Centro di Riferimento Oncologico (CRO) National Cancer ... · Unit of Pain Therapy and Palliative...

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Via Franco Gallini, 2 - 33081 Aviano - ITALY - Tel. +39 0434 659111 - Fax: +39 0434 652182 - www.cro.it 1

Centro di Riferimento Oncologico (CRO)National Cancer Institute, Aviano

Via Franco Gallini, 233081 Aviano - ItalyTel. +39 0434 659111Fax: +39 0434 652182www.cro.it

General ManagerPiero CAPPELLETTI

Scientific DirectorPaolo DE PAOLI

Medical Office DirectorMauro DELENDI

Administrative DirectorFranco SINIGOJ

CRO Aviano National Cancer Institute

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Via Franco Gallini, 2 - 33081 Aviano - ITALY - Tel. +39 0434 659111 - Fax: +39 0434 652182 - www.cro.it2

ORGANIZATIONAL STRUCTURE

Department of Molecular Oncology and Translational Medicine (DOMERT) Division of Experimental Oncology 1 Roberta MaestroDivision of Experimental Oncology 2 Alfonso ColombattiDivision of Experimental and Clinical Pharmacology Giuseppe ToffoliCore Facility 1 (CF1) on pharmaco-genomics/proteomics and tumor proteomics (PHAGE-TUPRO) of CBM (Molecular Biomedicine Center)

Department of Medical Oncology Umberto TirelliDivision of Medical Oncology A Umberto TirelliDivision of Medical Oncology B Angela BuonadonnaDivision of Medical Oncology C Diana CrivellariUnit of Cancer Bio-Immunotherapy Riccardo DolcettiUnit of High-Dose Chemotherapy & Cell Therapy Mariagrazia Michieli

Department of Clinical-Specialty Services & Support Division of Cardiology Nereo MeneguzzoDivision of Pharmacy Renzo LazzariniDivision of Anaesthesiology and Intensive Care Dario FantinUnit of Pain Therapy and Palliative Care Roberto BortolussiUnit of Psychological-Oncology

Department of Radiation Therapy and Imaging Diagnostics Mauro G. TrovòDivision of Radiation Oncology Mauro G. TrovòDivision of Radiology Luca BalestreriDivision of Medical Physics Elvira CapraDivision of Nuclear Medicine Eugenio Borsatti

Department of Surgical Oncology Francesco De MarchiDivision of Surgical Oncology Francesco De MarchiDivision of Gynecological Oncology Giorgio GiordaDivision of Gastroenterology Renato Cannizzaro

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OVERVIEW AND MISSION

The CRO National Cancer Institute (Centro di Riferimento Oncologico) was established in 1981 by the regional government of Friuli Venezia Giulia and began its activities in 1984 as one of 2 regional research institute hospitals in Northeast Italy at the border with Austria to the north and Slovenia to the east.It is located in Aviano (PN), in western Friuli within the province of Pordenone. Officially recognized by the Italian Ministry of Health in 1990, the CRO National Cancer Institute works to improve public health by advancing medical knowledge, providing outstanding specialty medical care to persons, and preparing tomorrow’s physicians, scientists and other health professionals in the field of oncology. It is a public, non-profit institute operating under the authority of the Italian

Health Ministry for the clinical & experimental research functions and shared in the governance by the Friuli Venezia Giulia region as for patient care. CRO is led by Franco Sinigoj, General Director since April 2007 and Dr. Paolo De Paoli, who has been the Center’s Scientific Director since January 2005.

Institutional purpose and operation Planning and carrying out laboratory and clinical

research with the aim of improving knowledge on the etiology and biology of malignant tumors as well as identifying new means of prevention, diagnosis and treatment;

Providing care and treatment to patients with malignant tumors, while identifying specific interdisciplinary therapies in accordance with scientific guidelines, also ensuring regular follow-up

and appropriate physical and psychic rehabilitation support;

Collecting, processing and disseminating information concerning epidemiological data and cancer-causing factors with the aim of achieving suitable measures of oncological, environmental, and professional prevention: promoting related healthcare training schemes;

Developing activities of theoretical and practical teaching, training and permanent education in oncology, also in collaboration with Universities and other national/ international Institutions;

Establishing appropriate forms of scientific collaboration in the oncological sector with agencies, institutions, Italian and foreign research laboratories, as well as other international organizations with the purpose of implementing coordinated programs;

Department of Laboratory Diagnostics and Cell Therapy Division of Blood transfusion, Immunohematology and Clinical Chemistry/Emergency Laboratory Mario MazzucatoDivision of Microbiology, Immunology, and Virology Giancarlo BasagliaDivision of Clinical and Experimental Oncohematology Valter GatteiDivision of Pathology Antonino CarboneUnit of Stem Cell Collection and Processing Mario MazzucatoUnit of Cancer Pathology Agostino Steffan

Breast Cancer Department Andrea VeronesiDivision of Medical Oncology C Andrea VeronesiDivision of Surgical Senology Samuele Massarut

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Participating in the creation of programs within the scope of its institutional purposes, indicated by National Health policy, and those indicated by the EU Oncology Committee;

Promoting and taking suitable initiatives to disseminate research results and acquired knowledge, particularly in Europe.

INNOVATOR IN BIOMEDICAL RESEARCH

In fiscal year 2006, CRO medical investigators received federal funding by the Ministry of Health and the National Institute of Health for specialized research grants; the Ministry of Education-University & Research, the AIRC (Italian Association for Cancer Research), LILT (Assoc. for Battle Against Cancer), ABO (Assoc. Biomedical Organizations), National Institute for Prevention & Security, the Friuli Venezia Giulia Region and various Foundations all awarded specific research grants. The Center also received research funding from the European Community ( V & VI Framework Programmes), the Association for International Cancer Research (UK) and Beneficentia Stiftung Foundation (Liechtenstein).

Research OverviewResearch at CRO contributes to the advancement of scientific knowledge, the prevention and treatment of disease, and the strengthening of our economy from collaborations with private industry. The current research activity has been reviewed since 2005 by consolidation of Line 1 with Line 2 attesting to a better organized transference activity of the Pre-Clinical & Epidemiological Department (now Department of Molecular Oncology & Translational Research). Therefore, clinical and experimental activity is now based on five research lines which are more homogeneous and coherent with the Institute’s objectives, all focused on biomedical research in oncology. New indicators for the evaluation of Departmental research activity in line with policy directives of the Health Ministry have been adopted. 1 Predisposing events and mechanisms of tumor

growth and progression: from natural history to identification of new diagnostic and therapeutic targets

2 Epidemiology and prevention of tumors. From

population to patient.3 Hematologic neoplasias4 Diagnosis and therapy of solid tumors5 Tumors associated with infectious agents. From

experimental and clinical laboratory to diagnosis, prognosis, and treatment

Clinical research is based on mono- and multidisciplinary therapeutic protocols (conservative surgery in breast cancer, combined chemotherapy and radiotherapy in locally advanced, non small-cell lung cancer, interdisciplinary treatment of soft tissue sarcomas and ovarian tumors). Innovative protocols concern:Phase I-II studies of new drugs in metastatic tumors; immunological therapy in human melanoma and other tumors; therapeutic schemes specifically designed for elderly patients and patients with AIDS.

Experimental research focuses on gene alterations as well as neoplastic transformation and progression; mechanisms of cell adhesion and migration; role of growth factors and growth factor receptors in hematological neoplasias; mechanisms of drug sensitivity and resistance; diet and cancer.

MULTIDISCIPLINARY RESEARCH FACILITY & TECHNOLOGY TRANSFER

The Core research facility CF1 : Pharmacogenomics and tumor proteomics is funded by the Consortium for Biomedical Molecular Medicine (AREA Science Park, Burlo Garofalo Hospital, Universities of Trieste and Udine, SISSA, Bracco Imaging, Eurospital, Italtbs, Diaco Laboratories, Transactiva and others) to provide facilities and resources for peer-reviewed clinical studies. Our goal is to play a major role in facilitating innovative scientific advances which will impact broadly across aspects of human health. Its development will allow it to mature into a vital resource for the CRO National Cancer Institute for quality technology transfer by interacting with other research institutes, industry, governmental institutions, development agencies, financial agencies and service centers. The research facility has generated potential deployment of intellectual property arising in

the course of dedicated research to foster economic development and allows the Institute to extend the impact of its research efforts; providing benefit to the public through useful products and services. Areas of priority interest are as follows: Oncology, Hepatology, Cellular Therapy.

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CROSS-DISCIPLINARY IN EDUCATION

The medical center and research institute is a model of community-based training and of inter-regional collaboration in medical education with a full-time staff of 170 clinical personnel (physicians, graduates), 489 technical and nursing staff, and 78 support staff (clinical & research fellow trainees).

Graduate EducationSeveral departmental programs have established fellowships where graduate students can conduct research training to reflect the cross-disciplinary nature of training in the sciences present within the Center. Opportunities include affiliation with such institutions as the Oncology Specialization Department of the University of Udine and a departmental relationship with many other Specialization departments in Medicine.Other conventions are active with Italian Universities in Catania, Catanzaro, Ferrara, Modena, Reggio Emilia, Padova, Parma and Trieste in which various researchers of CRO have institutional teaching positions. The research environment at the CRO National Cancer Institute offers graduate students a wealth of opportunities to advance their education. The newest tools in biomedical research are readily available and multidisciplinary research is fostered.The medical center and research institute provides advanced scientific training to Ph.D. students in biomedical research in a resource-rich, collaborative environment dedicated to scientific discovery and is planning to develop this mission by constructing a campus open to students worldwide but with particular attention to Eastern Europe in the future.

NATIONALLY RECOGNIZED FOR PATIENT CARE

The Medical Center is amongst the 8 research institute hospitals for cancer treatment in Italy and is a magnet hospital for specialized basic and clinical research in oncology.The clinical activity under research focuses on oncological surgery, conformal, intra-operative, stereotactic radiotherapy and IMRT (high-energy accelerators

– 6 to 18 MV – and an orthovoltage accelerator are in operation) and It is renowned for its programs in the medical treatment (intra-arterial chemotherapy, high-dosage chemotherapy) of the most frequent solid tumors, including rare neoplasias, and hematological neoplasias (lymphomas and chronic leukemias).As the region’s designated cancer specialization treatment hospital, the Medical center also offers integrated clinical care in Dermatology, Rehabilitation, Nephrology, Neurology, Opthamology, Orthopedics, and Pneumology through consultations within Specialized Divisions of the Pordenone General Hospital. Our clinics perform an average of 355,000 patient examinations per year and publish more than 180 scientific papers in journals with Impact Factors. Our physicians admit 8,800 patients a year (approximately 50 percent are extra-regional) to the Institute for medium-long term stays and day hospital treatment. Our physicians and medical department staff provide hospital care in all aspects of oncology with particular emphasis on Onco-Hematology, Breast Surgery, Onco-Geriatrics, Pharmacogenetics/genomics and serve youth (14-19 year olds) through a dedicated center in Radiation Therapy as well as the Youth Area.The medical center has the only Breast Cancer Department for conservation of physical integrity in surgery and therapeutic innovation in the region and is a leader in the Regional Cancer Registry serving for the implementation of bio-banks(i.e. the European human frozen tumor tissue bank, biological specimen banks for the evaluation of infection in cancer at a European network level, and a virtual network of National oncology bio banks).

Qualifying Medical Technologies For Diagnosis and Treatment Endoscopic diagnosis by a video capsule:

disposable, miniature video camera contained in a capsule for non-invasive visualization of the small intestine.

Radiation Oncology treatments include linear accelerators dedicated to Intensity Modulated Radiation Therapy (IMRT) and to Intra Operative Radiation Therapy (IORT),a full brachytherapy service and an innovative Hi-Art Tomotherapy system.

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Library, Psychology, Pain Therapy, Marrow Transplant, and Pediatric Radiotherapy.

Through its longstanding and close relationship with various volunteer associations both at the national and local level, the Center recognizes the importance of patient and family involvement in health-care decision making. Those of national importance are primarily: AIL (leukemia), ANDOS (breast surgery), ANGOLO (long term cancer survivors), ANLAIDS (battle against AIDS), LILT (battle against cancer).Many other local level associations provide daily support and entertainment (theater, music, manual activity labs) as well as providing to the needs of patients and their families during hospitalization and treatment phases. Beginning in 2006, a quarterly publication- “CRO news” has been adopted as a means of divulging free information to all the Center’s public.Yearly coordination by a reference person within the Center supports a philosophy of providing healthcare that encourages a spirit of partnership between patients, families, and medical professionals.

International RelationshipsCRO is involved in several international research networks and clinical studies within the framework of the European Organization for Research and Treatment of Cancer (EORTC), the European Organization for Cooperation on Cancer Prevention Studies (ECP), the European Organization of Cancer Institutes (OECI), the European Society for Medical Oncology (ESMO), the International Union Against Cancer (UICC) and the International Breast Cancer Study Group (IBCSG).Additionally, the CRO is involved in the Italian/American Program on Oncologic Pharmacogenomics of the Istituto Superiore di Sanità sponsored by the American National Institutes of Health.Of note, the Institute has recently established a partnership with Princess Margaret Hospital in Toronto, Canada to pool both Center’s renowned cancer knowledge and specialized expertise, support innovation in cancer education programs, promote E-health initiatives, and create opportunities for joint ventures.Moreover, an agreement between the Institute and The George Mason University - Manassas Virginia

Combined PET/CT, scanners producing image fusion; the functional data provided by 18F-FDG increase diagnostic accuracy over conventional PET and CT in a variety of malignancies for more accurate tumor diagnosis, staging, and treatment planning. A whole-body survey is the standard mode of acquisition.

Expression proteomics and functional proteomics are used to identify and characterize proteins in cancer with the use of the MALDI technique. Virtual microscopy and image analysis/quantitative pathology are used to characterize morphological and phenotypic features of neoplastic tissues.

The Center’s participation in Alleanza Contro il Cancro (ACC), promoted by the Ministry of Health in 2002, is fundamental to its networking capacity with other Italian medical centers and research institutes.In this way, research transference and collaborative initiatives with other national/international centers so as to divulge knowledge in as vast an area as possible are the result of active participation by CRO.Since 2003, notable work has been done as a part of the Italian-American agreement for collaborative studies in serum proteomics and phosphoproteomics for breast, colorectal, lung, and ovarian tumors.The Center has actively supported these studies by transferring material to the National Biobank (Milan) and strongly supporting internal studies on serum proteomics. Likewise initiatives aimed at personalization of cancer therapy by targeting predictive markers to allow precise administration of pharmaceutical therapeutics continues as new knowledge in this area becomes available.Since January 2007, the Youth Area was created for adolescents 14-24 years old to give them a dedicated space (both physical and social) appropriately designed to assuage their cancer treatment. Diagnostic procedures, staging, and therapy are undertaken for youth affected by lymphomas and solid tumors: musculo-skeletal, cerebral, melanomas, head & neck tumors, carcinomas, and rare tumors.The Area is not a new ward but a multidisciplinary space derived from the connection and collaboration of three Departments : Radiation Therapy & Imaging Diagnostics, Medical Oncology, Pediatrics and five Units: Scientific

(USA) has been signed, aiming at the education and preparation of students in the field of molecular medicine and proteomics. Both Institutes are involved in the implementation of programs involving their students, faculty, facilities and personnel

Registers and BiobanksCRO is the leader of the Regional Cancer Register (Registro Tumori di Popolazione della Regione Friuli Venezia Giulia) and participates in the following research projects (two are sponsored by the European Union; one is sponsored by the Italian Ministry of Health) aiming at the implementation of biobanks: European Human Frozen Tumor Tissue Bank.

The goal is to establish a European tissue bank comprising frozen tumor and normal tissue, patients’ data and virtual microscopy images of the stored tissues to facilitate translational cancer research.

Evaluation of the Role of infection in Cancer using Biological Specimen Banks. The goal is the creation and the implementation of a network of European bio-banks in order to engage competent cancer specialists in discussion on how to exploit the study base in the most optimal way for identification and evaluation of whether infections are risk factors for cancer.

Virtual Network of a National Oncologic Bio Bank.The goal is the implementation of software to be shared by the 7 Italian National Cancer Institutes and the standardization of collection and storage procedures.

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The Scientific DirectorateDirectorPaolo DE PAOLI, [email protected]+39 0434 659282

StaffPierangela BANDIZIOLMonica Elettra GISLONFrancesca LOLLO

Editorial OfficeNancy MICHILIN

Project Design/ Management, Technology TransferErmes MESTRONI

Clinical Trials Office, Andrea VERONESIEleonora BERTO, data managerDaniela QUITADAMO, data managerAntonella SPADA, data managerGianna TABARO, data managerElisa TURCHET, data managerAnnamaria COLUSSI, research nurseIvana SARTOR, research nurse

INTRODUCTION

The clinical-scientific activities of the Centro di Riferimento Oncologico of Aviano (CRO - National Cancer Institute) have increased over the years: ordinary hospitalizations, outpatient services, and the number of patients enrolled in clinical trials are growing.The results of laboratory and clinical research are extensively published in international scientific journals. 189 full papers were published in 2006 and 194 have been published and in press as of December 2007 in journals with a total impact factor of 772 and 791, respectively. In addition, there were approximately 150 publications in the form of book chapters, conference

papers or abstracts of preliminary results presented at national and international meetings.These research efforts have been supported by core grants from the Ministry of Health, the European Union, and an unceasing increase in our ability to compete for external funding. The transferral of innovations that emerge from laboratory research to clinical practice and have consequences for the persons affected by cancer is foremost in our Institute.

Clinical research based upon mono- and multidisciplinary trials in neoplastic pathologies (limited surgery in breast cancer, combined chemotherapy and radiation therapy in locally advanced non-small-cell lung cancer, inter-disciplinary treatment of malignant

lymphomas, soft tissue sarcomas and ovarian carcinomas) is at the basis of our engagement in the fight to overcome cancer and mitigate serious chronic illnesses deriving from exposure to relentless and forbidding infectious agents.Innovative treatment protocols concern: phase I-II studies of new drugs in advanced cancer; immunological therapy of human melanomas and other tumors; and therapeutic regimens specifically designed for elderly patients. One of the main research topics of the Center has been portrayed in the program for new diagnostic and therapeutic strategies in managing HIV infection, particularly in HIV-related tumors. The development of such research also covers the study of other infections and other infectious agents related to human carcinogenesis.Experimental research is focused on gene alterations and neoplastic transformation and progression; mechanisms of cell adhesion and migration; role of growth factors and growth factor receptors in hematopoietic malignancies; mechanisms of drug sensitivity and resistance; diet and cancer.

INDEPENDENT ETHICS COMMITTEE

The Independent Ethical Committee meets regularly to review an average of 50 new clinical protocols per year, both non-profit and sponsored by pharmaceutical companies with a total of 717 new patients enrolled in the year 2008 (1650 follow up).

CLINICAL TRIALS GROUP

It is a multidisciplinary group (which comprises the Clinical Trials Office-CTO), established in the year 2008 with the adoption of a statute. Its aims are:• Strategicplanningofclinicalresearch• Creationofaninformaticarchiveofongoingstudies• Increase of the number of CRO-based protocolsand increase of phase I/II studies• DevelopmentbyCROresearchersofdiagnosticandtherapeutic moleculesClinical Trials OfficeIts task is the activation, discussion and submission of clinical trials to the Independent Ethics Committee. After

Via Franco Gallini, 2 - 33081 Aviano - ITALY - Tel. +39 0434 659111 - Fax: +39 0434 652182 - www.cro.it

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approval, the Clinical Trials Office is in charge of the start-up, data collection, and interpretation of the protocols as well as maintaining contacts with sponsors.

ALLIANCE AGAINST CANCER

Alliance Against Cancer is an “excellence network” promoting and facilitating the exchange of: information, knowledge, data, scientific results, and personnel. It was created amongst Italian Cancer Institutes and to date several research projects have been developed within its framework.

FUND RAISING AND DONATIONS

Several private donors choose each year to sponsor our research and clinical activities. In the year 2008 a total of € 420.000 have been raised. Any information pertaining to the allocation of funds is available either on our website (www.cro.it) or by contacting the Scientific Directorate (+39 0434 659282).

THE INTERNATIONAL SCIENTIFIC COMMITTEE

The Institute provided itself with an International Scientific Committee, composed of prominent international scientists and researchers.The Committee’s mission is:• Planning and carrying out laboratory and clinicalresearch with the aim of improving knowledge on the aetiology and the biology of malignant tumours as well as identifying new means of prevention, diagnosis and treatment;• Developing activities of theoretical and practicalteaching, training and permanent education in oncology, also in collaboration with Universities and other national and international Institutions;• Establishing appropriate forms of scientificcollaboration in the oncological sector with bodies, institutions, Italian and foreign research laboratories, as well as other international bodies with the purpose of implementing co-ordinated programmes.

Claudio Basilico, M.D.Professor and Chair,Department of MicrobiologyNew York University School of Medicine, USA

Francesco Cavalli, M.D.Scientific Director, Institute of OncologyBellinzona, CHDirector, Division of Oncology Ospedale San Giovanni Bellinzona, CHPresident UICC

Silvio Garattini, M.D.Director, Mario Negri Institute for Pharmacological ResearchMilan, Italy

Riccardo Dalla-Favera, M.D.Director, Institute of Cancer Genetics; Percy and Joanne Uris Professor of Clinical Medicine; Professor of Pathology and Genetics & DevelopmentColumbia University, New York, USA

Mary K. Gospodarowicz, M.D., FRCPC, FRCR (Hon)Professor and Chair, Department of Radiation Oncology, Uni-versity of Toronto; Chief, Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario

Salvatore Siena, M.D.Head, The Falck Division of Medical Oncology, Niguarda Ca’ Granda Hospital, Milan, Italy

Vittorio Silano, Ph.D.National institute for the promotion of migrants’ health and the control of poverty-related diseases, Rome, Italy


The CRO Scientific Library is a Unit of the Scientific Directorate of the Institute http://www.cro.sanita.fvg.it/biblioteca/set_bibliotecascientifica.htm, specialized in oncology and related fields.The CRO National Cancer Institute is provided with a small-medium sized library: Staff: 3 full time employees, 2 of them professionals, 3 persons granted for an equal number of specific current projects Publication figures: the library holds approximately 3,500 periodicals both in print and online but about 6,000 currently accessible; 9,000 books devoted to both the scientific and non-scientific communities; approximately 15 different current databases; a budget of 280.000,00€ (2006) Services: Document Delivery – approximately 2,000 articles sent and 1,200 requested; many educational activities, either CME-oriented or not; management

The Scientific DirectorateScientific Library

Head, LibraryIvana [email protected]+39 0434 659248

StaffAssistant LibrarianLaura CIOLFI [email protected] PARRO [email protected] TURRIN (part time)

FellowsNancy MICHILIN [email protected] GIACOMELLOMichela FLORIO

Patients’ [email protected]

of the scientific production of the Institute’s staff (i.e. articles/Impact Factor, one of the key factors determining the financing of research) Standards are respected in the implementation of Online Public Access Catalogue of books via SBN, the Italian National Bibliographic Service http://sol.units.it/SebinaOpac/Opac?sysb=cro, Document Delivery, Grey Literature Archive http://www.cro.sanita.fvg.it/biblioteca/txt_archPub.htm an archive of educational materials accessible online, CRO authors’ publications Archive, Library webpage, the newly activated library BLOG Many current collaborations with eminent Institutions

Some features of the CRO library A special section for patients called “Biblioteca per i pazienti” (Patients’ Library): initiated in 1998 as a pilot

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project in Italy within this field. This service is intended for patients, relatives and citizens. The focus is on 3 main fundamentals: • dedicatedspace• adequatematerialwithattentiontocommunicativestyle and quality content• expertcounselingThe Patients’ Library is extensively involved in specific new projects such as: • theYouthArea,• theDrugInformationServiceforcitizens,• Exchanges with students raising awareness ofcancer-related problems and quality evaluation of the online health related information,• Publications representing patients’ expressions:thoughts, history, and drawings, • Socio-culturaleventsdevotedtothecommunity incollaboration with the local public libraries.

A deep involvement, as co-coordinator, in an Italian multicentric collaborative project with Research Institutes for divulging information to cancer patients is in progress.

Many participations in collaborative projects, e.g. since 1987 in the “GIDIF RBM collective catalogue and Document Delivery”; in the BIBLIOSAN project, http://www.bibliosan.it/; in the Open Access Institutional Repository of biomedical literature authored by Italian researchers, lead by Istituto Superiore di Sanità http://dspace.iss.it/dspace/handle/2198/24

A “natural” disposition to surveys and statistics concerning the services offered. This activity is included in a quality assurance program based on self-evaluation. As an example: A pilot project of Cancer Patient Library in Italy: the results of a customer satisfaction survey and its products, Health Information and Libraries Journal 2006, 23:266-274 accessible on http://eprints.rclis.org/archive/00008531/

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SELECTED PUBLICATIONS

• Truccolo Ivana, Bianchet Katia, Capello Fabia,Russell-Edu William, Dal Maso Luigino, Colombatti Alfonso, Ciolfi Laura, Tirelli Umberto, De Paoli Paolo. A pilot project of a cancer patient library in Italy: results of a customer-satisfaction survey and its products. Health Info Libr J 2006, 23 (4): 266-274

• Bianchet, Katia, Truccolo, Ivana, and De Paoli,Paolo. Health? A question of ...mass media. Cancer Librarians Section News 2007, Newsletter (42): 3-5

• TruccoloI.,BianchetK.,DalMasoL.,CognettiG.,De Paoli P. Knowledge and use of Internet as a health education tool by Italian high school students. JEAHIL 2009, 5 (2): 13-18


The Scientific DirectorateDivision of Epidemiology and Biostatistics

Division DirectorDiego SERRAINO, [email protected]

StaffEttore BIDOLI, ScD [email protected] DAL MASO, ScD [email protected] POLESEL, ScD [email protected] FORGIARIN, Cancer Registry Biologist

Unit DirectorRenato TALAMINI, ScD, Head of the Clinical Epidemiology & Assessment [email protected]

Research FellowsMauro LISE, ScD [email protected] ZUCCHETTO, [email protected] DE PAOLI, ScD

MISSION

The mission of the Epidemiology and Biostatistics Division is the prevention of human cancer through the elucidation of its distribution and causes.Since 1984, the Epidemiology and Biostatistics Division has been conducting analytical (e.g., case-control and cohort studies) and descriptive (e.g., analyses of incidence and mortality data) research.The Division’s investigation activity is conducted in collaboration with research groups from national and international institutions, deepening the understanding of cancer epidemiology and producing results with wide-ranging applications in oncology and statistics.

RESEARCH ACTIVITY-PROJECTS LIST

The Division focuses its research activity on five main fields to gain an understanding of the biochemical and genetic mechanisms underlying tumor development in supporting statistical methodology, study design, as well as the clinical response and survival of patients:

Analytical epidemiology studies:These investigations concern the relationship between cancer and lifestyle, environmental exposure, and genetic susceptibility which are conducted in different Italian areas. Their objectives are: (a) evaluating the impact of different lifestyle factors (i.e., physical activity, obesity, occupational exposure, a family history of

cancer) on the aetiology of cancer; and (b) establishing a bio-bank of biological samples (e.g.,tumour biopsies, blood, and urine) for the identification of parameters related to tumor development (e.g., genetic susceptibility or polymorphisms).

The impact of lifestyle on survival of cancer patients:Through a “record-linkage” approach, data derived from analytical epidemiology studies (e.g., case-control) on cancer aetiology are cross-matched with information from several computerized databanks (registry offices, cancer registries, and healthcare/hospital discharge databases).These databases offer the opportunity of: (a) estimating survival in cancer patients (cases); (b) assessing the impact of various factors (with regard to exposure and lifestyle) on survival and, possibly, on the development of neoplasm in controls.

Infectious agents and cancer:Approximately 15% of all cancers are associated with viral infections, and these cancers are particularly common in persons with deficits of the immune system – like HIV-infected people or persons who have undergone organ transplant.The relationship between chronic infections and the development of cancer is investigated through different approaches: (a) the implementation of epidemiological methods; (b) the assessment of the spread of infections,or potential oncogenes, in the population; (c) the evaluation of epidemiological aspects of tumors that occur with high frequency in people who have undergone organ transplant.

Registration and description of cancer distribution in the Friuli Venezia Giulia region:Since 1998, all the resident population in the Friuli Venezia Giulia region is under surveillance for the occurrence of cancer cases.The population-based Cancer Registry was established to guarantee a complete and accurate informative source with regard to all cases of cancer that are diagnosed in the region.The high qualitative standards -recognized at the national and international levels- offer a unique tool for understanding cancer distribution and its causes C

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in order to implement appropriate preventive actions and the management of cancer diagnosis, therapy, and care. Within this framework and in collaboration with the Regional Health Agency, a specific area is addressed to the evaluation of primary and secondary prevention programs in oncology.

Clinical and epidemiological assessment studies:They address the relationship between prognostic factors and cancer survival. This field of research supports a multidisciplinary action aimed at integrating the scientific activity of several professional figures, both within the Institute and in other research Institutes.Particularly significant objectives are supporting statistical methodology and data analysis for study design, as well as studying the clinical response and survival of patients with cancer.

Top 3 cancer sitesNational and Friuli Venezia Giulia RegionFemale: Breast, Colorectal, Leukemia-Lymphoma-MyelomaMale: Prostate, Lung, Colorectal

% most frequent tumors, excl.skin ,(site and sex incidence)

Italian Cancer Registries pool , (site and sex incidence)

Epidemiological Studies

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SELECTED PUBLICATIONS

• Riva E, Serraino D, Pierangeli A, Bambacioni F,Zaniratti S, Minosse C, Selleri M, Bucci M, Scagnolari C, Degener AM, Capobianchi MR, Antonelli G, Dianzani F; the Human Papillomavirus Study Group.Markers of human papillomavirus infection and their correlation with cervical dysplasia in human immunodeficiency virus-positive women. Clin Microbiol Infect 2007; 13(1): 94-7.

• SerrainoD,PiselliP,BusnachG,BurraP,CitterioF,Arbustini E, Baccarani U, De Juli E, Pozzetto U, Bellelli S, Polesel J, Pradier C, Maso LD, Angeletti C, Carrieri MP, Rezza G, Franceschi S; for the Immunosuppression and Cancer Study Group. Risk of cancer following immunosuppression in organ transplant recipients and in HIV positive individuals in southern Europe. Eur J Cancer 2007; 43(14): 2117--23.

• PoleselJ,TalaminiR,MontellaM,MasoLD,CrovatoM, Parpinel M, Izzo F, Tommasi LG, Serraino D, Vecchia CL, Franceschi S. Nutrients intake and the risk of hepatocellular carcinoma in Italy. Eur J Cancer 2007; 43, 2381-2387.

• BosettiC,RossiM,McLaughlinJK,NegriE,TalaminiR, Lagiou P, Montella M, Ramazzotti V, Franceschi S, LaVecchia C. Flavonoids and the risk of renal cell cancer. Cancer Epidemiol Biomarkers Prev 2007;16:98-101.

• GaleoneC,PelucchiC,TalaminiR,NegriE,MontellaM, Ramazzotti V, Zucchetto A, Maso LD, Franceschi S, La Vecchia C. Fibre intake and renal cell carcinoma: A case-control study from Italy. Int J Cancer 2007; 121 (8):1869-72.

• TalaminiR,PoleselJ,SpinaM,ChimientiE,SerrainoD, Zuccheto A, Zanet E, Franceschi S, and Tirelli U. The Impact of tobacco smoking and alcohol drinking on survival of patients with non-Hodgkin’s lymphoma. Int J Cancer 2007; 122: 1624-29.

• DalMasoL.,ZucchettoA.,TalaminiR.,SerrainoD.,Stocco C. F., Vercelli M., Falcini F., Franceschi S., [as member of PACE Working Group], Bidoli E., Polesel

J., Lise M. Effect of obesity and other lifestyle factors on mortality in women with breast cancer. Int J Cancer 2008, 123 (9): 2188-2194

• PoleselJ.,CliffordG.M.,RickenbachM.,DalMasoL., Battegay M., Bouchardy C., Furrer H., Hasse B., Levi F., Probst-Hensch N. M., Schmid P., Franceschi S. Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. AIDS 2008, 22 (2): 301-306

• Zucchetto A., Talamini R., Dal Maso L., Negri E.,Polesel J., Ramazzotti V., Montella M., Canzonieri V., Serraino D., La Vecchia C., Franceschi S. Reproductive, menstrual, and other hormone-related factors and risk of renal cell cancer. Int J Cancer 2008, 123 (9): 2213-2216

• DalMasoL.,PoleselJ.,SerrainoD.,LiseM.,PiselliP., Falcini F., Russo A., Intrieri T., Vercelli M., Zambon P., Tagliabue G., Zanetti R., Federico M., Limina R. M., Mangone L., De Lisi V., Stracci F., Ferretti S., Piffer S., Budroni M., Donato A., Giacomin A., Bellu F., Fusco M., Madeddu A., Vitarelli S., Tessandori R., Tumino R., Suligoi B., Franceschi S. Pattern of cancer risk in persons with AIDS in Italy in the HAART era. Brit J Cancer 2009, 100 (5): 840-847 (Br J Cancer)

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INTRODUCTION

Within the Institute, the mission of the chief Medical Officer is to provide the best health organization and supervise all clinical units for their medical duties.A close interaction with the Scientific Director and the Administration as well as an internal organization in several subunits make it easier to maintain the multiple functions of this unit under close control:1) secretariat;2) patients’ records archive;3) health surveillance;4) monitoring office;5) hygiene office;6) nursing office.

The Chief Medical Officer supervises and coordinates several working groups on various health-related matters as well as the Public Relation office, the prevention office, and the quality accreditation office.

The Medical Office

DirectorMauro DELENDI, [email protected]+39 0434 659507

StaffNurse CoordinatorsRoberto BIANCAT, NDNicoletta SUTER, ND

Unit for Development & Coordination of the Nursing Profession

EDUCATION AND TRAINING DIVISION

The mission of the Education and Training Office is to offer a thorough integration of the most advanced research with the best clinical practices in order to appropriately respond to the health needs of the patients. These functions are undertaken by applying a quality management system that also certifies the appropriateness and efficacy of formative events. Simultaneous record keeping, of strengths and weaknesses, by means of appropriate indicators guarantee continuous improvement in the education and training activities offered.The Office, with a staff composed of a Nursing Coordinator, two part-time nurses, a secretary and a psychologist fellow employed part-time, is part of the Medical Office Structure and acts in conjunction with the Scientific Directorate.

Educational goals favoring the formation of highly qualified and motivated professionals;

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internships.Training is also provided for Medical Doctors during their Oncology, Surgery, and Radiotherapy specialty courses. An active program of scientific seminars, scientific conferences for basic education and ones specific to oncological fields have been organized in strict relation with the Scientific Directorate’s programs. Several theses in disciplines as diverse as Medicine, Biology, Biotechnology, Pharmacy, Psychology and Nursing for different University degrees as well as Nursing Managerial Master programs have been coordinated in the quality of chairman and co-chairman.

Internships for high school studentsSince the early nineties, the Institute is involved in summer programs and internships for high school students with up to 20 students per year attending the laboratories for a limited period of time.

ACCREDITATION CANADA PROGRAM

The Institute has started the Accreditation Canada program. Accreditation Canada is a not-for-profit, independent organization accredited by the International Society for Quality in Healthcare (ISQua). it provides national and international health care organizations with an external peer review process to assess and improve the services they provide to their patients and clients based on standards of excellence. Accreditation Canada’s programs and guidance have helped organizations promote quality health care for over 50 years.

improving knowledge and competence of cancer research; involving all personnel in the attainment of the Institute’s goals and improving organization; promoting and empowering all professional staff members by providing adequate information; stimulating an open discussion among the different professionals and optimizing the translation of clinical research into clinical practice through promotion and development of regional, national, and European initiatives; disseminating educational materials from lectures through institutional grey literature intranet/internet archives to allow participant access and detailed study; providing tutorship for personal education and training by emphasizing human resource importance and value

The Education and Training Office is continuously analyzing the training and educational as well as the organizational needs at the National Cancer Institute in Aviano; providing systematic training and education for personnel in order to comply with the obligations of the national and regional Continuous Medical Education(CME) framework. In 2006 the Office provided about 15,670 credits to 1,615 people and in 2007 approximately 475 hours of CME education were reached in the first semester.The Institute’s CME Provider has proposed a large number of accredited events: they have attracted the interest and adhesion of internal staff members and external participants. The Office has taken care of the collection and registration of CME educational credits acquired by the employees through participation in internal and external events although some events have been accredited from other providers. In June 2007, the Office was accredited according to the ISO 9001:2000 for its educational and training activity.

University DegreesThe Institute is part of the training program for nurses, medical technicians, radiology technicians,and prevention technicians in collaboration with the Universities of Udine and Trieste. In particular, up to 83 tutors are dedicated to supporting students during their

CLINICAL ACTIVITY

Beds 150

Ordinary admissions 2,707

Day Hospital admissions 2,426


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The Administrative Directorate

DirectorMr. Franco [email protected]@cro.it+39 0434 659216

Administrative Group, Division of Scientific Research & Project AdministrationMr. Franco SINIGOJ,Director

Purchasing, Contracts, Business Management Division

Purchasing, Contracts, Business Management DivisionDirector, Mr. Franco [email protected]

General & Legal Affairs OfficeMr. Alessandro FALDON, Senior Manager, AttorneyPurchasing & Finance OfficeMrs. Raffaella CATTARUZZA, Senior ManagerBusiness Management Office

Human Resources (Personnel Policies) Division

Director

Mr. Franco SINIGOJLegal Entity AreaPersonnel Accounting Area

Technologies and Capital Equipment Division

DirectorMr. Ermes GREATTI, [email protected]

Supplies and Software Commodities UnitTechnologies UnitInformation Systems/Informatics Unit


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MISSION AND ADMINISTRATIVE ACTIVITIES OF THE UNITS

The Purchasing, Contracts and Business Management Division is composed of the following Offices to provide administrative staff an opportunity in the development of CRO-National Cancer Institute administrative processes and to support the activities of the General Director as well as certain functions of the Scientific Director: General & Legal Affairs Purchasing & Finance Business Management Treasury

The above-mentioned Division guarantees the creation of annual program schemes in adherence with regional guidelines and those of the Italian Health Ministry, a provisional budget and monitoring of expenses; the informational and business management of specialized research administration financing in collaboration with the Scientific Directorate, as well as its budgetary monitoring/accounting. Other operational duties include: Formal accounting management Periodic quarterly and annual budget planning and

monitoring Operational, general and analytical accounting and

fiscal management All activities related to stipulation of official deeds Management of an internal protocol and archive of

deeds/documents Corporate alliances through conventions /

agreements with other institutions Procedures for contractual agreements with

personnel such as experts, consultants, etc. Systematic registration of all examinations and in-

patients Acting as an institutional secretariat for internal

boards/committees

The Technologies and Capital Equipment Division manages: The purchase of all institutional commodities related

to the Institute’s objectives including scientific medical equipment, advanced technologies, and capital equipment investments.

the routine administration of the Information Systems/Informatics Unit and the management of a local area network as well as customer support.

The Personnel Policies Division guarantees the adequate completion of selection procedures for employment of personnel (including fellowship administration) as well as pension planning, assistance, and contributions for career management; the hiring of full-time personnel as well as the assignment of fellowships and personnel hired on a contractual basis. Additional activities include Labor union representation/relations, application of professional work contracts, and development of regulations for the independent medical activity of physicians.

PERSONNEL

THE CAMPUS PROJECT

In the year 2008 the Regional government approved the “Campus” project, a building completed devoted to host Italian and foreign researchers.

Graduates 170

Nurses and Health Technicians 489

Other 78

Total 737


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Faculty & Staff

Umberto TIRELLI, MDDepartment Director, Division DirectorPrincipal Investigator, Medical Oncology A

Sergio FRUSTACI, MDDivision Director, Medical Oncology BGastrointestinal Tumors, Sarcomas and Rare Tumors

Andrea VERONESI, MDDivision Director, Medical Oncology C

Riccardo DOLCETTI, MDUnit DirectorCancer Bio-immunotherapy

Mariagrazia MICHIELI, MDUnit DirectorCell Therapy and High-Dose Chemotherapy

The Department of Medical Oncology is composed of the following 3 Divisions and 2 Units: Medical Oncology A, Medical Oncology B, Medical Oncology C. In addition, the Department includes Units dedicated to Malignant Lymphomas, Head & Neck Cancer Treatment, Cell Therapy and High-Dose Chemotherapy, Cancer Bio-Immunotherapy, and Infectious Diseases.

For years the Department has been at the forefront of activity within the Centro di Riferimento Oncologico, both for quality of care and clinical research. The Divisions and Units share in-patient wards and out-patient clinical staff, including a large part of care for specific domains of tailored treatment such as for transplants, AIDS, elderly, and lymphomas among others and research covering breast, lymphomas, eldery, and patients having infectious diseases as well as tumors.

The Department staff uses a disease management team approach and participates in clinical and translational research projects in an integrated fashion. Concerning new lines of research, besides the elderly, there are Ministry of Health projects dedicated to long term survivors and cancer-free persons, within a specialized clinic supervised by Dr. Simonelli. Costs of chemotherapy regimens and issues related to cancer and the environment will be other areas of interest in our research endeavor. Our relationship with the volunteer organizations: Angolo, FLAI, FAVO and AIMAC will continue in close collaboration.Research publications, both for quality and number, remain high and are the first in order as compared to other Departments. Opportune leadership, environment, resources and necessary infrastructure for medical investigators, their staff, and medical students to conduct medical research while providing attentive primary care are guaranteed by the Department’s Director.


Department of Medical OncologyDivision of Medical Oncology A

Umberto TIRELLI, MDPrincipal Investigator & Department DirectorPhone +39 0434 659284Fax +39 0434 [email protected]

Associate DirectorsEmanuela VACCHER, MD [email protected] SPINA, MD [email protected]

StaffAlessandra BEARZ, MD [email protected] BERRETTA, MD [email protected] CHIMIENTI, MD [email protected] FRATINO, MD [email protected] MARTELLOTTA, MD [email protected] SANTAROSSA, MD [email protected] Ornella SCHIOPPA, MD [email protected] SPAZZAPAN, MD [email protected]

Fellows & Other PersonnelArben LLESHI, Research fellowAnnalisa GIACALONE, Research fellowPaola NIGRI, Research fellowErnesto ZANET, Research fellow

MISSION AND CLINICAL ACTIVITY

The Division’s mission is to provide the best treatment available for a number of oncological diseases to include hematological malignancies, head and neck tumors and esophageal cancer, genito-urinary tract tumors, lung tumors, HIV infection and HIV-associated malignancies, chronic fatigue syndrome and cancer-related fatigue.Both clinical and research activities focus on better care, supportive measures and innovative means to combat malignancies, tumors and cancer in their various manifestations, HIV infection and HIV-

associated malignancies, chronic fatigue syndrome and cancer-related fatigue. Cancer survivors and related psychological, biological and clinical problems will be assiduously reviewed in a dedicated clinic. Tumors potentially related to the environment and work activities constitute other activities of interest for our medical staff. The Division’s interaction with the Bone Marrow Transplantation Unit provides necessary support concerning inpatient care given the total number of 413 hospital admissions registered since 2006. In the same year, the outpatient clinical activity included 10.651 examinations, for a total of 3.956 intravenous chemotherapy administrations.

PROJECTS LIST- RESEARCH ACTIVITY

During 2006 the Division of Medical Oncology A has resolutely pursued the following issues:

1. Lymphomas, in particular in elderly patients, and those with HIV and HCV infections;2. Studies on bone marrow transplantation, feasibility and activity in lymphoma patients specifically the elderly and patients with virus-associated lymphomas;3. Studies on chemotherapy-induced immunological damage, mainly in the elderly and patients submitted to high-dose chemotherapy and bone marrow transplant;4. Etiopathogenic-based treatments of HIV and non-HIV related Kaposi’s sarcoma;5. Feasibility, toxicity and long-term follow-up of chemotherapy association with antiretroviral therapy;6. Pharmacokinetics and pharmacodynamic interaction between protease inhibitors and cytotoxic agents;7. Studies of biological drugs in lung cancer, focusing in particular on elderly patients;8. Studies of solid tumor treatments, with specific attention to gastrointestinal tumors and lung cancer, as well as to patients with HIV infection;9. Studies of dedicated treatments for the care of elderly patients older than 70 years

UNIT OF INFECTIOUS DISEASES

The study of HIV-related tumors encompasses many scientific disciplines. The management of these C

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patients is a highly specialized activity that requires expertise in clinical oncology, infectious diseases, virology, immunology, pathology, hematology and transplantation. This type of care is optimally achieved at specialized centers, as our Institute, characterized by significant and long-term multidisciplinary experience in HIV disease. Since 1986, the Italian Cooperative Group AIDS and Tumors (GICAT) has been activated in Aviano, aiming to promote the cooperation between clinical and basic research. All clinical trials proposed are carried out in Italy by the GICAT. Although the management of HIV-related tumors has progressively improved in recent years, their treatment is still a matter of controversy. Therefore, new acquisitions obtained by means of clinical trials, such as the ones proposed in this project, have a high potential to be transferred into clinical practice. In parallel to this research activity, two other sections on herpes viruses- and bacteria- associated cancers, have been activated. All these research activities are aimed at better defining the underlying pathogenic mechanisms with the final goal of developing new diagnostic and therapeutic strategies. Some of the results obtained so far have resulted in successful clinical application.


Current research activities involve:

HIV-related tumors:

• Epidemiological study on AIDS-defining and nonAIDS-defining cancers in the HAART era.

• Studyofinnovativetherapeuticstrategiesincludingthe association of chemotherapy(CT) with HAART.

• Pharmacokineticandpharmacogenetic studiesonCT-HAART combination therapy.

• Activationofsurveillanceandpreventionprograms.• Study on the role of HPV in the pathogenesis

and natural history of anogenital and oral cavity-oropharyngeal preneoplastic and neoplastic lesions.

• Study on the role of FDG-Positron EmissionTomography (PET) imaging for the diagnosis and response monitoring in patients with lymphomas and solid tumors.

In recent years, 8 phase II studies and one phase III study have been performed in HIV-infected patients with lymphomas or Kaposi’s Sarcoma (KS).Other ongoing studies:Phase II study with VEBEP plus HAART in HIV-associated HD.Phase II study with CODOX/M-IVAC in HIV-infected patients with Burkitt’s lymphoma.Phase II study with HDC and PBSC as first-line strategy in HIV-infected patients with NHL DLCL and IPI>2.Study on the impact of standard and HDC on the immune system and viral dynamics of co-infections (HCV, HBV), in HIV-patients with tumors.Study on the feasibility and efficacy of combination therapy with CT and boosted PI-based HAART.Study on long-term toxicity of CT-HAART,with specific emphasis on cardiovascular toxicity in patients with HAART-induced metabolic syndrome.

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Department of Medical OncologyDivision of Medical Oncology B

Sergio FRUSTACI, MDDirector Division of Medical Oncology [email protected]

Associate DirectorAngela BUONADONNA, MD [email protected]

StaffIn-patients section*Simona SCALONEAssistant physician [email protected] LOMBARDIAssistant physician [email protected]

Fellows & Other PersonnelMonica OLIVASecretary

* Shared with the Division of Medical Oncology C


• Coordinationandplanningoftheclinicalandclinical-research programs concerning the neoplastic diseases of the G.I. tract, bone and soft tissue sarcomas and rare tumors. • Multidisciplinary approach to themedical decisionshared with all the Units involved within the Hospital (Surgical Oncology, Radiation Therapy Oncology, Gastroenterology, Pathology, Radiology).• Planning of clinical trials inside and outside theHospital with participation in different cooperative Groups (Italian Sarcoma Group, Italian Trials on Medical Oncology, Italian Group on rare diseases, EORTC, Connective Tissue Oncology Society).

• Interaction with the Molecular Oncology andTranslational Medicine Department (DOMERT) in order to contribute to translational clinical trial activation.

The clinical activity, mainly performed on an outpatient basis, involves personnel of the Medical Oncology C Division, the Day-Hospital of the Medical Oncology Department and its Outpatient section. Treatment and follow-up is scheduled on a four days per week basis. One day is devoted to the external consultations for providing patients with a second opinion. Patients needing prolonged therapy or complicated chemotherapeutic programs are admitted to the in-patient section.

Clinical Research Activity-Projects List

G.I cancer: different protocols are open for gastric, colon and rectal cancer supported by the collaboration of the cooperative groups. Adjuvant trials on gastric cancer, colon cancer, rectal cancer are open; Protocols on molecular targeted therapies for colon cancer are ongoing or recently closed for the advanced stage of this disease. Sarcomas: The Unit is involved, having primary investigation responsibilities, in the chemotherapy program of the second Adjuvant study of the Italian Sarcoma Group for patients at high risk of relapse; different other studies are ongoing as concerns the advanced phases of disease. Ewing/PNET: this represents the typical disease needing a multidisciplinary approach that only a specialized Cancer Center can offer the patient for the attainment of a better outcome. GIST: the gastrointestinal stromal tumor is a relevant clinical and research topic at the National Cancer Institute in Aviano. Different cooperative protocols have been performed with imatinib, and sunitinib. The EORTC adjuvant study was recently opened and we were classified as the second Italian Center for accrual in a retrospective/prospective study which has enrolled 790 patients with the intention of defining the natural history of the disease previous to treatment and after the availability of an imatinib therapeutic regimen. Rare tumors: neuroendocrine, biliary tract tumors, hepatocarcinoma are just some examples of disease types in which prospective protocols are ongoing.

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Department of Medical OncologyDivision of Medical Oncology C *

Andrea VERONESI, MDDirector Division of Medical Oncology [email protected]

Associate DirectorsDiana CRIVELLARI [email protected] Donatella MAGRI [email protected] SORIO [email protected]

Maria Antonietta PIZZICHETTA, Prevention Unit,[email protected]

StaffRoberta CALACIONE [email protected] DE GIACOMI [email protected] DI LAURO, Assistant [email protected] FRESCHI, Assistant [email protected] LOMBARDI, Assistant [email protected] SCALONE, Assistant [email protected]

Fellows & Other Personnel Gianmaria MIOLO, specialty fellow Monica OLIVA, data manager Franca PARONUZZI, secretary

* Division of Medical Oncology C is a Unit of Breast Cancer Department


The Division of Medical Oncology C has 16 inpatient beds and 14 day-hospital beds; its clinical activities are concentrated on breast cancer, gynecological cancers, gastrointestinal tumors, sarcoma, melanoma and rare tumors. Besides its clinical and therapeutic activities, the Division is involved in predictive diagnostics and genetic counseling for the early diagnosis of cancer, particularly melanoma and precursor lesions as well as familial breast cancer within the context of BRCA germline mutation research.

The Division interacts with the Gastrointestinal Tumors, Sarcomas and Rare Tumors Unit (S. Frustaci, Director), providing the necessary support as far as inpatient care is concerned. In 2007, the Division’s outpatient clinical activity included 22,801* examinations and 2,244* day hospital admissions, with 6,443 intravenous chemotherapy administrations. Its yearly inpatient activity included 2,559 hospital admissions. The Division supports an infrastructure organization aimed at the conduction of controlled studies enabling the improvement of patient outcome while providing optimal clinical care.

Furthermore, a significant effort to reach the general public through dissemination of material for oncology prevention has been conducted. A special effort was made to publicize an educational DVD on breast cancer, produced in 2005, and directed to new patients and their families

*consolidated figures with the Division of Medical Oncology A

TEACHING AND TRAINING ACTIVITIES

Both intra- and extramural teaching activities are performed extensively. In particular, teaching positions are held within the Postgraduate Medical Specialty in Oncology of the University of Udine and the Dermatology Specialty of the University of Trieste; this also enables the Division to provide training for Specialty students. In addition, extramural teaching activities for both medical doctors and other personnel are fostered and conducted on an ongoing basis.


The main scientific interests of the Division include studies on the adjuvant treatment of breast cancer, particularly within the International Breast Cancer Study Group. Other fundamental aspects under management are metastatic breast cancer, gynecological tumors and melanoma (particularly its early detection) ;gastrointestinal cancers, sarcomas, and endocrine tumors are treated in collaboration with the Division of Medical Oncology B. The Division is engaged, within the Italy-USA oncoproteomics project, in the collection of sera in support of ongoing CRO clinical research seeking to develop and validate new methods of treating cancer through the identification of neoplasm proteins as they appear in various forms of cancer. At present collected sera from 561 subjects altogether has been attained.

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Department of Medical OncologyUnit of Cancer Bio-Immunotherapy

Riccardo DOLCETTI, MDDirector Unit of Cancer Bio-ImmunotherapyPhone +39 0434 659435/[email protected]@cro.it

StaffPaola ZANCAI, Research associateMichele MONTRONE, Consultant

FellowsJessica DAL COL, Research fellow Debora MARTORELLI,Research fellowElena MURARO, Research fellowElisa PASINI, Research fellow


The goal of the Unit is to develop and transfer into the clinic new strategies of bio- and immunotherapy for the prevention and treatment of human tumors, mainly those pathogenically related to infectious agents. The Unit is also actively involved in the design and validation of innovative assays of diagnostic and/or predictive value to improve the monitoring of specific biological and immunological responses in cancer patients treated with bio-immunotherapy protocols.

PROJECTS LIST-RESEARCH ACTIVITY

The Research of the Unit focuses on several areas including idiotypic vaccination for B-cell lymphoproliferations, adoptive cellular therapies, modulation of signalling properties of tumor cells and immune effectors to increase the efficacy of vaccines and immunotherapy. The Unit is also aimed at providing an environment

that facilitates and promotes collaborative interactions between basic, translational, and clinical investigators, and disseminating knowledge to stimulate new ideas in cancer immunology.

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Department of Medical OncologyCell Therapy & High-Dose Chemotherapy Unit

Mariagrazia MICHIELI, MDDirector Cell Therapy & High-Dose Chemotherapy UnitPhone +39 0434 659020/[email protected]

StaffMaurizio RUPOLO, Assistant [email protected]

Rosa MANUELE, Assistant


The Unit is devoted to the clinical/scientific organization and coordination of the different phases inherent to high dose chemotherapy programs followed by rescue utilizing hemopoietic stem cells, for patients affected by lymphomas, myelomas and chemosensitive solid tumors.Clinical protocols devoted to verifying the feasibility and activity of High Dose Chemotherapy with peripheral progenitor stem cells rescue in lymphoma patients has been currently administered.The specific interest is the application of these techniques in the elderly and in the co-infected population especially when the HIV or the HCV infection is present; as of the first semester of 2007, 25 patients with an HIV-related lymphoma have been treated.


The Unit is involved, along with other Units belonging to the Diagnostic Laboratory and Medical Oncology in the following innovative pre-clinical and scientific programs:• Innovative cellular therapy techniques specificallyfocused on vaccine adoptive cellular therapy or tissue repair processes through stem cell infusion. • Ex-vivo expansion of hemopoietic progenitorswith innovative tools or using other cell types, e.g. mesenchymal ones to improve the engraftment capability of the so-called “poor mobilizer” patients.• Impactofearlyviralinfectioninalowgraftfunctionof PBSC.• Impact of in vivo B depletion due to Rituximabassociated to conditioning regimens in the quality of PBSC engraftment.

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SELECTED PUBLICATIONS OF THE DEPARTMENT

• Caggiari L, Guidoboni M, Vaccher E, Barzan L,Franchin G, Gloghini A, Martorelli D, Zancai P, Bortolin MT, Mazzucato M, Serraino D, Carbone A, De Paoli P, Dolcetti R. High serum levels of soluble CD40-L in patients with undifferentiated nasopharyngeal carcinoma: pathogenic and clinical relevance. Infect Agent Cancer. 2007 Mar 1;2:5.

• FerreriAJ,DolcettiR,MagninoS,DoglioniC,CangiMG, Pecciarini L, Ghia P, Dagklis A, Pasini E, Vicari N, Dognini GP, Resti AG, Ponzoni M. A woman and her canary: a tale of chlamydiae and lymphomas. J Natl Cancer Inst. 2007 Sep 19;99(18):1418-9.

• Crivellari D, Aapro M, Leonard R, von MinckwitzG, Brain E, Goldhirsch A, Veronesi A, Muss H. Breast cancer in the elderly. J Clin Oncol 2007; 25: 1882-1890.

• Bowling J., Argenziano G., Azenha A., BandicJ., Bergman R., Blum A., Cabo H., Di Stephani A., Grichnik J., Halpern A., Hofman-Wellenhof R., Johr R., Kittler H., Kopf A., Kreusch J., Langford D., Malvehy J., Marghoob A., Menzies S., Ozdemir F., Peris K., Piccolo D., Pizzichetta M. A., Polsky D., Puig S., Rabinovitz H., Rubegni P., Saida T., Scalvenzi M., Seidenari S., Soyer H. P., Tanaka M., Zalaudek I., Braun R. P.: Dermoscopy key points: recommendations from the international dermoscopy society. Dermatology 2007, 214 (1): 3-5.

• Nicoletto M. O., Tumolo S., Sorio R., Cima G.,Endrizzi L., Nascimben O., Vinante O., Artioli G., Donach M., Cartei G.: Long-term survival in a randomized study of nonplatinum therapy versus platinum in advanced epithelial ovarian cancer. Int J Gynecol Cancer 2007, 17 (5): 986-992.

• Pagnanelli G., BonoR., PizzichettaM.A., TalaminiR., Ascierto P.A., Testori A., Stanganelli I.: Clinical and dermoscopic criteria related to melanoma sentinel lymph node positivity. Anticancer Res 2007, 27 (4C): 2939-2944.

• DalColJ.,ZancaiP.,TerrinL.,GuidoboniM.,PonzoniM., Pavan A., Spina M., Bergamin S., Rizzo S., Tirelli U., De Rossi A., Doglioni C., Dolcetti R. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 2008, 111 (10): 5142-5151

• Martorelli D., Houali K., Caggiari L., Vaccher E.,Barzan L., Franchin G., Gloghini A., Pavan A., Da Ponte A., Tedeschi R. M., De Re V., Carbone A., Ooka T., De Paoli P., Dolcetti R. Spontaneous T cell responses to Epstein-Barr virus-encoded BARF1 protein and derived peptides in patients with nasopharyngeal carcinoma: Bases for improved immunotherapy. Int J Cancer 2008, 123 (5): 1100-1107


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Breast Cancer Department

Faculty & Staff

Andrea VERONESI, MDDirector Breast Cancer Department, Division Director Medical Oncology [email protected]

Ezio CANDIANI, MDDivision DirectorSurgical Senology [email protected]

* Breast Cancer Department includes also Division of Medical Oncology C (see page 22)

MISSION AND CLINICAL ACTIVITIES

The principal objectives of this Department are tailoring patient management to evolving therapeutic modalities and technological innovations while exploring the feasibility of increasingly respectful surgical and non-surgical treatments that can maintain the patient’s physical integrity.Breast cancer is the first cause of cancer death among women in Italy and it is characterized by an emotional component probably greater than is present even in more lethal diseases. Traditionally, breast cancer is one of the areas where the professional and scientific contribution of the CRO National Cancer Institute has been most substantial, both from the quantitative and qualitative points of view, involving virtually all pre-clinical and clinical components of the Institute and representing therefore a model of multidisciplinary cooperation. Based upon these and other considerations, a Breast Cancer Department was activated in 2004. The Department is problem-oriented and its aims

and characteristics are based on the integration of professionals from different areas including Radiologists, Nuclear Medicine Specialists, Pathologists, Surgeons, Radiation Therapists, Medical Oncologists and Experimental Oncologists.The activity of the Department is organized in three areas managed by specific working groups: Patient Orientation. Aimed at simplifying and homogeneously organizing patient access procedures and their successive pathways, as well as avoiding complications and misunderstandings which are inherent in a complex organization serving a large patient population. This has been pursued through the identification of a nursing team which receives new potential patients and follows them during their diagnostic and therapeutic procedures, attempting to simplify these as much as possible and minimizing waiting times. A DVD to better inform patients and their families and friends was prepared in 2005 and popularized in 2006 and 2007.

Meetings. Plenary meetings are organized weekly (from 8 am to 9 am on Mondays) to discuss all new breast cancer cases. In these discussions many hundreds of cases have been discussed so far in order to optimize diagnosis and treatment and allow cases to be managed as homogeneously as possible.

Scientific Activity. Aimed at involving pre-clinical and clinical investigators in the planning and conducting of clinical studies. This is done through bi-monthly multidisciplinary meetings with the involvement of clinicians and pre-clinical researchers.

Guideline development. Institutional diagnostic and therapeutic guidelines are being developed and should be available in 2008.


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Breast Cancer DepartmentDivision of Surgical Senology

Ezio CANDIANI, MDDirector Division of Surgical [email protected]

StaffSamuele MASSARUT, MD [email protected] MILETO, MD [email protected]


The Division of Surgical Senology is primarily responsible for the surgical and reconstructive therapy related to neoplastic pathologies of the breast. The ward is equipped with 12 beds and 3 dedicated surgeons working in collaboration with other specialists within the Breast Cancer Department.Each year 500 operations are performed for new primary breast cancer. Half of these breast cancers are treated with conservation surgery and sentinel node biopsy.The IntraOperative RadioTherapy (IORT) procedure has been adopted since 2002 with 150 patients having been treated, initially in a pilot study and afterward with TARGIT (Targeted Intraoperative Radiotherapy)-an innovative clinical trial procedure adopted by University College in London. Immediate breast reconstruction is performed every time it is possible, usually with a two-stage procedure (expander + prosthesis), sometimes with a one-stage procedure (prosthesis). Delayed breast reconstruction is performed in some complicated cases, both with expander-prosthesis and flaps (Latissimus Dorsi, Tram).

Main surgery in the operating room is scheduled 3 days a week; ambulatory treatments, such as initial consultations, occupy 4 days a week, while clinical screenings, biopsies, dressings, and follow-up complete the Unit’s scheduled activities.

RESEARCH ACTIVITY

The issues of prevalent interest for investigators and those befitting applied and clinical research are the following: risk assessment of pre-neoplastic lesions; diagnosis and treatment of in situ Ductal Carcinoma; breast cancer screening; axillary node staging and sentinel node biopsy; intercostobrachial nerve sparing axillary dissection; reconstructive surgery with emphasis on skin sparing mastectomy with immediate reconstruction; primary chemotherapy trials in collaboration with the Division of Medical Oncology C; IntraOperative RadioTherapy either as a booster procedure or as sole treatment; the role of microenvironments on breast cancer prognosis; IBCSG (International Breast Cancer Study Group) trials with more than 1,100 patients enrolled.



• CrivellariDiana,AaproMatti, LeonardRobert,VonMinckwitz Gunter, Brain Etienne, Goldhirsch Aron, Veronesi Andrea, Muss Hyman. Breast cancer in the elderly. J Clin Oncol 2007, 25 (14): 1882-1890.

• GaspariniGiampietro,GionMassimo,MarianiLuigi,Papaldo Paola, Crivellari Diana, Filippelli Gianfranco, Morabito Alessandro, Silingardi Vittorio, Torino Francesco, Spada Antonella, Zancan Matelda, De Sio Livia, Caputo Antonio, Cognetti Francesco, Lambiase Antonio, Amadori Dino. Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer. Breast Cancer Res Tr 2007, 101 (3): 355-365.

• Karlsson Per, Cole Bernard F., Price Karen N.,Coates Alan S., Castiglione-Gertsch Monica, Gusterson Barry A., Murray Elizabeth, Lindtner Jurij, Collins John P., Holmberg Stig B., Fey Martin F., Thurlimann Beat, Crivellari Diana, Forbes John F., Gelber Richard D., Goldhirsch Aron, Wallgren Arne.The Role of the Number of Uninvolved Lymph Nodes in Predicting Locoregional Recurrence in Breast Cancer. J Clin Oncol 2007, 25 (15): 2019-2026.

• KeshaviahA.,DellapasquaS.,RotmenszN.,LindtnerJ., Crivellari D., Collins J., Colleoni M., Thurlimann B., Mendiola C., Aebi S., Price K., Pagani O., Simoncini E., Castiglione Gertsch M., Gelber R., Coates A., Goldhirsch A. CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials. Ann Oncol 2007, 18 (4): 701-708.

• Vaidya Jayant S., Massarut Samuele. Increasedtissue stiffness during mammography may contribute to carcinogenesis. Int J Surg 2007, 5 (3): 213.

• Bernardi D., Errante D., Galligioni E., Crivellari D.,Bianco A., Salvagno L., Fentiman I. S. Treatment of breast cancer in older women. Acta Oncol 2007, 1-13. • Bowling J., Argenziano G., Azenha A., Bandic

J., Bergman R., Blum A., Cabo H., Di Stephani A., Grichnik J., Halpern A., Hofman-Wellenhof R., Johr R., Kittler H., Kopf A., Kreusch J., Langford D., Malvehy J., Marghoob A., Menzies S., Ozdemir F., Peris K., Piccolo D., Pizzichetta M. A., Polsky D., Puig S., Rabinovitz H., Rubegni P., Saida T., Scalvenzi M., Seidenari S., Soyer H. P., Tanaka M., Zalaudek I., Braun R. P. Dermoscopy key points: recommendations from the international dermoscopy society. Dermatology 2007, 214 (1): 3-5.

• Joerger Markus, Huitema Alwin D. R., RichelDick J., Dittrich Christian, Pavlidis Nikolas, Briasoulis Evangelos, Vermorken Jan B., Strocchi Elena, Martoni Andrea, Sorio Roberto, Sleeboom Henk P., Izquierdo Miguel A., Jodrell Duncan I., Calvert Hilary, Boddy Alan V., Hollema Harry, Fety Regine, Van der Vijgh Wjf J. F., Hempel Georg, Chatelut Etienne, Karlsson Mats, Wilkins Justin, Tranchand Brigitte, Schrijvers Ad H. G. J., Twelves Christian, Beijnen Jos H., Schellens Jan H. M. Population pharmacokinetics and pharmacodynamics of Paclitaxel and Carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group. Clin Cancer Res 2007, 13 (21): 6410-6418.

• Nicoletto M. O., Tumolo S., Sorio R., Cima G.,Endrizzi L., Nascimben O., Vinante O., Artioli G., Donach M., Cartei G. Long-term survival in a randomized study of nonplatinum therapy versus platinum in advanced epithelial ovarian cancer. Int J Gynecol Cancer 2007, 17 (5): 986-992.

• Pagnanelli Gianluca, Bono Riccardo, PizzichettaMaria Antonietta, Talamini Renato, Ascierto Paolo A., Testori Alessandro, Stanganelli Ignazio. Clinical and dermoscopic criteria related to melanoma sentinel lymph node positivity. Anticancer Res 2007, 27 (4C): 2939-2944.

• Pignata S., FerrandinaG., ScarfoneG., Scollo P.,Odicino F., Selvaggi L., Katsaros D., Frigerio L., Mereu L., Ghezzi F., Manzione L., Lauria R., Breda E., Marforio G., Ballardini M., Vernaglia Lombardi A., Sorio R., Tumolo S., Costa B., Magni G., Perrone F., Favalli G.Extending the Platinum-Free Interval with a Non-Platinum Therapy

in Platinum-Sensitive Recurrent Ovarian Cancer. Results from the SOCRATES Retrospective Study. Oncology-Basel 2007, 71 (5-6): 320-326.

• Pizzichetta Maria A., Soyer H. Peter, MassoneCesare, Cerroni Lorenzo. Clinical and dermoscopic features of agminated blue nevus. Arch Dermatol 2007, 143 (9): 1225-1226. • Pizzichetta Maria Antonietta, Stanganelli Ignazio,Bono Riccardo, Soyer H. Peter, Magi Serena, Canzonieri Vincenzo, Lanzanova Giuseppe, Annessi Giorgio, Massone Cesare, Cerroni Lorenzo, Talamini Renato. Dermoscopic features of difficult melanoma. Dermatol Surg 2007, 33 (1): 91-99. • VeronesiUmberto,MaisonneuvePatrick,RotmenszNicole, Bonanni Bernardo, Boyle Peter, Viale Giuseppe, Costa Alberto, Sacchini Virgilio, Travaglini Roberto, D’Aiuto Giuseppe, Oliviero Pasquale, Lovison Francesco, Gucciardo Giacomo, Rosselli Del Turco Marco, Muraca Maria Grazia, Pizzichetta Maria Antonietta, Conforti Serafino, Decensi Andrea. Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J Natl Cancer I 2007, 99 (9): 727-737.

• Bernardi D., Errante D., Galligioni E., Crivellari D.,Bianco A., Salvagno L., Fentiman I. S. Treatment of breast cancer in older women. Acta Oncol 2007, 1-13.

• Crivellari D., Sun Z., Coates A. S., Price K. N.,Thurlimann B., Mouridsen H., Mauriac L., Forbes J. F., Paridaens R. J., Castiglione-Gertsch M., Gelber R. D., Colleoni M., Lang I., Del Mastro L., Gladieff L., Rabaglio M., Smith I. E., Chirgwin J. H., Goldhirsch A., [as member of Breast International Group and International Breast Cancer Study Group], Veronesi A., Magri M. D., Buonadonna A., Coran F., Borsatti E., Candiani E., Massarut S., Roncadin M., Arcicasa M., Carbone A., Perin T., Gloghini A. Letrozole Compared With Tamoxifen for Elderly Patients With Endocrine-Responsive Early Breast Cancer: The BIG 1-98 Trial. J Clin Oncol 2008, 26 (12): 1972-1979

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Department of Surgical Oncology

Faculty & Staff

Francesco DE MARCHI, MDDepartment Director, Division DirectorSurgical Oncology

Elio CAMPAGNUTTA, MDDivision DirectorGynecological Oncology

Renato CANNIZZARO, MDDivision DirectorGastroenterology

The Department of Surgical Oncology is comprised of the Divisions of Surgical Oncology, Gastroenterology, and Gynaecological Oncology. The Department is dedicated to the diagnosis, treatment and management of tumors of the gastrointestinal tract, liver, pancreas, lung, thyroid, sarcomas and melanoma, and gynaecological tumors. Moreover, special screening programs for the prevention and early detection of gastrointestinal and gynaecological tumors are offered. Most advanced technology for the diagnosis and treatment of cancer is available. A multidisciplinary team approach is used for

case discussion and a multimodality treatment approach is utilized when indicated. Clinical and translational research projects in collaboration with National and International research centers are underway. A platform for the development of translational research projects comprising a bio-bank in which tumor tissue, blood, and serum of patients are stored; databases with clinical and pathological data are also available.



The Division of Surgical Oncology is one of five Departmental divisions whose mission is to provide patients the most appropriate and effective treatment for cancer. Our division accomplishes this mission using a disease management team approach and participation in clinical and translational research projects that ultimately enable the discovery of targeted therapeutics and innovative treatment methods.In order to support optimal care for our patients and guarantee their safety and comfort, the Division is equipped with 28 inpatient beds, two operating rooms, a surgical room for minor operations, and an outpatient clinic. Furthermore, facilities for minimally invasive surgery and intra-operative radiotherapy (IORT) are also available. Each year 400 major and 350 minor surgical procedures are performed, 1300 initial clinical examinations and diagnoses are made, and 2400 follow-up visits are completed.

Medical investigators collaborate with physicians and surgeons to comply with therapeutic protocols whose major fields of interest concern:a) gastrointestinal surgery (treatment of tumors of the esophagus, stomach, small bowel, pancreas, colon and rectum; liver metastasis, hepatocarcinoma and cholangiocarcinoma; Gastrointestinal Stroma Tumors; hereditary colorectal cancer (-FAP and HNPCC-); laparoscopic surgery and diagnostic surgery, staging and treatment of GI cancers.b) thoracic surgery (video-assisted thoracoscopy for diagnosis, staging and treatment of lung cancer and mesothelioma; surgical treatment of lung cancer and mesothelioma; treatment of lung metastasis).c) soft tissue sarcomas (multimodality treatment for sarcomas of the retroperitoneum and limbs; surgical treatment of metastatic disease).d) melanoma (diagnosis and treatment of pre-neoplastic lesions; sentinel node biopsy; trials of specific active immunotherapy).

PROJECTS LIST-RESEARCH ACTIVITY 2007

Ongoing research studies that may lead to landmark publications and significant scientific accomplishments cover the main areas of serumproteomics and phosphoproteomics for the early diagnosis and molecular targeted therapy of cancer as well as the characterization of cancer stem cells in primary and metastatic tumors including gene expression profiling for the identification of prognostic and predictive molecular factors in solid tumors.The afore-mentioned clinical research techniques and experiences are conducted in collaboration with internal CRO Departments of Pathology and Experimental Oncology, and on a national level with the Istituto Superiore di Sanità in Rome (Italian National Health Institute), as well as internationally with the National Cancer Institute in Bethesda, Maryland and George Mason University in Virginia.

Department of Surgical Oncology Division of Surgical Oncology

Francesco DE MARCHI, MDDirector Division of Surgical [email protected]

StaffClaudio BELLUCO, MD [email protected] BERTOLA, MD [email protected] BREDA, MD [email protected] DAL MAS, MD [email protected] MARTELLA, MD [email protected] OLIVIERI, MD [email protected] PASQUOTTI, MD [email protected] SIGON, MD [email protected] FORLIN, MD

ConsultantsMario LISE, MD [email protected]

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Ongoing occupations of the Division include ordinary patient admission, Day Hospital admission and outpatient services. A fundamental enterprise of Gynecological Oncology is the collaborative integrated surgical research for the treatment of newly discovered gynecological neoplasias or relapsed types utilizing innovative associations of chemiotherapeutic / radiotherapeutic methods (intraoperative radiotherapy, intraperitoneal hyperthermal chemiotherapy); such activities, also undertaken in collaboration with external specialists, fulfill the objective of developing integrated, applied research projects. Furthermore, the Division is involved in the diagnosis and treatment of precancerous or initially invasive lesions of the lower genital tract; these services are also offered within the Regional Program for cancer screening. Particular attention is dedicated to the ultrasound and hysteroscopical assessment of endometrial abnormalities in breast cancer patients being treated with hormonal therapies.

Department of Surgical OncologyDivision of Gynecological Oncology

Elio CAMPAGNUTTA, MDDirector Division of Gynecological [email protected]

StaffLino DEL PUP, MD [email protected] DE PIERO, MD [email protected] GIORDA, MD [email protected] SISTO, MD [email protected] SOPRACORDEVOLE, MD [email protected] Grazia ZANIN, MD

ConsultantsMario CHIZZOLINI, MDFerdinando CALCAGNILE, MD

Established in 1988, the Gynecological Oncology Division is composed of four Units involved in: 1) surgical oncology; 2) lower genital tract colposcopy and laser therapy; 3) laparoscopic surgery; 4) hysteroscopy, gynecological ultrasound, ovarian protection consultations and procedures for oncological patients, gynecological oncology consultations and follow-up care.

The Division has 12 inpatient and 4 Day-hospital beds. Annually, clinical activity includes more than 500 major surgical, 200 laser and 500 day-surgery procedures; approximately 4000 clinical examinations including colposcopies and biopsies of the lower genital tract are performed as well. The major areas of care concern both basic and specialized procedures : surgical treatment of advanced neoplasias; surgery of recurrences in the pelvis, the abdomen, and retroperitoneum; early diagnosis and conservative treatment of pre-neoplastic, bordeline, and minimally invasive lesions; laser therapy of pre-neoplastic lesions of the lower genital tract ; loco-regional

chemotherapy using intra-peritoneal hyperthermic chemotherapy systems; intra-operative radio-therapy (IORT) for locally advanced cervical carcinoma.The Division is concerned that persons in general and its patients be provided with attentive care, therefore encouraging a spirit of partnership between physician and patient seen in the dedication addressed to palliative care and specialized home care including psycho-oncology for patients. Hence, this commitment is also visible through an engagement directed to cervical cancer screening for women in the Friuli Venezia-Giulia regional area.


Since 2005 essential fields of interest concerning clinical research studies include the following: intra-peritoneal hyperthermic chemotherapy in ovarian cancer recurrences; intra-operative radiation therapy in locally advanced cervical carcinoma (IORT); sentinel node detection in endometrial cancer; surgical treatment of recurrent vulvar cancer; surgical treatment of recurrent endometrial carcinoma; use of the percutaneous endoscopic gastrostomy (PEG) in intestinal occlusion for non-operable patients; hysteroscopic evaluation of the effects of tamoxifen regimens on endometrial hyperplasia during adjuvant therapy of mammary carcinoma.


Department of Surgical Oncology Division of Gastroenterology

Renato CANNIZZARO, MDDirector Division of [email protected]

StaffMara FORNASARIG, [email protected] LACCHIN, [email protected] MAIERO, Consultant


The Gastroenterology Division, whose initial activity began in 1986, is engaged in assistance and research activities pertaining to Oncological Gastroenterology as well as preventive, diagnostic and therapeutic functions for primitive and secondary neoplasias of the gastrointestinal tract.The Division is composed of:a) a Clinical Section, dealing with gastroenterology and hepatology consulting and extending also to ultrasound imaging; Day Hospital consultations and inpatient activities pertaining to its Departmentb) an Endoscopy Section, regarding diagnosis and operative functions, as well as activities dedicated to oncological digestive physiopathology.The Division participates in the coordination of clinical-scientific decision making processes pertaining to prevention, diagnosis, and therapy of primitive and secondary neoplasias of the gastrointestinal tract. This is done in collaboration with the Divisions of Surgical Oncology, Medical Oncology B and Radiation Oncology within the CRO Institute.

In fact, the Division actively participates in the educational activities of the Institute occupying itself with research and teaching functions for primitive and secondary neoplasias of the digestive system. Each year approximately1500 diagnostic endoscopies of the superior digestive tract, 1600 diagnostic endoscopies of the inferior digestive tract, 700 therapeutic procedures, 900 gastroenterological consultations and 250 functional tests, are performed for inpatients and outpatients.Particular attention is devoted to echo-endoscopic staging with FNAB of digestive cancer, enteroscopy with pillcam, percutaneous endoscopic gastrostomy for decompression and nutritional purposes, brachytherapy, APC and laser treatments. Furthermore, the Division is involved in the evaluation of quantitative liver function in HCV positive non-Hodgkin’s lymphoma and hepatocellular carcinoma.


In its second decade of activity, the Division continues to concentrate on research programs in pursuit of the

following areas of interest: the identification of FAP, AFAP, MAP and HNPCC families; enteroscopy with pillcam in patients with Familial Adenomatous Polyposis, including investigations on the utility of a pillcam in cancer of the small intestine; Barrett’s esophagus familiarities; the relationship between Helicobacter pylori infections and prevention of gastric cancer in relatives of patients with gastric malignancies; the diagnosis and therapy of gastrointestinal and hepatic damage by chemotherapy and/or radiotherapy; the early diagnosis of non-Hodgkin’s lymphoma in celiac disease; neuroendocrine tumors of the digestive system; the role of echoendoscopy in the staging and follow-up of digestive cancer and the efficacy of brachytherapy in esophageal cancer.

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• PetricoinE.F.,BellucoC.,AraujoR.P.,LiottaL.A.The blood peptidome: a higher dimension of information content for cancer biomarker discovery. Nat Rev Cancer 2006, 6 (12): 961-967.

• Fornasarig M., Minisini A. M., Viel A., Quaia M.,Canzonieri V., Veronesi A. Twelve years of endoscopic surveillance in a family carrying biallelic Y165C MYH defect: report of a case. Dis Colon Rectum 2006, 49 (2): 272-275

• Maggioni A., Benedetti Panici P., Dell’Anna T.,Landoni F., Lissoni A., Pellegrino A., Rossi R. S., Chiari S., Campagnutta E., Greggi S., Angioli R., Manci N., Calcagno M., Scambia G., Fossati R., Floriani I., Torri V., Grassi R., Mangioni C. Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Brit J Cancer 2006, 95 (6): 699-704.

• MammanoE.,BellucoC.,SciroM.,MencarelliR.,Agostini M., Michelotto M., Marchet A., Nitti D. Epidermal growth factor receptor (EGFR): mutational and protein expression analysis in gastric cancer. Anticancer Res 2006, 26 (5A): 3547-3550.

• PillaL.,PatuzzoR.,RivoltiniL.,MaioM.,PennacchioliE., Lama E., Maurichi A., Massarut S., Marchiano A., Santantonio C., Tosi D., Arienti F., Cova A., Sovena G., Piris A., Nonaka D., Bersani I., Di Florio A., Luigi M., Srivastava P. K., Hoos A., Santinami M., Parmiani G. A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes Gp96, in combination with GM-CSF and interferon-alpha in metastatic melanoma patients. Cancer Immunol Immun 2006, 55 (8): 958-968.

• Pastrello C., Baglioni S., Tibiletti M. G., Papi L.,Fornasarig M., Morabito A., Agostini M., Genuardi M., Viel A. Stability of BAT26 in tumours of hereditary nonpolyposis colorectal cancer patients with MSH2 intragenic deletion. Eur J Hum Genet 2006, 14 (1): 63-68.

• DelPupL.,CampagnuttaE.,GiordaG.,DePieroG., Sopracordevole F., Sisto R. Fertility preservation methods for female neoplastic patients. Radiol Oncol 2006, 40 (3): 175-181.

• DeReV,SimulaMP,CaggiariL,OrtzN,SpinaM,Da Ponte A, De Appolonia L, Dolcetti R, Canzonieri V, Cannizzaro R. Protein expression profile of celiac disease patient with aberrant T cell by two-dimensional difference gel electrophoresis. Ann N Y Acad Sci. 2007 Aug;1109:429-40.

• DeReV,SimulaMP,CaggiariL,OrzesN,SpinaM,Da ponte A, De Appollonia L, Dolcetti R, Canzonieri V, Cannizzaro R. Proteins specifically hyperexpressed in a coeliac disease patient with aberrant T cells. Clin Exp Immunol. 2007 Jun;148(3):402-9

• Puppa G, ShozuM, Perin T, Nomura K, GloghiniA, Campagnutta E, Canzonieri V. Small primary adenocarcinoma in adenomyosis with nodal metastasis: a case report. BMC Cancer. 2007 Jun 20;7:103.

• GehoDH,LuchiniA,GaraciE,BellucoC,PetricoinE, Liotta LA. Nanotechnology in clinical proteomics. Nanomed. 2007 Feb;2(1):1-5.

• Fensterer H, Radlwimmer B, Sträter J, BuchholzM, Aust DE, Julié C, Radvanyi F, Nordlinger B, Belluco C, Van Cutsem E, Köhne CH, Kestler HA, Schwaenen C, Nessling M, Lutz MP, Lichter P, Gress TM; EORTC Gastrointestinal (GI) Group. Matrix-comparative genomic hybridization from multicenter formalin-fixed paraffin-embedded colorectal cancer tissue blocks.BMC Cancer. 2007 Apr 2;7:58.


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Department of Radiation Therapy and Imaging Diagnostics

Faculty & Staff

Mauro G. TROVÒ, MDDepartment Director, Division Director Principal Investigator, Radiation Oncology

Sandro MORASSUT, MDDivision Director, Radiology

Elvira CAPRA, PhysicistDivision Director, Medical Physics

Marino CIMITAN, MDDivision Director, Nuclear Medicine

The Department of Radiation Therapy is composed of the following Divisions and Unit: Radiation Oncology, Radiology, Nuclear Medicine, and Medical Physics. The Departmental team, uniting highly trained research personnel in multiple areas, helps facilitate the day-to-day delivery of radiation therapy services, provides excellent local and regional care in oncological medicine and assists both inpatients and outpatients in a supportive and efficient environment. The Department Director provides the leadership, environment, resources and necessary infrastructure for medical investigators, their staff, and medical students working in the CRO-National Cancer Institute setting to conduct medical research.


Department of Radiation Therapy and Imaging DiagnosticsDivision of Radiation Oncology

Prof. Mauro G. TROVÒ, MDDirector Division of Radiation OncologyPhone +39 0434 659.523FAX + 39 0434 [email protected]

StaffMauro ARCICASA, MD [email protected] BORTOLUS, MD [email protected] BOZ, MD [email protected] GIGANTE, MD [email protected] GOBITTI, MD [email protected] INNOCENTE, MD [email protected] MASCARIN, MD [email protected] Radiotherapy Emilio MINATEL, MD [email protected] RONCADIN, MD [email protected] ABU RUMEILEH, MD [email protected]

Assistant Directors FellowsGiovanni FRANCHIN, MD Tiziana FURLAN, PsychologistIMRT Conformal Radiation Therapy Stefano REN KAISER, PhysicistAntonino DE PAOLI, MDIntra-Operative Radiation Therapy


The Radiation Oncology Division is on two sites, about 17 km apart: at the Centro di Riferimento Oncologico in Aviano and at the General Hospital in Pordenone. It consists of 3 parts: 1 inpatient ward (10 beds, 2 day-hospital beds), 2 high-energy areas, 1 non-sealed radionuclide therapy section.The Division provides consultation, treatment and follow-up for patients requiring radiation therapy for cancer and employs sophisticated technologies to provide each patient with an individual comprehensive treatment plan.The Division also provides combined chemo-

radiotherapy treatments in a wide variety of tumor types.In addition, a separate adolescent section (Teenager’s Cancer Unit) has been designed for teenage and young adult patients (ages 10 - 24) with a view to creating an environment that is warm and more comfortable for young patients.

The Division has active programs in pre-clinical and clinical research, which include advanced radiotherapy methods such as conformal, stereotactic and intraoperative radiotherapy (IORT), non-sealed radionuclide therapy, HDR-brachytherapy and IMRT.The Division is also resolutely involved in research

projects focusing on multidisciplinary approaches involving combined chemo-radiotherapy of various types of tumors (including pediatric tumors). Particular emphasis is placed on the detection and prevention of local recurrences.The Radiation Oncology Division provides more than 40,000 radiation treatments per year and treats approximately 2,200 patients each year. Of those, 2,000 are new patients.

FacilitiesThe Division offers a full range of radiotherapy equipment for the treatment of cancer. This includes: 1 HI-ART TomoTherapy system 5 linear accelerators (Varian Clinac 2100CD, Varian Clinac 2100c, Varian Clinac 600c, Siemens Mevatron, Siemens Primis) with both photon and electron capabilities, electronic portal imagers and MLC, including one linear accelerator dedicated to IMRT and one partially dedicated to IORT and stereotactic x-ray therapy 2 simulators (Varian Ximatron, Oldeft ct 0600) 1 dedicated CT-simulator (MHTI) 1 orthovoltage unit (Therapax DXT300) 1 microSelctron-HDR for brachytherapy Varis Vision integrating Eclipse treatment planning system and treatment delivery 3D-CRT and conventional treatment planning networked workstations C

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The Division provides multiple ways to deliver radiation therapy: conventional external beam radiation therapy three-dimensional conformal radiation therapy (3-D CRT), which delivers high radiation dose to tumors but safeguards healthy tissue intensity modulated radiation therapy (IMRT), is a revolutionary new modality in which radiation beams are shaped by 120 computer-controlled collimator leaves that wrap the radiation dose around the tumor, thus sparing healthy tissue TomoTherapy Highly Integrated Adaptive Radiotherapy (HI-ART)The TomoTherapy HI-ART system combines an advanced form of Intensity Modulated Radiation Therapy (IMRT), the accuracy of CT scanning technology, and advanced tools for planning and delivering radiation therapy in one machine. stereotactic radiation therapy, a minimally invasive method to treat benign and malignant intracranial brain tumors and arteriovenous malformations without harming neurological function. intraoperative radiation therapy, which is the application of radiation directly to the tumor or the tumor bed during surgery. targeted intraoperative radiotherapy (Targit) for breast cancer: a novel therapeutic approach that allows intra-operative radiotherapy to be safely and accurately delivered to the target tissues in a standard operating theater. It employs a miniature electron-beam-driven X-ray source called INTRABEAM. radiopharmaceutical therapy: the internal radiation is delivered by radioactive chemical compounds which the patient takes or receives through injection. the GliaSite System, for the treatment of recurrent malignant brain tumors involves delivering focused amounts of radiation (I125) directly into a tumor cavity through a balloon catheter. brachytherapy, radioactive sources are temporarily placed through the catheters implanted in the tumor (called high-dose rate or HDR brachytherapy). half body irradiation.


The main scientific interests of the Division include new studies in which novel pharmaceutical compounds with molecular targets are utilized: Cetuximab in association with radiotherapy in esophageal and head & neck cancers; Gefitinib and chemoradiation plus IORT in rectal cancer and further development of clinical research in IORT, including acquisition of dedicated equipment that will accompany that which is already present in the operating theater for breast intra-operative radiotherapy. Other fundamental activities in which to engage at present include augmenting conformal radiotherapy treatment options with full Tomotherapy where possible, as well as the development of clinical projects for lung, head & neck, esophagus, prostate and pediatric tumors.Other significant aspects under management that will be continued, advanced or intensified include High Dose Rate and radiopharmaceutical regimens to include thyroid cancer, brachytherapy by the GliaSite method for surgically treated cerebral tumors, and ultrasound therapy (HIFU) for locally advanced prostate tumors.

TEACHING AND TRAINING ACTIVITY

Teaching is available through affiliated centers: Residency Programs in Oncology (University of Udine) and Radiotherapy (University of Milan, University of Modena), Technical Radiology School of the University of Udine. The Division is also actively involved in teaching & training activities both at the Institute and in outside centers especially as regards the investigation and development of novel techniques in step with the continuous advancement of technology and clinical applications.

IMRT CONFORMAL RADIATION THERAPY UNIT

The purpose and mission of a Unit dedicated to Conformal therapy within the Department is to treat patients affected by neoplasms located around organs at risk relevant for co-morbidity and, in an attempt to limit the damage, enable the radiation oncologist to

provide a better quality of life for those individuals.• Allowing the routine use of 3-D Conformalradiotherapy techniques in daily clinical practice instead of a 2-D modality, with special regard to base of skull tumors, nasopharynx and oropharynx cancer, mediastinal and lung tumors.• Treating a selectedpatient populationby IntensityModulated Radiation Therapy (IMRT) to improve conformal dose adherence, thereby affording the potential to decrease the spectrum of normal tissue toxicities.• Delivering IMRT with strict attention to qualityassurance through a close collaboration with the

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Physics Department and a careful clinical practice.The aim of the Unit’s clinical practice is to treat all patients affected by locally advanced disease, radically curable with high doses of Radiotherapy, with sophisticated technological equipment.Conventional radiotherapy, with the employment of static fields shaped by blocks and modulated by single beam wedges or a tissue compensator, will be reserved only to palliative cases.In contrast, IMRT delivered by individually modulated fields, using a sliding window technique and having as its primary purpose the delivery of variable dose intensities through the segment of each treatment field, will be the treatment of choice for Head and Neck cancer and selected thoracic tumors.The capacity of Conformal radiotherapy and even more of Intensity Modulated therapy to limit the dose to normal tissue structures can reduce the severe toxicity endured by salivary glands, the spinal cord, the auditory anatomy, the jaw, the heart (with special regard to left ventricular portion), and healthy lung tissue. In addition, the employment of IMRT will allow dose escalation and differential dose painting, achieving “in field tumor boosting” by a Simultaneous Integrated Boost (SIB) technique.


Research has long been a strength of the Radiation Therapy and Imaging Diagnostics Department, and will expand the Unit’s ability to implement and value Conformal radiotherapy and especially IMRT in curable patients, in association with neo-adjuvant or concomitant chemotherapy, using a “non conventional dose-fractionation”.Specifically an estimate of the impact of this new radiotherapeutic approach on disease free and overall survival, with special attention given to late severe toxicity through a careful patient follow up, will serve to reach meaningful study results and improved patient care. In particular, this approach will be accomplished for nasopharyngeal young adult patients and lung cancer patients having received surgery, but it will not yet be operable for relevant co-morbidity cases.

INTRA-OPERATIVE RADIATION THERAPY UNIT

The Intraoperative Radiation Therapy (IORT) Program has been activated at our Institute since 1999 in order to offer specialized care. The clinical and technical features and objectives of the IORT Unit are the following:• Development and coordination of the InstitutionalIORT Program with all involved Units (Surgical and Gynecological Oncology, Anesthesiology, Medical Physics and Radiation Oncology)• Coordination of the Quality Assurance Group forIORT activity• PlanninganddevelopmentofIORT-orientedclinicalresearch in the area of specific interest (gastrointestinal and gynecological diseases and sarcomas) and to involve in the IORT program other Institutional Disease Management Teams interested in IORT (Breast Unit, Pediatric Unit)• Development of Inter-Institutional collaboration inIORT activity (AIRO-IORT group, European ISIORT group)

Clinical activity involves dedicated physicians, physicists, technical and nursing staff in each Unit involved in the IORT Program.A multidisciplinary approach to clinical case discussion, patient selection, treatment and follow-up is used. One IORT treatment per week is planned utilizing a traditional facility (patient transportation) and one IORT per week is planned utilizing a dedicated facility (Intra-Beam System in operating room) for breast cancer.In 2006, 76 patients underwent IORT; 47 patients (29 Sarcomas, 8 Rectal and 8 GYN cancer) with traditional facility (patient transportation) and 29 patients with breast cancer (dedicated facility in operating room).


Considering that every new advance in cancer monitoring and treatment involves painstaking research, intra-operative radiation (IORT) remains at present an investigational approach. Several clinical trials are ongoing at our Institute to evaluate the applications within the operating theater at the time of tumor excision

of the specified modality, the possibilities of supportive chemotherapeutic treatment as appropriate, and strategies aimed at conservation of healthy surrounding tissue.

Soft Tissue Sarcomas: The Unit is involved, as Coordinating Center, in the multicentric Phase II trial of the Italian Sarcoma Group (ISG) on pre-operative and intra-operative treatment of retroperitoneal sarcomas. IORT, as a part of local treatment aimed at a limb-sparing approach, is also included in the adjuvant chemotherapy Phase III trial of the ISG.

Rectal Cancer: is an area of active investigation in combined modality treatment for IORT. A collaborative phase I-II trial with IORT and target therapy has been concluded and data have been reported at the American Society for Therapeutic Radiology and Oncology (ASTRO) convention in 2006.

Cancer of the Uterine Cervix: a phase II trial with combined modality treatment including IORT is ongoing for locally advanced disease (stage IIb-III). Preliminary results have been reported at national and international meetings.

Breast Cancer: represents an area of emerging interest in IORT investigation. An International Phase III trial (TARGIT: targeted intra-operative radiotherapy) is ongoing to test the hypothesis of this modality delivery versus a more conventional strategy for breast conservation with the active participation of the Breast

Unit of our Institute. The preliminary data have been published in 2006 [Int J Radiat Oncol Biol Phys 66(5): 1335-1338, 2006].

Finally, pilot studies are ongoing in Gastric and Pancreatic Cancer to explore the feasibility of IORT in conjunction with innovative combined modality programs.


Department of Radiation Therapy and Imaging DiagnosticsDivision of Radiology

Luca BALESTRERI, MDDirector Division of [email protected]

StaffMaria Renata CATALDO, MD [email protected] CORAN, MD [email protected] LA GRASSA, MD [email protected] TOMMASI, MD (Consultant)Martina URBANI, MD [email protected] VENTURINI, MD [email protected]

Radiology technicians Other PersonnelFlora BATTISTELLA, Traditional Diagnostics Lorna FUSAZCoordinator Luigi PALAZZOLOMara DANELUZZI, High Technology Coordinator Rita PAVANAnna BONGIOVANNIFortunato CAMPAGNARenato FERRIPatrizia FURLANSabina PIAZZONSandro ROMANINPaola TELLAN

MISSION AND DIAGNOSTIC ACTIVITY

The mission is to provide the radiological imaging procedures for an early diagnosis, staging, and follow-up of patients with various neoplastic diseases referred to the Institute for treatment.In addition, a wide variety of radiological investigations within the fields of neurology and orthopaedics are offered to the general population.EQUIPMENT

The Division of Radiology is equipped with a complete range of up-to-date imaging technology to serve cancer

patients:

1.5 Tesla MRI 32-row CT scan angiography system digital mammography mammotome system conventional x-ray equipment 2 ultrasound devices 1 thermoablation set

Approximately 25000 radiological examinations are performed annually, including 5000 CT scans,

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in the Region.AIDS-related malignancies represent an important field of diagnostic activity. In such pathologies, the radiology experience started during the early 80’s when the Institute became the reference center of CIGAT(Italian Cooperative Group on AIDS and Tumors). The main activity is dedicated to staging neoplasms and supporting pathologic diagnosis by image- guided core biopsy, especially in lymphomatous disorders. AIDS-related infectious diseases are also an important field of diagnostic activities.


In the field of research, the Division of Radiology has taken part in multicentric Italian studies such as the comparative multimodality surveillance of women at genetic-familial high risk for breast cancer (BRCA1 and BRCA2 genetic mutations) in which the diagnostic accuracy of the clinical examination, ultrasound, mammography and breast MRI are compared. Furthermore, the Division participates in the Italian Multicentric Polyp Accuracy Group of CT Colonography in order to evalute the accuracy of CT-Colonography in comparison to conventional optical colonoscopy.In the near future, the same study will concern the efficacy of Computer Assisted Diagnosis (CAD) comprising the use of a special software program designed to automatically detect polyps in the CT images of colonography. Another study is ongoing regarding the comparison in diagnostic accuracy between MRI and PET CT in the detection of persistent or relapsing disease in head & neck cancer treated with chemotherapy and radiotherapy. In addition, a large study comparing the accuracy of endoscopic US, MRI, and pathological results in the re-staging of rectal carcinoma after chemotherapy and radiotherapy has recently been conducted.Finally, a new study is being conducted concerning the efficacy of hepatic tumor treatment either with thermoablation alone or in association with beads as vehicles for doxorubicin administration.Senology Section: in order to ensure the best level of early diagnosis a diagnostic package including clinical examination, mammograms and ultrasound is

performed. In selected cases a MRI mammography is also performed. According to standard follow-up protocols maximal attention is devoted to the control of patients after surgery for breast malignancies or dysplasia.Mammographic pre-operative localization and cytologic or histological sampling of non-palpable breast lesions are currently performed using stereotactic equipment (Mammotome) or ultrasound-guided devices in addition to the conventional procedures.In the field of Senology, the Radiology Division offers MRI of the breast for surgical planning either in cases of suspected multifocality lesions, or as a diagnostic problem-solving tool, otherwise for screening in high-risk patients. The radiologist in-charge of the Senology section is part of the team responsible for the planning of a local Government project of breast screening.

5000 MRI scans, 5000 mammographies plus other examinations such as ultrasound, chest, skeletal, and contrast investigations. The Division also provides CT colonography tests (since 2002) and second-level controls within the breast cancer “regional screening program” (since January 2006).Conventional radiology: is almost completely performed using a new computed radiography system that allows electronic processing of the images. A PACS system available in the near future will integrate data for digital archiving and, using the fiber optic network, will send the images and related information in real-time to the Clinical Divisions.

CT Section: it is using a “state of the art” spiral CT technology: CT angiography, and three dimensional reconstruction to more accurately stage disease and dictate preoperative planning and includes CT-guided interventional procedures.

MRI Section: most of the MRI activity is focused on the staging of different neoplasms: head and neck both primary and metastatic malignancies, metastatic involvement of bone marrow by breast cancer, spine localization of multiple myeloma and soft tissue and bone sarcomas. New sequences are tested to improve the feasibility of contrast-enhanced angio-MR of thoracic, abdominal and peripheral vessels.

Interventional Radiology Section: the most frequent invasive radiological procedures performed at the Division include: CT- and US-guided biopsies of deep lesions, breast biopsies (both stereotactic and US-guided), drainages (including biliary drainage), alcoholization and chemoembolization of liver lesions, vertebroplasty and thermoablation procedures.Regarding the treatment of liver malignancies: while primary liver tumors are treated by trans-arterial chemoembolization and/or trans-hepatic thermoablation US-guided, liver metastases are approached by trans-arterial chemotherapy according to clinical protocols.Vertebroplasty procedures are performed both in osteoporotic and metastatic lesions, and thermoablation in liver, pulmonary, and kidney tumors either as first choice or as a palliative of treatment. For these kinds of therapies, the Institute is currently the leading Center


Department of Radiation Therapy and Imaging DiagnosticsDivision of Medical Physics

Elvira CAPRA, PhysicistDirector Division of Medical [email protected]

Assistant DirectorGiovanna SARTOR, [email protected]

StaffMichele AVANZO, [email protected] CAPPELLETTO, [email protected] DASSIE, Physicist [email protected] DRIGO, Physicist [email protected]


The mission of the Medical Physics Division is to provide scientific and technical support for the clinical, teaching and research activities of the Institute’s therapeutic and diagnostic services.In particular, collaborations exist with the Divisions of Radiation Oncology, Radiology and Nuclear Medicine to assure high quality patient care with advanced diagnostic and therapeutic equipment.

The Division’s activities associated with the practice of the Department’s clinical activity are: provision of consultation and evaluation in purchasing radiological equipment commissioning of radiological equipment utilized for medical purposes to include acceptance testing, measurement of beam parameters, and provision of support for “Quality Assurance” procedures/protocols planning, developing and checking radiation treatment plans for accuracy in conjunction with the radiation oncologist for external radiation therapy (X and electrons):including IORT with low-energy electrons

and photons, high dose-rate brachytherapy treatments (HDR), and non-sealed radionuclide therapy. During 2006 the Division of Medical Physics has played an integral role in major equipment renovations for optimization of imaging and therapy in the Department such as replacement of the old gammacamera with a dual head gammacamera, replacement of the used CT scanner with a new helical 32-slice CT scanner and installation of a Tomotherapy Hi-Art System. The latter is a treatment system which integrates planning, image-guidance and helical delivery to provide continuous rotational irradiation of the patient, thus obtaining dose painting around the tumor and sparing healthy tissue. Despite the complexity of the machine, the System was accepted, tested and commissioned, including its quality assurance protocol, in a very short time. Installation started at the end of February 2006, while the first patient was treated at the beginning of May.

Another significant task in the year was the set-up of the Gliasite radiation procedure. Gliasite is a promising therapy designed for the treatment of brain tumors by delivering radiation from a liquid radioactive source

inserted within the cavity created by the surgical removal of the tumor. The main effort of the Medical Physics Division was aimed at fulfilling the national and local legislation requirements and suggested by good clinical practice to achieve radiation protection of the patient, personnel, and the environment.On the dosimetric front, a great effort was made to commission the Varian 2100 CD enhanced dynamic wedge facility on the Eclipse Treatment Planning System (TPS). Experimental spatial dose distribution generated by non physical wedges was compared with dose distribution calculated by TPS: the work showed that the TPS adequately reproduces any dynamic wedge beam.Work continued on the provision of treatment plans for conformal, intensity modulated and stereotactic radiotherapy; dosimetric measurements and quality control programs for all clinical ionizing radiation emitting devices within the Institute was successfully carried out in routine activity.


Participation in TARGIT-A, an international randomized controlled trial to compare targeted intraoperative radiotherapy with conventional post-operative radiotherapy after conservative breast surgery for women with early stage breast cancer.

Study of comparison EBT radiochromic and EDR2 radiographic films to determine which type of film is more accurate for dose verification in Hi-Art Tomotherapy System treatments.

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Department of Radiation Therapy and Imaging DiagnosticsDivision of Nuclear Medicine

Marino CIMITAN, MDDirector Division of Nuclear [email protected]

StaffTania BARESIC, MD [email protected] BORSATTI, MD [email protected] RUFFO, MD

Nuclear Medicine TechniciansRosa TATTA (Coordinator) [email protected] PAPAISEmiliano CHIORBOLI

Support StaffMartina TOFFOLI (Secretary)[email protected] CANCIAN (Registered Nurse)Dolores GERIN (General Nurse)Andrea D’INCÀ LEVIS (Archivist)

MISSION

The Division of Nuclear Medicine is committed to improving tumor diagnosis, therapy and research through the use of radioactive nuclides (99mTc, 111In, 131I, 123I, 125I, 90Y, 69Ga, 18F).Clinical activity consists in providing diagnostic information for staging, re-staging and therapy response evaluation in all kinds of tumors, using traditional gamma emitters and positron emitters for PET imaging.A particular task of the Division, in teamwork with Radiation Oncology, is the utilization of beta-emitter isotopes for radiopharmaceutical oncological therapy.Moreover, an important volume of ordinary clinical engagement of the Division deals with diagnostic ultrasound for screening and follow-up of cancer patients.The main clinical and research objectives are:

an early and definitive diagnosis of malignancy metabolic molecular imaging of tumors both prior to and after treatment development of radionuclide therapies as a new treatment option for malignant disease development of high resolution ultrasound for preoperative characterization of radioisotopically detected superficial structures such as sentinel nodes.

EQUIPMENT AND CLINICAL ACTIVITY

The Division is equipped with up-to-date nuclear and ultrasound technology: Double-headed SPECT/CT gamma camera GE Infinia, installed in 2006• PET/CTscannerGEDiscoveryLS,installedin2004• Acuson Sequoia 512 ultrasound system, installed

in1998 and recently updated

Approximately 1800 scintigraphy examinations, 2600 PET-CT scans and 6200 ultrasound examinations have been performed during 2006. In teamwork with Radiation Oncology about 35 radiometabolic treatments for thyroid cancer, 10 local radiation therapies for recurrent brain tumors (GliaSite system), and 4 immuno-radiotherapies for non-Hodgkin’s lymphoma were delivered in the past year.

Diagnostic Procedures 2006 Ultrasonography*Conventional abdominal ultrasound for staging and follow-up of cancer patients*Small organ high resolution ultrasound for characterization of superficial structures (thyroid, breast, lymph-nodes)

Nuclear Oncology • Imagingusing111In-labelledsomatostatinanalogue(Octreoscan)• Imagingusing131Iodine• Imagingusing123I-MIBG• Sentinel node scintigraphy (melanoma, breast ,thyroid and lung cancer) • Whole-bodyskeletalscintigraphy• Three-phaseskeletalscintigraphy• Thyroidscintigraphy• Parathyroidglandscintigraphy• Dynamicrenalscintigraphy


Positron Emission Tomography (PET/CT)Oncology is the main application of PET/CT in the world and this is especially true in our cancer research Institute. The Division performs examinations in this modality to reach a differential diagnosis between benign and malignant lesions, perform molecular imaging, and allow tumor staging and re-staging.In ordinary clinical activity PET/CT imaging has shown its value in improving the global diagnostic accuracy in detecting malignancies, and in a better monitoring of the response to radio-chemotherapy in cancer patients. In the past year, an important contribution of morpho-metabolic PET/CT imaging consisted in improving radiotherapy planning for a better management of patients. This result was achieved with appropriate teamwork between Nuclear Physicians and Radiation Oncologists of the same Department.The Division is unfortunately not equipped with a cyclotron, and can therefore utilize the only the 18F isotope whose longer half-life allows it also to be supplied from another site. In spite of this criticism, although18F-Fluor-2-deoxy-D-glucose (FDG) is the main tracer used in our Division, other PET 18F tracers are currently used, such as 18F-Fluor-ethyl-tyrosine (FET) for brain tumors, 18F-Fluor-methyl-choline (FCH) for recurrent prostate cancer, and 18F-DOPA for neuroendocrine tumors.

Radiopharmaceutical Tumor TherapyThe Nuclear Medicine Division works in co-operation with Divisions of Radiation Oncology and Medical Physics in planning radiopharmaceutical treatments for both inpatients and outpatients.The following are radioisotopes used for therapy: 131I-radioiodine for thyroid cancer, 125I-radioiodine (IOTREX) for brachy-radiotherapy of recurrent brain tumors, 90Y-ibritumomab tiuxetan (Zevalin) for non-Hodgkin’s lymphoma, 153Sm-lexidronam (Quadrament) for palliative treatment of bone pain in patients with bone metastases.

PROJECT LIST AND RESEARCH ACTIVITY

Previous scientific interests of the Division included traditional diagnostic gamma emitter imaging, such as Octreoscan, in the management of neuroendocrine tumors, mammoscintigraphy in patients with indeterminate breast lesions, and sentinel node detection in breast cancer and melanoma.The current main research activities are dedicated instead to diagnostic PET/CT, particularly in the evaluation of new 18F-tracers besides FDG. We successfully utilized 18F-Methyl-Coline (FCH) in the management of suspected recurrent prostate cancer and 18F-Ethyl-Tyrosine (FET) in evaluation of recurrent brain tumors. An ongoing field of research activity is also the evaluation of PET/CT imaging in staging and early re-staging of lymphomas and the management of HIV+ patients.

Close collaboration with oncologists has contributed to a great interest in new fields of oncological PET applications. In fact, metabolic PET/CT imaging for tailoring radiotherapy treatments and early evaluation of response in solid tumors during chemotherapy have been two main applications of clinical PET in our Institute in the past year, and a promising application for both is expected in the near future.At last diagnostic ultrasound, a basic examination in most cancer patients in every hospital, will promote the development of a line of research in our Institute. The implementation of an ultrasound device with new more sensitive small organ probes together with a more extensive use of contrast ultrasound media is now foreseen. This should allow a shift from ordinary clinical ultrasound to clinical research that will include ultrasound molecular imaging.

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• Caggiari L, Guidoboni M, Vaccher E, Barzan L,Franchin G, Gloghini A, Martorelli D, Zancai P, Bortolin MT, Mazzucato M, Serraino D, Carbone A, De Paoli P, Dolcetti R. High serum levels of soluble CD40-L in patients with undifferentiated nasopharyngeal carcinoma: pathogenic and clinical relevance. Infect Agent Cancer. 2007;2:5.

• CimitanM,BortolusR,Morassut S,Canzonieri V,Garbeglio A, Baresic T, Borsatti E, Drigo A, Trovò MG. [(18)F]fluorocholine PET/CT imaging for the detection of recurrent prostate cancer at PSA relapse: experience in 100 consecutive patients. Eur J Nucl Med Mol Imaging. 2006 Dec;33(12):1387-98.

• BriaE,CeribelliA,TrovòMG,GelibterA,GiganteM,Calabro E, Cuppone F, Cognetti F, Terzoli E, Pastorino U. Non-small cell lung cancer: early stages. Ann Oncol. 2006;17 Suppl 2:ii17-21. Review.

• Auperin A, Le Pechoux C, Pignon JP, Koning C,Jeremic B, Clamon G, Einhorn L, Ball D, Trovò MG, Groen HJ, Bonner JA, Le Chevalier T, Arriagada R; Meta-Analysis of Cisplatin/carboplatin based Concomitant Chemotherapy in non-small cell Lung Cancer (MAC3-LC) Group. Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol. 2006;17(3):473-83.

• BozG,DePaoliA, InnocenteR,RossiC,TosoliniGC, Bassi C, Falconi M, Pederzoli P, Trovò MG. Radiotherapy and chemotherapy in pancreatic cancer. Topical issues and future perspectives.JOP. 2006;7(1):122-30.

• DePaoliA,ChiaraS,LuppiG,FrisoML,BerrettaGD,Del Prete S, Pasetto L, Santantonio M, Sarti E, Mantello G, Innocente R, Frustaci S, Corvo R, Rosso R. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable rectal cancer: a multicentric phase II study. Ann Oncol 2006; 17(2):246-251.

• Schima W, Hammerstingl R, Catalano C, Marti-Bonmati L, Rummeny EJ, Montero FT, Dirisamer A, Westermayer B, Bellomi M, Brisbois D, Chevallier P, Dobritz M, Drouillard J, Fraioli F, Jesus Martinez M, Morassut S, Vogl TJ. Quadruple-phase MDCT of the liver in patients with suspected hepatocellular carcinoma: effect of contrast material flow rate. AJR Am J Roentgenol. 2006;186(6):1571-9.

• GuariseA,VenturiniS,FaccioliN,PinaliL,MoranaG. Role of magnetic resonance in characterising extrahepatic cholangiocarcinomas. Radiol Med 2006; 111(4):526-538.

• CimitanM, Bortolus R,Morassut S, Canzonieri V,Garbuglio A, Baresic T, Borsatti E, Drigo A, Trovò MG. “((18)F) fluorocholine PET/CT imaging for the detection of recurrent prostate cancer at PSA relapse: experience in 100 consecutive patients” Eur J Nucl Med Mol Imaging. 2006; 33(12):1387-1398.

• FallaiC,BolnerA,SignorM,GavaA,FranchinG,Ponticelli P, Taino R, Rossi F, Ardizzoia A, Oggionni M, Crispino S, Olmi P. Long-term results of conventional radiotherapy versus accelerated hyperfractionated radiotherapy versus concomitant radiotherapy and chemotherapy in locoregionally advanced carcinoma of the oropharynx. Tumori. 2006;92(1):41-54.

• Frustaci S, Berretta M, Comandone A, Bidoli E,De Paoli A, Gherlinzoni F, De Pas T, Barbieri E, Pertici M, Apice G, Picci P; Italian Sarcoma Group. Adjuvant treatment of high-risk adult soft tissue sarcomas: a survey by the Italian Sarcoma Group. Tumori. 2006; 92(2):92-97.

• BalestreriL,MorassutS,BernardiDetal.EfficacyofCT-guided percutaneous needle biopsy in the diagnosis of malignant lymphoma at first presentation. Clinical Imaging.2005; 29(2):123-127.

• CimitanM.,BortolusR.,MorassutS.,CanzonieriV.,Garbeglio A., Baresic T., Borsatti E., Drigo A., Trovò M. G. Reply [[18F]fluorocholine PET/CT in the assessment of bone metastases in prostate cancer]. Eur J Nucl Med Mol I 2007, 34 (8): 1318-1319

• Dassie A., Drigo A., Avanzo M., Salvador I., RenKaiser S., Sartor G., Capra E. Verifiche dosimetriche su piani di trattamento per tomoterapia: Un anno di esperienza [One year experience in dose verifications for tomotherapy plans]. Rivista Medica 2007, 13 (3): 49-56

• MascarinM., FranchinG.,GiganteM.,MinatelE.,Drigo A., Dassie A., Sartor G., Rumeileh I. A., Innocente R., Avanzo M., Cappelletto C., Capra E., Borsatti E., De Cicco M., Trovò M. G. Tomotherapy: When the patient is a child or an adolescent: hopes, results and issues. Rivista Medica 2007, 13 (3):21-28

• RumeilehI.A.,BortolusR.,FranchinG.,GobittiC.,Innocente R., Minatel M., Trovò M. G. TomoThinking in un dipartimento di radioterapia [TomoThinking in a Radiation Oncology Department]. Rivista Medica 2007, 13 (3): 15-20

• Sardanelli F., Podo F., D’Agnolo G., Verdecchia A.,Santaquilani M., Musumeci R., Trecate G., Manoukian S., Morassut S., De Giacomi C., Federico M., Cortesi L., Corcione S., Cirillo S., Marra V., Cilotti Anna, Di Maggio C., Fausto A., Preda L., Zuiani C., Contegiacomo A., Orlacchio A., Calabrese M., Bonomo L., Di Cesare E., Tonutti M., Panizza P., Del Maschio A. Multicenter comparative multimodality surveillance of women at genetic-familial high risk for breast cancer (HIBCRIT study): interim results. Radiology 2007, 242 (3): 698-715

• FranchinG.,MinatelE.,PolitiD.,GobittiC.,TalaminiR., Vaccher E., Savignano M. G., Trovo M., Sulfaro S., Barzan L. Postoperative reduced dose of cisplatin concomitant with radiation therapy in high- risk head and neck squamous cell carcinoma. Cancer 2009, 115 (11): 2464-2471

• ReA.,MichieliM.,CasariS.,AllioneB.,CattaneoC.,Rupolo M., Spina M., Manuele R., Vaccher E., Mazzucato M., Abbruzzese L., Ferremi P., Carosi G., Tirelli U., Rossi G. High dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for AIDS-related lymphoma: long term results of the GICAT study with analysis of prognostic factors. Blood 2009, Epub (ahead): of print-


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The Department of Laboratory diagnostics and Cell therapy is composed of the following 4 divisions as well as 4 Units: Blood Transfusion, Immunohematology and Clinical Chemistry, Pathology, Microbiology, Virology and Immunology, Stem Cells Laboratory and Clinical & Experimental Oncohematology.The Department team is composed of highly trained research personnel and provides excellent facilities in multiple areas of laboratory diagnostics for in and outpatients. Cell therapy is available for local and national care of oncological patients.The Department Director provides the leadership, environment, resources and necessary infrastructures for

Department of Laboratory Diagnostics and Cell Therapy

Faculty & StaffLuigi DE MARCO, MDDepartment Director,Division DirectorBlood Transfusion, Immunohematology, and Clinical Chemistry/Emergency Laboratory

Giancarlo BASAGLIA, MDDirectorMicrobiology, Immunology, and Virology Unit

Valter GATTEI, MDDivision DirectorClinical & Experimental Oncohematology

Antonino CARBONE, MDDivision DirectorPathology

Mario MAZZUCATOUnit DirectorStem Cell Collection and Processing

Agostino STEFFANUnit DirectorCancer Pathology

local medical investigators and those from other Institutes and Universities, their staff and medical students to conduct clinical and laboratory medical research.



The mission of the Division, established in 1989, is to provide the best haemocomponents for clinical and surgical activities of the Institute. It actively participates with other Divisions within and outside our Institute in clinical and scientific research protocols.

The Division is composed of the following 4 laboratories: Immunohaematology and Transfusion Medicine, Immunodiagnostic, Haematology, and Haemostasis, including a unit for Vascular Biology and one for Biochemistry of Haemostasis.The whole blood collection and productive apheresis procedures increased continuously during the last

Department of Laboratory Diagnostics and Cell TherapyDivision of Blood transfusion, Immunohematology and Clinical Chemistry/

Emergency Laboratory

Luigi DE MARCO, MDDirector, Blood Transfusion, Immunohematology and Clinical Chemistry Division, Laboratory Diagnostics and Cell Therapy Department [email protected]

PhysiciansMaria Rita COZZI, [email protected] COZZI, [email protected] DA PONTE, [email protected] TASSAN TOFFOLA, [email protected]

Fellows & Other PersonnelMonica BATTISTON, Research [email protected]

years providing all the needed haemocomponents for the patients of the Institute and taking part in the haemocomponent self-sufficiency of the Friuli Venezia Giulia Region. New kinds of donation such as multicomponent and double red cell unit apheresis donations have become available to collect the right haemocomponents at the appropriate time (target collection). Therapeutic apheresis has now become an available therapy for patients needing plasma exchange, and plasmafiltration. The Emonet software implementation has been further developed to allow the complete management of Donor-Receiver data; giving the opportunity of sharing the data with the entire Region’s blood bank, offering in

this way a great advantage for the control and safety of transfusions. Haemovigilance and evaluation of appropriateness of all the haemocomponents requests have become deep-rooted activities toward total clinical governance.The Immunometry and Hormonal Dosage Unit increased the number of tumoral markers measured and began testing for celiac disease (anti transglutaminase antibodies).The Haematology laboratory has improved its diagnostic capabilities thanks to the two new instruments able to measure new useful parameters in haematological diagnosis.The laboratory of Haemostasis has increased the number of genetic mutations studied and confirmed its leadership position in the field of thrombotic and haemorragic disease. ADAMTS 13 studies are ongoing to improve the diagnosis and microangiopathic anemia. Cytofluorimetric diagnosis has gone a step further, performing more tests in thrombotic diseases and broader quality control for haemocomponents.

TEACHING AND TRAINING ACTIVITIES

Teaching is ongoing within the Graduate Medical Specialty in Oncology of the University of Udine and at the Nursing School of the University of Udine.

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During the year 2007, the Biochemistry of Haemostasis Unit has taken part in research studies with the Biochemical and Medical Department of Padova University and with the National Cancer Institute I.R.C.C.S.- Policlinico, Milano University.The Vascular Biology Unit has kept studying the interaction between cells and various substrates under controlled flow. The biophysics and biochemical effects due to platelet adhesion and activation on the extracellular matrix (such as von Willebrand factor and proteoglicans) were specifically pursued. Aiming at improving this line of research, a new, more performant, imaging software has been developed for better analyzing functional changes in fast moving cells.The Units within this Division have been involved in the following research projects: “Multivalent interaction platelet-leukocyte-tumor cell as target for antiangiogenetic and anti metastatic therapies”; ASI (Italian Space Agency) “A new “in vitro” closed filtration device which detects thrombus formation under different shear forces”, “Platelet adhesion and activation onto different substrates under flow conditions”.The Vascular Units cooperate with the Aviano Experimental Oncology Unit 2, Scripps Research Institute La Jolla (CA, USA), I.R.C.C.S. Mario Negri Sud in S. Maria Imbaro (CH), Chemical Engineering Department of Padova University and with National Cancer Institute I.R.C.C.S.- Policlinico, Milano University.

Activities in progressClinical activity has included universal leukodepletion with in line filtration allowing a further improvement of the quality of blood products thanks to reduction in HLA alloimmunization, febrile non-haemolitic transfusion reactions and CMV transmission.Such improvements have been continuously monitored thanks to a deep commitment to haemovigilance and daily evaluation of all the haemocomponent requests. New donation techniques, as multicomponent and single donor double red cell unit apheresis, have been introduced toward haemocomponent target collection.Therapeutic apheresis is widely used for treating patients eligible for plasma exchange or plasmafiltration. Research activity will address the study of cellular

adhesion under flow conditions, with a special attention being paid to the study of the mechanisms regulating haemostasis (repair of vascular damage), neoangiogenesis (in cooperation with the Division of Experimental Oncology 2) and the biophysical phenomenon of stem cell adhesion to the extracellular matrix and bone marrow stroma (in collaboration with the Division of Experimental Oncology 2 and the Clinical and Experimental Research in Haematology Unit).

In addition, our Division will coordinate a research team financed by ASI (Italian Space Agency) on the development of “A Novel System for In Vitro Detection of Gravity Effects on Primary Haemostasis”.Furthermore, our Division will participate in an international randomized double blind study on the effect of “Low Molecular Weight Heparin in the Treatment of Malignancy, MALT-STUDY”.

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Department of Laboratory Diagnostics and Cell TherapyUnit of Stem Cell Culture and Processing

Director:Mario MAZZUCATO, [email protected]

Staff:Luciano ABBRUZZESE,[email protected]


The Unit is devoted to supporting stem cell therapy within the Institute and other organizations within other regions as declared in the National Healthcare plan. Its clinical activity involves selecting patients and donors, stem cell collection, conservation and manipulation in order to proceed with autologous and homologous stem cell transplantation as well as cell therapy in general. In order to perform these activities it collaborates with the Division of Blood transfusion, Immunohematology and Clinical Chemistry/Emergency Laboratory. The Unit proposes and performs experimental protocols aimed at cryoconservation, collection and manipulation of blood cells for clinical purposes.

Sources of cell culture include peripheral circulation, bone marrow, and umbilical cord blood. The Unit is accredited by GITMO (Italian Bone Marrow Transplant

Group) in the Friuli Venezia Giulia Region according to the standard procedures as defined in legislation from 2003. The Unit assists the activity of transfusion and laboratory medicine of the Division to which it pertains following the operating guidelines defined by its Director. The Unit also is an interface with other structures of the Department for the development of research on hemopoietic stem cells.The URM-CSE Division is also intensely involved in stem cell collection and cryopreservation for patients undergoing high-dose chemotherapy within the Department’s laboratories. Therapeutic apheresis has now become an available therapy for patients needing peripheral blood stem cell collection and PBSC has become standard therapy for certain hematological malignancies with dozens of procedures performed every year including patients suffering from HIV-related lymphoma. High dose chemotherapy with PBSC

High dose chemotherapy with PBSC recovery was supported with collection and infusion of PBSC in more than 50 patients.We will focus on the optimization of collection, selection, freezing and preservation of peripheral blood stem cells and the multiparametric evaluation of patients treated with high-dose chemotherapy, in order to rationalize necessary transfusion support (in collaboration with the Division of Medical Oncology B).


Department of Laboratory Diagnostics and Cell TherapyCancer Pathology Unit

Director:Agostino STEFFAN, [email protected]


• Laboratoryfortheclinicalvalidationofroutinecancerbiomarkers• Evaluation / validation and implementation of newcancer biomarkers• Laboratoryforperformingclinical/diagnosticcheck-ups for hemorrhaging and thrombotic diseasesin cancer, together with the Division of Blood transfusion, Immunohematology and Clinical Chemistry/Emergency Laboratory• Cytofluorimetric analyses for plateletimmunopathology• Assists in thetransfusionand laboratoryactivityofthe designated Division in accordance with the Director’s guidelines • Participatesintheresearchprogramsofthecancernetworks

In order to accomplish all the aforementioned activities the Unit is an interface with other structures of the Department and especially for the discovery through research of new cancer biomarkers.

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Department of Laboratory Diagnostics and Cell TherapyDivision of Microbiology, Immunology, and Virology

Giancarlo BASAGLIA, Director of the Microbiology, Immunology, and Virology Division [email protected]

Bacterial, Mycotic and Parasitology Diagnostic Unit

StaffCristina CAFFAU, MD [email protected] TEDESCHI, BiSc [email protected] ZANUSSI, BiSc [email protected]

Research FellowsMariateresa BORTOLIN, BiSc Alessia MARUS, BiScChiara PRATESI, BiSc


The Division of Microbiology and Virology is dedicated to the laboratory diagnosis and study of the etiological and pathogenic relationship between microbial infections and development of selected tumors. The aims of the Division are to decipher, through research, the microbiological and immunological aspects of morbidity in the immunocompromised host to treat and prevent disease. Established in 1992, the Division is composed of four areas: Bacteriology/Mycology, Clinical Virology, Clinical Immunology, and Biotechniques. The chief constituent activity of the subdivisions are studies involving the relationship between cancer and infectious agents, viral diseases, immunological and molecular biology aspects underlying tumor development in the immunocompromised host.The Division performs clinical and research analyses primarily through the use of the following instruments: a Real Time PCR, a safety Level III laboratory, a DNA sequencing apparatus, a flow cytometer in addition

to other instruments necessary for the amplification of DNAs and RNAs and viral load measurement. Samples relevant to epidemiological and laboratory research are maintained in a biological bank. Since 2005 its clinical diagnostic activities are supported and monitored through a continuous quality project that includes internal and external control mechanisms (ISS, Neqas UK, EU Concerted Action).Our lab studies within the Bacteriology/Mycology Section serve to diagnose bacterial and mycotic infectious diseases for inpatients and outpatients. Helicobacter pylori is routinely cultured from biopsies obtained from gastric cancer patients as well as non-neoplastic subjects for the assessment of the antibiotic resistance profile of the samples. One area of interest concerns the microbiological aspects of blood-borne and central venous catheter (CVC) infections while another matter receiving special attention is the control of hospital-acquired infectious disease with subsequent epidemiological reports profiling the antibiotic resistance of the most frequently isolated micro-organisms present in the Institute.

The Clinical Virology Section attends to the needs of the Division by studying viral replication in patients having virus-associated cancers and primarily through viral load quantitation of EBV in order to provide supportive care to patients affected with the associated cancers. Further, it fulfills the function of supplying enriching research techniques for innovative immunological assays using synthetic peptides, recombinant antigens and cell lines as well as introducing quantitative assays that measure viral load into clinical practice. Genomic sequencing of the HIV polymerase gene is also routinely performed here to map resistance to antiretroviral therapies.The immunological diagnosis of immunoglobulin disorders in patients with immunodeficiency and cancer is performed in the Clinical Immunology Section. This work has broad relevance to subjects undergoing autologous stem cell transplantation that include lab procedures involving cytoflourimetric determination of lymphocyte subsets; a practice that is also extended to HIV+ and neoplastic disease patients. By means of molecular biology methods in the Biotechniques Section, we have developed pre-clinical assays that can further be introduced into clinical practice. Particular attention has been paid to the relationship between these projects and the development of molecular biology assays as well.

PROJECTS LIST –RESEARCH ACTIVITY

Our core investigation activity is conducted in the following research studies and on essential new research programs that investigate the immunological and virological aspects of cancer in aging:• ImmunologicalaspectsofHIVinfectionandofHIV-associated tumors• Mechanismsdrivingimmunologicalreconstitutionincancer patients undergoing chemotherapy or stem cell transplantation• Immunological and virological aspects of HHV-8associated tumors• Immunogenetics and EBV replication in patientswith undifferentiated nasopharyngeal carcinomas• Immunogeneticsofgastriccancerpatientsandfirst-degree relatives; its relationship with the genetics of H. pylori strains• TechnicalandmanagerialaspectsofBiobanking


Department of Laboratory Diagnostics and Cell TherapyDivision of Clinical and Experimental Oncohematology

Valter GATTEI, MDDivision Director Clinical & Experimental Oncohematology [email protected]

StaffPietro BULIAN, MD [email protected] DEGAN, BSc [email protected] Maria ROSSI, BSc [email protected] FellowsMichele DAL BODania BENEDETTIDebora LORENZON

ConsultantsRiccardo BOMBENAntonella ZUCCHETTO


The Division, established in September 1992 and presently included within the Laboratory Diagnostics and Cell Therapy Department, is devoted to providing a specific laboratory support for clinical activities, as well as to address precise research issues in the field of hematological oncology.The clinical activity comprises the diagnosis/follow-up of patients with hematological malignancies and the monitoring/characterization of hematopoietic stem cells for patients undergoing stem cell transplantation.The research activity of the Division is mainly focused on the identification of molecular and immunophenotypic diagnostic/prognostic profiles of hematological malignancies and to this end it comprises a core facility for “gene expression profiling” (GEP).Efforts are finalized at offering a “state-of-the-art”

diagnostic flowchart for leukemia and lymphoma by utilizing an integrated approach which includes morphology, immunophenotyping and assessment of the genetic lesion associated with most hematopoietic tumors.

• Morphological and immunophenotypical onco-hematological diagnostic activitiesMorphological and immunophenotypical analyses carried out for newly diagnosed or follow-up patients on perpheral blood samples, bone marrow aspirates, lymph node suspensions, and fine-needle aspirates. The laboratory is equipped with a single-laser and two double-laser flow cytometers. • Molecular onco-hematological diagnostic activity Several protocols of (RT)-PCR have been currently set-up encompassing the most common chromosomal

translocations involved in the pathogenesis of leukemias, including BCR/ABL [t(9;22) M-BCR], BCR/ABL [t(9;22) m-BCR], BCR/ABL [t(9;22) µ-BCR], AML1/ETO [t(8;21)], PML/RARα [t(15;17)], CBFβ/MYH11 [inv(16)], MLL/AF4 [t(4;11)], E2A/PBX1 [t(1;19)], TEL/AML1 [t(12;21)], ALK/NPM [t(2;5)], BCL2/IgH [t(14;18) MBR], BCL2/IgH [t(14;18) mcr], BCL1/IgH [t(11;14) MTC], API2/MLT [t(11;18)], B cell clonality (FR1-JH/CDR3-JH). In addition: i) detection of the mutational status of IgVH genes in B-cell chronic lymphocytic leukemia (B-CLL) for prognostic evaluation, ii) Fluorescence-in-situ hybridization (FISH) for 11q-, +12, 13q-, 17p- evaluation in B-CLL. The laboratory is equipped with a real-time PCR machine and instruments for GEP.

• Monitoring and characterization of hematopoietic progenitorsThis activity is to provide a complete monitoring for patients undergoing stem cell transplantation, including standard in vitro colony assays (CFU-GM, CFU-GEMM, BFU-E, LTC-IC) and evaluation of the absolute number of CD34-expressing stem cells.

PROJECTS LIST – EXPERIMENTAL RESEARCH ACTIVITY

Our efforts are aimed at clarifying various aspects of the physiopathology of B cell chronic lymphocytic leukemia (B-CLL), as well as at identifying novel molecular and immunophenotypical prognostic markers to be introduced in routine clinical activities.

• Mutational status of IgVH genes and prognostic relevance - in addition to the identification of unmutated and mutated IgVH gene status, other features of Ig genes are evaluated, including evidence of antigen-driven selection, preferential usage of IgVH gene segments, usage of stereotyped “IgVH-CDR3-IgVL” combinations (refining the prognostic assessment of CLL by identifying stereotyped BCR combinations associated with different prognosis as well as identifying putative “antigens” responsible for neoplastic transformation or Ig combination to be used as targets for immunotherapy).

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• “Unmutated” B-CLL, intraclonal diversification and expression of markers of mature B lymphocytes – the aim of these studies is to provide compelling evidence for the post-germinal center origin of B-CLL; • IgVH gene mutational status and expression of enzymes of the “somatic hypermutation (SHM) machinery”- expression studies of activation-induced cytidine deaminase (AID), uracil-N-glicosylase (UNG), translesion DNA polymerases in B-CLL without evidence of antigen-driven selection; the aim is to compare the SHM machinery of B-CLL cells with that of normal B cell subsets.

Besides these molecular studies, other studies of immunophenotypical characterization of B-CLL cells are performed; since data analysis is carried out by applying the same algorithms usually employed in GEP, we have named this research area “surface-antigen expression profiling” (SEP):

• “Immunophenotypic clustering” and “immunophenotypic signature” of B-CLL with different prognoses; by means of the application of unsupervised and supervised analyses, we have previously identified 12 phenotypic markers whose differential expression allowed the identification of B-CLL subsets with different prognoses;

Expression of some of these markers has been investigated in detail : among them CD49d has been found to have an expression pattern closely related to that of a well-known negative prognosticator for B-CLL, i.e. CD38 ; consistently ,CD49d expression was found to be associated with bad prognosis either in unselected B-CLL, or in a cohort of early stage cases. Studies are currently ongoing aimed at investigating the microenvironmental interactions occuring in CD38+/ CD49d+B-CLL explaining the more aggressive clinical behavior of this B-CLL subset. The complete disclosure of such a network may reveal alternative therapeutic targets to be introduced in therapy of this B-CLL subset.

• Telomerase activity in B-CLL with different IgVH gene mutational status and prognosis; the study is carried out in collaboration with the University of Padua

(A. De Rossi); • In vitro studies of apoptosis induction in B-CLL cells; these studies are carried out in close collaboration with research groups of the University of Ferrara; in these studies B-CLL cells are exposed in vitro to non-genotoxic drugs (Nutlins) activators of the p53 apoptotic pathway; GEP of B-CLL cells, bearing or not,deletions/ mutations of p53 genes and exposed in vitro to these drugs will allow identification of cases responsive to p53 activator treatment and identify some as yet undiscovered alternative pathways followed by non-genotoxic p53 activators to overcome impairments of the p53 metabolic pathway. Characterization of hematopoietic progenitorsThe Division along with other Lab Diagnostic and Medical Oncology Departmental Units is involved in projects aimed at investigating the possibility to ex-vivo expand hematopoietic progenitors and/or to utilize other cell types, e.g. mesenchymal stem cells, to improve the engraftment capability of the so-called “poor mobilizer” patients.

Activity of the “microarray core facility” The activities of the microarray core facility are mainly focused on GEP in projects of interest, including:• GEP in B-CLL; this study compares specific B-CLL subsets, including cases with mutated or unmutated IgVH gene configurations, expressing or not molecules previously identified as prognosticators, expressing specific IgVH-CDR3-IgVL combinations, exposed in vitro to specific drugs, or bearing specific chromosomal alterations. • GEP in leukemic blasts of acute myeloid leukemia (AMLs); these studies are aimed at comparing the GEP of blast cells from primary or secondary AMLs and blast cells from myelodysplastic syndromes;• GEP of hematopoietic precursors; the goal of these studies is to compare the GEP of peripheral blood hematopoietic progenitors, ex-vivo expanded progenitors, progenitors purified from cord blood etc.

GEP studies are carried out by using an Operon 2.0 platform (21,329 probes) or the Agilent 4x44k (44,000 probes, 4 replicates per slide)platforms; hybridizations were made by using a dual-labeling strategy, with

conventional or real-time PCR to validate results. The introduction of platforms aimed at investigating the microRNome will represent the next step for these activities.

Collaborations• Università degli Studi “Tor Vergata”, Cattedra di

Ematologia, Roma, Dott. G. Del Poeta, Dott. F. Buccisano, Prof. A. Venditti, Prof. S. Amadori

• Università degli Studi del Piemonte Orientale“Amedeo Avogadro”, Unità di Ematologia, Prof. G. Gaidano, Dr. D. Capello

• Università Cattolica del Sacro Cuore, Istituto diEmatologia, Roma Dott. L. Laurenti

• Università degli Studi La Sapienza, Istituto diEmatologia, Roma, Prof. R. Foa’

• ICGEBOutstation-Monterotondo,CNRCampus“A.Buzzati-Traverso”, Roma, Dott. D. Efremov

• UniversitàdegliStudidiSiena,PoliclinicoLeScotte,Unita’ Operativa di Ematologiae Trapianti, Siena, Dott. F. Forconi

• Università degli Studi diModena e Reggio Emilia,Dipartimento di Oncologia ed Ematologia, Modena, Prof. R. Marasca, Dott. R. Maffei

• Università degli Studi di Udine, Cattedra diImmunologia, Udine, Prof. C. Pucillo

• UniversitàdegliStudidiFerrara,Prof.GiorgioZauli,Prof. Paola Secchiero

• DipartimentodiFisica,INFN,UniversitàdiBologna,Prof. R. Campanini

• Laboratorio di Immunogenetica, Università degliStudi di Torino, Prof. F. Malavasi, Dott. S. Deaglio

• Università degli Studi di Trieste, Cattedra diImmunologia, Prof. Francesco Tedesco

• Università degli Studi di Palermo, Dipartimento diPatologia, Dott. C. Tripodo

• Cardiocentro Ticino, Lugano (Switzerland), Dr. G.Astori

• Laboratorio di Oncologia Sperimentale, IstitutoOncologico della Svizzera Italiana, Bellinzona (Switzerland), Dott. Francesco Bertoni


Department of Laboratory Diagnostics and Cell TherapyDivision of Pathology

Antonino Carbone, MDDirector Division of [email protected]

StaffVincenzo CANZONIERI, [email protected] VOLPE, [email protected] PERIN, [email protected] ROSSI, MDAnna Maria CILIA, [email protected]


The Division’s mission centers on the support of clinical and translational research through the biopathological characterization of tumors that are mostly studied and treated in the Institute (i.e. lymphoma, melanoma, soft tissue sarcoma, ovarian carcinoma, gastrointestinal carcinoma and rare tumors).The Division of Pathology is organized into 9 sections: 1) Surgical Pathology 2) Diagnostic Cytopathology and Screening3) Diagnostic Immunopathology and in situ molecular analysis4) Classical and molecular cytogenetics and cell culture; 5) Morphometric analysis and quantitative pathology6) Telepathology 7) Tissue bank 8) Autoptic section9) Educational section

The main diagnostic objectives in molecular pathology of the Division are pursued:by using immunohistochemistry for the bio-pathological characterization of neoplasia (Lymphoma,Sarcoma, Melanoma); differential diagnosis of neoplasia; identification of markers for target therapies (ER, PgR, HER2, EGFR, VEGF);

by using in situ hybridization for the identification of viral sequences (EBV, HPV, CMV…) clonality (k, l) gene amplification (HER2, EGFR, c-Myc…) chromosome aneuploidy (chr. 17..);

by using PCR for the definition of clonality (TCR, VDJ) identification of translocations (BCL1, BCL2)

The following summarize Clinical activity data for the year 2006:No. of histopathological analyses 9,618No. of diagnostic consultations 496No. of cytopathological analyses 1654No. of PAP tests 3,196Total no. of paraffin-embedded blocks 52,778No. of paraffin-embedded tissue blocks 52,610No. of cell blocks 168Total no. of immunohistochemical analyses (for immunodiagnosis and/or biological characterization of neoplasms) 11,193Performed on paraffin-embedded tissue sections 11,088Performed on frozen tissue sections 105Performed on cytospin preparations 526Total no. of in situ molecular analyses (EBER, HPV, HHV- 8, Kappa mRNA, LAMBDA mRNA, FISH) 320No. of in situ molecular analyses (for research purposes) 807No. of samples snap frozen and stored at –80°C 744No. of cytogenetic analyses 6

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PROJECTS LIST – RESEARCH ACTIVITY

Research projects are oriented towards lymphoproliferative disorders of both the immunocompetent and the immunodepressed host (HIV-infected, post-transplant) and to the characterization of soft tissue sarcomas, gastrointestinal cancer, ovarian cancer, breast pathology and rare tumors. From a methodological point of view, the Division is planning to integrate the immunohistochemical approach with Western Blotting techniques and the cytogenetic approach with molecular cytogenetics.The Division also aims to introduce image analysis and quantitative pathology in addition to conventional microscopic analysis in order to correlate morphological results with the differential expression of proteins encoded by proto-oncogenes or oncosuppressor genes involved in the cellular differentiation and the cell cycle.

Research projects of the Pathology Division are oriented to implement innovative protocols for the extraction of nucleic acids from fixed and paraffin-embedded tissue sections to molecular diagnosis of tumors and biomolecular characterization of anaplastic large cell lymphomas, HCV-related lymphomas and HIV-associated lymphomas, as well as HHV8 associated lymphomas (oral plasmoblastic lymphoma, primary effusion lymphoma and atypical variants of Burkitt’s lymphoma),Within the framework of the sarcoma study group innovative protocols devoted to the production of antibodies against chimeric proteins produced by fusion genes derived from specific translocations are being developed. The evaluation of histo-prognostic factors in ovarian carcinoma, colorectal cancer and carcinoma of the breast are also actively pursued.The Division participates in research projects for cancer stem cell characterization, proteomics, and phosphoproteomics. It also collaborates in various projects of Tissue Bank Organization at the institutional, national and international levels. The Division of Pathology is a member of the Italian Telepathology Network “TESEO” together with the other Italian National Cancer Institutes



• Machin M, Santomaso A, Mazzucato M, CozziMR , Battiston M, De Marco L, Canu P. Single platelet tracking across sequences of microscopical images: application to platelet adhesion under flow. Ann Biomed Eng. 2006; 34 (5): 833-46.

• Zucchetto A, Bomben R, Dal Bo M, Bulian P,Benedetti D, Nanni P, Del Poeta G, Degan M, Gattei V. Reply to Pittner et al. Leukemia. 2006;20(3):528-9.

• BuccisanoF,MaurilloL,GatteiV,DelPoetaG,DelPrincipe MI, Cox MC, Panetta P, Consalvo MI, Mazzone C, Neri B, Ottaviani L, Fabroni D, Tamburini A, Lo-Coco F, Amadori S, Venditti A. The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia. Leukemia 2006; 20 (10):1783-9.

• Zucchetto A, Bomben R, Dal Bo M, Sonego P,Nanni P, Rupolo M, Bulian P, Dal Maso L, Del Poeta G, Del Principe MI, Degan M, Gattei V. A scoring system based on the expression of six surface molecules allows the identification of three prognostic risk groups in B-cell chronic lymphocytic leukemia. Journal of Cell Physiology 2006;207(2):354-363.

• DelPrincipeMI,DelPoetaG,BuccisanoF,MaurilloL, Venditti A, Zucchetto A, Marini R, Niscola P, Irno Consalvo MA, Mazzone C, Ottaviani L, Panetta P, Bruno A, Bomben R, Suppo G, Degan M, Gattei V, de Fabritiis P, Cantonetti M, Lo Coco F, Del Principe D, Amadori S. Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood. 2006; 108(3):853-61.

• BuccisanoF,MaurilloL,GatteiV,DelPoetaG,DelPrincipe MI, Cox MC, Panetta P, Consalvo MI, Mazzone C, Neri B, Ottaviani L, Fraboni D, Tamburini A, Lo-Coco F, Amadori S, Venditti A. The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia. Leukemia. 2006;20(10):1783-9.

• G Puppa, T Perin, V Canzonieri Comment on:”Clinico pathological Investigation of “Tumor Nodules” in Colorectal Cancer. Surg Today 2006; 36:944-945.

• FornasarigM,Minisini,AM,VielA,QuaiaM,CanzonieriV, Veronesi A. Twelve years of endoscopic surveillance in a family carrying biallelic Y165C MYH defect: report of a case. Dis Colon Rectum 2006;49(2):272-5.

• Talamini R, Polesel J, Montella M, Dal Maso L,Crovatto M, Crispo A, Spina M, Canzonieri V, La Vecchia C, Franceschi S. Food groups and risk of non-Hodgkin lymphoma: a multicenter, case-control studyin Italy. Int J Cancer. 2006;118(11):2871-6.

• RiegmanPH,OomenMH,DinjensWN,OosterhuisJW, Lam KH, Spatz A, Ratcliffe C, Knox K, Mager R, Kerr D, Pezzella F, Van Damme B, Van De Vijver M, Van Boven H, Morente MM, Alonso S, Kerjaschki D, Pammer J, Lopez-Guerrero JA, Llombart-Bosch A, Carbone A, Gloghini A, Teodorovic I, Isabelle M, Passioukov A, Lejeune S, Therasse P, Van Veen EB. TuBaFrost: European virtual tumor tissue banking. Adv Exp Med Biol 2006;587:65-74.

• Basaglia G, Stocco Calzavara S, Pancino A,Sperandio P, Tomasini ML, De Paoli P. Diagnostica microbiologica delle infezioni associate all’utilizzo di cateteri venosi centrali: considerazioni generali e studio in pazienti immunocompromessi. Microbiologia Medica 2006; 21: 21-27.

• DePaoliP.Immunologicalandvirologicalaspectsofautologous stem cell transplantation in HIV+ patients. Microbes and Infection 2006; 8: 2563-2568.

• Bomben R, Dal Bo M, Capello D, Benedetti D,Marconi D, Zucchetto A, Forconi F, Maffei R, Ghia EM, Laurenti L, Bulian P, Del Principe MI, Palermo G, Thorselius M, Degan M, Campanini R, Guarini A, Del Poeta G, Rosenquist R, Efremov DG, Marasca R, Foa R, Gaidano G, Gattei V. Comprehensive characterization of IGHV3-21-expressing B-cell chronic lymphocytic leukemia: an Italian multicenter study. Blood 2007; 109(7):2989-98.

• TedeschiR,BloiguA,OgmundsdottirH,MarusA,Dillner J, De Paoli P, Gudnadottir M, Koskela P, Pukkala E, Lehtinen T, Lehtinen M. Activation of maternal EBV infection and risk of acute leukemia in the offspring Am J Epidemiol 2007; 165: 134-37.

• Tedeschi R, Pin E, Bidoli E, Marus A, Pratesi C;Bortolin MT, Zanussi S, Vaccher E, Dolcetti R, De Paoli P. Serum antibody response to lytic and latent Epstein Barr Virus antigens in undifferentiated nasopharyngeal carcinoma patients from a non-endemic area. Clinical and Vaccine Immunology 2007;14(4):435-41.

• Caggiari L, Guidoboni M, Vaccher E, Barzan L,Franchin G, Gloghini A, Martorelli D, Zancai P, Bortolin MT, Mazzuccato M, Serraino D, Carbone A, De Paoli P, Dolcetti R. High serum levels of soluble CD40-L in patients with undifferentiated nasopharyngeal carcinoma:pathogenic and clinical relevance. Infectious Agents and Cancer 2007; 2:5.

• Casonato Alessandra, De Marco Luigi, GallinaroLisa, Sztukowska Maryta, Mazzucato Mario, Battiston Monica, Pagnan Antonio, Ruggeri Zaverio M. Altered von Willebrand factor subunit proteolysis and multimer processing associated with the Cys2362Phe mutation in the B2 domain. Thromb Haemost 2007, 97 (4): 527-533.

• DePaoliPaolo,PratesiChiara,BortolinMariaTeresa.The Epstein Barr virus DNA levels as a tumor marker in EBV-associated cancers. J Cancer Res Clin Oncol 2007, 133 (11): 809-815

• SpessottoP.,ZucchettoA.,DeganM.,WassermanB.,Danussi C., Bomben R., Perris R., Canzonieri V.,Radillo O., Colombatti A., Gattei V. Laminin-332 (Laminin-5) is the major motility ligand for B cell chronic lymphocytic leukemia. Matrix Biol 2007, 26 (6): 473-484.

•MazzucatoM.,SantomasoA.,CanuP.,RuggeriZM.,De Marco L.. Flow dynamics and homeostasis. Ann Ist Super Sanità 2007, 43 (2): 130-138.

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• Chuahan Ak, Kisucka J, Cozzi MR, Walsh MT,Moretti FA, Battiston M, Mazzuccato M, De Marco L, Baralle FE, Wagner DD, Muro AF. Prothrombotic effects of fibronectin isoforms containing the EDA domain.Arterioscler Thromb Vasc Biol. 2008, 28 (2):296-301.

• Gattei V, Bulian P, Del Principe MI, ZucchetoA, Maurillo L, Buccisano F, Bomben R, Dal Bo M, Luciano F, Rossi FM, Degan M, Amadori S, Del Poeta G. Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia. Blood 2008, 111(2):865-873.

• Pratesi C., Simonelli C., Zanussi S., TalaminiR., Bortolin M. T., Tedeschi R., Marus A., Caffau C., Michieli M., Tirelli U., De Paoli P. Recent thymic emigrants in lymphoma patients with and without human immunodeficiency virus infection candidates for autologous peripheral stem cell transplantation. Clin Exp Immunol 2008, 151 (1): 101-109

• BenedettiD.,BombenR.,DalBoM.,MarconiD.,Zucchetto A., Degan M., Forconi F., Del Poeta G., Gaidano G., Gattei V. Are surrogates of IGHV gene mutational status useful in B-cell chronic lymphocytic leukemia? The example of Septin-10. Leukemia 2008, 22 (1): 224-226

• Tedeschi R.,Marus A., Bidoli E., Simonelli C., DePaoli P. Human herpesvirus 8 DNA quantification in matched plasma and PBMCs samples of patients with HHV8-related lymphoproliferative diseases. J Clin Virol 2008, 43 (-): 255-259

• ZucchettoA.,BenedettiD.,TripodoC.,BombenR.,Dal Bo M., Marconi D., Bossi F., Lorenzon D., Degan M., Rossi F. M., Rossi D., Bulian P., Franco V., Del Poeta G., Deaglio S., Gaidano G., Tedesco F., Malavasi F., Gattei V. CD38/CD31, the CCL3 and CCL4 Chemokines, and CD49d/Vascular Cell Adhesion Molecule-1 Are Interchained by Sequential Events Sustaining Chronic Lymphocytic Leukemia Cell Survival. Cancer Res 2009, 69 (9): 4001-4009


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Department of Clinical-Specialty Services & Support

Faculty & Staff

Marcello DE CICCO, MDDepartment Director, Division DirectorAnaesthesiology and Intensive Care

Nereo MENEGUZZO, MDDivision DirectorCardiology

Renzo LAZZARINI, PharmDDivision DirectorPharmacy

Roberto BORTOLUSSI, MDUnit DirectorPain Therapy and Palliative Care

Maria Antonietta ANNUNZIATA, MDPaola ZOTTI, MDPsychological Oncology Unit


The Department of Clinical-Specialty Services & Support is composed of the following three Divisions: Anaesthesiology and Intensive Care, Cardiology, and Pharmacy. In addition, the Department includes a Pain Therapy and Palliative Care Unit and a Psychological Oncology Unit.The Divisions and Units share in-patient wards and out-patient clinics, and incorporate a large part of care and research for specific domains of medical and surgical cancer and supportive therapies. The Department staff provides care using a patient management team approach and participating in clinical and translational research projects in an integrated fashion. The cultural principle, which characterizes

the attitudinal basis shared by all the members of the Department, is to offer patients with cancer and colleagues a careful service and the most effective support.The Department Director, Dr. M. De Cicco, provides the leadership, environment, resources and necessary infrastructure for medical investigators, their staff, and medical students working in the CRO-National Cancer Institute setting to conduct medical research.


Department of Clinical-Specialty Services & SupportDivision of Cardiology

Nereo MENEGUZZO, MDDirector Division of [email protected]

StaffChiara LESTUZZI, [email protected] VIEL, [email protected] TARTUFERI, [email protected]


The evaluation and follow-up of patients undergoing potentially cardiotoxic chemotherapies (anthracyclines and others) or therapeutic thorax and mediastinum irradiations as well as the evaluation of patients enrolled in new Protocols are the principal objectives of the Division. The management of any cardiac problem (congestive heart failure, arrhythmias, acute ischemic heart disease, pericardial effusion, metastatic cardiac, pericardial tumors, and other ailments) that can involve in- and out-patients referring to the Hospital include routine activity procedure.Furthermore, cooperation with the Intensive Care Unit in the management of cardiac emergencies and baseline evaluation of patients undergoing major abdominal and thoracic surgery are fundamental to appropriate care within the Institute. The Cardiology Division has been active since 1984 as an outpatient clinic. In the first years, only basic clinical cardiology was performed.

Since 1991 trans-thoracic echocardiography has been available. In November 1999 functional cardiology (treadmill stress test, Holter monitoring, myocardial nuclear scanning) was also initiated. Presently the Cardiology Division is composed of three main sections: basic clinical cardiology (L. Tartuferi) functional cardiology : stress test, Holter monitoring

(E. Viel) echocardiography (C. Lestuzzi)

Annually the Cardiology Division performs about: 9,000 electrocardiograms; 3,800 clinical cardiologic examinations; 2,700 M-mode, 2D and Doppler echocardiograms; 1000 Holter ecg monitoring exams; 600 Treadmill stress tests; 150 Holter pressure monitoring exams


The research activity of the Division has been focused mainly on the following programs.Prospective evaluation of neoplastic pericarditis treatment involving comparison of local (intrapericardial) chemotherapy versus systemic chemotherapy alone. Clinical and echocardiography follow-up, genomic studies and clinical management of patients with anthracycline induced-cardiomyopathy. Cardiology evaluation of breast cancer patients receiving adjuvant trastuzumanb. Surveillance of cardiac toxicity of bevacizumab and tyrosine kinase inhibitors. Screening and follow-up of elderly patients undergoing antineoplastic therapies. Clinical and non-invasive evaluation of patients before (clinical evaluation and echocardiography) and during (clinical evaluation, treadmill, Holter) treatment with the 5- FU regimen (high dosage and prolonged infusion): research on the incidence of symptomatic and asymptomatic cardiotoxicity. Long term cardiologic follow-up of radiation cardiopathy in patients treated with mediastinal radiation therapy.

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Department of Clinical-Specialty Services & SupportDivision of Anaesthesiology and Intensive Care

Marcello DE CICCO, MDDirector, Division of Anesthesiology & Intensive Care [email protected]

StaffDario FANTIN, MD [email protected] DirectorCarlos Alejandro BERTUZZI, MD [email protected] BORTOLUSSI, MD [email protected] CASERTA, MD [email protected] FABIANI, MD [email protected] FRACASSO, MD [email protected] Luisa MALAFRONTE, [email protected] MATOVIC, MD [email protected] PEGOLO, MD [email protected] SANTANTONIO, MD [email protected]


The mission of the Division is to offer patients the most appropriate and effective treatment in the setting of Anesthesia, Intensive Care and Emergency Resuscitation, Parenteral and Enteral Nutrition, Pain Therapy Procedures, and Insertion of Medically Supportive Devices. The Division accomplishes this mission together with participation in interdisciplinary activities for transplants or other innovative methods of treatment, as well as activities linked to clinical and translational research projects. Since its establishment in 1984, the Anaesthesiology and Intensive Care Division’s duties include clinical and research activities focused on both surgical and medical oncology patients.Annually, the surgical activity at CRO includes more than 2000 operations with either general, loco-regional

or blended anaesthesia. A computerised monitoring system is used in order to collect data from all devices connected to patients and record the anaesthetic procedures. Post-operative pain treatment is provided to all patients following appropriate clinical protocols. The anaesthesiology staff is trained to perform transesophageal echocardiography both in operating theater and Intensive Care Units (ICU), as well as supporting invasive endoscopic, radiological and urological procedures.The Intensive Care Unit (350 patients/year) is equipped with 4 beds having sophisticated ventilators and complete invasive and non-invasive monitoring. Special beds are also available to avoid decubitus problems. In addition to the usual invasive and non-invasive hemodynamic systems, new devices are available for monitoring hemodynamic functions like PiCCO and Hemosonic systems.

The Intensive Care Unit activity is mainly devoted to patients subjected to major radical surgery with extensive fluid changes and/or risk factors for cardiopulmonary and metabolic events. Patients with severe sepsis and septic shock or mono/multiorgan failure secondary to heavy oncological treatments (CT and/or RT or IORT). Patients needing monitoring and maintenance of vital organ function during highly cardiotoxic oncological therapies are cared for in this specialized area.Central venous catheterization for chemotherapy, autologous BMT, plasmapheresis and parenteral nutrition, permanent pleural drainage and artificial nutrition are other fundamental concerns of the anaesthesiology staff.


Metabolic response, insulin resistance and glutathione synthesis after major cancer surgery are some of the major concerns of our research projects. These are carried out in close collaboration with other Divisions

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and Units, both at the clinical and laboratory level. The main objectives of the studies are to evaluate “the role of tight glycemic control (versus a moderate hyperglycemia) to improve muscle amino acids metabolism and liver glutathione synthesis ”, “the response of muscle protein and glutamine kinetics to branched chain-enriched amino acids”, and “the role of leucine supplementation in glycemic control and muscle insulin sensitivity ”in surgical intensive care patients with cancer. Muscle protein and amino acids kinetics are determined using an infusion of a stable isotope of amino acids, the leg arteriovenous balance technique, and mass spectrometric analyses. In this setting, another study is aimed at evaluating the role of a specialized oral diet (diet enriched with arginine, Ω-3 fatty acids and RNA) administered in the pre-operative period in modulating the post-operative immunocompetence and reducing septic morbidity in patients subjected to major oncological surgery and intraoperative radiotherapy (IORT). Other fields of interest are closely linked to patient care, and support specific areas of clinical research such as: the correlation between the patient’s psycological profile and the degree of post-operative pain after elective oncological surgery (in tight collaboration with the Psycho-Oncology Unit), and the prophylaxis of thromboembolic complications associated with central venous catheters.



The Pharmacy Division’s mission is to provide, in accordance with Good Clinical Practices and Good Manufacturing Practices, personalized treatments for cancer patients. It is organized with a central laboratory for handling of antiblastic drugs and it is provided with a centralized storage for drugs, medical supplies, and diagnostics to keep the store volume at the lowest levels in the wards and department laboratories.The Pharmacists manage the orders for supplies keeping accurate records, planning, and rationalizing the activity. The database of materials is continuously kept up to date.The Division’s personnel is involved in intramural Committees (infections, blood and blood derivatives usage, decubitus ulcers, ethical, education and training) as well as extramural ones, as it is part of the territorial planning and managing system for a correct and rationalized drug acquisition and distribution. Furthermore, the Pharmacy Division is involved in developing prototype machines for semi-automatic drug handling.

Since December 2006, the Division has adhered to a regional law and provides direct distribution of prescribed medicines to patients dismissed from the hospital in order to more efficiently allow patients to manage their conditions and maintain the management costs of the Region’s expenditure on pharmaceuticals low.All patients dismissed from the Institute (including day hospital and visiting patients receiving examinations only) residing in Friuli Venezia Giulia with prescriptions for A or H level medicines lasting a maximum of 30 days are eligible for the new service. Concerning education and training, the Pharmacists collaborate with the Pharmacy Specialization School of the University of Trieste in order to initiate the educational network of the future Clinical Pharmacy Specialization School.

Department of Clinical-Specialty Services & SupportDivision of Pharmacy

Renzo LAZZARINI, PharmacistDirector Division of [email protected]

StaffPaolo BALDO, Pharmacist [email protected]

FellowsSara CECCOElisa GIACOMIN

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Department of Clinical-Specialty Services & SupportUnit of Pain Therapy and Palliative Care

Roberto BORTOLUSSI, MDDirector Unit of Pain Therapy & Palliative [email protected]

MISSION AND CLINICAL ACTIVITIES

The mission of the Unit is the control of physically and psychologically distressing symptoms of both medical and surgical cancer inpatients and outpatients.The activities of the Unit are performed in collaboration with the Anaesthesiology and Intensive Care Division, whose medical and nursing staff is involved in clinical practice and research programs.Pain medication treatments with opioids and other analgesic drugs in the post-operative phase are steadily reviewed by the Unit, responsible for the “pain-free hospital”project. Analgesic pharmacotherapy, invasive analgesic procedures, neurostimolatory and psychological techniques are used to control cancer or oncological treatment-related pain.

RESEARCH ACTIVITY

Within the Institute’s spirit of fostering optimal patient care and supporting experimental research to advance in the battle against cancer the Pain Therapy Unit’s fields of major interest for ongoing research are as follows: the effectiveness of opioid rotation in advanced cancer patients with pain unresponsive to morphine; side effects and tolerability of different opioid regimens; side effects and efficacy of gabapentin and pregabalin in the treatment of neuropathic pain; including efficacy and tolerability of opioid therapy in ageing patients.


Department of Clinical-Specialty Services & SupportUnit of Psychological Oncology

Staff

Maria Antonietta ANNUNZIATA,[email protected] ZOTTI, [email protected]

MISSION

Its mission is to provide psychosocial support in order to improve the quality of life for both inpatients and outpatients as well as their relatives. Clinical activities include supplementing medical care and psychological support at the request of MDs, nurses, palliative care personnel, patients, and relatives.


Within psycho-oncological research, studies to investigate the psychological impact of genetic testing of hereditary tumors are ongoing, with the aim to evaluate, by means of MMPI, POMS and COPE questionnaires and of the Paykel scale, the adaptation to risk factors. Moreover, a study on the psychological impact of autologous bone marrow transplantation by means of FACT–BMT, STAI 1-2 and POMS questionnaires is

ongoing. A study aimed to validate in Italian a self-report questionnaire on cancer related fatigue (I.E. the Revised Piper Fatigue Scale) was undertaken. Another study aimed to validate in Italian a questionnaire on psychological stress, burnout and “compassion fatigue” of health personnel (i.e. ProQOL- R IV by B. H. Stamm) is ongoing. A prospective, multicentric trial to validate the quality of life in patients affected by locally advanced rectal cancer, treated with neoadjuvant radio-chemotherapy and surgery, is represented by the Psychologists for the Italian assessment portion of the MSKCC Bowel Function Instrument by L K Temple et al. Trial on the quality of life and psychological status of patients with laryngeal tumors.Lastly, a new multi-center project on cancer survivors, financed by the Ministry of Health, is in its starting phase.

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• De Cicco M., Matovic M., Pacenzia R., FantinD., Caserta M., Bortolussi R., Fabiani F., Fracasso A., Santantonio C., Nigri P., Veronesi A. Short-Term Acenocumarine (A) or Dalteparine (D) for the prevention of Central Venous Catheter-Related Thrombosis (CVCRT) in cancer patients. A randomized controlled study based on serial venographies. 42nd Annual Meeting ASCO, Atlanta, June 2-6, 2006. J Clin Oncol 2006, 24(18S): 180S

• Biolo G, De Cicco M, Dal Mas V, Lorenzon S,Antonione R., Ciocchi B, Barazzoni R, Zanetti M, Dore F, Guarnieri G. Response of muscle protein and glutamine kinetics to branched-chain-enriched amino acids in intensive care patients after radical cancer surgery. Nutrition 2006, 22 (5): 475-482.

• Hrovatin E, Viel E, Lestuzzi C, Tartuferi L, ZardoF, Brieda M, Dametto E, Piazza R, Antonini-Canterin F, Vaccher E, Meneguzzo N, Nicolosi G L. Severe ventricular dysrhythmias and silent ischemia during infusion of the antimetabolite 5-fluorouracil and cis-platin. J Cardiovasc Med 2006, 7 (8): 637-640.

• Biolo G, Antonione R, De Cicco M. Glutathionemetabolism in sepsis. Crit Care Med 2007, Vol 35 n. 9: 591-595.

• DeCiccoM,MatovicM,SantantonioC,BortolussiR, Pacenzia R. Epidemiology, risk factors and preventive strategies of catheter-related bloodstream infection. Minerva Anestesiologica 2007, 73 (10): 237-239.

• BaldoP,BertolaA,BasagliaG,MoneghiniM,SorioR, Zibardi E, Lazzarini R and De Paoli P. A centralized Pharmacy Unit for cytotoxic drugs in accordance with Italian legislation Journal of Evaluation in Clinical Practice, 13 (2007) 265–271

• Baldo P, Lazzarini R. Safe Handling of CytotoxicDrugs. Hospital Pharmacy Europe, Issue 34, September/October 2007:33-35.


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Department of Molecular Oncology and Translational Medicine (DOMERT)

Faculty & Staff

Alfonso COLOMBATTI, MDCore Lab & Division Director, Experimental Oncology 2

Roberta MAESTRO, PhDDivision DirectorExperimental Oncology I

Giuseppe TOFFOLI, MDDivision DirectorExperimental and Clinical Pharmacology

The Department of Molecular Oncology and Translational Research, composed of two Divisions of Experimental Oncology and a Clinical and Experimental Pharmacology Division, focuses on advancing knowledge of the molecular mechanisms that regulate normal and abnormal cellular processes, notably cancer. We are strong advocates for basic research at the CRO-National Cancer Institute but also encourage and facilitate strong interactions with laboratories in the clinical departments in order to readily translate our findings into useful tools for a better management of cancer patients. The Department (over 1,200 square meters) has extensive resources to pursue biochemical,

molecular, cellular and developmental biological experiments. Investigators have access to an animal facility and the Department is equipped with a DNA sequencer, confocal microscopy, HPLCs and mass spectrometers, FACS cell sorter, fluorescent two-D gel analyzer, pulse field electrophoresis, ultracentrifuges, beta-counter, and microarray analyzer.The Department faculty members are well funded for their research through both extramural and intramural grants. Our Department has a strong commitment to training high school as well as graduate students and postdoctoral fellows.


MISSION

The Division of Experimental Oncology 1 is dedicated to improving our understanding of the mechanisms through which a normal cell overcomes its physiological constraints on proliferation and differentiation and transforms into a tumor cell.By identifying genes and pathways which contribute to tumorigenesis, it is anticipated that this information will not only improve our comprehension of the fundamental events that give rise to cancer, but will also lead to

the identification of new diagnostic and prognostic biomarkers as well as novel strategies for more effective therapeutic interventions.We are particularly interested in identifying the mechanisms that convert oncogene-induced pro-apoptotic or pro-senescence signals into pro-tumorigenic signals. The molecular gear that controls this signalling shift represents a major target for molecularly targeted therapies.Through the implementation of genetic screens in mammalian cells we have already isolated a number


Division of Experimental Oncology 1

Roberta MAESTRO, PhDDirector Division of Experimental Oncology [email protected]

Associate Director Alessandra VIEL, PhD [email protected]

StaffDaniela GASPAROTTO, PhD [email protected] MODENA, PhD [email protected] PICCININ, PhD [email protected] QUAIA, PhD [email protected] SANTAROSA, PhD [email protected]

FellowsAngela CARAGNANOLaura DEL COLAlessandra GRIZZOChiara PASTRELLOElisa PIN

of new genes that are capable of antagonizing either oncogene-induced apoptosis or senescence and affect tumor prognosis (Twist, Dermo, Seladin). These investigations are conducted along with the generation of in vitro models of transformation of primary cells and the isolation of cancer stem cells to pinpoint the minimal genetic requirements for the transformation of a human cell.Finally, studies on hereditary forms of cancer are carried out to better decipher the process of neoplastic transformation from cancer “committed” cells and develop new diagnostic procedures and genetically tailored therapeutic approaches. C

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Division of Experimental Oncology 2

Alfonso COLOMBATTI, MDDirector Division of Experimental Oncology 2 [email protected]

StaffDonatella ALDINUCCI, [email protected] BALDASSARRE, MD [email protected] BELLETTI, PhD [email protected] DOLIANA, PhD [email protected] SPESSOTTO, PhD [email protected] MONGIAT PhD [email protected] PERRIS PhD [email protected] SCHIAPPACASSI, [email protected]

Fellows Martina SCAPOLAN PhD student, Univ. UdineEva ANDREUZZI,fellow Alessandra CAPUANO fellowAlessandra SILVESTRI PhD student, Univ. Udine Stefania BERTON PhD student, Univ. TriesteAndrea NICOLOSI, PhD student, Univ. Udine Carla DANUSSI PhDAlessandra PETRUCCO PhD student, Univ. Udine Giovanni LIGRESTI PhD student, Univ. UdineIlenya PELLIZZARI PhD student, Univ. Udine Francesca LOVAT PhD student, Univ. PadovaEmanuela SCIRO Specialist student, Univ. Padova Stefano MARASTONI PhD student, Univ. UdineEliana PIVETTA Specialist student, Univ. Udine

MISSION

The mission of the Division is to clarify the invasive phenomena of tumor cells using different cellular and molecular systems by applying innovative technological approaches in relation to the multiple interactions with the extracellular matrix (ECM).The ECM represents a very complex structured mixture of constituents that are fundamental for tissueorganization and cell survival. More specifically, one of

our goals is to find new molecular targets that could be used as innovative anti-cancer therapies by investigating which intracellular pathways or molecular targets are able to coordinately govern the proper alternation of cell divisions and cell movements. Cell motility in vitro and in vivo is mainly due to the reorganization of actin and tubulin cytoskeletons that ensure a proper dynamics to this process. We are focussed on the role of a family of small cell cycle inhibitory proteins, named CKI (p21waf1, p27kip1

and p57kip2) that are able to bind and inactivate several Cyclin/CDK complexes. The goal is to highlight new molecular connections between cell cycle control and regulation of cell adhesion, motility, or even differentiation.Bone metastasis represents one of the major problems in tumor biology in a number of tumors such as breast cancer. Thus, a further area of our research includes the mechanisms of metastasis in the bone, the biology of osteoclasts and the regulation of their mutual interactions (tumor cells and bone cells), and bone remodelling with an approach combining molecular biology with functional morphology and behaviour of tumor cells in vitro. Molecular biology of the extracellular matrix and transgenesis includes programs dealing with the role played by cell surface proteoglycans and drug resistance in hematological and solid neoplasias, the pro-apoptotic function of members of the EMILIN family, the analysis of tumor development in KO mice for EMILIN family members (EMILIN1 and EMILIN2), and the alteration of lymphoid system development. Ongoing studies involve the potential use of bone marrow mesenchymal precursors as vehicles for phage display libraries peptides for in vivo cell tracking.

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Division of Experimental and Clinical Pharmacology

Giuseppe TOFFOLI, MDDirector Division of Experimental & Clinical Pharmacology [email protected]

StaffGiuseppe CORONA, PhD (chemist)Erica CECCHIN, PhD (molecular biologist) Vallì DE RE, PhD (molecular biologist)

FellowsPaola BIASON, PhD student, Univ. PadovaLaura GAVAGNIN, statistician fellowElena DE MATTIA, fellowGiulietta SINIGAGLIA, biologist fellowLaura CAGGIARI, biologist fellowMaria Paola SIMULA, biologist fellowMariangela DE ZORZI, biologist fellowDelores MARIN, fellowAlessandro PAVAN, fellow

MISSION

The Experimental and Clinical Pharmacology Division is a multidisciplinary translational research group that seeks to:

Identify and validate pharmacogenetic/genomics markers useful to optimize and personalize anticancer treatments. Perform phase I-II clinical trials to investigate new strategies or to optimize existing therapies. Undertake drug discovery and development of new anticancer drug formulations based on new innovative delivery vectors as nanomaterial and biomaterial. Research and develop immunotherapy strategies against HCV- associated cancer.The principal aim of the Division is to gain knowledge

on the mechanisms that are at the basis of a large difference among individuals in the way they respond to anticancer treatment.Research mainly focuses on discovering the role of specific genetic determinants that influence the expression levels and activity of drug metabolizing enzymes, transporters and receptors directly involved in the efficacy and toxicity of anticancer agents (pharmacogenetics/genomics).The results of such research activity will be helpful to optimize drug therapy by increasing the efficiency and reducing the risks of unwanted side-effects. The Division collaborates with Regional, National and International Clinical Centers in the development and performance of clinical phase I and II trials to evaluate new chemotherapy strategies and identify new predictive molecular markers on pharmacological effect.

This research is supported by innovative genomic, proteomic, and metabolomic approaches; necessary resources for supporting clinical trials.The Division is traditionally involved in the pharmacokinetic investigations that are applied to support pharmacogenetics/genomics studies and in the understanding of the clinical relevance of metabolic interaction occurring during the co- administration of different drugs. The overall aim of the research is to optimize and personalize treatments in each individual patient.Recently, in an attempt to improve anticancer treatment, the Division in collaboration with drug Companies and University centers has embraced a research program addressed to develop new anticancer delivery vectors based on targeted biomaterial and nano particles in order to guarantee selectivity of treatment.


Immuno-pharmacology represents a relatively new research activity of the Division; mainly addressed to the identification of novel immunological targets useful to develop antibody, recombinant proteins, and vaccine-based therapy to manage HCV associated disease. In order to perform these studies, the Division has been continually exploring novel technologies for genetic and drug analysis as well biomarker identification.These are principally based on mass spectroscopy, 2D-PAGE analysis, Pyrosequencing, Real time PCR, the use of automatic sequencers and molecular approaches which guarantee high sensitivity and selectivity with a high throughput to perform large screening studies. Technological resources and expertise for in vitro studies are available including a wide array of cell models for drug resistance and drug targeting, a panel of hybridomas, and recombinant proteins. Virtual molecular, biological, and clinical databases of patients are the object of the Division’s studies.

PROJECTS LIST AND RESEARCH ACTIVITY

Pharmacogenetics/genomics represents one of the main research topics of the Division. Investigations have been made in different tumor models including: metastatic breast carcinoma patients treated with exemestane as first line therapy, to define predictive markers of response colon cancer treated with an oxaliplatin-based adjuvant therapy, to highlight genetic determinants of neurotoxicity prostate cancer with a taxotere-based treatment to discover polymorphisms related to toxicity and response to treatment

Phase I-II clinical studies based on a pharmacogenetics/genomics approach have been designed to prospectively evaluate the possibility of a genetic profile-tailored chemotherapy; including an irinotecan dose-finding study based on the UGT1A1*28 polymorphism in metastatic, colorectal cancer patients treated with the FOLFIRI regimen, now active at the Experimental and Clinical Pharmacology Division. A wider approach pursued by our group is the research

of bio-markers to better define diagnostic/prognostic evaluations of the patients. In particular, new approaches will be considered for studying genetics, early molecular diagnosis and prognostic factors relevant for HCC and the analysis of glutathione S-transferase system expression profiles will be evaluated as markers of therapy outcome in advanced lung cancer patients. In our research activity, proteomic investigations are mainly addressed to identification of peptide and protein markers associated with the pharmacological response to carboplatin and paclitaxel treatments.New strategies for drug delivery based on nanotechnology to overcome pharmacoresistance are now in a pre-clinical stage of development at the Experimental and Clinical Pharmacology Division.Pharmacokinetic research activity is focused on the evaluation of the effect of co-administered HIV protease inhibitors on pharmacokinetics and pharmacodynamics of anticancer agents used in therapy of patients with HIV-related malignancies. Pharmacokinetics analysis also supports pharmacogenetic studies with irinotecan, exemestane and docetaxel. Molecular immunogenetic, proteomics, or immunoproteomics approaches designate the research basis for the study of HCV and other autoimmune-related diseases. These basic studies are strictly associated with translational studies aimed at implementing new targeted approaches as well as defining the molecular determinants that underlie cancer development and sensitivity to new target therapies introduced in clinical practice, i.e. anti-HCV and/or rituximab treatment for HCV-lymphoproliferation. Ongoing studies carried out last year, mainly identification and characterization of immunocomplexes produced by hosts with associated HCV-cryoglobulinemia, have formed the model for the development and production of recombinant proteins potentially reactive against the HCV-NS3 enzyme and autoimmune antigens for a vaccine strategy in HCV–related diseases.

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of CBM (Molecular Biomedicine Center)

Staff (part-time)Alfonso COLOMBATTI, MD [email protected] TOFFOLI, MD [email protected] CORONA, PhD [email protected] CECCHIN , PhD [email protected] DOLIANA, PhD [email protected] MONGIAT, PhD [email protected]

Fellows (part-time)Maria Pia SIMULA, specialistGiovanni LIGRESTI, PhD student Univ. UdineStefano MARASTONI, PhD student Univ. UdinePaola BIASON, PhD student, Univ. Padova

MISSION

The CBM Core Facility in Pharmaco-genomics/proteomics (here and on PHAGE-TUPRO) comprises an advanced Facility focusing on basic and applied research and services. It is conceived as an integrated Laboratory with the following mission:1. To create a multidisciplinary, collaborative, and

comprehensive Anticancer Agents Research Group with the capabilities to identify and evaluate polymorphisms in drug metabolizing enzymes, transporters, or targets relevant to anticancer agents.

2. To determine the association between new and previously identified polymorphisms (genotype) and

variability in toxicity and/or response to anticancer agents (phenotype).

3. To search for markers and targets for therapeutics intervention in cancer and other major diseases.

4. To set up technology platforms useful in application on proteomics from research to diagnostics.

EQUIPMENT

MALDI-TOF Voyager DE-PRO Applera mass-spectrometer; 2D gel workstation and PDQuest software; Typhoon fluorescent image analysis system of high sensitivity for 2D gel; automatic spot picking and processing; Q-Trap Applera; three micro HPLC; one nano HPLC; sequencer (pyrosequencing).

Pharmaco-genomics/proteomicsBiomedical research is defining the molecular mechanisms of pharmacological effects, genetic determinants of disease pathogenesis, and functionally important polymorphisms in genes that govern drug metabolism and disposition. Variation in genotype is independent of individual drugs, but forms the basis for variation in response to drugs. The effects can be profound toxicity in treatments that have a narrow therapeutic index and are differentially affected by polymorphic enzymes. Genetic variations in response to drugs can cause measurable differences in clinical outcomes such as rates of cure, morbidity, side effects, and death. Since nearly all drug targets are proteins, there is a clear incentive to apply proteomics as a


complementary approach to pharmaco-genomics research. The scope is also to search for markers and targets for therapeutic intervention and to identify affected signalling pathways in tumors.

Serum proteomicsChanges in serum proteins that signal histopathological states, such as cancer, are useful diagnostic and prognostic biomarkers. Unfortunately, the large dynamic concentration range of proteins in serum makes it a challenging proteome to effectively characterize. This approach is included within the framework of the Italy-USA Program on Cancer Pharmacogenomics (Oncoproteomics for early diagnosis and targeted therapy of cancer) of which CRO-IRCCS is a partner aiming at validating of proteomic techniques and personnel exchanges and in the simultaneous analysis of selected samples.

Topics of interest include but are not limited to:genotypic variations in enzymes affecting drug

activitypharmaco-kinetics and pharmaco-dinamics

parameters in standard and innovative therapiesidentify in vitro proteome signatures of human/

murine cellular models and tumors identify functional protein-protein associationsidentify signatures of infectious agents related to

cancer.

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• GasparottoD,MaestroR.Molecularapproachestothe staging of head and neck carcinomas. Int J Oncol. 2007 Jul;31(1):175-80.

• SpessottoP,ZucchettoA,DeganM,WassermanB,Danussi C, Bomben R, Perris R, Canzonieri V, Radillo O, Colombatti A, Gattei V. Laminin-332 (Laminin-5) is the major motility ligand for B cell chronic lymphocytic leukemia. Matrix Biol. 2007 Apr 11;

• Vecchione A, Baldassarre G, Ishii H, NicolosoMS,Belletti B, Petrocca F, Zanesi N, Fong LY, Battista S, Guarnieri D, Baffa R, Alder H, Farber JL, Donovan PJ, Croce CM. Fez1/Lzts1 absence impairs Cdk1/Cdc25C interaction during mitosis and predisposes mice to cancer development. Cancer Cell. 2007 Mar;11(3):275-89.• Aldinucci D, Lorenzon D, Stefani L, GiovagniniL, Colombatti A, Fregona D. Antiproliferative and apoptotic effects of two new gold(III) methylsarcosinedithiocarbamate derivatives on human acute myeloid leukemia cells in vitro. Anticancer Drugs. 2007 Mar;18(3):323-32.

• Caggiari L, Folgori A, Rehermann B, De Re V.Identification of four novel MHC-C alleles in chimpanzees. Tissue Antigens. 70, 69-79, 2007.

• DeReV,CaggiariL,SimulaM,DeVitaS,SansonnoD, Dolcetti R. B-Cell Lymphomas Associated With HCV Infection. Gastroenterology, 132,1205-1207, 2007.

• ToffoliG,CecchinE.Clinicalimplicationsofgeneticpolymorphisms on stomach cancer drug therapy. Pharmacogenomics J 7 (2): 76-80, 2007.

• MongiatM., LigrestiG.,Marastoni S., LorenzonE.,Doliana R., Colombatti A. Regulation of the Extrinsic Apoptotic Pathway by the Extracellular Matrix Glycoprotein EMILIN 2. Mol Cell Biol 27 (20):7176-7187, 2007. • ToffoliG.,DeMattiaE.,CecchinE.,BiasonP.,MasierS., Corona G. Pharmacology of epidermal growth factor inhibitors. Int J Biol Markers Suppl. 4: S24-239, 2007.

• SeragliaR.,Molin L., Tonidandel L.,Pucciarelli S.,Agostini M., Urso E.D., Bedin C., Quaia M., Nitti D., Traldi P. An investigation on the nature of the peptide at m/z 904, overexpressed in plasma of patients with colorectal cancer and familial adenomatous polyposis. J Mass Spectrometry 42 (12):1606-1612, 2007.

• PonzdeLeonM.,BertarioL.,GenuardiM.,LanzaG., Oliani C., Ranzani G. N., Rossi G.B., Varesco L., Venesio T., Viel A. Identification and Classification of Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome): Adapting Old Concepts to Recent Advancements. Report from the Italian Association for the Study of Hereditary Colorectal Tumors Consensus Group. Dis Colon Rectum 50(12):2126-2134,2007.

• Virgintino D., Girolamo F., ErredeM., CapobiancoC., Robertson D., Stallcup W.B., Perris R., Roncali L. An intimate interplay between precocious, migrating pericytes and endothelial cells governs human fetal brain angiogenesis. Angiogenesis 10 (1):35-45, 2007

• AnsieauS.,BastidJ.,DoreauA.,MorelA.P.,BouchetB. P., Thomas C., Fauvet F., Puisieux I., Doglioni C., Piccinin S., Maestro R., Voeltzel T., Selmi A., Valsesia-Wittmann S., Caron de Fromentel C., Puisieux A. Induction of EMT by Twist Proteins as a Collateral Effect of Tumor-Promoting Inactivation of Premature Senescence. Cancer Cell 2008, 14 (1): 79-89

• Gasparotto D., Rossi S., Bearzi I., Doglioni C.,Marzotto A., Hornick J. L., Grizzo A., Sartor C., Mandolesi A., Sciot R., Debiec-Rychter M., Dei Tos A. P., Maestro R. Multiple Primary Sporadic Gastrointestinal Stromal Tumors in the Adult: An Underestimated Entity. Clin Cancer Res 2008, 14 (18): 5715-5721

• DanussiC.,SpessottoP.,PetruccoA.,WassermannB., Sabatelli P., Montesi M., Doliana R., Bressan G. M., Colombatti A. Emilin1 Deficiency Causes Structural and Functional Defects of Lymphatic Vasculature. Mol Cell Biol 2008, 28 (12): 4026-4039

• AldinucciD.,LorenzonD.,CattaruzzaL.,PintoA.,Gloghini A., Carbone A., Colombatti A. Expression of CCR5 receptors on Reed-Sternberg cells and Hodgkin

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• SchiappacassiM.,LovatF.,CanzonieriV.,BellettiB.,Berton S., Di Stefano D., Vecchione A., Colombatti A., Baldassarre G. p27Kip1 expression inhibits glioblastoma growth, invasion, and tumor-induced neoangiogenesis. Mol Cancer Ther 2008, 7 (5): 1164-1175

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