEA Study. 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Am J Clin Nutr 2013; 97: 1107-1120 [IF 6.504] 528 Vermeulen E., Zamora-Ros R., Duell E.J., LujánBarroso L., Boeing H., Aleksandrova K., Bueno-DeMesquita H.B., Scalbert A., Romieu I., Fedirko V., Touillaud M., Fagherazzi G., Perquier F., MolinaMontes E., Chirlaque M.-D., Vicente Argüelles M., Amiano P., Barricarte A., Pala M.V., Mattiello A., Saieva C., Tumino R., Ricceri F., Trichopoulou A., Vasilopoulou E., Ziara G., Crowe F.L., Khaw K.-T., Wareham N.J., Lukanova A., Grote V.A., Tjønneland A., Halkjær J., Bredsdorff L., Overvad K., Siersema P.D., Peeters P.H.M., May A.M., Weiderpass E., et al. Dietary flavonoid intake and esophageal cancer risk in the european prospective investigation into cancer and nutrition cohort. Am J Epidemiol 2013; 178: 570-581 [IF 4.78] 529 Vermorken J.B., Licitra L., Stöhlmacher-Williams J., Dietz A., Lopez-Picazo J.M., Hamid O., Hossain A.M., Chang S.-C., Gauler T.C. Phase II study of pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck. Eur J Cancer 2013; 49: 2877-2883 [IF 5.061] 530 Vermorken J.B., Stöhlmacher-Williams J., Davidenko I., Licitra L., Winquist E., Villanueva C., Foa P., Rottey S., Skladowski K., Tahara M., Pai V.R., Faivre S., Blajman C.R., Forastiere A.A., Stein B.N., Oliner K.S., Pan Z., Bach B.A. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamouscell carcinoma of the head and neck (SPECTRUM): An open-label phase 3 randomised trial. Lancet Oncol 2013; 14: 697-710 [IF 25.117] 174 [IF 3.162] publications N° Authors Title Journal IF 531 Verpelli C., Carlessi L., Bechi G., Poli E.F., Orellana D., Heise C., Franceschetti S., Mantegazza R., Mantegazza M., Delia D., Sala C. Comparative neuronal differentiation of self-renewing neural progenitor cell lines obtained from human induced pluripotent stem cells. 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Stud Health Technol Inform 2013; 186: 46-50 539 Walker L.C., Whiley P.J., Houdayer C., Hansen T.V.O., Vega A., Santamarina M., Blanco A., Fachal L., Southey M.C., Lafferty A., Colombo M., De Vecchi G., Radice P., Spurdle A.B. Evaluation of a 5-Tier scheme proposed for classification of sequence variants using bioinformatic and splicing assay data: Inter-reviewer variability and promotion of minimum reporting guidelines. Hum Mutat 2013; 34: 1424-1431 540 Zaffaroni N. Preface: MicroRNAs as novel cancer biomarkers and therapeutic targets. Crit Rev Oncog 2013; 18: 541 Zamora-Ros R., Fedirko V., Trichopoulou A., González C.A., Bamia C., Trepo E., Nöthlings U., Duarte-Salles T., Serafini M., Bredsdorff L., Overvad K., Tjønneland A., Halkjær J., Fagherazzi G., Perquier F., Boutron-Ruault M.-C., Katzke V., Lukanova A., Floegel A., Boeing H., Lagiou P., Trichopoulos D., Saieva C., Agnoli C., Mattiello A., Tumino R., Sacerdote C., Bueno-De-Mesquita H.B., Peeters P.H.M., Weiderpass E., Engeset D., Skeie G., Argüelles M.V., Molina-Montes E., Dorronsoro M., Tormo M.J., Ardanaz E., Ericson U., Sonestedt E., et al. Dietary flavonoid, lignan and antioxidant capacity and risk of hepatocellular carcinoma in the European prospective investigation into cancer and nutrition study. Int J Cancer 2013; 133: 2429-2443 [IF 0.922] [IF 5.213] [IF 6.198] 175 back to contents SCIENTIFIC REPORT 2013 N° Authors Title 542 Zamora-Ros R., Ferrari P., González C.A., Tjønneland A., Olsen A., Bredsdorff L., Overvad K., Touillaud M., Perquier F., Fagherazzi G., Lukanova A., Tikk K., Aleksandrova K., Boeing H., Trichopoulou A., Trichopoulos D., Dilis V., Masala G., Sieri S., Mattiello A., Tumino R., Ricceri F., BuenoDe-Mesquita H.B., Peeters P.H.M., Weiderpass E., Skeie G., Engeset D., Menéndez V., Travier N., Molina-Montes E., Amiano P., Chirlaque M.-D., Barricarte A., Wallström P., Sonestedt E., Sund M., Landberg R., Khaw K.-T., Wareham N.J., et al. Breast Cancer Res Dietary flavonoid and lignan intake Treat 2013; 139: and breast cancer risk according to 163-176 menopause and hormone receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. 543 Zamora-Ros R., Forouhi N.G., Sharp S.J., González C.A., Buijsse B., Guevara M., van der Schouw Y.T., Amiano P., Boeing H., Bredsdorff L., ClavelChapelon F., Fagherazzi G., Feskens E.J., Franks P.W., Grioni S., Katzke V., Key T.J., Khaw K.T., Kühn T., Masala G., Mattiello A., Molina-Montes E. The association between dietary flavonoid and lignan intakes and incident type 2 diabetes in European populations: the EPIC-InterAct study. Diabetes Care 2013; 36: 3961-3970 [IF 7.735] 544 Zamora-Ros R., Knaze V., Luján-Barroso L., Romieu I., Scalbert A., Slimani N., Hjartåker A., Engeset D., Skeie G., Overvad K., Bredsdorff L., Tjonneland A., Halkjær J., Key T.J., Khaw K.-T., Mulligan A.A., Winkvist A., Johansson I., Bas Bueno-De-Mesquita H., Peeters P.H.M., Wallström P., Ericson U., Pala V., De Magistris M.S., Polidoro S., Tumino R., Trichopoulou A., Dilis V., Katsoulis M., María Huerta J., Martínez V., Sánchez M.-J., Ardanaz E., Amiano P., Teucher B., Grote V., Bendinelli B., Boeing H., Förster J., Pala V., et al. Differences in dietary intakes, food sources and determinants of total flavonoids between Mediterranean and non-Mediterranean countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Br J Nutr 2013; 109: 1498-1507 [IF 3.302] 545 Zamora-Ros R., Knaze V., Romieu I., Scalbert A., Slimani N., Clavel-Chapelon F., Touillaud M., Perquier F., Skeie G., Engeset D., Weiderpass E., Johansson I., Landberg R., Bueno-De-Mesquita H.B., Sieri S., Masala G., Peeters P.H.M., Grote V., Huerta J.M., Barricarte A., Amiano P., Crowe F.L., Molina-Montes E., Khaw K.-T., Argüelles M.V., Tjønneland A., Halkjær J., De Magistris M.S., Ricceri F., Tumino R., Wirfält E., Ericson U., Overvad K., Trichopoulou A., Dilis V., Vidalis P., Boeing H., Förster J., Riboli E., et al. Eur J Clin Nutr 2013; Impact of thearubigins on the 67: 779-782 estimation of total dietary flavonoids in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. [IF 2.756] 546 Zamora-Ros R., Rothwell J.A., Scalbert A., Knaze V., Romieu I., Slimani N., Fagherazzi G., Perquier F., Touillaud M., Molina-Montes E., Huerta J.M., Barricarte A., Amiano P., Menéndez V., Tumino R., de Magistris M.S., Palli D., Ricceri F., Sieri S., Crowe F.L., Khaw K.T., Wareham N.J. Dietary intakes and food sources of phenolic acids in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Br J Nutr 2013; 110: 1500-1511 [IF 3.302] 547 Zanaboni F., Grijuela B., Giudici S., Cormio G., Babilonti L., Ghezzi F., Giorda G., Scambia G., Franchi M., Lorusso M., Ditto A., Lorusso D., Raspagliesi F. Weekly topotecan and cisplatin (TOPOCIS) as neo-adjuvant chemotherapy for locally-advanced squamous cervical carcinoma: Results of a phase II multicentric study. Eur J Cancer 2013; 49: 1065-1072 [IF 5.061] 548 Zanoni I., Spreafico R., Bodio C., DiGioia M., Cigni C., Broggi A., Gorletta T., Caccia M., Chirico G., Sironi L., Collini M., Colombo M.P., Garbi N., Granucci F. IL-15 cis Presentation Is Required for Optimal NK Cell Activation in Lipopolysaccharide-Mediated Inflammatory Conditions. Cell Rep 2013; 4: 1235-1249 176 Journal IF [IF 4.469] publications N° Authors Title Journal IF 549 Zinzani P.L., Viviani S., Anastasia A., Vitolo U., Luminari S., Zaja F., Corradini P., Spina M., Brusamolino E., Gianni A.M., Santoro A., Botto B., Derenzini E., Pellegrini C., Argnani L. Brentuximab vedotin in relapsed/ refractory Hodgkin's lymphoma: The Italian experience and results of its use in daily clinical practice outside clinical trials. Haematologica 2013; [IF 5.935] 98: 1232-1236 550 Zompatori M., Mascalchi M., Ciccarese F., Sverzellati N., Pastorino U. Screening for lung cancer using lowdose spiral CT: 10 years later, state of the art. Radiol Med 2013; 118: 51-61 551 Zsiros J., Brugieres L., Brock P., Roebuck D., Maibach R., Zimmermann A., Childs M., Pariente D., Laithier V., Otte J.-B., Branchereau S., Aronson D., Rangaswami A., Ronghe M., Casanova M., Sullivan M., Morland B., Czauderna P., Perilongo G. Lancet Oncol 2013; Dose-dense cisplatin-based chemotherapy and surgery for children 14: 834-842 with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm, feasibility study. [IF 1.461] [IF 25.117] 177 back to contents ongoing supported projects 179 SCIENTIFIC REPORT 2013 180 back to contents ongoing supported projects 181 SCIENTIFIC REPORT 2013 182 back to contents back to contents ongoing clinical studies ONGOING CLINICAL STUDIES Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 BREAST CARCINOMA 32/03 Prognostic significance of blood concentrations of F. Berrino testosterone and insulin in women with early breast cancer 2003 Observational 2467 Closed accrual 06/04 Immunization of patients with locally advanced/ A. M. Gianni metastatic breast and ovarian cancer with autologous monocyte-derived dendritic cells loaded with apoptotic/necrotic autologous tumor cells exposed to heat shock 2004 Pilot 4 Closed accrual 68/05 A phase II, single arm, multicentre study to evaluate the efficacy and safety of the combination of Omnitarg and Herceptin in patients with HER2 positive metastatic breast cancer G. V. Bianchi 2006 II 7 Closed accrual 39/06 A randomized, open-label, 2-arm, multicentre, A. Moliterni phase III study to evaluate the efficacy and safety of bevacizumab in combination with Trastuzumab/ docetaxel compared with Trastuzumab/Docetaxel alone as first line treatment for patients with HER2 positive locally recurrent or metastatic breast cancer. 2006 III 14 Closed accrual 37/07 Randomized trial of diet, physical activity and breast F. Berrino cancer recurrences: the DIANA-5 study 2007 - 1.667 Closed accrual 47/07 A randomized multicentric international phase II study of Herceptin® and docetaxel versus docetaxel in association with OmnitargTM and Herceptin® versus OmnitargTM and Herceptin® in the treatment of locally advanced HER-2 positive breast cancer, inflammatory or early breast cancer G. Bianchi 2007 II 28 Closed accrual 18/08 Phase II study. Safety of the scheme of adjuvant or primary sequential chemotherapy in operable breast cancer at high risk (AT x 3 - CMF x 3) A. Moliterni 2008 II 352 Closed accrual 76/08 Tevere project: primary prevention of breast cancer F. Berrino by diet, physical activity or Metformin assumption 2009 III 350 100 16/09 A randomized, multicenter, phase III open-label G. Bianchi study of the efficacy and safety of trastuzumabMCC-DM1 vs capecitabine+lapatinib in patients with HER2-positive locally advanced or metastatic breast cancer who have received prior trastuzumabbased therapy 2009 III 6 Closed accrual 33/09 A phase Ib, open label, dose escalation study of the safety and pharmacology of P13-kinase inhibitor GDC-0941 in combination with paclitaxel and bevacizumab in patients with locally recurrent or metastatic breast cancer 2009 Ib 22 5 S. Cresta 185 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated 63/09 A randomized phase III, double-blind, placebocontrolled multicenter trial of daily everolimus in combination with trastuzumab and vinorelbine, in pretreated women with HER2/neu over-expressing locally advanced or metastatic breast cancer G. Bianchi 15/11 Phase Total patients Patients enrolled in 2013 2010 III 8 Closed accrual The SERISCAFFOLD Use in reconstruction postM. Nava market study for tissue support and repair in directto-implant breast reconstruction surgery 2011 Observational 4 Closed accrual 43/07 A multinational double-blind, randomized phase IIb cooperative group study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with chemotherapy and/or endocrine therapy in patients with locally recurrent or metastatic Breast cancer G. Mariani 2007 IIb 26 Closed accrual 101/11 Effect of oral red clover on the symptoms of menopausal syndrome induced by adjuvant hormonal treatment in women with a diagnosis of breast cancer C. Ferraris 2012 IV 77 53 102/11 A randomized, two-arm, open label, multicenter G. V. Bianchi phase II trial assessing the efficacy and safety of pertuzimab given in combination with trastuzumab plus in aromatase inhibitor in first line patients with HER 2-positive and hormone receptor-positive advanced (metastastic and locally advanced) breast cancer 2011 II 2 1 29/12 A phase III prospective, two-cohort nonrandomized, multi-centre, miltinational, open label study to assess the safety of asisted-and self-admnistered subcutaneous trastuzumab as adjuvant therapy in patients with operable HER-2positive early breast cancer 2013 III 5 5 51/12 Identification of genes associated with toxicity from L. Lozza radiation in breast cancer patients 2012 Observational 87 56 64/12 An open-label, multi-center, expanded access study for postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer who have progressed following prior endocrine therapy, investigating the treatment of everolimus (RAD001) in combination with exemestane G. Mariani 2012 III 32 69/12 NY-ESO1, MAGE-A3, PRAME and WT1 expression in different groups of breast carcinoma A. Tessari 2012 Observational 84 5 81/12 A randomized, blinded, single center study to assess the incidence of surgical site infections in breast cancer surgery after preoperative skin preparation with chlorhexidine 2% in alcohol 70% (CHLORAPREP ®) versus 10% povidone-iodine M. Langer 2013 IV 757 757 92/12 A randomized trial comparing sentinel lymph node R. Agresti biopsy vs no axillary surgical staging in patients with small breast cancer and a negative preoperative axillary assessment. 2013 - 35 35 186 G. Mariani Closed 28/01/13 34 ongoing clinical studies Study Code Title Coordinator Activated 109/12 SHARE - Cyberknife Partial Breast Irradiation for Early Stage Breast Cancer. A phase I prospective study L. Lozza 111/12 Metabolic disorders and breast cancer 116/12 Phase Total patients Patients enrolled in 2013 2013 I 15 15 R. Agresti 2012 Observational 1442 1284 Assessment of the performance of tomosynthesis as diagnostic tool in adjunct to mammography in women with dense breasts evaluated also with breast ultrasound C. Ferranti 2013 Observational 205 205 125/12 A multicenter, single arm study of trastuzumab emtansine (T-DM1) in HER2 positive locally advanced or metastatic breast cancer patients who have received prior anti-HER2 and chemotherapybased treatment G. V. Bianchi 2013 III 5 5 127/12 Impact of acellular dermal matrix in reduction of surgical complexity of breast reconstructions with implants M. Nava 2013 IV 15 15 146/12 Pre-operative evaluation of distress thermometer in breast cancer patients R. Agresti 2013 Observational 1.000 1.000 148/12 Screening of women at high family-genetic risk of P. Panizza breast cancer with only MRI: prospective randomized study with cost-effectiveness analysis (ISS-HIBCRIT3 – ISS High Breast Cancer Risk Italian Study n. 3) 2013 - 38 38 01/13 A phase II, open label, single arm trial of neoadjuvant S. Di Cosimo therapy in patients with triple negative breast cancer evaluating the efficacy of eribulin mesylate following anthracycline and taxane and correlative science studies attempting to identify predictors of response 2013 II 1 1 02/13 Circulating miRNAs as biomarkers predictive of breast cancer relapse M. G. Daidone 2013 Observational 41 41 24/13 A multicenter, open-label, dose escalation, Phase S. Cresta I study of LJM716 administered intravenously in combination with trastuzumab in patients with HER2 overexpressing metastatic breast cancer or gastric cancer 2013 I 4 4 26/13 Neoadjuvant chemotherapy with nab-paclitaxel in women with HER2-negative high-risk breast cancer ETNA (Evaluating Treatment with naoadjuvant Abraxane) A. Moliterni 2013 III 1 1 39/13 Hepatic trans-arterial chemoembolization (TACE) in metastatic breast cancer S. Cresta 2013 49/13 Postmastectomy radiotherapy in reconstructed L. Lozza breast: evaluation of dose distribution in partially and completed inflated tissue expanders 55/13 A randomized, multicenter, open-label phase III study to evaluate the efficacy and safety of trastuzumab emtansine versus trastuzumab as adjuvant therapy for patients with HER2-positive primary breast cancer who have residual tumor present pathologically in the breast or axillary lymph nodes following preoperative therapy G. V. Bianchi Closed 04/12/13 Observational 15 15 2013 - 5 5 2013 III 1 1 187 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated Closed Phase 59/13 Expression of NY-ESO-1, PD1-L, miRNA profile in triple negative metastatic breast cancer S. Cresta 2013 28/06/13 Observational 32 32 60/13 Study of regional lymph node metastases in breast cancer and comparison in terms of predictive diagnostics between Positron Emission Tomography with FluoroDeoxyGlucose (FDG-PET) and sentinel lymph node biopsy identified with lymphoscintigraphy and radio-guided surgery R. Agresti 2013 15/09/13 Observational 145 145 66/13 Risk for breast cancer related lymphoedema after selected axillary lymph node dissection in patients with node positive breast cancer M. Gennaro 2013 01/11/13 Observational 60 60 67/13 Risk for local relapses after breast conserving surgery in patients with ductal carcinoma in situ of the breast M. Gennaro 2013 Observational 250 Closed accrual 89/13 Analysis of MRI semeiotic patterns in hereditary breast carcinoma G. Trecate 2013 Observational 150 150 Randomized controlled trial of diet and physical activity in carriers of BRCA mutation P. Pasanisi 2013 - 20 106/13 01/09/13 Total patients 20 Patients enrolled in 2013 111/13 Assessment of breast cancer progression risk based E. Tagliabue on extracellular matrix characteristics 2013 Observational 200 200 115/13 Pilot study for the identification of miRNA predictive of chemotherapy response with gemcitabine in metastatic breast cancer S. Cresta 2013 Observational 39 39 127/13 Long term results from INT-HER study: retrospective evaluation of adjuvant trastuzumab in unselected HER2 positive breast cancer patients. Single institution experience F. De Braud 2013 Observational 296 296 131/13 Role of extracellular matrix in breast cancer response to chemotherapy E. Tagliabue 2013 Observational 100 Closed accrual 133/13 Analysis of MRI semeiotic patterns in invasive breast carcinoma not combined with contrast uptake G. Trecate 2013 Observational 16 16 165/13 Observational study to assess the impact of hormonal treatment with aromatase inhibitors on the psychological dimension of patients with breast cancer C. Borreani 2013 Observational 1 1 67/09 Multicenter, randomized, open label study evaluating A. Moliterni a poly(AFP-ribosio) polymerase-1(PARP-1) inibitor, SAR240550 (BSI-201), administered twice weekly or weekly, in combination with gemcitabine/carboplatin, in patients with Triple Negative breast Cancer (mTNBC) 2010 18/03/13 II 8 Closed accrual 05/10 A randomized, open label, phase II study to evaluate G. Mariani the safety, tolerability and efficacy of trastuzumab in combination with vinorelbine in patients with metastatic HER-2 positive breast cancer who have cardiovascular diseases 2010 31/01/13 II 1 1 188 31/12/13 15/12/13 ongoing clinical studies Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 35/10 Evaluation of [18F]FLT-PET/CT in early monitoring E. of response to primary medical therapy in patients Bombardieri with breast cancer and as in vivo indicator of cellular proliferation 2010 30/04/13 - 15 Closed accrual 46/10 A multicenter, multinational phase II study to assess the clinical safety and feasibility of T-DM1 sequantially with anthracycline based chemotherapy, as adjuvant or neoadjuvant therapy for patients with early stage HER2-positive breast cancer 2011 12/06/13 II 1 Closed accrual 43/11 Dual ERbB1/ErbB2 Inhibitor lapatinib and or the A. Moliterni anti-diabetic biguanide metformin as treatment in metastatic breast cancer ER+HER2- to modulate the response after progression to first line hormonal therapy 2011 04/12/13 II 10 3 86/11 An open label randomized phase 1b/2 study of PF04691502 in combination with letrozole compared with letrozole alone in patients with estrogen receptor positive, HER2 negative early breast cancer 2011 15/07/13 I-II 3 Closed accrual 93/11 An open-label, multicenter extension study of G. V. Bianchi trastuzumab- MCC-DM1 (T-DM1) administered as a single agent or in combination with other anticancer therapies in patients previously treated with the equivalent T-DM1 regimen in a Genentech and / or F. Hoffmann-La Roche Ltd. - sponsored - T-DM1 study 2011 21/10/13 II 1 Closed accrual 87/12 Adipose tissue derived mesenchymal stem cells: immunophenotypic and functional characterization M. Nava 2012 01/10/13 Observational 60 Closed accrual 89/12 Recent trends in axillary and sentinel lymph node dissection practices among breast cancer patients– an international comparison M. Sant 2012 30/06/13 Observational 1421 658 G. Bianchi S. Cresta GASTROINTESTINAL CANCERS 28/04 Open label randomized, multicenter phase III study of adjuvant chemotherapy in radically resected adenocarcinoma of the stomach or gastroesophageal junction: comparison of sequential treatment (CPT11 + 5-FU/LV TXT + CDDP versus a 5-FU/LV regimen) M. Di Bartolomeo 2005 21/01/13 III 71 Closed accrual 54/06 Phase III, randomised, double-blind, stratified, comparative, placebo controlled, parallel group, multicentre study to assess the effect of deep subcutaneous injections of lanreotide autogel 120 mg administered every 28 days on tumour progression free survival in patients with non functioning entero-pancreatic endocrine tumour. R. Buzzoni 2006 19/09/13 III 1 Closed accrual 25/07 A study of the genetic polymorphisms of patients with gastrointestinal stromal tumors (GIST) and of their predictive value of clinical activity of tyrosin kinase inhibitors P. Casali 2007 30/01/13 Observational 36 Closed accrual 189 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated Closed Phase 32/07 The Global Observational registry colllecting Longitudinal Data on Advanced GIST patients (GOLD reGISTry) P. Casali 2007 25/02/13 Observational 54 Closed accrual 69/07 A double-blind, randomised, multicenter, phase III study of bevacizumab in combination with capecitabine and cisplatin versus placebo in combination with capecitabine and cisplatin, as firstline therapy in patients with advanced gastric cancer M. Di Bartolomeo 2007 22/01/13 III 9 Closed accrual 17/04 A phase II, open label study of PTK787/ZK222584 in P. Casali the treatment of metastatic Gastrointestinal Stromal Tumors (GISTs) resistant to imatinib mesylate 2005 II 22 Closed accrual 75/06 A prospective randomized, open-label trial comparing Sirolimus-containing versus mTOR -inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. V. Mazzaferro 2006 II 39 Closed accrual 09/07 LIVER MATCH. An Italian multicentric study to evaluate the impact of donor-recipient matching in the outcome of liver transplantation at short, medium and long term E. Regalia 2007 - 54 Closed accrual 08/08 Accrual of patients with colorectal cancer and of healthy sisters/brothers for studies on genetic risk factors T. Dragani 2008 - 1258 106 52/07 A randomized trial investigating the role of FOLFOX-4 regimen duration (3 versus 6 months) and bevacizumab as adjuvant therapy for patients with stage II/III colon cancer M. Di Bartolomeo 2007 III 131 Closed accrual 27/08 Perioperative treatment with COI-E (capecetabine, oxaliplatin, irinotecan and cetuximab) of liver metastasis of colorectal carcinoma potentially resectable although at high risk of recurrences R. Buzzoni 2008 II 34 6 38/08 A phase III randomized, double-blind, placebocontrolled study of sorafenib as adjuvant treatment for hepatocellular carcinoma after surgical resection or local ablation (STORM) V. Mazzaferro 2008 III 46 Closed accrual 01/09 Open label extension study of lanreotide autogel 120 mg in patients with non functioning enteropancreatic endocrine tumour R. Buzzoni 2009 III 1 Closed accrual 21/09 A randomized, open-label, multicenter phase III study to evaluate the efficacy and safety of nilotinib versus imatinib in adult patients with unresectable or metastatic gastrointestinal stromal tumors P. Casali 2009 III 1 Closed accrual 12/09 Capecetabine in combination with oxaliplatin, irinotecan and bevacizumab (COI-B regime) as first. line therapy for metastatic colorectal cancer: a phase II ITMO study M. Di Bartolomeo 2009 26/06/13 II 33 Closed accrual 24/09 A randomized, double-blind, multicenter phase III study of brivanib plus best supportive care (BSC) versus placebo plus BSC in subjects with advanced hepatocellular carcinoma (HCC) who have failed or are intolerant to sorafenib V. Mazzaferro 2009 17/05/13 III 6 Closed accrual 190 15/10/13 Total patients Patients enrolled in 2013 ongoing clinical studies Study Code Title Coordinator Activated 79/09 Observational study of plasma levels of Imatinib in patients with gastrointestinal stromal tumor P. Casali 2010 Observational 80 7 80/09 Controlled extension of conventional criteria for liver tranplantation in hepatocellular carcinoma (HCC): a prospective validation study V. Mazzaferro 2009 II 32 7 21/10 A phase II, open label study to evaluate the activity and safety of Everolimus in association to Imatinib in PDGFRA-D842V unresectable or metastatic gastrointestinal stromal tumours (GISTs) as first line treatment P. Casali 2010 II 5 2 80/10 A randomized, double-blind, placebo-controlled P. Casali phase III of regorafenib plus best supportive care versus placebo plus best supportive care for subjects with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite prior treatment with at least imatinib and sunitinib 2011 III 10 Closed accrual 14/11 ITACA-S- 2 (Intergroup trial in adjuvant R. Buzzoni chemotherapy for adenocarcinoma of the stomach) comparison of the efficacy of a peri-operative versus a post-operative chemotherapy treatment in patients with operable gastriic cancer and assessment of the benefit op a post-operative chemo-radiotherapy 2011 III 1 Closed accrual 30/11 Phase 2 placebo-controlled double-blind trial of dasatinib added to gemcitabinae for subjects with locally-advanced pancreatic cancer R. Buzzoni 2011 II 5 Closed accrual 75/11 DOVIGIST: Phase II trial to evaluate the efficacy and safety of Dovitinib (TKI258) in patients with gastrointestinal stromal tumors refractory and/or intolerant to imatinib P. Casali 2011 II 3 Closed accrual 85/11 Phase I dose escalation study of S. 78454 (HDACi) in combination with FOLFOX in patients with locally advanced or metastatic digestive cancer F. de Braud 2011 I 8 2 94/11 Evaluation of diagnostic accuracy of diffusionweighted magnetic resonance (DW-MRI) and perfusion magnetic resonance (DCE-MRI) in the dilation of mesorectal lymph nodes in colorectal cancer D. Scaramuzza 2011 Observational 32 0 A randomized, open-label, multicenter phase IIIb M. Di study comparing two trastuzumab dosing regimens, Bartolomeo each in combination with cisplatin/capecitabine chemotherapy, as first-line therapy in patients with HER 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease 2011 III 7 1 Efficacy of tandem treatment with [90Y-DOTA, E. Seregni Tyr(3)] Octreotate and [177LuDOTA, Tyr(3)] Octreotate in patients with neuroendocrine tumour overexpressing somatostatin receptors and refractory to conventional therapy 2012 II 52 28 100/11 06/12 Closed Phase Total patients Patients enrolled in 2013 191 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated 15/12 Pseudomixoma peritonei: prognostic analysis of micro-RNA and other factors using tissue M. Deraco 2012 Observational 24 11 16/12 Multicenter Italian study on the CEUS assessment R. Lanocita of Response of colorectal cancer metastasis Treated with Avastin 2012 IV 2 0 22/12 A randomized, double-blind, multicenter, Phase III study of everolimus (RAD001) plus best supportive care versus placebo plus best supportive care in the treatment of patients with advanced NET of GI or lung origin - RADIANT-4 R. Buzzoni 2012 III 23 Closed accrual 31/12 Peritoneal Mesothelioma: Optimize Outcomes by the Integration of new Prognostic Factors and Potential Therapeutic Targets in a Individualized Treatment based on Molecular Characterization and Chemosensitivity Profile on Primary Cultures M. Deraco 2012 II 16 12 42/12 A multi-center, open-label study to assess F. de Braud pharmacokinetics of TKI258 in adult cancer patients with normal and impaired hepatic function 2012 I 8 2 60/12 "A Randomized, Open-label, Two-Arm Phase II Trial Comparing the Efficacy of Sequential Ipilimumab versus Best Supportive Care Following First-line Chemotherapy in Subjects with Unresectable Locally Advanced/Metastatic Gastric or GastroEsophageal Junction Cancer” Maria Di Bartolomeo 2012 II 16 8 73/12 Identification of circulating tumor cells in blood of patients with advanced colorectal cancer and assessment of their modifications during treatment with cetuximab or panitumumab, alone or associated with chemotherapy F. de Braud 2012 Observational 52 25 74/12 A Multicenter, Single arm, Open Label Clinical Trial to Evaluate the Safety and Health-Related Quality of Life of Aflibercept in Patients with Metastatic Colorectal Cancer (mCRC) Previously Treated with an Oxaliplatin-Containing Regimen Maria Di Bartolomeo 2012 III 15 Closed Accrual 97/12 A randomized, phase III, multicenter, doubleblid, placebo-controlled study evaluating the efficacy and safety of onartuzumab (MetMab) in combination with metastatic HER2 negative, METPositive Gastriesophageal cancer Maria Di Bartolomeo 2012 III 18 17 99/12 An open-label phase IIIb study of regorafenib in patients with metastatic colorectal cancer (CRC) who have progressed after standard therapy M. Di Bartolomeo 2013 III 15 Closed accrual A multicenter, two stage, phase II study, evaluating the efficacy of oral BEZ235 plus best supportive care (BSC) versus placebo plus BSC in the treatment of patients with advanced pancreatic neuroendocrine tumors (pNET) after failure of mTOR inhibitor therapy R. Buzzoni 2013 II 6 Closed accrual 102/12 192 Closed Phase Total patients Patients enrolled in 2013 ongoing clinical studies Study Code 107/12 Title Coordinator Activated Randomized, couble-blind, phase 3 study of TAS102 plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic colorectal cancer refractory to standard chemotherapies M. Di Bartolomeo Closed Phase Total patients Patients enrolled in 2013 2013 III 9 Closed accrual 117/12 Identification of circulating biomarkers of resistance F. de Braud to antiangiogenic treatment in patients with advanced colorectal cancer and assessment of their modification during therapy with antiangiogenic drugs (bevacizumab, aflibercept and regorafenib) 2012 Observational 56 55 139/12 A phase II, multicenter, open-label, randomized study evaluating the efficacy and safety of Folfiri + MEHD7945A versus Folfiri + Cetuximab in second line in patients with KRAS Wild type metastatic colorectal cancer M. Di Bartolomeo 2013 II Closed accrual 149/12 The EGF rs4444903 AG polymorphism in relationship to detection rate and tumour size at diagnosis in patients undergoing surveillance for HCC and to HCC doubling time V. Mazzaferro 2013 03/13 Identification of Genetic Circulating Biomarkers for the Early Diagnosis of Colorectal Cancer 07/13 Observational 58 58 M. A. Pierotti 2013 Observational 115 115 A Phase III, Randomized, Double-Blind Study of Tivantinib (ARQ 197) in Subjects with MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated with One Prior Systemic Therapy V. Mazzaferro 2013 III 9 9 35/13 Prospective randomized phase II trial comparing mandatory second-look surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery, vs. standard postoperative follow-up in patients at high risk of developing colorectal cancer peritoneal metastases D. Baratti 2013 - 3 3 36/13 Identification of Genetic Circulating Biomarkers for monitoring and early detection of recurrence in surgically treated colorectal Cancer patients. M. Gariboldi 2013 Observational 65 65 50/13 Perioperative treatment with COI-B (Capecitabine, Oxaliplatin, Irinotecan and Bevacizumab) of high risk or borderline resectable colorectal cancer liver metastases F. De Braud 2013 II 7 7 79/13 A multicenter, stratified, open, randomized, E. Seregni comparator-controlled, parallelgroup phase III study comparing treatment with 177Lu-DOTA0Tyr3-Octreotate to Octreotide LAR in patients with inoperable, progressive, somatostatin receptor positive midgut carcinoid tumours 2013 III 1 1 87/13 Retrospective-prospective observational study on the natural history of brain metastases from colorectal cancer F. De Braud 2013 Observational 39 39 IL-6-related inflammation signatures as a predictive marker of recurrence in liver cancer patients V. Mazzaferro 2013 Observational 30 30 110/13 01/07/13 4 193 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 126/13 Prospective observational study on the impact of genetic polymorphisms on the occurrence of chemotherapy-induced toxicity in gastrointestinal epithelial neoplasms F. De Braud 2013 Observational 9 9 137/13 A Single-Arm, Open Label Study of Aflibercept as Maintenance Therapy Following Induction with Aflibercept in Combination with XELOX, as FirstLine Treatment for Metastatic Colorectal Cancer Patient M. Di Bartolomeo 2013 I-II 2 2 141/13 "A prospective, single-arm, multicenter, uncontrolled, open-label Phase II trial of refametinib (BAY 86-9766) in patients with RAS mutant Hepatocellular Carcinoma 141/13 A prospective, single-arm, multicenter, uncontrolled, V. open-label Phase II trial of refametinib (BAY 86Mazzaferro 9766) in patients with RAS mutant Hepatocellular Carcinoma (HCC) 2013 II 8 8 159/13 DNA-seq analysis for prediction of outcome to first line irinotecan versus oxaliplatin-based regimens in advanced colorectal cancer patients enrolled in a randomized phase II, prospective study M. Gariboldi 2013 Observational 43 43 61/09 An uncontrolled open label multicenter phase II safety study of BAY73-4506 in patients with hepatocellular carcinoma (HCC) V. Mazzaferro 2010 09/07/13 II 2 Closed accrual 64/10 The role of natural fluorescence of plasma in colorectal cancer patients E. Leo 2010 30/04/13 - 200 Closed accrual 14/12 Post-traumatic growth and psycho-social adaptation in patients submitted to liver transplant C. Borreani 2012 12/11/13 Observational 233 10 44/09 A randomized, double-blind, placebo-controlled, F. Raspagliesi 2009 phase 3 study to assess the efficacy and safety of weekly farletuzumab (MORAb-003) in combination with carboplatin and taxane in subjects with platinum-sensitive ovarian cancer in first relapsed 10/01/13 III 3 Closed accrual 46/07 Prostate cancer research international: active surveillance (PRIAS) R. Valdagni 2007 - 327 50 54/07 Identification of Men with a genetic predisposition to Prostate Cancer: Target Screening in BRCA1/2 mutation carriers and controls - the IMPACTstudy N. Nicolai 2008 - 16 5 10/09 Carboplatin and Paclitaxel administered every three F. Raspagliesi 2009 weeks vs Carboplatin and Paclitaxel administered weekly to patients with ovary carcinoma: multicentric randomized study III 39 Closed accrual 65/09 LION - Lymphadenectomy in ovarian neoplasm. An open randomized prospective multicenter trial. A project of the AGO Study Group - 32 Closed accrual GENITAL APPARATUS 194 F. Raspagliesi 2010 ongoing clinical studies Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 68/09 A multi-centre, open-label, randomised, two arm F. Raspagliesi 2010 phase III trial of bevacizumab plus chemotherapy versus chemotherapy alone in patients with platinum-resistant, epithelial ovarian, fallopian tube or primary peritoneal cancer III 3 Closed accrual 71/09 A phase III study to evaluate the efficacy and safety of pazopanib monotherapy versus placebo in women who have not progressed after first line chemotherapy for epithelial ovarian, fallopian tube, or primary peritoneal cancer F. Raspagliesi 2010 III 2 Closed accrual 22/10 An open label, phase II study of vaccination with surviving peptides emulsified in Montanide ISA 51VG after IMP 321TM injection in prostate carcinoma patients with biochemical failure L. Rivoltini 2010 II 26 Closed accrual 38/10 Tandem transplantation of autologous hematopoietic progenitors in relapsed/refractory patients with metastatic germinal tumors R. Salvioni 2010 II 44 15 50/10 Multicentric observational study DUE-01: urinary S. Villa and erectile dysfunction after radical external beam therapy in localized prostate cancer 2010 Observational 148 47 03/11 A phase III, randomized, double-blind trial of weekly F. Raspagliesi 2011 paclitaxel plus AMG386 or placebo in women with recurrent partially platinum sensitive or resistant epithelial ovarian, primary peritoneal or fallopian tube cancers III Closed accrual 11/11 Breathing analysis by electronic nose for detection of ovarian cancer in general population and in population at risk F. Raspagliesi 2011 Observational 159 29 61/11 Randomized multicentric study comparing the efficacy of additional cytoreductive surgery vs exclusive chemotherapy in patients with platinumsensitive recurrent ovarian cancer F. Raspagliesi 2011 IV 7 5 63/11 NGR018: randomized phase II study of NGR-hTNF plus pegylated liposomial doxorubicin (PLD) versus PLD in platinum-resistant ovarian cancer F. Raspagliesi 2011 II 33 Closed accrual 87/11 A Randomized phase III study comparing stabdard first-line docetaxel prednisone to docetaxel prednisone in combination with custirsen (CGX011) in men with metastatic castrate resistant prostate cancer G. Procopio 2011 III 5 Closed accrual 95/11 Active surveillance “SA INT” in prostate cancer patients with low progression risk R. Valdagni 2011 Observational 40 20 105/11 A randomized controlled study on the effectiveness of first-line chemotherapy (carboplatin and paclitaxel) versus chemo-immunotherapy (carboplatin-paclitaxel-oregovomab) in patients with advanced epithelial ovarian, adnexal or peritoneal carcinoma F. Raspagliesi 2011 II 11 0 106/11 A randomized phase II study of carboplatin and paclitaxel +/- cetuximab, in advanced and/or recurrent cervical cancer F. Raspagliesi 2011 II 13 3 12 195 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated 107/11 Phase III International Multicenter Randomized Study Testing the Effect on Survival of Prolonging Platinum-free Interval in Patients With Ovarian Cancer Recurring Between 6 and 12 Months After Previous Platinum Based Chemotherapy F. Raspagliesi 2013 108/11 Randomized multicentric phase II study with weekly D. Lorusso pazopanib plus taxolo versus weekly taxolo alone in platinum-resistant or refractory ovarian carcinoma 2011 67/10 A prospective evaluation of plasma levels of R. Valdagni inflammatory markers in radiotherapy treatment of prostate cancer and relationship with acute and late rectal toxicity 2010 02/12 A phase III randomized, double-blind, placebocontrolled, multi-center study of AMG 386 with paclitaxel and carboplatin as first-line treatment of subjects with FIGO stage III-IV epithelial ovarian, primary peritoneal or fallopian tube cancers 18/12 Closed Phase Total patients Patients enrolled in 2013 III 8 8 II 16 10 Observational 25 Closed accrual III 11 3 A randomized phase II trial of carboplatin-paclitaxel F. Raspagliesi 2012 compared to carbplatin-paclitaxel-bevacizumab in advanced (stage III-IV) or recurrent endometrial cancer II 21 16 19/12 A phase II randomized Open label study of MM-121 F. Raspagliesi 2012 in combination with paclitaxel versus paclitaxel alone in patients with platinum resistant/refractory advanced ovarian cancer II 11 5 20/12 F. Raspagliesi 2012 Phase II study of trabectedi (Yondelis) in BRCA1 e BRCA2 mutation carrier and BRCA ness phemotype advanced ovarian cancer patients II 18 9 32/12 A phase II, open-lebal, singlie-arm, non randomized, multicenter study to evaluate the efficacy of oral TK258 as second-line therapy in patients with either FGFR2 mutated or wild-type advanced and/ or metastatic endometrial cancer F. Raspagliesi 2012 II 10 5 33/12 Study of circulanting biological factors in gynecological cancer (ovary, uterine cervix, endometrium) F. Raspagliesi 2012 Observational 29 1 50/12 Does Palliative Chemotherapy Improve Symptoms in Women with Recurrent Ovarian Cancer? Measuring subjective improvement as well as objective response to estimate the benefit of palliative chemotherapy in women with platinum resistant or refractory ovarian cancer F. Raspagliesi 2013 Observational 27 27 68/12 Rare tumors in gynecologic oncology: retrospective and prospective collection data on diagnosis and treatment of rare gynecologic neoplasia D. Lorusso 2012 Observational 281 100 70/12 Evaluation of the geriatric care needs and pathways R. Valdagni after initial treatment in elderly patients with urogenital cancer (prostate, kidney, bladder and penis) 2012 Observational 78 70 196 F. Raspagliesi 2012 03/10/13 ongoing clinical studies Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 110/12 Phase II study of the Pan-HER inhibitor Dacomitinib A. Necchi (PF-00299804) for patients with locally advanced or metastatic squamous cell carcinoma of the penis 2013 II 1 1 123/12 Phase II study of single-agent Pazopanib (Votrient®) A. Necchi for patients with relapsed or refractory germ-cell tumors (GCT) 2013 II 13 13 124/12 Radium-223 Chloride (Alpharadin) in Castrationresistant (Hormone-Refractory) Prostate Cancer Patients with Bone Metastasis G. Procopio 2013 III 7 Closed accrual 126/12 A multicenter study in patients with stage III-IV epithelial ovarian cancer treated with carboplatin/ paclitaxel with bevacizumab: clinical and biological prognostic factors D. Lorusso 2013 IV 52 52 12/13 NGR018: Randomized phase II study of NGR-hTNF plus an anthracycline versus an anthracycline alone in platinum-resistant ovarian cancer F. Raspagliesi 2013 II 12 Closed accrual 25/13 A Phase 3, Randomized, Double-Blind Trial of Pegylated Liposomal Doxorubicin (PLD) Plus AMG 386 or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer F. Raspagliesi 2013 III 14 Closed accrual 30/13 A. Necchi Brentuximab vedotin (SGN-35) as salvage therapy for males with advanced and platinum-resistant germ-cell tumors. An open label, single group, phase 2 trial 2013 II 2 2 33/13 External radiotherapy for intermediate or high risk prostate cancer: Irradiation of the pelvis and boost to the prostate in two 9 Gy fractions S. Villa 2013 - 3 3 82/13 A Double-blind, Placebo-controlled, Randomized, Phase 2 Study to Evaluate the Efficacy and Safety of Maintenance Therapy With PankoMab-GEX™ After Chemotherapy in Patients With Recurrent Epithelial Ovarian Carcinoma F. Raspagliesi 2013 II 3 3 101/13 Pertuzumab in Platinum-resistant low HER3 mRNA epithelial ovarian cancer (Pertuzumab nel carcinoma ovarico epiteliale a bassa espressione di mRNA di HER3, resistente al platino) D. Lorusso 2013 III 5 5 17/11 An open-label study of abiraterone acetate in subjects with metastatic castration-resistant prostate cancer who have progressed after taxanebased chemotherapy G. Procopio 2011 13/12/13 III 37 Closed accrual 22/11 Multicentre, single-arm, open label, clinical trial G. Procopio intended to provide early access to cabazitaxel in patients with metastatic hormone refractory prostate cancer previously treated with a docetaxelcontaining regimen and to document safety of cabzitaxel in these patients 2011 04/07/13 III 6 Closed accrual 197 back to contents SCIENTIFIC REPORT 2013 Study Code 96/11 111/11 Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 Evaluation of a software allowing fusion of prostate magnetic resonance and transrectal ultrasound images C. Fallai 2011 31/12/13 Observational 16 8 Registry of treatment patterns in patients with metastatic castration-resistant prostate cancer (mCRPC) with progression during or after docetaxel-based regimen G. Procopio 2011 18/03/13 Observational 43 17 HEAD & NECK AND THYROID TUMORS 04/09 Phase II, multicenter, open-labe, single arm trial to evaluate the safety and efficacy of oral E7080 in medullary and iodine-131 refractory, unresectable differentiated thyroid cancers, stratified by histology L. Licitra 2009 II 11 Closed accrual 05/09 An internationall, randomized, double-blinded, phase 3 efficacy study of XL184 versus placebo in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer L. Licitra 2009 III 9 Closed accrual 29/10 Sorafenib in recurrent and/or metastatic salivary gland carcinomas L. Locati 2010 II 37 Closed accrual 40/10 Phase II study of preoperative TPF chemotherapy in locally advanced resectable oral cavity squamous cell cancer in order to improve the rate of pathological complete response L. Licitra 2010 II 9 2 65/10 A double-blind, randomized phase III study L. Licitra evalutating the efficacy and safety of Sorafenib compared to placebo in locally advanced/metastatic RAI-refractory differentiated thyroid cancer 2011 III 5 Closed accrual 07/11 A randomized, international, open-label. Multicentre, phase III study to assess the effect of a patient outreach program on the percentage of time patients with locally advanced or metastatic medullary thyroid cancer experience grade 2 or higher adverse events during the first 12 months of treatment with vandetannib L. Licitra 2011 III 8 Closed accrual 35/11 Cetuximab and Cisplatin with or without Paclitaxel in recurrent/metastatic head and neck cancer L. Licitra 2012 II 13 8 44/11 Randomized, double-blind, multicenter twostage adaptive phase 3 study of intravenous adnìministration of REOLYSIN (Reovirus type 3 dearing) in combination with paclitaxel and carboplatin versus the chemotherapy alone in patients with metastatic or recurrent squamous cell carcinoma of the head and neck who have progressed on or after prior platinum-based chemotherapy L. Licitra 2011 III 9 Closed accrual 198 ongoing clinical studies Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 45/11 A single arm, open-label, phase II, multicentre study, L. Licitra to assess the safety of vismodegib (GDC-0449) in patients with locally advanced or metastatic basal cell carcinoma 2011 II 34 8 57/11 A randomised, double-blind, placebo-controlled, L. Licitra 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 2011 III 3 2 68/11 A randomised, open.label, phase III study to L. Licitra evaluate the efficacy and safety of oral afatinib (BIBW 2992) versus intravenous methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who have progressed after platinum-based therapy 2011 III 24 18 69/11 A phase 2, multi-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of ALD518 in the reduction of oral receiving concomitant chemotherapy and radiotherapy L. Licitra 2011 II 17 3 70/11 An open -label, multi-center phase II study of the BRAF inhibitor RO5185426 in patients with metastatic or unresectable papillary thyroid cancer (PTC) positive for the BRAF V600 mutation and resistant to radioactive iodine L. Licitra 2011 II 1 Closed accrual 71/11 A multicentre, randomized, double-blind, placebo-controlled, phase III trialof E7080 in 131I-Refractory differentiated thyroid cancer L. Licitra 2011 III 15 Closed accrual 91/11 Radioiodine therapy of differentiated thyroid carcinoma with maximized activity based on individualized dosimetry E. Seregni 2011 II 8 1 35/12 An international, randomized, double-blind, two-arm study to evaluate the safety and efficacy of vandetanib 150 and 300 mg/day in patients with unresecable locally advanced or metastatic medullary thyroid carcinoma with progressive or symptomatic disease L. Licitra 2012 IV 13 Closed accrual 36/12 Continuing access ti the tyrosine kinase inhibitor of vegfr-2, ag-013736 (A406) for patienys previously receiving ag-013736 in clinical trias L. Licitra 2012 III 1 Closed accrual 44/12 TP53 as a biomarker to personalize chemotherapy for patients with head and neck cancer P. Bossi 2012 Observational 8 0 76/12 Neoadjuvant afatinib based treatment strategies L. Licitra followed by surgery in squamous cell carcinoma of the head and neck: an EORTC NOCI-HNCG window study 2012 II 7 8 199 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 29/13 Multidisciplinary approach for poor prognosis sinonasal tumors: Phase II study of chemotherapy, photon and heavy ion radiotherapy integration for more effective and less toxic treatment in inoperable patients. L. Licitra 2013 II 4 4 37/13 Retrospective study on first line treatments in patients with recurrent and/or metastatic head and neck squamous cell carcinomas: dose intensity, toxicity, combinations used P. Bossi 2013 04/12/13 Observational 70 70 38/13 Cross-sectional study for the evaluation of P. Bossi dysphagia and aspiration caused by IMRT + chemotherapy in oropharyngeal tumors oropharynx 2013 01/10/13 Observational 110 110 69/13 INduction chemoThERapy followed by CEtuximab Plus definiTive radiOtheRapy versus radiation plus cisplatin L. Licitra 2013 III 1 88/13 Linguistic validation of quality of life questionnaire MDASI-HN P. Bossi 2013 92/13 "A Randomised, Double-Blind, Placebo-Controlled, Multi-Centre Phase III Study to Assess the Efficacy and Safety of Vandetanib (CAPRELSA™) 300 mg in Patients with Papillary or Poorly Differentiated Thyroid Cancer That Is Either Locally Advanced or Metastatic Who Are Refractory or Unsuitable for Radioiodine (RAI) Therapy” L. Licitra 112/13 Development of an EORTC questionnaire for the assessment of quality of life in thyroid cancer patients (EORTC QLQ-THY) Phase I / II L. Locati 2013 Observational 18 121/13 "Phase II multicenter randomized, double blind, L. Licitra placebo controlled study assessing the efficacy of buparlisib (BKM120) plus paclitaxel vs. placebo plus paclitaxel in patients with platinum pre-treated recurrent or metastatic head and neck squamous cell carcinoma” 2013 II 1 1 15/11/13 Observational 56 56 2013 III 3 3 Closed accrual HEMATOLOGIC MALIGNANCIES 34/05 Multicentric randomized phase III study that A. M. Gianni, compares high-dose chemotherapy with rituximab P. Corradini and autotransplantation of circulating hemopoietic precursors with CHOP with rituximab administered every 14 days as first-line therapy for patients at high risk with large B-cell non-Hodgkin’s lymphoma 2005 31/07/13 III 40 Closed accrual 44/06 Intensive chemo-immunotherapy as first-line in adult patients with peripheral T-cell Lymphoma P. Corradini 2006 31/01/13 II 15 Closed accrual 59/09 Phase I/II of desamethasone, ofatumumab and bendamustine (TREANDA) (DOT) as first-line treatment of mantle-cell lymphoma (MCL) in the elderly A. M. Gianni 2009 27/08/13 I-II 13 Closed accrual 200 ongoing clinical studies Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 32/04 Prospective observational study in the adult with Burkitt’s lymphoma of a polychemotherapy scheme in use in pediatrics A. M. Gianni, M. Di Nicola 2004 Observational 21 3 02/05 A multicenter, open label study of oral melphalan, P. Corradini and CC-5013 (Revlimid) (MPR) as induction therapy in elderly newly diagnosed multiple mieloma patients 2005 I-II 4 Closed accrual 12/06 A phase II, multicenter study of bortezomib, pegylated liposomal doxorubicin, dexamethasone (PAD) as induction and melphalan 100 mg/m2 (MEL 100) as transplant, in elderly newly diagnosed multiple myeloma patients P. Corradini 2006 II 12 Closed accrual 13/06 A phase III, multicenter, randomized open label study of velcade, melphalan, prednisone and thalidomide (V-MPT) versus velcade, melphalan, prednisone (V-MP) in elderly untreated multiple myeloma patients P. Corradini 2006 III 9 Closed accrual 14/06 A phase 3, prospective, randomized clinical study with velcade-thalidomide-dexamethasone versus thalidomide-dexamethasone for previously untreated patients with symptomatic multiple myeloma who are candidates to receive double autologous transplantation P. Corradini 2006 III 13 Closed accrual 28/06 Zevalin at myeloablative doses in aggressive lymphomas of elderly patients P. Corradini 2006 III 4 Closed accrual 50/06 A phase II, multicenter study of meplphalan 100 mg/m2 (MEL 100) as transplant, Revlimid and Prednisone (RP) as consolidation and Revlimid alone as maintenance in elderly newly diagnosed multiple myeloma patients. P. Corradini 2006 II 12 Closed accrual 67/06 A phase II, multi-center, randomized, open label P. Corradini study of Velcade, Doxorubicin and Dexamethasone (PAD) vs Thalidomide and Dexamethasone (TD) in advanced and refractory multiple myeloma patients. 2007 II 3 Closed accrual 38/07 A multicentric randomized trial in adult patients P. Corradini with acute myelogenous leukemia (AML) to compare: 1) a standard-dose versus high-dose remission induction regimen, and 2) an autologous blood stem cell transplantation versus an autologous blood cell-supported multicycle highdose chemotherapy program,, within a risk-oriented postremission strategy reserving allogeneic stem cell transplantation for high-risk cases 2007 III 11 Closed accrual 48/07 Reduced intensity conditioning with high-dose rituximan followed by allogeneic transplantation of hematopoietic cells for the treatment of relapsed/ refractory B-cell non Hodgkin's lymphomas P. Corradini 2007 II 20 4 55/07 Treatment with imatinib mesylate (Glivec) of severe P. Corradini chronic scleroderma-like GVHD, refractory to conventional immunosuppressive therapy 2008 II 8 Closed accrual 201 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated 63/07 Lombardy registry of HCV positive lymphomas P. Corradini 2008 Observational 7 Closed accrual 02/08 A phase 3, multicentre, randomized, controlled A.M. Gianni, study to determine the efficacy and safety of P. Corradini lenalidomide, melphalan and prednisone (MPR) versus melphalan (200 mg/m2) followed by stem cell transplant in newly diagnosed multiple myeloma subjects 2008 III 16 Closed accrual 34/08 Randomized study comparing intravenous busulfan (i.v. BU;Bulsivex) plus fludarabine (BUFLU) versus intravenous busulfanplus Cyclophosphamide (BUCY2) as conditioning regimes prior to allogenic hematopoietic stem cell transplantation (ALLOHSCT) in patients (aged >=40 and <=55 years) with acute myeloid leukemia (AML) in complete remission (CR) P. Corradini 2008 III 4 Closed accrual 49/08 Multicentre clinical study with early treatment intensification in patients with high-risk Hodgkin lymphoma, identified as FDG-PET scan positive after two conventional BVD courses A. M. Gianni, P. Corradini 2008 II 49 14 09/09 Phase III study comparing rituximab-supplemented A. M. Gianni, ABVD (R-ABVD) with ABVD followed by involved- P. Corradini field radiotherapy (ABVD-RT) in limited-stage (stage I-IIA with no areas of bulk) Hodgkin's lymphoma 2009 III 12 2 13/09 Safety and efficacy of lenalidomide as main therapy in patients with newly diagnosed multiple myeloma following a tandem autologous-allogeneic transplant P. Corradini 2009 II 1 0 39/09 A phase 3 intergroup multicentre, randomized, controlled 3 arm parallel group study to determine the efficacy and safety of lenalidomide in combination with dexamethasone (Rd9 versus melphalan, prednisone and lenalidomide (MPR) versus cyclophosphamide, prednisone and lenalidomide (CPR) in newly diagnosed multiple myeloma subjects P. Corradini 2009 III 16 Closed accrual 46/09 A phase 3, multicentre, randomized, controlled study to determine the efficacy amd safety of ciclophosphamide, lenalidomide and dexamethasone (CRD) versus melphalan (200 mg/m2) followed by stem cell transplant in newly diagnosed multiple myeloma subjects P. Corradini 2009 III 11 Closed accrual 69/09 A multicenter, randomized, doble-blind, placebo controlled phase III study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed multiple myeloma P. Corradini 2010 III 12 Closed accrual 76/09 Brief induction chemoimmunotherapy with P. Corradini rituximab + bendamustine + mitoxantrone followed by rituximab in elderly patients with advanced stage previously unrtreated follicular lymphoma 2010 II 4 Closed accrual 202 Closed Phase Total patients Patients enrolled in 2013 ongoing clinical studies Study Code Title Coordinator Activated 07/10 Monitoring of human polyomavirus reactivation in patients with lymphoproliferative disease treated with chemotherapy, chemotherapy and rituximab, and rituximab alone P.Corradini 12/10 A phase I/II, multicenter, open label study of pomalidomide cyclophosphamide and prednisone (PCP) in patients with multiple myeloma relapsed and/or refractory to lenalidomide 13/10 Prospective audit on stem cell mobilization in malignant lymphoma Closed Phase Total patients Patients enrolled in 2013 2010 - 8 0 P. Corradini 2010 I-II 11 Closed accrual P. Corradini 2010 Observational 8 Closed accrual 27/10 Randomized phase II trial on primary chemotherapy M. Di Nicola with high-dose methotrexate and high-dose cytarabine with or without thiotepa, and with or without rituximab, followed by brain irradiation vs high-dose chemotherapy supported by autologous stem cells transplantation for immunocompetent patients with newly dignosed primary CNS lymphoma 2010 II 2 1 31/10 A randomized, double-blind, placebo-controlled A. M. Gianni phase 3 study of SGN-35 (brentuximab vedotin) and best supportive care (BSC) versus placebo and BSC in the treatment of patients at high risk of residual Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT) 2010 III 7 Closed accrual 48/10 Intensified program including bendamustine followed by PBSC mobilization and high dose therapy and autograft for patients with relapsed or resistant CD 20+ follicular Non Hodgkin Lymphoma: a multicenter, pivotal GITIL study P. Corradini 2010 II 2 0 56/10 A randomized, open label study of Ofatumumab and P. Corradini Bendamustine combination therapy compared with Bendamustine monotherapy in indolent B-cell nonHodgkin's lymphoma unresponsive to Rituximab or a Rituximab-containing regimen during or within six months of treatment 2013 III 2 2 57/10 A phase III trial comparing bertozomib, P. Corradini cyclofosfamide and dexamethasone versus lenalidomide cyclofosfamide and dexamethasone in patients with multiple myeloma at first relapse 2010 III 15 6 83/10 A phase III, double-blind, randomized, placebocontrolled, multicenter clinical trial to study the safety, tolerability, efficacy and immunogenicity of 212 in recipients of autologous hematopoietic cell transplants P. Corradini 2010 III 3 0 86/10 Prognosis of patients with relapsed/refractory HL treated with IGEV induction therapy before HDCT with AHSCT P. Corradini 2011 - 1 Closed accrual 08/11 A multicenter phase II study of subcutaneous velcade plus oral melphalan and prednisone or plus oral cyclophosphamide and prednisone or plus prednisone in newly diagnosed elderly multiple myeloma patients P. Corradini 2011 II 3 Closed accrual 203 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated Cardiac biomarkers and innovative echocardiographic parameters as predictors of cardiotoxicity in B-cell non-Hodgkin/Hodgkin's lymphoma patients treated with anthracyclines or high-dose chemotherapy P. Corradini 2011 Observational 26 23 33/11 A phase III, multicenter, open.label. Randomized P. Corradini trial comparing the efficacy of GA 101 (RO50722759) in combination with CHOP (G-CHOP) versus rituximab and CHOP (R-CHOP) in previously untreated patients with CD20-positive diffuse large B-cell lymphoma (DLBCL) 2011 III 14 6 34/11 An open-label, single-arm, phase I study of AEB071 P. Corradini (a protein kinase C inhibitor) in patients with CD79mutant diffuse large B-cell lymphoma 2011 I 12 2 37/11 A multicenter, open label phase II study of P. Corradini carfilzomib, cyclophosphamide and dexamethasone in newly diagnosed multiple myeloma patients 2011 II 2 Closed accrual 58/11 A phase 3, Randomized, open label trial of lenalidomide/dexamethasone with or without elotuzumab in relapsed or refractory multipl myeloma P. Corradini 2011 III 3 Closed accrual 72/11 An open label non randomized phase 2 study evaluating SAR3419, an anti-CD19 antobodymaytansine conjugate administred as single agent by intrevnous infusion to patients with relapsed or refractory D19+ diffuse large B cell lymphoma A. M. Gianni 2011 II 3 Closed accrual 80/11 Prospective, phase I/II, non -randomized, open label, P. Corradini multicenter study to determine safety and efficacy of Nilotinib in a population with steroid-refractory/ or steroid-dependent cGVHD 2011 I-II 1 0 89/11 A randomized phase III study to compare P. Corradini Bortezomib, melphalan, prednisone (VMP) with high dose melphalan followed by Bortezomib, Lenalidomide, Dexamethasone (VRD) consolidation and Lenalidomide maintenance in patients with newly diagnosed multiple myeloma 2011 III 21 14 53/12 A open label, phase 2, non randomized, multicentre trial to assess the feasibility of induction treatment with 5-Azacitidine (5-AZA) followed by allogeneic stem cell transplantation (allo-SCT) or continued 5-AZA treatment in patients without a suitable -sibling or unrelated- stem cell donor with IPSS Int2/High risk myelodysplastic syndromes (MDS) P. Corradini 2012 II 3 1 66/12 A phase III multicenter, randomized study P. Corradini comparing consolidation with 90YTTRIUMLABELED IBRITUMOMAB TIUXETAN (ZEVALIN®) radioimmunotherapy vs autologous stem cell transplantation (ASCT) in patients with relapsed follicular lymphoma (FL) aged 18-65 years 2013 III 2 2 110/11 204 Closed Phase Total patients Patients enrolled in 2013 ongoing clinical studies Study Code 80/12 Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 Bendamustine, lenalidomide and rituximab (R2-B) P. Corradini combination as a second-line therapy for first relapsed-refractory mantle cell lymphomas: a phase II study 2013 II 1 Closed accrual 112/12 Observational retrospective/prospective study in Hodgkin’s Lymphoma and Anaplastic Large Cell Limphoma patients who received SGN35 according to compassionate use (named patient program) P. Corradini 2013 Observational 4 Closed accrual 113/12 Extracorporeal photopheresis for the treatment of acute and chronic steroid-resistant Graft Versus Host Disease (GvHD): a multicenter, retrospective, observational study P. Corradini 2013 Observational 9 9 131/12 A randomized open-label multicenter phase II trial evaluating the safety and activity of DCDT2980S in combination with Rituximab or DCDS4501A in combination with Rituximab in patients with relapsed or refractory B-cell Non-Hodgkin’s lymphoma A. M. Gianni 2013 II Closed accrual 132/12 Allogeneic hematopoietic stem cell transplantation P. Corradini for patients with chemorefractory or relapsed Hodgkin's lymphoma: a retrospective, observational study 2013 133/12 Chronic Lymphocytic Leukemia (CLL) Registry: a prospective, observational study within the Rete Ematologica Lombarda P. Corradini 138/12 A multicenter, single-arm, open-label study with pomalidomide in combination with a low dose of dexamethasone in subjects with refractory or relapsed and refractory multiple myeloma 144/12 An open-label phase II study of BKM120 in patients with relapsed and refractory diffuse large B-cell lymphoma, mantle cell lymphoma and follicular lymphoma 151/12 06/06/13 Observational 53 53 2013 Observational 12 12 P. Corradini 2013 III 28 28 P. Corradini 2013 II 3 3 Genetics-driven targeted management of lymphoid A. M. Gianni malignancies. Improving molecular characterization and diagnosis of hairy cell leukemia and classical hodgkin lymphoma 2013 Observational 2 Closed accrual 11/13 Myeloablative Conditioning, followed by Unmanipulated Haploidentical Bone Marrow Transplantation and post-transplant high dose Cyclophosphamide , for Patients with Hematologic Malignancies: a Phase II study P. Corradini 2013 II 2 2 31/13 A multicenter, open label, study of weekly P. Corradini carfilzomib, cyclophosphamide and dexamethasone (wCCyd) in newly diagnosed multiple myeloma (MM) patients 2013 I-II 4 4 41/13 Clinical outcome in patients with myelodysplastic syndrome receiving allogeneic stem cell transplant from unrelated donor: impact of donor availability and transplant procedure timing 2013 Observational 4 4 P. Corradini 01/12/13 2 30/08/13 205 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated 51/13 An observational prospective study on fertility and gonadal function in young adult female patients with lymphoma or sarcoma, who choose to undergo fertility preservation by mature ovocytes cryopreservation before starting chemotherapy S. Viviani 2013 52/13 Multicentric retrospective study evaluating L. Devizzi the efficacy and the tolerability of four doses of Rituximab followed by involved field radiotherapy in non bulky stage I-II follicular Lymphoma (grade 1-2) 2013 57/13 A phase I/II study of Danusertib in Combination with romidepsin in adult patients with mature peripheral T-Cell lymphoma (PTCL) A. M. Gianni 63/13 An open label, single arm, phase II study of nilotinib 300 mg BID in newly diagnosed CPCML patients, in order to verify disappearance of CD34+/lin-Ph+ cells from bone marrow during treatment 86/13 Closed Phase Total patients Patients enrolled in 2013 Observational 3 3 Observational 19 19 2013 II 1 1 P. Corradini 2013 II 1 1 Identification of possible genetic causes responsible P. Corradini of a familiar form of Multiple Myeloma 2013 Observational 2 Closed accrual 100/13 Multi-center, phase II study to assess the safety and efficacy of haploidentical bone marrow transplantation using reduced intensity conditioning (RIC) regimen and post-transplant cyclophosphamide, in patients with poor prognosis lymphomas P. Corradini 2013 II 2 113/13 Role of T memory stem cell in the process of immune reconstitution following bone marrow transplantation P. Corradini 2013 Observational 11 11 149/13 Retrospective observational study on monitoring of serum levels of TARC and PET results of patients with Hodgkin's lymphoma undergoing allogenic hematopoietic stem cell P. Corradini 2013 22 22 150/13 Treatment with bendamustine in relapsed/ refractory patients with Hodgkin's lymphoma already treated with brentuximab vedotin. An observational retrospective multicenter study S. Viviani 2013 10/11/13 Observational 4 4 97/11 Non invasive prediction of acute Graft-Verus-Host Disease following allogeneic hematopoietic cell transplantation by circulating miRNA profiling P. Corradini 2011 30/06/13 Observational 47 Closed accrual 27/12 Retrospective assessment of the effficacy of P. Corradini bendamustine in patients with relapsed/refractory Hodgkin's lymphoma after high-dose chemotherapy or allogenic transplantation:experience of the FIL center 2012 28/02/13 Observational 7 Closed accrual 34/12 An open label phase II study on the use of Panobinostat in combination with bortezomib and dexamethasone as induction in miltiple myeloma patients candidate to high-dose therapy 2012 22/03/13 II Closed accrual 206 P. Corradini 30/09/13 2 4 ongoing clinical studies Study Code 45/12 114/12 Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 Correlation between the frequencies of myeloid derived suppressor cells (MDSC) present in matched unrelated donors (MUD) grafts and the incidence of aGvHD following allogeneic hematopoietic cell transplantation P. Corradini 2012 30/06/13 Observational 40 Closed accrual Observational retrospective/prospective study in Hodgkin’s Lymphoma and Anaplastic Large Cell Limphoma patients who received SGN35 according to compassionate use (named patient program) A. M. Gianni 2012 03/01/13 Observational 16 Closed accrual LUNG CANCER 35/07 A phase II study of NGR-hTNF administered as N. Zilembo single agent every 3 weeks in patients affected by advanced or metastatic malignant pleural mesothelioma previously treated with no more than one systemic therapeutic regimen 2007 20/05/13 II 4 Closed accrual 74/09 A randomized, multicenter, open-label phase 3 study of gemcitabine-cisplatin chemotherapy plus IMC-11F8 versus gemcitabine-cisplatin chemotherapy alone in the first-line treatment of patients with squamous stage IIIb or IV non-small cell lung cancer (NSCLC) 2010 27/11/13 III 6 Closed accrual 53/05 Spiral CAT, biomarkers and proteomic analysis, U. Pastorino associated to a program of primary prevention for the early diagnosis of lung cancer: randomized study in subjects at high risk: project MILD 2006 - 4.099 Closed accrual 18/07 START - stimulating Targeted Antigenic Responses To NSCLC M. Platania 2007 III 5 Closed accrual 27/09 Randomized phase II study of NGR-hTNF in combination with standard chemotherapy versus standard chemotherapy alone in previously untreated patients with advanced non-small cell lung cancer (NSCLC) N. Zilembo 2009 II 31 Closed accrual 66/09 Multicenter phase III randomized study of cisplatin N. Zilembo and etoposide with or without bevacizumab as firstline treatment in extensive stage (ED) small cell lung cancer (SCLC) 2013 III 1 1 75/09 A randomized, multicenter, open-label phase 3 study of pemetrexed-cisplatin chemotherapy plus IMC-11F8 versus pemetrexed-cisplatin chemotherapy alone in the first-line treatment of patients with non squamous stage IIIb or IV nonsmall cell lung cancer (NSCLC) N. Zilembo 2010 III 9 Closed accrual 10/10 HSRL-02-2007 PROSE: Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib versus Chemotherapy in Patients with Inoperable Non–Small Cell Lung Cancer N. Zilembo 2010 III 2 Closed accrual 23/10 Phase III randomized trial of BIBW 2992 plus weekly paclitaxel versus investigator's choice of chemotherapy following BIBW 2992 monotherapy in non-small cell lung cancer patients failing previuos erlotinib or geftinib treatment M. Platania 2010 III 5 Closed accrual N. Zilembo 207 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated 45/10 An exploratory phase II study of pemetrexed and ciplatin as preoperative chemotherapy in the treatmnet of stage IIIAN2 nonsquamous non small cell lung cancer U. Pastorino 72/10 The airINTrial: a prospective randomized phase III trial of the use of different modalities of pleural aspiration for the management of breath loss after lung surgical resection 21/11 Phase Total patients Patients enrolled in 2013 2011 II 13 1 F. Leo 2011 III 580 30 BioMILD: a prospective study of efficacy of plasma microRNA as first line test for early dignosis of lung cancer U. Pastorino 2013 Observational 1.004 1.004 52/11 An open label two-stage study of orally administered BKM120 in patients with metastatic non-small cell lung cancer with activated PI3K pathway F. De Braud 2012 II 3 1 92/11 Phase III randomized, open-label study of the F. de Braud efficacy and safety of crizotinib versus pemetrexed/ cisplatin or pemetrexed/carboplatin in previously untreated patients with non-squamous carcinoma of the lung harboring a traslocation or inversion event involving the anaplastic lymphoma kinase (alk) gene locus 2011 III 2 Closed accrual 83/11 Prospective randomized study on efficacy of autologous adipose tissue with Stem Cells to prevent air-leaks after laser pulmonary metastasectomy 2011 II 17 Closed accrual 21/12 A randomized, open-label. Multicenter, phase 3 M. Platania study to compare the efficacy and asafety of eribulin with treatment of physician's choice in subjects with advanced non-smal celle lung cancer 2012 III 8 Closed accrual 40/12 A randomized, phase II, multicenter, double-blind, F. de Braud placebo-controlled study evaluating the efficacy and safety of MetMab in combination with paclitaxel + cisplatin or carboplatin as first -line treatment for patients with stage IIIb (T4 disease) or IV squamous non-small cell lung cancer (NSCLC) 2012 II 1 Closed accrual 41/12 A randomized, phase II, multicenter, double-blind, placebo-controlled study evaluating the efficacy and safety of MetMab in combination with either bevacizumab +platinum + paclitaxel or pemetrexed + platinum as first -line treatment for patients with stage IIIb or IV non-squamous non-small cell lung cancer (NSCLC) F. de Braud 2012 II 11 Closed accrual 48/12 Be-positive: Beyond progression after tki in egfr positive NSCLC patients M. Garassino 2012 Observational 4 0 49/12 Maintanance metronomic per os navelbine in advanced NSCLC patients after previous platinum based chemotherapy: a mutlicenter randomized best supportive care controlled phase II study MANILA M. Platania II 5 208 U. Pastorino 2013 Closed 20/12/13 5 ongoing clinical studies Study Code Title Coordinator 63/12 Phase II study of oral PHA-848125AC in patients with thymic carcinoma previously treated with chemotherapy 100/12 Phase Total patients Patients enrolled in 2013 M. Garassino 2012 II 12 6 An Open-label Randomized Phase III Trial of BMS936558 versus Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung Cancer (NSCLC) M. Garassino 2013 III 8 Closed accrual 136/12 A multicenter, open-label, randomized phase II study to evaluate the efficacy of AUY922 vs pemetrexed or docetaxel in NSCLC patients with EGFR mutations who have progressed on prior EGFR TKI treatment N. Zilembo II 2 2 137/12 An Open-Label Randomized Phase III Trial of BMS936558 versus Docetaxel in Previously Treated Metastatic Non-squamous Non-small cell Lung Cancer (NSCLC) M. Garassino 2013 III 11 Closed accrual 34/13 Phase II study of oral PHA-848125AC in patients with malignant thymoma previously treated with multiple lines of chemotherapy Marina Garassino II 2 2 61/13 POST-ALK: observational study of treatment and outcome after crizotinib in advanced ALK-positive NSCLC patients M. Garassino 2013 Observational 7 7 65/13 Post-operative pulmonary complications in major abdominal surgery. A prospective multicenter observational study F. Piccioni Observational 122 Closed accrual 99/13 Phase I Study of Single Agent MK-3475 in Patients with Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma M. Garassino 2013 I 12 12 E-Cigarette and Normal Cigarette Sidestream Analysis and Comparison Project R. Boffi - 3 Closed accrual II 2 Closed accrual III 37 Closed accrual III 21 Closed accrual 108/13 98/11 A phase II, open lebel, multicenter, randomized F. de Braud study to assess the rfficacy and safety of GSK1120212 compared with docetaxel in 2nd line subjects with targeted mutations (KRAS, NRAS, BRAF, MEK1) in locally advanced or metastatic nonsmall cell lung cancer (NSCLC stage IIIBwet-IV) Activated Closed 2013 2013 2013 2013 2011 24/09/13 MELANOMA 52/08 A double-blind, randomized, placebo-controlled phase III study to assess the efficacy of recMAGE-A3 + AS15 ASCI as adjuvant therapy in patients with MAGE-A3 positive resected stage III melanoma 42/09 An open label, multicenter, phase III trial of ABI-007 M. Del vs dacarbazine in previously untreated patients Vecchio with metastatic malignant melanoma M. Santinami 2009 2009 209 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated 06/10 BRIM 3: a randomized, open-label, controlled, multicenter, phase III study in previuosly untreated patients with unresectable stage IIIC or stage IV melanoma with V600E BRAF mutation receiving RO5185426 or dacarbazine M. Del Vecchio 24/10 The TEAM trial (Tasigna efficacy in advanced melanoma): A randomized, phase III, open label, multi-center, two-arm study to compare the efficacy of Tasigna® versus dacarbazine (DTIC) in the treatment of patients with metastatic and/or inoperable melanoma harboring a c-Kit mutation M. Del Vecchio 25/10 An open, dose-escalation phase I/II study to assess the safety, immunogenicity and clinical activity of rec-PRAME + AS15 Antigen-specific Cancer Immunotherapeutic as first-line treatment of patients with PRAME-positive metastatic melanoma 33/10 Phase Total patients Patients enrolled in 2013 2010 III 10 Closed accrual 2010 III 11 Closed accrual M. Santinami 2010 I-II 12 Closed accrual An open-label, multicenter, randomized, phase Ib/ II study of E7080 in combination with dacarbazine versus dacarbazine alone as first line therapy in patients with stage IV melanoma M. Del Vecchio Ib-II 9 Closed accrual 34/10 A phase II single arm study of the combination of Ipilimumab and fotemustine in patients with nonresectable stage III or stage IV melanoma M. Santinami 2010 II 9 Closed accrual 62/10 An open phase I study of immunization with the rec-NY-ESO-1 + AS15 antigen-specific cancer immunotherapeutic in patients with NY-ESO-1 positive unresectable and progressive metastatic cutaneous melanoma M. Santinami 2010 I 26 0 01/11 A phase III randomized, open-label study comparing M. Del GSK1120212 to chemotherapy in subjects with Vecchio advanced or metastatic BRAFV600E/K mutationpositive melanoma 2011 III 5 Closed accrual 16/11 An open-label, multicenter expanded access study of RO5185426 in patients with metastatic melanoma M. Del Vecchio 2011 III 78 Closed accrual 39/11 Identification of circulating microRNAs as potential indicators of progression in metastatic melanoma L. Rivoltini 2011 Observational 248 146 40/11 A study of immunomodulatory effect of BRAF and MEK inhibitors in melanoma patients L. Rivoltini 2011 Observational 65 23 76/11 An open-label, multicenter, single arm, phase I dose.escaltion with efficacy tail extension study of Vemurafenib (RO5185426) in pediatric patients with surgically incurable and unresctable stage IIIC or stage IV melanoma harboring BRAFV600 mutations A.Ferrari 2013 I 1 1 23/12 A Randomized Double-Blind phase III study of Ipilimumab Administered at 3 mg/kg vs at 10 mg/ kg in subjects with previously treated or untreated unresectable or metastatic melanoma M. Del Vecchio 2012 III 40 Closed accrual 210 2010 Closed ongoing clinical studies Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 28/12 Tracing the melanoma lineage: cancer stem cells and M. Santinami 2012 genetic noise Observational 26 Closed accrual 37/12 Malignant skin lesions in patients with cancer: an observational prospective study A. T. Caraceni 2012 Observational 99 77 38/12 A phase III, randomized, double-blinded study comparing the combination of the BRAF inhibitor, dabrafenib and the MEK inhibitor, trametinib to dabrafenib and placebo as first-line therapy in subjects with unresectable (Stage IIIC) or metstatic (STAGE IV) BRAF V600E/K mutation-positive cutaneous melanoma F. de Braud 2012 III 20 Closed accrual 52/12 A phase III, randomised, open-label study comparing M. Del the combination of the BRAF inhibitor, dabrafenib Vecchio and the MEK inhibitor, trametinib to the BRAF inhibitor vemurafenib in subjects with unresectable (stage IIIc) or metastatic (stage IV) BRAF V600E/K mutation positive cutaneous melanoma 2013 III 13 Closed accrual 58/12 Potentiating clinical and immunological effects of chemotherapy by neutralizing acidic pH at tumor site: a phase II randomized study in melanoma patients M. Santinami 2012 II 4 1 71/12 A phase II study of intratumoral application of M. Santinami 2012 L19IL2/L19TNF in melanoma patients in clinical stage III or stage IV M1a with presence of injectable cutaneous and/or subcutaneous lesions II 9 7 103/12 A multicentre, open label, randomized Phase II trial Filippo De of the MEK inhibitor pimasertib or dacarbazine in Braud previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma 2012 II 8 7 106/12 An open-label, single-arm, phase II, multicenter study to evaluate the efficacy of vemurafenib in metastatic melanoma patients with brain metastases M. Del Vecchio 2013 II 1 Closed accrual 140/12 A Randomized, Open-Label Phase 3 Trial of BMS936558 versus Investigator's Choice in Advanced (Unresectable or Metastatic) Melanoma Patients Progressing Post Anti-CTLA-4 Therapy M. Del Vecchio 2013 III 2 Closed accrual 143/12 COMBI-AD: A phase III randomized double blind M. Santinami 2013 study of dabrafenib (GSK2118436) in COMBInation with trametinib (GSK1120212) versus two placebos in the ADjuvant treatment of high-risk BRAF V600 mutation-positive melanoma after surgical resection. III 13 13 "A Phase 3, Randomized, Double-Blind Study of BMS-936558 vs Dacarbazine in Subjects with Previously Untreated Unresectable or Metastatic Melanoma III 9 9 42/13 F. De Braud 2013 211 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 43/13 A phase III, double-blind, placebo-controlled study F. De Braud of vemurafenib versus vemurafenib plus GDC0973 in previously untreated BRAFV600-mutation positive patients with unresectable locally advanced or metastatic melanoma 2013 III 11 Closed accrual 44/13 A randomized, Phase III study of Fotemustine versus M. Del the Combination of Fotemustine and Ipilimumab Vecchio in Patients with Metastatic Melanoma with brain metastasis 2013 III 3 3 94/13 A Phase 3, Randomized, Double-Blind Study of M. Del Nivolumab Monotherapy or Nivolumab Combined Vecchio with Ipilimumab Versus Ipilimumab Monotherapy in Subjects with Previously Untreated Unresectable or Metastatic Melanoma 2013 III 13 13 III 2 Closed accrual SARCOMAS 25/08 A multinational, randomized, double-blind placebo controlled study of AVE8062 (25 mg/ m2) administered every 3 weeks, in patients with advanced -stage soft tissue sarcoma treated with cisplatin (75 mg/m2) after failure of antracycline and ifosfamide chemotherapies P. Casali 2008 31/03 EUROpean Bone Over 40 Sarcoma Study. A European treatment protocol for bone-sarcoma in patients older than 40 years P. Casali 2003 II-III 13 1 46/03 Ifosfamide at high doses in prolonged continuous infusion by a portable infusion system in soft-tissue sarcomas typical of the adult in an advanced phase in second/further line chemotherapy R. Bertulli 2004 II 21 Closed accrual 01/04 Gemcitabine in leiomyosarcoma in an advanced phase in second or further line of chemotherapy R. Bertulli 2004 II 15 Closed accrual 31/05 EpSSG RMS 2005 - A protocol for non metastatic Rhabdomyosarcoma A. Ferrari 2005 III 102 8 32/05 EpSSG NRSTS 2005. A protocol for localized nonrhabdomyosarcoma soft tissue sarcomas A. Ferrari 2005 III 155 12 53/06 Trabectedin (ET743) in metastatic or locally advanced cell liposarcoma pretreated with chemotherapy P. Casali 2006 II 27 Closed accrual 45/08 A randomized, multicenter, phase III trial of Trabectedin (yondelis) versus doxorubicin-based chemotherapy as first-line therapy in patients with traslocation related sarcomas (TRS) P. Casali 2008 III 3 Closed accrual 62/08 Open label, multi-center, phase 2 study denosumab in subject with giant cell tumor of bone P. Casali 2008 II 26 1 78/09 A phase II randomized - non comparative - study onthe activity of trabectedin or gemcitabine + docetaxel in metastatic or locally relapsed uterine leiomyosarcoma pretreated with conventional chemotherapy P. Casali 2010 II 4 0 212 13/03/13 ongoing clinical studies Study Code Title Coordinator Activated 30/10 Randomized phase II study evaluating two doses of NGR-hTNF administered either as single agent or in combination with doxorubicin in patients with advanced soft tissue sarcoma (STS) P. Casali 44/10 Phase II study on imatinib in combination with RAD001 in advanced chordoma 66/10 Localized high-risk soft tissue sarcomas of the A. Gronchi extremities and trunk wall in adults: an integrating approach comprising standard vs histotype-tailored neoadjuvant chemotherapy 85/10 Evaluation of the role of immunosuppressive mechanisms in the prognosis and response to treatment with targeted therapy drugs in sarcoma patients 05/11 Closed Phase Total patients Patients enrolled in 2013 2010 II 11 Closed accrual S. Stacchiotti 2011 II 30 7 2010 II 36 12 L. Rivoltini 2010 Observational 143 15 Translational study on modulation of gene transcription induced by Trabectedin in patients with myxoid/round cell liposarcoma P. Casali 2011 - 0 06/11 A retrospective study on retroperitoneal sarcomas A. Gronchi 2011 19/11 A randomized, open label, multicenter, phase 3 study to compare the efficacy and safety of eribulin with dacarbazine in subjects with soft tissue sarcoma P. Casali 28/11 Rabdomiosarcoma of adults. An observational prospective study 59/11 31/12/13 2 Observational 210 Closed accrual 2011 III Closed accrual R. Bertulli 2011 Observational 6 0 STARSS: a phase III randomized STudy of preoperative RAdiotherapy plus Surgery versus surgery alone for patients with Retroperitoneal Sarcoma (RPS) A. Gronchi 2011 III 12 8 73/11 ABCB1/P- glycoprotein expression as factor for the biologic stratification of the metastatic osteosarcoma of the extremities: a prospective study R. Bertulli 2011 II 16 2 13/12 Tailore Beta-catenin mutational approach in extraabdominal sporadic desmoid tumor patients A. Gronchi 2013 Observational 11 11 119/12 Y-IMAGE: a non-interventional multicenter, prospective study to evaluate treatment outcome assessment methods used in routine clinical practice on patients with advaced soft tissue sarcoma treated with trabectedin according to the Summary of Product Characteristics (SmPC) P. G. Casali 2013 Observational 7 7 Observational study of whole-trascriptome and S. Stacchiotti 2013 whole-exome sequencing analysis in tumor samples of extraskeletal myxoid chondrosarcoma, malignant myoepithelioma, and dermatofibrosarcoma protuberans with or without fibrosarcomatous component Observational 8 8 54/13 4 213 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated 114/13 Patients with atipical osteosarcoma and/or are not elegible in other ISG clinical trials R. Bertulli 2013 168/13 Retrospective study of anthracycline-based chemotherapy in extraskeletal myxoid chondrosarcoma S. Stacchiotti 2013 Closed Phase Total patients Patients enrolled in 2013 Observational 1 1 31/12/13 Observational 11 11 12/09/13 II 7 Closed accrual III 6 0 URINARY APPARATUS 41/08 A randomized, open label, multi-center phase II G. Procopio study to compare bevacizumab plus RAD001 versus interferon alfa-A plus bevacizumab for the first-line treatment of patients with metastatic clear cell carcinoma of the kidney 2008 53/07 Sunitinib treatment of renal adjuvant cancer G. Procopio (S-TRAC): a randomized double-blind phase 3 study of adjuvant sunitinib vs placebo in subjetcs with high risk RCC 2007 81/11 Retrospective analysis of sorafenib as the first or second target therapy administered in mRCC patients. Three years Italian experience G. Procopio 2011 51/08 Axitinib (AG 013736) as second line therapy for metastatic renal cell cancer: AXIS trial G. Procopio 11/10 14/01/13 Observational 25 Closed accrual 2008 III 5 Closed accrual Phase II study of sunitinib in metastatic renal cancer G. Procopio with non-clear cell histology 2010 II 11 Closed accrual 52/10 A phase II study of neoadjuvant Cisplatin and Gemcitabine plus Sorafenib for patients with transitional cell carcinoma of the bladder R. Salvioni 2010 II 26 2 09/11 A randomized, double.blind, placebo-controlled 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 12 Closed accrual 10/11 Biotech of prostate cancer N. Zaffaroni 2011 Observational 113 62 32/11 An open-label, randomized, multicenter, phase III study to compare safety and efficacy of TK1258 versus soafenib in patients with metastatic renal cell carcinoma after failure of anti-angiogenic (VEGF-targeted and m-TOR inhibitor) therapies G. Procopio 2011 III 4 Closed accrual 09/12 An open label pharmacokinetic and tolerability study of cabazitaxel in patients with solid tumors with moderately and severely impaired and with normal renal function F. De Braud 2012 I 5 Closed accrual 46/12 Evaluation of microRNA expression in prostate cancer for the identification of novel diagnostic and prognostic markers D. Zaffaroni 2012 Observational 13 12 47/12 The decision making of patients with prostate cancer in multidisciplinary visit R. Valdagni 2013 Observational 97 97 214 ongoing clinical studies Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 62/12 A randomized, open label, multicenter phase 2 G. Procopio study, to evaluate the efficacy of Sorafenib in patients with advanced Renal Cell Carcinoma (RCC) after a radical resection of the metastases. 2012 II 12 10 65/12 PRINCIPAL: A Prospective Observational Study of Real World Treatment Patterns and Treatment Outcomes in Patients with Advanced or Metastatic Renal Cell Carcinoma Receiving Pazopanib G. Procopio 2012 Observational 22 13 90/12 Study for the validation of PROSQOLI (Prostate Cancer Specific Quality of Life Instrument). A questionnaire for the assessment of health-related quality of life in patients with prostate cancer R. Valdagni 2013 Observational 19 19 94/12 A Phase 3, Randomized, Double-blind, Controlled Study of Cabozantinib (XL184) vs. Prednisone in Metastatic Castrationresistant Prostate Cancer Patients who have Received Prior Docetaxel and Prior Abiraterone or MDV3100 G. Procopio 2013 III 7 Closed accrual A Randomized, Open-Label, Phase 3 Study of BMS- G. Procopio 936558 vs. Everolimus in Subjects with Advanced or Metastatic Clear-Cell Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy 2013 III 14 Closed accrual 62/13 Retrospective Observational Study of Sunitinib administered in schedule 2/1-2/1 (2 week on-1 week off for an overall cycle lenght of 6 weeks) in patients with metastatic Renal Cell Carcinoma (mRCC): RAINBOW Study G. Procopio 2013 98/13 A phase Ib/II study of GDC-0068 or GDC-0980 with G. Procopio abiraterone acetate versus abiraterone acetate in patients with castration-resistant prostate cancer previously treated with docetaxel-based chemotherapy 162/13 Retrospective analysis of eventual relationship between previous AWS (Antiandrogen withdrawal sindrome) and response to Enzalutamide in Docetaxel refractory metastatic castrate-resistant prostate cancer (mCRPC) patients 01/12 Phase II study of the fully human monoclonal antibody against transforming growth factor-beta (TGFß) receptor ALK1 (PF-03446962) in relapsed or refractory urothelial cancer (UC) failing first-line treatment 108/12 31/10/13 31/08/13 Observational 16 16 2013 I-II 1 1 G. Procopio 2013 Observational 9 9 A. Necchi 2012 09/09/13 II 10 14 PEDIATRIC TUMORS 41/01 Protocol for evaluation and therapy of the diencephalohypophysial alterations in pediatric patients with cerebral neoplasms E. Seregni, E. Bombardieri 2001 31/12/13 Observational 460 15 31/07 Guidelines for the treatment of patients with localized resectable neuroblastoma and analysis of prognostic factors R. Luksch 2007 01/06/13 - Closed accrual 16 215 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated Closed Phase 47/11 Quality of life and personality factors in patients recovered from osteosarcoma in evolutive age towards a deeper understanding of long-term adaptation C. Meazza 2011 30/10/13 Observational 43 4 55/11 A phase III, randomized, double-blind, active comparator-controlled clinical trial, conducted under in house blinding conditions, to examine the efficacy and safety of aprepitant for the prevention of chemotherapy induced nausea and vomiting (CINV) in pediatric patients M. Casanova 2011 07/11/13 III 6 Closed accrual 26/95 Immunotherapy (IL-2 and activated circulating mononucleate cells) and pre/post-surgical antineoplastic chemotherapy in the primary treatment of osteosarcoma C. Meazza 1995 II 86 2 40/01 Protocol NB-AR-01: First European Cooperative Study for high-risk neuroblastoma R. Luksch 2002 III 58 5 12/03 Second protocol for diagnosis and treatment of ependymoma in a pediatric age M. Massimino 2003 Observational 49 1 13/03 Non-controlled clinical study for the treatment of Ewing’s sarcoma in relapse R. Luksch 2003 II 2 14/03 Wilms’ tumor: diagnostic-therapeutic protocol AIEOP 2003 F. Spreafico 2003 Observational 116 10 16/03 Germ cell tumors: diagnostic-therapeutic protocol AIEOP 2003 M. Terenziani 2003 III 103 6 17/05 Phase II protocol with combined chemotherapy and 131I-MIBG in the treatment of patients with neuroblastoma resistant or in relapse (I-METCH) R. Luksch 2005 II 1 Closed accrual 08/07 LCH-III. Treatment protocol of the third S. Catania international study for Langerhan's cell histiocytosis 2007 III 56 14 13/08 Open-label, multi -center, randomized, two stage adaptive design study of the combination of bevacizumab with standard chemotherapy in minor patients with metastatic rhabdomyosarcoma, nonrhabdomyosarcoma soft-tissue sarcoma or Ewing sarcoma/soft tissue primitive neuroectdermal tumour M. Casanova 2008 II 10 Closed accrual 17/08 HL PED 2008 Hodgkin’s lymphoma. A therapeutic protocol for sequels reduction M. Terenziani 2008 II 25 8 22/09 A phase II study on the efficacy of dose intensification in patients with non-metastatic Ewing’s sarcoma P. Casali, R. Luksch 2009 III 26 15 25/09 Therapeutic protocol with high-dose chemotherapy, P. Casali, R. radiotherapy, maintenance therapy with low-dose Luksch Cyclophosphamide and anti-COX2 in metastatic Ewing’s sarcoma: ISG/AIEOP study 2009 II 25 15 57/09 Phase II single-arm study of temozolomide in M. Casanova combination with topotecan in refractory or relapsing neuroblastoma and other pediatric solid tumors 2009 II 7 Closed accrual 216 Total patients 23 Patients enrolled in 2013 ongoing clinical studies Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 2 0 53/10 Phase 1/2combined dose ranging and randomised, R. Luksch open-label, comparative study of efficacy and safety of plerixafor in addition to standard regimens for mobilisation of haematopoietic stem cells into peripheral blood, and subsequent collection by apheresis, vesus standard mobilisation regimens alone in pediatric patients, aged 2 to<18 years, with solid tumours eligible for autologous transplants 2011 I-II 84/10 Evaluation and treatment of bone mass and body composition alterations in pediatric patients with oncological disease of central nervous system 2010 Observational 43 38 02/11 A phase I study of LDE225 in pediatric patients with M. Casanova recurrent or refractory medulloblastoma or other tumors potentially dependent on the Hedgehogsignaling pathway 2011 I Closed accrual 20/11 "Neurocognitive outcome correlated to radiation dose and diffusion-tensor MRI information (DTI) in children focally irradiated for primitive pediatric malignant brain tumours M. Massimino 2011 Observational 21 7 46/11 A phase II open-label. Randomized, multi-centre comparqative study of bevacizumab-based therapy in paediatric patients with newly dignosed supratentorial high-grade glioma M. Massimino 2011 II 4 48/11 Immunohistochemical and molecular analysis of a pediatric series of salivary glands cancer from the Istituto Nazionale dei Tumori, Milan L. Locati 2011 Observational 16 Closed accrual 49/11 International randomized phase ii trial of the combination of vincristine and irinotecan with or without temozolomide (VI or VIT) in children and adults with refractory or relapsed rhabdomyosarcoma M. Casanova 2011 II 1 07/12 Nimotuzumab and vinorelbina concomitantly to radiation and as maintenance for newly diagnosed diffuse pontine glioma in childhood M. Massimino 2012 Observational 16 5 43/12 European Low an Intermediate Risk Neuroblastoma R. Luksch 2013 III 4 93/12 PanCareSurFup: PanCare Childhood and Adolescent M. Cancer Survivor Care and Follow-up Studies Terenziani 2013 Observational 164 Closed accrual 145/12 A phase III multi-center, open-label, randomized, controlled study of the efficacy and safety of oral LDE225 versus temozolomide in patients with Hhpathway activated relapsed medulloblastoma 2013 III 2 147/12 Assessment of symptoms in children and adolescents S. Macchi with malignant disease during treatment 2013 Observational 33 33 05/13 Re-induction protocol for patients with high-risk neuroblastoma at first relapse R. Luksch 2013 II 1 1 14/13 Intergroup trial for children or adolescents with b-cell NHL or B-AL: evaluation of rituximab efficacy and safety in high risk patients F. Spreafico 2013 II 2 2 E. Seregni M. Casanova 8 8 2 4 2 217 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 1 1 16/13 A phase I/II dose schedule finding study of R. Luksch CH14.18/CHO continuous infusione combined with subcutaneous aldesleukin (IL-2) in patients with primary refractory or relapsed neuroblastoma. A SIOPEN Study 2013 I-II 68/13 The school activity during cancer treatment in developmental age: a survey about limits and resources through the administration of a questionnaire to parents 2013 Observational 33 33 80/13 A Phase I, open-label, dose escalation study of M. Casanova LDK378 in pediatric patients with malignancies that have a genetic alteration in anaplastic lymphoma kinase (ALK) 2013 I 5 90/13 Study of equivalence eco abdomen CT abdomen in pediatric patients with Hodgkin's lymphoma M. Terenziani 2013 The point of view of adolescents with cancer A. Ferrari 2013 147/13 G. Casiraghi 31/12/13 5 Observational 10 10 Observational 24 24 Observational 108 10 PALLIATIVE CARE 23/11 A no-profit observational, prospective study C. Ripamonti describing the presence and intensity of nausea, vomiting (N/V), of related symptoms and of subjective feeling of malaise in patients with the following neoplasms: head and neck , lung (NSCLC/ SCLC) and pleural, urothelial, male genital apparatus (germinal neoplasm, penile spinocellular carcinoma) treated first with chemotherapy including drugs with high/moderate vomiting risk and in inter cycle phase 2011 36/10 An open-label randomized controlled clinical trial to compare the analgesic efficacy of therapeutic strategies with Oxycodone, Fentanyl and Buprenorphine versus Morphine in patients with cancer-related pain of moderate-severe intensity, since the start of third-step treatment of the WHO analgesic scale A. Caraceni 2011 IV 23 4 Sublingual Fentanyl versus subcutaneous morphine for the management of severe cancer pain episodes in patients on opioid treatment: a double-blind randomized non-inferiority trial A. Caraceni 2013 IV 5 5 123/13 27/09/13 MISCELLANEA 77/06 Phase II study oh PHA-739358 administered by a 24-Hour IV infusion every 14 days in advanced/ metastatic breast, ovarian, colorectal, pancreatic, small cell lung and non-small cell lung cancer L. Celio 2007 26/09/13 II 10 Closed accrual 03/07 A randomized, double-blind, placebo-controlled, multicenter phase III study in patients with advanced carcinoid tumor receiving Sandostatina LAR and RAD001 10 mg/die or Sandostatin LAR and placebo R. Buzzoni 2007 04/06/13 III 8 Closed accrual 218 ongoing clinical studies Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 19/08 An open-label, non-randomized, dose esclation, G. Capri safety and pharmacokinetics phase I study of AVE8062 in combination with cisplatin administered on day 1 followed by docetaxel on day 2, every 3 weeks, in patients with advanced solid tumors 2008 23/05/13 I 19 Closed accrual 42/10 An open-label, non-randomized dose escalation, safety and pharmacokinetics phase I studyof ombrabulin (AVE8062) in combination with bevacizumab administered by intravenous infusion every 3 weeks in patients with advanced solid tumors G. Capri 2010 08/01/13 I 4 Closed accrual 67/11 Role of genetic profile in the evaluation of the smoker and personalization of anti-smoking therapies R. Boffi 2011 31/12/13 - 330 140 82/11 Feasibility study of autologous adipose tissue Stem- U. Pastorino Cells transplantation in 10 chest-wall resections with prosthetic replacements 2011 17/05/13 I 10 1 66/05 Registry of congenital malformations in Lombardy G. Tagliabue 2006 Observational 19431 2366 40/07 Dose-finding study of Caelix and RAD001 in patients with advanced solid tumors S. Cresta 2007 I 23 Closed accrual 12/08 An open-label, safety, pharmacockinetics and pharmacodynamic dose escalation phase Ib study of pazopanib in combination with epirubicin or doxorubicin in subjects with advanced solid tumors G. Capri 2008 Ib 54 Closed accrual 32/09 Epidemiologic studies on environmental risk factors A. Decarli and their interactions with genetic factors of bladder cancer and sarcomas 2009 Observational 680 353 35/09 Efficay of thermal treatment for respiratory airways U. Pastorino in heavy smokers 2009 - 468 Closed accrual 47/09 A phase I, open label, multicenter, study to assess the safety, tolerability and pharmacology of AZ D2281 in combination with liposomal doxorubicin (Caelyx) in patients with advanced solid tumors 2009 I 8 Closed accrual 54/09 Phase Ib study of CC-5013 and paclitaxel in patients G. Capri with advanced solid tumors 2009 I 11 Closed accrual 16/10 The role of spiritual and religiuos behaviours and C. Ripamonti beliefs as search of meaning, in the coping with cancer. Pivotal study on factibility and on the impact of a religiuos intervention 2010 Observational 25 4 32/10 Dose-escalation, PK and safety study with single agent CetuGEX in patients with locally advanced and/or metastatic cancer S. Cresta 2010 I 6 Closed accrual 54/10 Phase II study of nilotinib efficacy in pigmented villo-nodular synovitis/tenosynovial giant cell tumour (PVNS/TGCT) P. G. Casali 2011 II 5 Closed accrual S. Cresta 219 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated Closed Phase Total patients Patients enrolled in 2013 30 1 55/10 Evaluation of the response according to dimensional C. Morosi and tissue criteria using contrast-enhanced amplifier ultrasonography in patients with soft tissue sarcomas or gastrointestinal stromal tumors (GIST) after molecular target therapies - CONTICANET 2010 - 27/11 Role of chemotherapy in trastuzumab cytotoxic activity E. Tagliabue 2011 Observational 11 Closed accrual 41/11 Prospective, phase II randomized to compare busulfan-fludarabine reduced-intensity conditioning (RIC) with thiotepa-fludarabine RIC regimen prior to allogeneic transplantation of hematopoietic cells for the treatment of myelofifrosis P. Corradini 2011 II 1 0 42/11 SUTNET Trial: biological and clinical phase II study of sunitinib in patients with unresectable and/or metastatic pheochromocytomas/paragangliomas R. Buzzoni 2011 II 16 7 56/11 A phase I dose-escalation study of PHA-739358 administered in combination with docetaxel or gemcitabine or bevacizumab or carboplatin in adult patients with advanced solid tumors, including Hodgkin's and non-Hodgkin's lymphoma A. Guidetti 2011 I 11 1 84/11 Interventional study, non-pharmacological, multicenter, randomized, controlled, open-label, aimed at preventing Alzheimer's disease with nutrition V. Krogh 2012 I-II 13 Closed accrual 104/11 An open label, multicenter, expanded access study P. Corradini of INC424 for patients with primary myelofibrosis (PMF) or post polycythemia myelofibrosis (PPV MF) or post-essential thrombocythemia myelofibrosis (PET-MF) 2011 III 4 2 112/11 Toremifene in desmoid tumor: prospective clinical C.Colombo trial and identification of potential molecular targets 2011 II 12 8 08/12 Hypercoagulation screening as an innovative tool for risk assessment, early diagnosis and prognosis in cancer 2012 Observational 229 151 12/12 A non-interventional retrospective correlation P. Casali of tumor mutation status to clinical benefit from the SU011248, A6181036 treatment protocol titled: a treatment protocol for patients with gastrointestinal stromal tumor who are ineligible for participation in other SU011248 protocols and are refractory to or intolerant of imatinib mesylate 2012 Observational 11 Closed accrual 25/12 Identification and validation of microRNAs as novel biomarkers and therapeutic targets in diffuse malignant peritoneal mesothelioma N. Zaffaroni 2012 Observational 62 7 39/12 A phase I dose escalation study of NMS-1191372 in adult patients with advanced/metastatic solid tumors F. de Braud 2012 I 13 220 F. de Braud 23/07/13 16 ongoing clinical studies Study Code Title Coordinator Activated Closed 59/12 Identification of Polymorphisms Predicting Bevacizumab-Related Side Effects: SToPtrial M. Di Bartolomeo 2012 Observational 63 23 61/12 A Phase 1b, multi-center, open label, dose escalation F. de Braud study of oral LDE225 in combination with BKM120 in patients with advanced solid tumors 2012 I 3 1 75/12 A Phase 1a/1b, Multi-Center, Open-Label, Dose F. De Braud Finding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the Pleiotropic Pathway Modifier CC-122 Administered Orally to Subjects with Advanced Solid Tumors, Non-Hodgkin’s Lymphoma or Multiple Myeloma 2013 I 6 6 82/12 A multicenter, multinational, randomized study A. of standard vs patients adapted protocols in Marchianò MultiDetector Computed Tomography (MDCT) of the chest, abdomen, liver or aorta (Tailored CT study) 2013 03/07/13 - 62 62 86/12 The experience of pain in cancer patients: features and possible solutions. A national research (Epidemiological Study of Pain in Oncology - ESOPO) R. Buzzoni 2012 15/05/13 Observational 163 3 91/12 Database of patients with bone metastases from germ cell cancer - An international database of the G3 consortium A. Necchi 2012 07/03/13 Observational 48 6 104/12 Incidence of thromboembolic events during chemotherapy in metastatic/advanced cancer patients R. Buzzoni 2012 Observational 9 3 105/12 The Lombardy Rare Donor Programme F. Arienti 2012 Observational 34 22 122/12 Phase 1b study of the tumor-targeting human L19TNFalfa monocloonal antibody-cytokine fusion protein in combination with doxorubicin in patients with advanced solid tumours F. De Braud 2013 I 8 134/12 Informative Note Project on Informed Consent: understandability and usefulness of informed consent in clinical interventional trials C. Borreani 2013 Observational 20 20 135/12 Expectations, experiences and preferences of patients and physicians involved in the informed consent process for Phase 2 and Phase 3 clinical trials: construction of a model C. Borreani 2013 Observational 10 10 150/12 Epidural catheter related early complications. The experience of the Fondazione IRCCS Istituto Nazionale dei Tumori. F. Piccioni 2013 Observational 1696 1696 15/04/13 Phase Total patients 8 Patients enrolled in 2013 06/13 Cross-tumoral phase 2 clinical trial exploring P. G. Casali crizotinib (PF-02341066) in patients with advanced tumors induced by causal alterations of ALK and/or MET ("CREATE") 2013 II 8 8 10/13 A Phase I open-label dose escalation study with expansion to assess the safety and tolerability of INC280 in patients with c-MET dependent advanced solid tumors 2013 I 3 3 F. De Braud 221 back to contents SCIENTIFIC REPORT 2013 Study Code Title Coordinator Activated 21/13 Variation of respiratory function and chest wall mechanics after resection and rib-like costal reconstruction F. Piccioni 2013 22/13 Airway management in thoracic surgery F. Piccioni 2013 32/13 Multicenter, randomized, double-blind, placebo controlled, study to evaluate the activity of a ginger (Zingiber officinale) food supplement in the management of nausea in patients receiving highly emetogenic treatments and standard antiemetogenic therapy P. Bossi 46/13 An open-label, multi-center everolimus roll-over protocol for patients who have completed a previous Novartis sponsored everolimus study and are judged by the investigator to benefit from continued everolimus treatment 56/13 Closed 22/10/13 Phase Total patients Patients enrolled in 2013 - 9 9 Observational 201 201 2013 - 33 33 R. Buzzoni 2013 IV 2 Closed accrual Italian Oncologic Pain multiSetting - Multicentric Survey (IOPS-MS) A. T. Caraceni 2013 Observational 30 30 76/13 An open label phase I dose finding study of BI 860585 administered orally in a continuous dosing schedule as single agent and in combination with exemestane or with paclitaxel in patients with various advanced and/or metastatic solid tumours F. De Braud 2013 I 3 3 77/13 Dose escalation, safety, pharmacokinetic F. De Braud and pharmacodynamic, first in man study, of SAR125844 single agent administered as slow intravenous infusion in adult patients with advanced malignant solid tumors 2013 I 18 18 107/13 PreveDi (Prevention Disease) - Prevention of chronic degenerative diseases A. Villarini 2013 - 150 150 109/13 Oncology nutritionDay in Hospitals worldwide C. Gavazzi 2013 Observational 139 139 129/13 Evaluation of outpatients's needs with solid or haematological tumors at the S.S.D. "Supportive Care Unit" C. Ripamonti 2013 Observational 200 200 130/13 Tumor molecular markers able to predict benefit from trastuzumab treatment E. Tagliabue 2013 Observational 70 70 132/13 Analysis of the expression levels of biomarkers in the blood of healthy donors M. G. Daidone 2013 Observational 90 90 143/13 Innovative approaches in the treatment of giant congenital nevi melanocytes A. Colombetti 2013 - 10 160/13 Evaluation of the effect and tolerability of pneumatic pressure therapy in the treatment of lymphedema of the upper and lower limbs, secondary to cancer surgery A. T. Caraceni 2013 Observational 112 222 09/12/13 10 Closed accrual ongoing clinical studies back to contents SCIENTIFIC REPORT 2013 SCIENTIFIC REPORT 2013 Editor Marco A. Pierotti Coordinator Aurora Costa Editorial management and Graphic Design Rosaria Parentela Collaborators Daniela Majerna, Cecilia Melani Copy editing and Translation Patrick Moore Photographer Massimo Brega Contribution to Graphics realization Andrea Spinazzola Studio Luvié Fondazione IRCCS Istituto Nazionale dei Tumori Via G. Venezian, 1 - 20133 Milan - Italy Scientific Directorate Tel. +39 02 2390 2300 Fax +39 02 2390 3141 [email protected] http://www.istitutotumori.mi.it Printed in June 2014 by M4, Milan This report is printed on premium certified stock from well managed sustainable forests. Cover: Fedrigoni Ispira Purezza 360 g/sm. Internal pages: Fedrigoni Xper white 140 g/sm. Copyright © 2014 Fondazione IRCCS Istituto Nazionale dei Tumori. No part of this communication may be cited, reproduced, stored in a retrieval system, or transmitted by electronic or other means without prior written permission of the Scientific Director and the appropriate investigator. 224
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