Introduction 5. Scientific Directorate 8. Ethics Committee 13. Education and Training 14. Clinical Activity Data 22. Surgery Department 27

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4 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

5 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 PUBLICATIONS 125 ONGOING PROJECTS SUPPORTED BY EXTERNAL ORGANIZATIONS 179 ONGOING CLINICAL STUDIES 185 3

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7 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

8 SCIENTIFIC REPORT 2013 back to contents 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

9 introduction At the time of writing, the crude impact factor (IF) in 2013 had reached a value of for a total of 550 scientific papers published, amounting to an average IF of 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 Impact Factor Published Papers

10 SCIENTIFIC REPORT 2013 back to contents SCIENTIFIC DIRECTORATE SCIENTIFIC DIRECTOR Marco A. Pierotti, PhD 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 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 8

11 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

12 SCIENTIFIC REPORT 2013 back to contents 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

13 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

14 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 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

15 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 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 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 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 Scientific Secretariat Paolo G. Casali, Bianca M. Francucci Administratives Michaela De Palo, Raffaella Didoné, Patrizia Polo 13

16 SCIENTIFIC REPORT 2013 back to contents 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

17 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

18 SCIENTIFIC REPORT 2013 back to contents 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

19 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

20 SCIENTIFIC REPORT 2013 back to contents 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