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Departments, Divisions and Units

Further details of the programmes of Divisions and Units are available upon request together with copies of published articles. We invite also to visit our website:

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45 IEO — Scientific Report 2009 — Ongoing research 2010

Division of Epidemiology and Biostatistics Patrick MAISONNEUVE, Eng Director, Epidemiology Unit

STAFF Epidemiologist Biostatistician: Sara Gandini, PhD Biostatisticians: Davide Radice, MSc, Luigi Santoro, MSc, Edoardo Botteri, MSc, Sara Raimondi, MSc, Simona Iodice, MSc Nutritionist: Patrizia Gnagnarella, MSc Data Managers: Barbara Santillo, Elena Albertazzi, PhD, Barbara Bazolli, MSc Clercks Tumour Registry: Laura Manghi, Bruno Montanari Fellows Tumour Registry: Nadia Burzoni, Marina Alfieri, Marco Martinetti Scientific Secretariat: Nadia Bellani Biostatistical consultant: Vincenzo Bagnardi, PhD Visiting Professors: Albert Lowenfels, MD (New York Medical College), Matthias Löhr, MD (Karolinska Institute) Editor, FIGO Annual Report: Sergio Pecorelli, MD, PhD Administrative assistant, FIGO Editorial Office: Lucia Zigliani, BA

Nicole Rotmensz, MSc Director, Data Quality Control Unit

Activities 2009.

The division of epidemiology and biostatistics is conducting epidemiological research activity on a wide range of topics, focusing on patients with cancer or on patients at increased risk of developing the disease. It has throughout its existence, developped international collaborative research programmes and as a result, the majority of the research activities involve co-operation with scientists from a range of disciplines, both intra-mural and extra-mural. The division is involved in the development and management of the clinical research databases of the hospital and has responsibility upon data quality control. It is also running the IEO hospital-based tumour registry. The division also provides consultation in a wide range of areas including the statistical design of experiments and clinical trials, including sample size calculations and randomization schemes, protocol development, database management, analysis of data and interpretation of results, preparation of interim reports and manuscripts. In addition, the division has developed a strong expertise in the field of statistical modelling and in the conduct of meta-analyses, providing important information to public-health policy makers and clinicians. In particular, assembling data from 67 independent studies, we showed that the two most studied Vitamin D Receptors (VDR) polymorphisms (FokI and BsmI) are associated with the risk of cancer of breast, skin and prostate and possibly affect cancer risk at any site in Caucasians. We also suggested a possible role of these VDR polymorphisms in cutaneous malignant melanoma (CMM) risk and prognosis. We previously showed, summarizing data from randomized trials, that vitamin D supplementation was associated with a significant reduction (7%) in total mortality in healthy subjects. Thus, in order to assess whether vitamin D supplementation could improve prognosis of CMM, we designed an Italian

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multicentre trial in stage II resected melanoma patients aiming to evaluate the effect of Vitamin D supplementation (2000 IU/day) on disease free survival and to study the relationship between the biology of VDR and (i) vitamin D metabolism (ii) CMM prognosis. The findings from this study will be of large interest because Vitamin D could have anticancer benefits for a wide spectrum of cancers.

stromal sarcomas, adenosarcomas, and carcinosarcomas) and for the updating of the section on gynaecological tumours of the 7th Edition of the UICC TNM Classification of Malignant Tumours. During 2009, the division participated in 70 articles published on peer-reviewed journals, with an overall impact factor of 308.

Since 1994, the division acts as the data centre for the International Federation of Gynecology and Obstetrics (FIGO). In 2008, a web-based interface was developed for the data collection for the future volumes of the Annual Report on the Results of Treatment in Gynecological Cancers. The Editorial Office has also been responsible for the revision of the staging for the carcinoma of the vulva, cervix uteri and corpus uteri, for the new classification and staging for uterine sarcomas (i.e. leiomyosarcomas, endometrial

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The Division of Cancer Prevention and Genetics Bernardo BONANNI, MD Director

STAFF Deputy Director: Aliana Guerrieri-Gonzaga, MSc Senior Assistant: Davide Serrano, MD Senior Lab Assistant: Harriet Johansson, MSc Assistant: Massimiliano Cazzaniga, MD, Monica Barile, MD Clinical Monitor: Clara Varricchio, MD Resident: Matteo Lazzeroni, MD Lab Assistant: Debora Macis, MSc Research Nurse : Irene Feroce Nurse: Alessandra Panichi Technician: Mara Jo Miller Data Manager: Serena Mora, Giorgia Bollani, Chiara Bresciani Secretary: Alessandra Rossi, Raffaella Falcone Patient Manager: Angela Maniscalco Scientific Consultant: Andrea Decensi, MD

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Activities 2009. The Division of Cancer Prevention and Genetics is essentially dedicated to clinical research on the prevention of solid tumors and clinical management (risk assessment, surveillance and preventative treatment) of subjects at higher-than-average risk for various types of cancer. In order to develop new strategies of cancer prevention the Division’s multidisciplinary staff (including oncologists, geneticist, biologists, research nurses, data managers) is committed to conduct clinical trials with the main aim to validate various drugs, micronutrients, natural compounds as preventive agents. Most of the research efforts are currently focused on chemoprevention trials on breast, ovarian, colorectal and lung cancer. The target population is heterogeneous but includes mainly two groups of at-risk subjects; 1) patients with (previously resected) precancerous conditions (such as breast ductal intraepithelial neoplasias, colon adenomas); 2) healthy individuals who carry one or more risk factors (such as family history, germinal mutations, high levels of androgens or estradiol or IGF-1, use of HRT, metabolic syndrome/insulin resistance, breast lobular intraepithelial neoplasia or athypical hiperplasia, high mammography density, peripheral lung “ ground glass opacities” etc). These at-risk subjects are initially selected, followed and preferably enrolled in chemoprevention trials. We have an established experience on various types of trials, including: a) phase II studies on surrogate endpoint biomarkers; b) larger phase III, multiinstitutional trials on clinical endpoints (cancer incidence); c) pre-surgery, “window-of-opportunity” studies in patients candidate to surgical treatment for primary breast cancer in order to test the efficacy of new and “old” drugs on breast cancer cell proliferation (measured by Ki-67 on baseline biopsy and then on the specimen after 3-4 weeks of drug treatment), and other tissue and circulating biomarkers. Since phase III trials typically last several years before providing results, we put much effort in the creation and

with the ultimate goal of a more effective, less toxic, tailored prevention treatment. Increasing research and clinical assistance have been recently dedicated in our Division to the selection, surveillance, risk-reduction strategies in subjects at very high risk, being carriers of constitutional genetics mutations (BRCA1 and 2, MLH1, MLH2, MSH6, APC, MYH, TP53, CDKN2A) in strict collaboration with the genetic lab at the IEO-IFOM campus. We have in fact an established high risk clinic (HRC) run by our staff and involving a multidisciplinary group of specialists (radiologists, pathologists, surgeons, gynecologists, endoscopists, psycologists). Our HRC provides to the public the possibility of cancer risk assessment, genetic counselling and testing, tailored surveillance and prevention programs, psychological support, nutritional and physical activity guidelines, access to chemoprevention trials or off-trial personalised treatment, up to prophylactic surgery in highly selected subjects.

conduction on phase II trials, studying how candidates biomarkers of risk (in different organs and in the blood) are modulated by preventive compounds. We utilize a large spectrum of potentially useful preventive agents, including SERM’s (Selective Estrogen Receptor Modulators), AI's (Aromatase Inhibitors), retinoids, NSAID’s (Non-Steroidal Anti-Inflammatory Drugs), corticosteroids, statins, metformin, TK-inhibitors, preferably using the minimal active doses. Considerable effort is also being put in pharmacogenomic studies, such as those on CYP2-D6, in order to stratify patients in different classes of tamoxifen metabolizers,

During 2009 we performed more than 2,600 visits in our prevention outpatients’ clinic. Whereas in our HRC service we offered 200 counselling sessions, 184 subjects underwent genetic test, we found 33 BRCA1 mutations, 29 BRCA2, 98 wild type and 16 true negative subjects. Eight subjects, were found carriers of other gene alternations (including 1 familial adenomatous polyposis and 5 Lynch syndromes). We coordinate various national research networks collaborating in multicentre phase III studies. We have also a long established research collaboration with international institutions, including the US National Cancer Institute, the M.D. Anderson’s Consortium for Chemoprevention Trials, Cancer Research UK, the University of Pennsylvania and the University of Bergen. In 2009, the Division published 22 articles in international peer reviewed journals with a total Impact Factor of over 105. The teaching activities included: Master in Senology, University of Milan; Master in Senology, University of Siena; Postgraduate Course in Pharmaco-oncology, University of Milan; Scuola Italiana Senologia (SIS).

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Division of Pathology and Laboratory Medicine Giuseppe VIALE, MD, FRCPath Division Director

STAFF Director, Cytopathology Unit: Chiara Casadio, MD Director, Diagnostic Histopathology Unit :Giuseppe Pelosi, MD, MIAC Division Co-Director: Giuseppe Renne, MD Deputy Director: Giancarlo Pruneri, MD Senior Assistant: Angelica Sonzogni, MD Assistant: Luca Bottiglieri, MD, Elisa De Camilli, MD, Clementina Di Tonno, MD, Fausto Maffini, MD, Mauro G. Mastropasqua, MD, Michele Masullo, MD, Eleonora Pisa, MD, Paola Rafaniello Raviele, MD Research Assistant: Leila Russo, MD, Sara Leoncini, MD Deputy Director: Patrizia Dell’Orto, DSc Senior Assistant: Michela Manzotti, DSc Research Assistant: Elvira Benini, DSc, Olivia Blasi, DS Data Manager: Stefania Andrighetto, DSc, Francesca Lombardi, DSc Chief Technician: Alessandra Cavallon Technician: Enrica Bresaola, Giancarlo Camerino, Carla Camia, Laura Chiapparini, Gabriele Citelli, Gianluca De Marzo, Silvia Di Vincenzo, Flavia Giarratano, Stefania Grappeggia, Paola Lento, Luana Lippolis, Mara Lusiardi, Chiara Scacchi, Mila Schiavi, Francesco Spinelli, Tania Tamagni, Marilisa Valente Research Technician: Paolo Lopedote, Simona Pessina, Viviana Stufano, Chiara Zanetti Scientific Secretary: Luana Balestra Secretary: Elena Calvi, Giuseppina Figini, Cristina Messina Auxiliary: Giuseppe Barbaro, Adele Bevivino

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Activities 2009.

The Division of Pathology and Laboratory Medicine includes the Units of Diagnostic Histopathology, of Diagnostic Cytopathology, of Laboratory Medicine and of Laboratory Haematology-Oncology. This report focuses on the activity of the first two Units, which has included 19,793 histological diagnoses and 11,706 cytologic diagnoses (4,963 fine needle aspiration biopsies or extravaginal exfoliation cytology samples and 6,743 PAP tests), with 3,058 cases seen in consultation for a second opinion and 3,676 frozen section examinations for intraoperative diagnosis. Among the different tumor types, we have examined 3,455 breast samples, 1,798 biopsies of sentinel lymph nodes, over 2000 surgical specimens of gynaecological pathology, over 900 specimens of thoracic pathology and 329 malignant melanomas. Besides a diagnostic laboratory supplied with the most updated equipments for histologic and cytologic investigations, the Division includes two functional sections of immunohistochemistry and molecular pathology supplied with automatized instruments that are able to offer extensive immunophenotyping and molecular characterization of normal and tumor tissues by using a large array of monoclonal and polyclonal antibodies, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR) techniques. More than 40,000 immunohistochemical reactions, 1,055 FISH assays, 2,136 PCR analyses and 3,724 direct sequencing have been routinely carried out in 2009 for tumor geno-phenotyping, including the immunohistochemical evaluation of estrogen and progesterone receptors, HER-2 and EGFR in tumors for tailoring individual therapy; the characterization of malignancies from unknown primary sites; the assessment of gene amplification in carcinomas and gene translocation in malignant non-Hodgkin lymphomas and soft tissue tumors; and the mutational analysis assessment of several genes, including EGFR, K-ras, PDGFRA/B and c-kit. The research activities accomplished during 2009 have been related to the clinical implications of micrometastases and isolated tumor cells in sentinel lymph nodes of breast carcinoma patients, to chemoprevention trials for breast and

lung carcinoma, to the pathologic and molecular characterization of spiral computed tomography scan-detected lung carcinoma, to the modulation of receptor status of tumor cells by therapy, and to the search for new biological parameters and the assessment of their clinical implications in patients with laryngeal, mammary, pulmonary and colonic carcinomas, melanomas, and lymphoproliferative disorders. Research activities also included the methylation status evaluation of lung cancers, the mutational analysis of EGFR, PDGFRA, PDGFRB and c-kit genes and the detection of cell-free circulating nucleic acids (DNA&RNA) in the plasma of cancer patients. All these activities have required extensive immunophenotyping and molecular characterization of tumor tissues, using

automatized immunostainers, PCR-, real time PCR-based and FISH techniques, tissue microarrays, and laser capture-assisted microdissection for tumor cell enrichment. The research activities of the Division, including the studies performed in collaboration with several Divisions of the European Institute of Oncology, including Experimental Oncology, Senology, Medical Oncology, Head&Neck Surgery, Gynaecology, Thoracic Surgery, and Chemoprevention, have resulted in 77 full articles published during 2009 in peer-reviewed international journals, with an overall IF of 416.74 (mean IF: 5.412). The Division hosts the Postgraduate Medical School in Pathology of the University of Milan.

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Diagnostic Histopathology Clinical Unit Giuseppe PELOSI, MD, MIAC Director

STAFF It overlaps functionally with that of the Division of Pathology and Laboratory Medicine

Activities 2009. The 2009 clinical activity of the Diagnostic Histopathology Unit has regarded the consultation and revision duties on fellows, residents and staff pathologists working at the Division of Pathology and Laboratory Medicine. Particular attention has been pointed as internal referring pathologist to thoracic and mediastinal tumors, endocrine tumors including thyroid and adrenal glands, neuroendocrine tumors of the gastroenteropancreatic tract and lung, soft tissue tumors, malignancies from unknown primary sites, testicular tumors and non-neuroendocrine gastrointestinal tumors. Another important activity of the Diagnostic Histopathology Unit in 2009 has concerned the mutational analyses after PCR amplification and direct sequencing of EGFR (exon 18, 19, 20 &21: 206 examined tumors, with 840 PCR and 1648 direct sequencing reactions), K-ras (codon 12, 13&61: 445 examined tumors, with 890 PCR and 1780 direct sequencing reactions), PDGFRA/B (exon 12, 14&18: 10 examined tumors, with 60 PCR and 120 direct sequencing reactions) and c-kit (exon 9, 11, 13&17: 22 examined tumors, with 52 PCR and 176 direct sequencing reactions) for tailoring therapy. As institutional formation activity, two weekly courses for pathologists, technicians and biologists regarding basic and advanced issues of pathology have been activated in 2009 and carried out in the

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frame January-June 2009 and September-December 2009: these internal courses have been credited with 18 and 7 ECM points by the Italian Health Ministry, respectively. During the same year, a multi-institutional Italian project has been activated under the guidance of the Diagnostic Histopathology Unit, the so-called INSPECTOR (Italian Network for the Study of Pulmonary Endocrine Cell TumORs) project that has been funded by an external company. This is an observational, retrospective, study involving 8 different Italian large hospitals, which will raise surgically excised tumors dating back to 1987 and up to the end of December 2007. Main end-points of the project, which has been approved by the Ethic Committee of the European Institute of Oncology, are to construct a vast collection of surgically excised neuroendocrine tumors (the expected number is between 1500-2000) favoring diagnostic, prognostic and targeted therapy studies, to validate the current WHO classification criteria and possibly identify additional diagnostic tools that may be clinically relevant, and to participate in international projects on pulmonary neuroendocrine tumors with a proactive role. Furthermore, another multiinstitutional Italian project has been put forward in 2009 by the Diagnostic Histopathology Unit for investigating the issue of the epithelial-mesenchymal transition in pulmonary sarcomatoid carcinomas, which are uncommon variants of non-small cell lung carcinomas. In particular, the research activities of the Diagnostic Histopathology Unit accomplished during this year have regarded the mutational analysis of K-ras, EGFR, HER-2, b-RAF e PI3K in pulmonary sarcomatoid carcinomas, the pathologic and molecular implications of screening detected lung and colorectal adenocarcinomas, and the detection of telomerase activity in sputum samples of high-risk patients belonging to a randomized phase II trial of budesonide versus placebo in population with screening detected lung nodules. A large series of pulmonary adenocarcinomas arising in young people or non-smoker patients have been under investigation for

the detection of several genetic alterations, including FISH analysis of EGFR and HER-2 and mutation analysis of K-ras, EGFR, HER-2 and c-Met.

realizing the so-called therapeutic pathology, the name of this clinical unit will be accordingly changed in 2010 into Diagnostic and Molecular Histopathology Unit.

The research activities of the Diagnostic Histopathology Unit, including studies performed in collaboration with the Divisions of Pathology and Laboratory Medicine, Thoracic Surgery, Experimental Oncology, Medical Oncology, and Chemoprevention, have resulted in 15 full articles published during 2009 in peer-reviewed international journals, with an overall IF of 83.71 (mean IF: 6.907). To stress the importance of the molecular approach to the diagnosis, prognosis and predictive judgment of tumors

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Unit of Laboratory Medicine Maria Teresa SANDRI, MD Director

STAFF Deputy Director: Rita Passerini, DSc, Laura Zorzino, DSc Assistant: Annalisa Cattaneo, DSc, Donatella Gritti, DSc, Paola Lentati, DSc, Giovanna Randine, DSc, Michela Salvatici, DSc Chief Technician: Manuela Sesia Technician: Edvige De Angelis, Giuseppina Facchi, Lorena Moretti, Ngounou Ngassa Adeline, Nicola Panarese, Marco Picozzi, Teresa Roth, Ermenenziana Soccio, Alessio Tricca, Valentina Urso Fellow: Laura Bava, DSc, Cristina Cassatella, DSc, Daniela Riggio, DSc Secretary: Elena Campanato, Simona Caneo, Erika Platano Auxiliary: Andrea Sartori

Activities 2009. The Unit of Laboratory Medicine encompasses the fields of hematology, biochemistry, coagulation, tumor markers, infectious disease serology, drug monitoring and microbiology. It serves both in- and out-patients, and the total number of tests performed during the 2009 was about 800.000. Moreover, the Unit organizes the supply of blood products through a dedicated team. All the analyzers are recent and updated, and the different areas are very well integrated, allowing a global and comprehensive vision of the patient. The everyday internal quality controls, and the participation to external quality assessment programs, both organized by the Regione Lombardia or by Private Companies, guarantees the reliability of the test results. Moreover the laboratory has implemented and maintains a quality management system, which fulfills the requirements of the ISO 9001:2000 standard, and in October received the accreditation JCI specific for laboratories. A very recent computerization system online connects the lab with the wards, so that the results of the tests are very rapidly available for the physician, immediately after the validation process. The lab. is also in charge of the organization of the Transfusional Service, which derives its technical procedure from the Centro Trasfusionale e di Immunologia dei Trapianti di Milano. Besides traditional diagnostic laboratory tests, the Unit is involved in different research activities. Studies are ongoing evaluating the prognostic and predictive value of circulating tumor cells in prostate, breast and colon cancer, using innovative and updated equipment that allows not only the separation and enumeration of tumor cells, but also their characterization. Moreover with the Unit of Preventive Gynecology studies are ongoing looking at the role of different high-risk HPV genotypes in the development of pre-malignant lesions and in the follow-up of patients submitted to conization. We are also involved in the study

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of the potential use of the newly introduced vaccination against HPV infection for the prevention of cervical cancer. Lastly, the early detection of chemotherapy-induced cardiotoxicity represents a field of intensive study, with the use of circulating biomarkers for the identification of patients at high-risk of developing myocardial damage. During 2009, the Unit published 4 research papers, with an overall Impact Factor of 6.832.

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Unit of Diagnostic Cytology Chiara CASADIO, MD Director

STAFF Senior Cytotechnologist: Laura Chiapparini Cytotechnologist: Enrica Bresaola, Mara Lusiardi, Chiara Scacchi Technologist: Silvia Di Vincenzo Technologist, Fellow: Agnese Baglivo

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Activities 2009. The Unit of Diagnostic Cytology performs cytologic diagnoses for both in- and outpatients. The total number of tests in 2009 was 11,743; 4,982 of them were fine needle aspiration or extravaginal exfoliative cytology samples and 6,761 were Pap tests (mainly liquid based samples). All the cytotechnologists are involved in the preparation and in the screening of the slides. They are also encouraged to actively participate in updating courses. In the last year all of them prepared posters to be presented at different congresses. In October 2009, the Unit organized a theorical –practical course on liquid-based mammary cytology which was accredited for continuing medical education. 450 fine needle aspirations of palpable breast nodules and of superficial lymph nodes were performed by two cytopathologists, while a third cytopathologist performed about 50 ultra sound guided fine needle aspirations of non palpable breast lesions. The daily internal quality control system, based on the review of 10% randomly choosen cases according to a computer-mediate selection, guarantees the reliability and accuracy of the test results. A computerized system online connects the department with the wards, so that the diagnoses are immediately available to the physician, just after the validation process. Moreover the laboratory has implemented and maintains a quality management system, which fulfills the requirements of JCI, and in October received the accreditation JCI specific for laboratories. Besides traditional diagnostic cytology, the Unit is involved in different research activities, including the studies performed in collaboration with the Laboratory Medicine Unit on circulating tumor cells in breast cancer, with the Division of Chemoprevention on Breast Ductal Lavages (DL) and with the IARC (Lyon, France) on the presence of HPV types in DL specimens and cervical tumours .

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Laboratory Unit of Clinical Haematology-Oncology Francesco BERTOLINI, MD, PhD Director

STAFF Vice-Director: Patrizia Mancuso,Biol Sci D, Cristina Rabascio, Biol Sci D Senior Assistant: Chiara Corsini, Biol Sci D, Ines Martin-Padura, Biol Sci D Assistant: Angelica Calleri, Biol Sci D, Giuliana Gregato, Biol Sci D Fellow: Alice Agliano, Biotechnol Sci D, Paola Marighetti, Biotechnol Sci D, Anna Bono, Biotechnol Sci D Technician: Cinzia Massaro, Pierluigi Antoniotti, Jessica Quarna, Secretary: Patrizia Passeri

Activities 2009.

The diagnosis of haematological malignancies and stem cell processing are the two major clinical activities of the laboratory, which is now ISO9001, JACIE and JC certified. More than 100 stem cell collections were processed in the past year for autologous or allogeneic use and more than 1,300 blood and marrow samples were studied by flow cytometry, PCR, immunohistochemistry, FISH and cytogenetics. The repository of plasma, serum and whole blood samples from leukaemia, lymphoma and myeloma patients includes nearly 6,200 frozen samples from untreated patients at first diagnosis and from patients longitudinally followed after remission or relapse. Trafficking and angiogenic potential of cancer, stem and endothelial cells are the main research interests of the laboratory. We have developed and validated at the preclinical and clinical level a number of surrogate assays of angiogenesis and anti-angiogenic drug activity that are currently used worldwide in many clinical trials where cancer patients are treated with anti-angiogenic therapies. In the last two years, these assays have been found to predict the clinical outcome of breast cancer patients treated with anti-angiogenic therapies (Dellapasqua et al, JCO 2008; Calleri et al, Clin Cancer Res 2009) and to be of help to define the most active combination of anti-angiogenic drugs and cytotoxics (Shaked et al, cancer Cell, 2008; Mancuso et al, Clin Cancer Res 2009). We are currently leading an international effort toward the standardization of the measurement of these surrogate markers. In collaboration with IEO Department of Experimental Oncology and IFOM we are investigating novel preclinical models of human haematological malignancies that are used to investigate new drugs and new therapeutic procedures. Finally, in collaboration with the University of Bologna we have defined a novel class of cancer stem cells in chronic myeloid leukemia (Lemoli et al, Blood 2009).

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Department of Medicine Division of Medical Oncology Aron GOLDHIRSCH, MD Director

STAFF Senior Deputy Directors: Giuseppe Curigliano MD Ph.D., Nicola Fazio MD Assistant: Marzia Locatelli Fellows: Luca Fumagalli, Michela Squadroni Chief Nurse: Loredana Lunghi Nurses: Antonella Angeli, Francesca Arrigoni, Laura Bistocchi, Paola Bonvini, Denise Bucci, Simonetta Chiericati, Alessia Gandini, Cinzia Grimaldi, Federica Facciola, Svetlana Milosevic, Chiara Pari, Tatiana Porro, Samira Sallak, Sabrina Turin, Andrea Zanoni Technical Support: Christine Agnu, Sofia Basile, Maria Bivacco, Rosina Lavia, Luciana Mosca Administration and Secretariat: Emanuela Colautti Secretary: Maria Cristina Cracas Data Management: Raffaella Ghisini, Sabrina Boselli, Laura Adamoli, Eloise Scarano, Marta Revuelta, Davide Pastrello, Simona Giudici

Activities 2009.

The Department of Medicine incorporates the entire area of care and research for specific domains of cancer medicine: Solid tumors, hematological malignancies and lymphomas, clinical pharmacology and development of new anti-cancer drugs, support and palliative care and psycho-oncology. The mission of our Department is to provide expert, compassionate care to adults with cancer while advancing the understanding, diagnosis, treatment, cure, and prevention of cancer and related diseases. Our Department also provides training for new generations of physicians, designs programs that promote knowledge particularly among high-risk and underserved populations, and disseminates innovative patient therapies and scientific discoveries to our patients across Italy and throughout Europe. We pursue excellence relentlessly and with integrity in all that we do, adhering always to the highest standards of conduct. We provide compassion and respect for those in our care and for one another. We foster the spirit of inquiry, promoting collaboration and innovation across traditional boundaries while celebrating individual creativity. The Department is organized into divisions and units, which share in-patient wards, and outpatient clinics, including a Day Hospital. Care and research in specific fields characterize the activities of the Unit of Clinical Pharmacology and New Drugs, the Unit for Supportive and Palliative Care, and the Unit of Psycho-Oncology and Research on Quality of Life. The Divisions and Units provide care and conduct research in an integrated fashion. Priority of clinical research include tailored treatment for patients with various diseases. Innovative treatments include targeted molecules to specific cancer cellular components, to cancer vessels and experimental use of anti-cancer

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vaccines. The cultural principle, which characterizes the attitudinal basis, shared by all the members of the Department, is: “Let innovative research flourish on the ground of the best care available”. During 2009, the Division of Medical Oncology provided 2.317 admissions in its ward (20 beds), and 396 in a single day hospitalization program. The Division of Clinical Hemato-Oncology provided care for 494 patients in its in-patient ward (20 beds). The overall outpatient activities of the Department involved at least 38624 consultations at the clinics and 4767 treatments at the Day Hospital Unit. At least 7170 patients were treated within the framework of research trials, 622 newly

entered studies during the year 2009. Hemathological and immunological diagnostics and support of treatment, as well as translational research are conducted at the dedicated laboratory of the Division of HematoOncology. Most, if not all, research projects are being carried out in close collaboration with other Divisions and Units both at the clinical and laboratory levels.

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Unit for Medical Care – Day Hospital Franco NOLÈ, MD Director

STAFF Senior Deputy Director: Maria Giulia Zampino MD Deputy Director: Elisabetta Munzone MD Senior Assistants: Ida Minchella MD, Daniela Cullurà MD Assistants: Maria Cossu Rocca, MD, Elena Verri, MD, Elena Magni, MD, Cristina Marenghi, MD, Angela Esposito, MD Fellows: Angela Sciandivasci MD (Since February 2009), Maria Cristina Petrella MD (Since December 2009), Gaetano Aurilio MD Data Manager: Laura Adamoli, Marta Alonso Revuelta Secretaries: Daniela Bargiggia, Monica Croce Chief Nurse: Alessio Piredda (since August 2009) Nurses: Tiziana Auciello, Elena Bocchiola, Barbara Lazzaroni, Colette Mc Donnel, Laura Poloni, Elena Taraschi, Alessandra Tonali, Adriana Zallocco, Claudia Zencovich, Ivan Limardi Auxiliaries: Maria Stella Di Giglio, Maria Iannitelli, Antonietta Lavia, Lidia Orlando, Tenca Cristina

Activities 2009.

The Unit is involved in clinical research on solid tumors. In particular, the Unit is interested in prospective phase II and III trials addressed to investigate the role of novel anti-cancer drugs, innovative strategies or new therapeutic and tailored approaches with particular interest in Advanced Breast Cancer, Head & Neck Cancer, Gastro-intestinal Tumours, Urogenital Cancer and Melanoma. During 2009, the overall outpatient activities involved more than 16.000 treatments in patients with solid tumors. The scientific activity is also involved in translational research and research of new prognostic and predictive factors to individualize treatment and to guide therapeutic decisions in clinical practice. The collaboration with clinicians and basic researchers in other departments and divisions of the same institution is encouraged and ensured by regular meetings and discussions in the context of Disease Units tumor-specific. Similarly, the national and international cooperation is supported and the unit participates in and promotes a number of prospective multicenter studies. A specific attention is given to quality of life through the investigation of new strategies such as the “metronomic” administration of continuous low dose chemotherapy in collaboration with basic researchers in order to explore possible antiangiogenic mechanisms of this approach. The ongoing research programs include the evaluation of prognostic and predictive value of circulating tumour cells in advanced and operable breast cancer; in castration resistant prostate cancer, in gastrointestinal and head & neck cancer, with the aim to better characterize the behaviour of these disease and to individualize the treatment

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Unit of Research in Medical Senology Marco COLLEONI, MD Director

STAFF Putative Director: Rosalba Torrisi, MD Assistants: Alessandra Balduzzi, MD, Silvia Dellapasqua, MD, Anna Cardillo, MD, Emilia Montagna, MD, Giuseppe Cancello MD, Monica Iorfida. MD, Elisabetta Campagnoli MD (till 5-2009) Secretariat: Simona Puddu, Monica Croce

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Activities 2009. The Unit of Research in Medical Senology provides care and conduct research in an integrated fashion in the field of Medical Senology, mainly in the neoadjuvant and adjuvant setting, The principle shared by members of the Unit is that increased participation in clinical trials would increase learning about the disease and improve patient care. Research projects are being carried out in close collaboration with other Divisions and Units at the EIO and with National and International Cooperative Groups. International trial cooperation, focused on questions relevant for patient care and biological principles represent one of the major commitment for the Unit in particular in the adjuvant setting. A collaborative approach involving the development of new agents and investigation of their optimal integration in therapy programs will best ensure progress for improved patient care. Studies focusing on safety, quality of life, subjective side effects and personal costs are routinely incorporated in the patients care. Assessment of factors, which are associated with response or resistance to therapy and exploration of new therapies accordingly to baseline prognostic features are considered as a priority in the development of the best multimodal strategy including sequence of local and systemic treatments. Research studies are conducted to define the value of new high-throughput technologies in assessing the level of risk and likelihood of response to specific therapies, in order to improve our knowledge and lead to better tailoring of therapies. Such an approach brings clinical research closer to the individual patient.

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Division of Clinical Pharmacology and New Drugs Filippo DE BRAUD, MD Director

STAFF Director of Medical Oncology Unit of Respiratory Tract and Sarcomas: Tommaso De Pas, MD Deputy Directors: Cristina Noberasco, MD Senior Assistent: Chiara Catania, MD Assistants: Gianluca Spitaleri, MD, Angelo Delmonte, MD Translational research: Francesca Toffalorio, MD Ph.D. Research Nurses: Alessandra Milani, Livio Libutti, Elena Bocchiola Data Managers: Sabrina Boselli, Valentina Sinno, Fabio Vecchio Secretaries: Marcella Netti, Sonja Raffaele Addamo

Activities 2009. The activity formally established in 2001 was implemented year by year with the objective of developing new drugs and to promote “translational research”. Within this remit we propose not only to develop treatments using new molecular compounds but also to determine new therapeutic strategies. In both cases we aim to optimise benefits and minimise toxicity. We are therefore committed to finding a clinical way to finalize the attractive hypothesis of being able to personalise treatment on the basis of the biological characteristics of the disease and on pharmacogenomic data of the patient. The number of ongoing studies as well as the implementation of the new Molecular Medicine programme in IEO endorsed the creation of a specific Division to which Unit for Lung cancer, sarcomas, and rare tumors belongs. All “first-in-man studies” as well early phase II studies and the all clinical studies for lung cancer and sarcomas will be carried out here, to ensure vigorous quality of monitoring and care during these intensive protocols. In 2009 we designed and/or conducted dose-finding studies of novel agents antivascular, antiangiogenic, cytokine fusion protein, tyrosine kinase inhibitors administered alone or in combination with classic cytotoxic drugs in patients with solid tumor. Overall 25 studies have been conducted: 4 translational, 11 Phase I, 5 Phase II, 5 Phase III trials. Liaison with the IEO labs will be intimate, and the whole gamut of genomics and proteomics will be available for clinical application. We also collaborate with Italian Association of Medical Oncology (AIOM) and we published together an Italian survey concerning euthanasia, life sustaining treatment and acceleration of death. We concluded and published the study concerning the development of an “anthropocentric” transformation of the waiting that is strongly evoked by most cancer patients. To improve the quality of care within the research programs from 2009 the following actions were endorsed: a) We are performing a study to understand cultural and

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emotional aspects of patients with cancer when facing the choice of whether to participate in a clinical trial; We are cooperating with Italian Association of Medical Oncology (AIOM) developing a new informed consent model (ICFM) in medical oncology. b) We are cooperating with IFOM (Fondazione Istituto FIRC di Oncologia Molecolare) in co-planning of scientific work to improve the selection of patients based on genetic data. We intend to use yeast Saccharomyces cerevisiae as a model system to identify drug responsive genes that will be then validated in human cells and tissues. A concomitant screening on yeast model/phase I trial will be performed to identify mutants that exhibit resistance or hypersensitivity to drug treatments.

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Supportive and Palliative Care Unit Alberto SBANOTTO, MD Director

STAFF Head nurse (from 01/04/08): Angela Cocquio, RN Fellow: (from 01/09/08): Beatrice Dedor, MD Secretary: Maria Cristina Cracas

Activities 2009.

Supportive and Palliative Care are increasingly important in Oncology: prolonged survival of patients, new cancer treatments-related side effects and complications, especially neurological ones, challenge clinicians everyday. The main area of intervention of the Unit are bedside consultations, for all the clinical wards of the Institute, mainly concerning chronic pain problems, symptoms and special syndromes (e.g. dyspnoea, delirium, peritoneal carcinomatosis, inoperable bowel obstruction) and selected postoperative pain items; during 2009 about 750 inpatients visits have been performed. The Outpatients Clinic is mainly devoted to cancer pain syndromes: about 1000 visits have been performed, including a dedicated clinics for Radiotherapy patients, where difficult problems are often encountered, like painful radiotherapy-induced stomatitis and bone incident pain. Continuity of care is extremely important for cancer patients and their families, most of them living far from the European Institute of Oncology. Telephone calls, emails, faxes are important tools for these purposes. By an agreement with the Fondazione Lucè Onlus, the IEO implemented a nurse-supervised Call Centre for supporting patients and families faced with clinical problems related to therapies or cancer. During the first 3 years of activity about 4000 telephone calls have been received, concerning about 1700 patients; analysis of customers’ satisfaction questionnaires gave very promising results. During year 2009 this kind of intervention has been implemented and more clinical wards involved. Another area of intervention is The Pain Free Hospital Project, where the Unit is closely involved. The main aims of the project are to increase awareness of pain and improve pain and symptoms control at the IEO. The project is involved in teaching, monitoring pain and ensuring better availability of drugs. An online periodical Newsletter is being implemented and an Online Pain Course has been conceived.

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By a recent agreement with the Local Health Agency, we are planning an Home Care Service, for advanced cancer patients living in the south area of Milan and in some of the surrounding small towns. It will be implemented during the year 2010.

tion. Other areas of research concern the treatment of incident vertebral pain by percutaneous interventions and stomatitis radiotherapy-induced in head and neck patients.

Scientifical programs Areas of research concern chronic pain syndromes in cancer and supportive models for Continuity of Care in Oncology. Scientifical programs included a collaboration in the Cancer Pain Study, a multicentre trial about pain epidemiology, developed in collaboration with the Mario Negri Institute, whose results are under way of publica-

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stress management for oncology staff using different techniques; movies-cinema, relaxation and guided imagery techniques. Research interests The main research interests of the Psycho-Oncology Unit are the evaluation of the psychological impact of breast surgery and patients’ quality of life (Didier et al, Breast Cancer Res Treat, 2009). In collaboration with the Divisions of Senology (Dr. Luini), Reconstructive Plastic Surgery (Prof. Petit) and the Department of Medicine (Prof. Goldhirsch) we study the psychological and body image impact of breast loss, sat-

isfaction with cosmetic results of breast reconstruction, with a specific attention to nipple sparing mastectomy (Petit et al, Breast Cancer Res Treat, 2009) which is now included in the routine of the Breast Division. The impact of breast surgery and cancer treatments on sexuality are also assessed. We have developed a specific questionnaire that is being validated. The assessment of patient and family satisfaction with the telephone follow-up, performed by the psychologists of the Gigi Ghirotti Foundation, is ongoing.

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Division of Clinical Haemato-Oncology Giovanni MARTINELLI, MD Director

STAFF Director of Allogeneic Transplantation Unit - Pregnancy and Fertility Project Leader: Fedro Peccatori, MD PhD Deputy Directors: Alessandra Alietti MD, Emilia Cocorocchio MD, Daniele Laszlo MD, Rocco Pastano, MD, Alberto Agazzi MD Assistants: Anna Vanazzi MD, Simona Bassi MD, Paola Bertazzoni, MD, Federica Gigli MD, Fellows: Giovanna Andreola MD, Angelo Gardellini, MD, Luca Nassi MD, Simona Sammassimo MD, Visitors: Prof. Enzo Bonmassar MD Data Managers: Liliana Calabrese, Mara Negri Data Managers fellows: Francesca Torti Data Entry: Maria Teresa Lionetti Secretaries: Daniela Antoniotti, Tiziana Masala Head Nurse: Tiziana Suardi (until October), Laura Orlando (from November) Scientific nurses: Sarah Liptrott, MSc, BN (Honse) Nurses: Antonella Autiero, Aleksandra Babic, Cristina Berti, Luca Casellato, Gloria Cavedini, Margherita Clerici, Claudio Di Leverano, Francesca Di Titta, Rossana D’Oria, Cristina Grossi, Dania Infante, Bruno Lucchetti, Roberta Magri, Fatima Mariano, Montanari Annalisa, Francesca Rossetti, Lara Roveda, Enrico Sari, Marta Vicedomini. Auxiliaries: Romina Bianco, Antonella Ferrari, Patrizia Lombardi, Mihaela Mirosanu

Activities 2009.

Our mainstream is the treatment of leukemia, lymphoma, Hodgkin’s disease, multiple myeloma and improvement of the quality of life of patients and their families. In the past, only few people affected by haematological diseases survived. Now, thanks to advances in treatments, more than 70 % of patients are successfully cured. Thus, a new challenge arises: the study of the long-term effects of treatments. During 2009 the Haematoncology Scientific Committee/ Task Force Haemato-Oncology continued to actively meet every month. Multidisciplinary discussion with different specialists including radiologists, pathologists, nuclear medicine doctors, radiation therapists, psychologists, laboratory doctors and nurse staff added new insight in the clinical case management with a dedicated path for patients eligible for clinical trials. Twenty-six new trials were discussed and 12 have been activated.

Other 9 studies are in preparation for ethics committee presentation. Particular attention was given to improve patients quality of life. The Fertility Counseling group continued its activity in collaboration with “Fondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena”, and “ Centro Florence “ in the clinical management and research on patients with tumours in pregnancy or patients who de-

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sire pregnancy after cancer treatments, including the use of techniques of assisted reproduction and cryopreservation of ovarian tissue, sperms and oocytes. 148 patients received a reproductive counselling either before or after oncological treatment. Three patients had their oocytes frozen before chemotherapy, and 5 froze their sperm for fertility preservation. Within the Division of Clinical Haemato-Oncology, the Allogeneic Transplant Unit performs allogeneic transplants with reduced conditioning or myeloablative regimens, from sibling and unrelated donors, principally for patients with haematologic malignancies. In 2009, 11

allogeneic transplantations and 59 autologous transplants were performed. In order to improve clinical results and reduce acute toxicities, including Graft Vs Host disease, the use of TLI / ATG in malignant haematological diseases was implemented. This regimen, firstly developed at Stanford University, has the peculiarity to skew graft activity toward host tolerance, maintaining high anti-tumour activity and reducing overall transplant related mortality. The same regimen has been proposed for “triple negative” refractory breast cancer patients, a difficult clinical situation with few treatment options.

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A new study to determine if engraftment can be achieved safely in patients with high-risk hematologic malignancies who undergo non-myeloablative BMT from HLA-haploidentical donors is in preparation. In 2009 Dr Giovanna Andreola came back from Harvard University to establish immunological monitoring of patients with haematological malignancies after allogeneic transplant. The Haemostasis-Clotting outpatient Unit provides assistance and guidance in solving problems concerning haemostasis and thrombosis in oncological patients at IEO. In 2009, 456 patiens were visited (281 internal consults and 175 outpatients visits), with an increase of about 30% compared to 2008. In collaboration with SAKK we have begun to investigate the prognostic role of PET in patients affected by diffuse large B cell lymphoma. In particular we evaluated if an early positive PET after 2 cycles of dose dense chemoimmunotherapy (R-CHOP 14) can be used to identify a group of patients having a poor prognosis. Our team is currently working with immunotherapy protocols in non-Hodgkin lymphomas (NHL). Clinical results showed that the combination of immunotherapy with conventional chemotherapy led to improvements in response rates in NHL. Radio-labelled immunotherapy, which combines the benefits of monoclonal antibody targeting with therapeutic doses of radiation is a promising step forward in the treatment of malignant lymphomas. We recently concluded the experience of such treatment in marginal extranodal malignant Lymphoma relapsing or resistant to conventional treatment. During 2009 the Hematoncology Division continued the collaboration with different scientific groups. With Southern Europe New Drug Office (SENDO) we have taken part in a phase I clinical trial. The principal objective of this study was to determine the maximum tolerated dose

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(MTD) and treatment regimen of a new drug (CEP-18770). In this study we have enrolled six patients affected by multiple myeloma. With the International Extra nodal Lymphoma Study Group (IELSG) we have continued the enrolment of patients in already ongoing studies and we have collaborated in elaborating new projects concerning patients with extra nodal genital lymphomas and extra nodal breast lymphomas. Regarding trials with IEO as sponsor we have continued the enrolment of patients in our first line treatment studies designed for naïve patients with Hodgkin Lymphoma or Multiple Myeloma reaching a sample size of 44 and 23 patients respectively. The last year we have completed the administrative iter of a new multicentre clinical trial, promoted by IEO and financed by an AIFA grant. The objective of this study is to assess the efficacy of a new treatment in improving overall survival of patients with MGMT deficient refractory acute leukaemias. In our Institute the study has been opened in May and we have just obtained the EC approval from the other participant centres. Communities get benefit from a spirit of collaboration and co-operation between local Governments and health institutions. In this framework, our research group was invited for a membership in REL, a network established by Lombardy Region for optimizing assistance and cure for patients affected by haematological disease. REL also defines criteria for the accreditation of transplant centres operating at regional level. In 2009, our team produced 38 articles published on scientific journals with an overall impact factor of 200 points.

Cardiology Unit Carlo CIPOLLA, MD Director

STAFF Senior Deputy Directors: Maurizio Civelli, MD, Giuseppina Lamantia, MD Research Doctorate, Senior Deputy Director: Daniela Cardinale, MD, PhD Senior Assistant: Nicola Colombo, MD Assistant: Alessandro Colombo, MD Consultant: Cesare Fiorentini, MD, PhD, University of Milan Fellow: Sarah Cortinovis, MD, Maria Antonietta Dessanai, MD Secretaries: Elena Gaibor, Paola Lasagna Chief Nurse: Arnaldo Zanelotti Nurses: Maria Di Leo, Enza Dossena, Monica Lischio, Anna Zubani Data Manager: Irene Vetrano OTA: Maria Iannitelli Consultant Smoke Cessation Center: Elena Calvi, MD, Psychologist Fellow Smoke Cessation Center: Annalisa Rausei, MD, Psychologist

Activities 2009.

Cardiology Unit’s activities relate to pre and postoperative cardiologic assessment, respiratory function evaluations, general internal medicine consultations, antismoking activities, extensive clinical monitoring and therapy for internal wards and treatment of emergencies. The specific cardiological activity is strongly oriented to the diagnosis and therapy of cardiac disorders in order to detect and treat comorbidities (42% of EIO cancer patients present concomitant cardiovascular diseases) as well as potential or evident consequences of oncologic treatments (cardiotoxicity). Cardiological evaluations, either clinical or instrumental, are present in over 100 scientific research protocols of the Institute.

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In 2009 the Unit performed: a) cardiological assessment of 12.225 internal and outpatients; b)complete echocardiographic and Doppler colour evaluations in 3243 patients; c) respiratory physiopathology diagnostic and assistance (1818); d)over 100 antismoking activities for patients and employees; e) clinical consultations and/or echocardiographic examinations for over 2500 patients enrolled in different Division's scientific protocols: f) overall 47787 written official reports. Cardiology Specific Activities Diagnosis of cardiotoxicity Cardiotoxicity is a possible complication of chemotherapy (CT). The clinical manifestation of cardiotoxicity can range, in its more typical form - chronic cardiotoxicity - from transient asymptomatic left ventricular dysfunction to cardiac death. This is a growing problem in the setting of clinical oncology due to the tendency in using progressively higher doses of anthracyclines, as well as combined treatments with synergistic cardiac toxic properties. Also newer compounds, as thyrosin kinasis inhibitors, antiangiogenic drugs, and monoclonal antibodies potentially deserve cardiotoxic implications. The clinical implications of cardiotoxicity are particularly relevant in those cancer patients in which onset of cardiac dysfunction, even asymptomatic, seriously limits their therapeutic opportunities and negatively impacts on clinical outcome. At present oncologic guide-lines recommend regular cardiac function assessment (generally by echocardiography or MUGA scan) to detect CT-induced cardiac damage in an early phase. Cardiologic surveillance is required during CT to allow administration of the highest dose without inducing cardiac injury, and after completion of CT to identify cardiac damage at an early preclinical stage. This is made, in order to limit, by means of pharmacologic intervention, the progression of cardiac dysfunction. The weak point of such an approach is that cardiotoxicty is

usually detected when cardiac damage has already occurred. Furthermore, most methods used in clinical practice to detect cardiotoxicity, including echocardiography and radionuclideangiocardiography, seemed to have shown low sensitivity and poor predictive value. In particular, the evidence of an unaffected heart function does not exclude the possibility of future cardiac deterioration. In our clinical practice we utilize different tools for the early identification of patients at increased risk of cardiotoxicity: biomarkers of myocardial damage, like Troponin I and N-terminal-proB-Type Natriuretic Peptide (Nt-proBNP), and low-dose dobutamine stress-echocardiography that allows early detection of left ventricular contractile reserve reduction. For all of them, an accurate predictive value has been demonstrated by our investigations. The possibility of early identifying patients who will develop myocardial dysfunction represents a “golden opportunity” for both oncologists and

cardiologists. It allows discriminating, in a very early phase, long before heart function impairment and symptoms manifestation have occurred, patients at high risk of cardiotoxicity from those with a good cardiologic prognosis. As a consequence, most patients can be excluded from a long-term expensive and awkward monitoring program with diagnostic methods like echocardiography and radionuclide angiocardiography. On the other hand, in selected high-risk patients, a strategy based on serial cardiac function evaluations can be planned, and a preventive pharmacological therapy started. Prevention and treatment of cardiotoxicity CT-induced cardiotoxicity can result in a cardiomyopathy generally considered to be irreversible, and leading to congestive heart failure and cardiac death. Clinical manifestations of cardiotoxicity may appear months or even years after the end of CT, and are preceded, in most cases, by asymptom-

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atic left ventricular dysfunction. In no monitored patients, symptoms of congestive heart failure usually represent the first manifestation of cardiotoxicity. In our very recently published experience, most patients receiving adequate treatment, including ACE-inhibitors, betablockers, diuretics, and anti-aldosterone agents, and closely monitored, experience a relevant improvement in clinical status and cardiac function, in some cases a complete recovery, and a better cardiologic prognosis. For the optimization of cardiologic therapy we usually monitor Nt-proBNP levels, which are related to the clinical and prognostic status of patients with congestive heart failure. Diagnosis and management of neoplastic pericardial effusion Malignant pericardial effusion and cardiac tamponade are common complications of several different neoplastic diseases, and have a critical impact on patients’ quality of life and survival. Therefore, the prompt and successful therapy of pericardial disease is crucial in order to increase life expectancy, and improve clinical status. Accordingly, malignant pericardial effusion should not be considered a terminal event, but a treatable condition requiring a true therapeutic intervention. On the basis of our previous studies, we routinely perform pericardiocentesis (PC) as an emergency life-saving procedure. In our experience on almost one hundred patients no clinically relevant untoward side effects were experienced. In this setting however, when PC is utilized only as a drainage technique for symptoms relieve, it is associated with a very high incidence of early pericardial effusion recurrences. In order to prevent pericardial recurrences, we do not consider PC a mere palliative approach but we associate to the fluid withdrawn also an intrapericardial “oncologic therapy” with both chemotherapeutic and "etiologic" properties. In addition to the reduction of pericardial effusion recurrences, this percutaneous strategy has been proved to be safe and effective in the prevention of neoplastic disseminations that can complicate surgical procedures of pericardial drainage. Furthermore, quality of life and life expectancy of treated patients usually improve.

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Chemotherapy induced ECG abnormalities and regulatory QT monitoring. The evaluation of ECG abnormalities in CT treated patients is routinely performed in our clinical practice. In addition to serial ECG evaluations, we settled an ECG telemetry system to continuously monitor high-risk patients and easily detect arrhythmias and conduction disturbances. Several distinct ECG changes have been described during or soon after the administration of chemotherapeutic drugs: ECG abnormalities may result in ST-segment and T-wave changes, decreased QRS voltage, and prolongation of the QT interval. CT-induced arrhythmias and conduction disturbances include ventricular, supraventricular and junctional tachycardias, and atrioventricular and bundle-branch blocks. In particular, a prolongation in QT interval is associated with onset of severe life-threatening ventricular arrhythmias, named “torsades de points”. In order to more precisely identify a possible pro-arrhythmic substrate induced by CT drugs, we perform, in selected high-risk patients, also the evaluation of heart-rate variability. Research Activities 2009 Cardiotoxicity: Early Diagnosis Markers of myocardial damage: Troponin I. Cardiac toxicity represents one of the most important longterm side effects of high-dose chemotherapy with a strong impact on patient’s quality of life and survival. The clinical course can range from transient asymptomatic left ventricular dysfunction to cardiac death. The possible development of biochemical markers able to identify cardiac damage in an early phase is strategic for both therapeutic and prognostic reasons. In previous studies we demonstrated that troponin I (TNI) is a sensitive and specific marker of myocardial injury after high-dose chemotherapy, and is able to predict, in a very early phase, the development of future cardiac dysfunction, as well as its severity. More recently, we extended this observation to a larger population with a longer follow-up, in which a wide spectrum of cardiologic adverse events was considered. Our study clearly showed that the risk of cardiac

events in cancer patients can be predicted by the evaluation of TNI release pattern after chemotherapy. Indeed, most patients with TNI increment soon after HDC developed a significant reduction of left ventricular function in the first year after HDC. A close relationship between the TNI peak value and the degree of cardiac dysfunction during the follow up was found. TNI is also an important predictor of clinical events, as well as anticipating the development of cardiac dysfunction. This finding has important clinical implications and provides an intriguing rationale for the development of pharmacological strategies counteracting cardiac dysfunction and cardiac complications occurrence. Hemodynamic markers: Nt-proBNP Natriuretic peptides have recently emerged as biomarkers potentially useful in the diagnosis and prognostic stratification of patients with heart failure. Particularly, Nt-proBNP is released from the heart in response to a cardiac overload. Preliminary data from our ongoing trial suggest that serial early measurements of plasma Nt-proBNP may represent a useful tool to identify patients at high risk of developing myocardial dysfunction. We planned a further prospective study to clarify either if TNI and Nt-proBNP give the same kind of information, or if their combined evaluation allows a better stratification of the cardiac risk of cancer patients treated with high-dose chemotherapy. Identification of left ventricular contractile reserve impairment: low-dose dobutamine stress-echocardiography Dobutamine stress echocardiography (DSE) is widely used in patients with coronary artery disease or dilated cardiomyopathy, and allows the evaluation of left ventricular contractile reserve (LVCR). In cancer patients treated with anthracyclines, we have assessed LVCR by low-dose DSE, in order to detect subclinical left ventricular dysfunction, as a possible early index of cardiotoxicity. In our study, patients with early reduction of LVCR, showed a significant decrease of left ventricular ejection fraction (LVEF) one year after the end of treatment. This information was obtained in a very early phase, when patients were still receiving HDC and when

rest LVEF reduction was not detectable yet. Based on these findings, DSE can be considered a safe and useful method for the early identification of patients likely to develop late cardiac dysfunction after HDC. Cardiotoxicity Prevention: a new prophylactic approach The possibility to identify patients at higher risk of developing late myocardial dysfunction by cardiac biomarkers (TNI, Nt-proBNP) provides a rationale for the development of prophylactic strategies directed against CT-induced cardiotoxicity. Considering the results of our published studies, a possible clinical application of these markers is the evaluation of pharmacological strategies in selected high-risk patients, with the aim to prevent acute cardiac damage, left ventricular dysfunction, and cardiac events. Two different therapeutic strategies could be implemented in order to reduce the clinical impact of cardiotoxicity: 1) use of specific cardiologic treatments given to cancer patients during CT in the attempt of preventing or blunting the rise of these markers; 2) use of cardiologic treatments given only to those selected cancer patients showing an increase in these markers after CT. This with the aim to interfere with the natural evolution of cardiac toxicity, and prevent the occurrence of left ventricular dysfunction and cardiac adverse events. In particular, the increase of troponin I (TNI) soon after CT is a strong predictor of left ventricular dysfunction and poor cardiologic outcome. We hypothesize that cardioprotective therapies that might limit or prevent the TNI rise after CT, as well as cardiologic treatments that interfere with TNI persistence, could improve cardiac prognosis of these patients. As activation of the renin-angiotensin system has been proved to be involved in the development and progression of cardiac dysfunction in several clinical settings, and has been suggested to have a role in the occurrence of CT-induced cardiotoxicity, we investigated with very positive results the role of treatment with an ACE-inhibitor, enalapril, in the prevention of left ventricular dysfunction in high-risk cancer patients (those with TNI rise after CT). Our data confirm that prophylactic treatment with enalapril effectively prevents the occurrence of asymptomatic left ventricular dysfunction and overt heart

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failure in these patients. Intrapericardial Treatment Pericardial disease and pericardial involvement are increasingly common complications of neoplastic diseases which can be life-threatening, not only in patients with unresponsive or aggressive terminal malignancies, but also in patients with otherwise favourable prognosis. Different methods may be used to treat malignant pericardial effusions, but the gold standard treatment in this subset of patients is yet to be defined. In particular, percutaneous pericardiocentesis (PC) is associated with a very high incidence of early pericardial effusion recurrences (up to 40%). We performed a prospective, controlled, interventional study in order to investigate short-term safety and effectiveness of PC followed by intrapericardial infusion of an active antiblastic, sclerosing agent, thiotepa, in patients with large malignant pericardial effusion. The results of our study have clearly showed that PC plus thiotepa is a low-cost, low-risk, and safe therapeutic approach, and should seriously be considered as a first choice procedure in approaching neoplastic pericardial effusions. Since 2008 we designed a prospective trial to evaluate clinical and prognostic relevance of intrapericardial TNI determination, and to evaluate the possible role of Nt-proBNP, as a marker of hemodynamic impairment, in defining the clinical indication to PC, in addition to echocardiographic evaluation and in the monitoring of pericardial effusion recurrences. Scientific cooperations for new research avenues Several scientific cooperations have been established in order to study new elements concerning cardiotoxicity not only classically regarding antracyclines, but also new anticancer drugs (monoclonal antibodies, thyrosin kinasis inhibitors and anti angiogenetic agents); some common pathways signalling regarding and their potential translational implications; we deeply thank for great efforts and help: Daniel Lenihan, Cardiovascular Research, Vanderbilt University, Nashville, Tennessee; Fabio Ciceri, Hematoncology and Bone Marrow Transplantation, Ospedale San Raffaele, Milano;

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Giancarlo Marenzi, Unità Coronarica, Centro Cardiologico Monzino, Milano; Roberto Latini, Laboratory of Cardiovascular Pharmacology, Istituto Mario Negri, Milano; Marco Giorgio, IFOM-IEO Campus, Milano. A new avenue of research oriented to the study of endothelial modifications possibly related to cardiotoxicity related inflammatory proteins production enhanced by different chemotherapic agents has initiated in collaboration with Istituto Clinico Humanitas – Milan (Scientific Direction Prof . Alberto Mantovani). Cardiotoxicity Treatment: chemotherapy induced cardiotoxicity can result in a cardiomyopathy to be irreversible and leading to congestive heart failure and death; in our experience most patients receiving adequate treatment (including beta-blockers, ACE-inhibitors, diuretics, anti-aldosterone agents) expressed relevant improvement in clinical status and cardiac function; the efficacy of ACE inhibitors and betablockers has been proven in the clinical setting of either high dose chemotherapy and conventional antiblastic treatments; Cooperative protocols were initiated in collaboration with Centro Cardiologico Monzino - Milan (Intensive Coronary Care – Dr. Giancarlo Marenzi) and San Raffaele Hospital – Milan (Hematoncology and Bone Marrow Transplantation Unit – Dr. Fabio Ciceri). In 2009: a) the Unit successfully organized the fourth cycle of the “Incontri di Cardiologia Clinica”, 15 monographic workshops with invited guests discussing specific cardiological or cardio-oncological issues. b) Ready to be opened in 2009 the first Italian “Centro di Cardioncologia” (Dr. Daniela Cardinale) that will take care of all the comprehensive cardiologic and oncologic comorbidities aspects, statistically increasing in the overall population), and the “Centro Antifumo” (Dr. Giuseppina Lamantia) as a new antismoking activity strongly integrated to the clinical and research activities of the Cosmos protocol for the early diagnosis of lung cancer in smokers (Dr Giulia Veronesi).

c) In September 2009 at EIO the first International Congress on Cardioncology was successfully organized and the International Cardioncology Society (ICOS) was founded ( The clinical and scientific rational of ICOS is due to the fact that an increasing number of patients is presenting oncologic and cardiologic comorbidities , this because of an increasing number of long-term cancer survivors, the aging of the population, as well as the increased incidence and prevalence of oncologic and cardiologic comorbidities. Accordingly, in order to provide the optimal treatment in every situation, there is a fast growing need for comprehensive and proficient management of patients who host the two comorbidities and for those cancer patients condemned to be located in a scale of higher risks in developing cardiovascular problems because of their clinical history and oncologic treatment. A multidisciplinary approach to avoid the possibility that the development of a second disease leads to a reduction of therapeutic opportunities for cancer patients has become a major clinical goal. Cardioncology, a new medical issue aims at investigating: New strategies for early, pre-clinical diagnosis of chemotherapy related cardiotoxicity Evidence-based indications for cardiovascular follow up of different cancer treatments with “old” and “new” pharmacological drugs. Risk stratification and prevention of cardiac effects of cancer multiple, combined and sequential therapeutic strategies Interdisciplinary expertise needed to face combined cardiac and oncologic comorbidities All aspects concerning the concomitant presence of primary or secondary heart (myocardial and pericardial) involvement.

monoclonal antibodies and target therapies) Radiotherapy Immunoradiotherapy Locoregional treatments High-dose chemotherapy Multiple, combined and sequential cancer treatments; It promotes basic biology research on anticancer drugs mechanisms of cardiotoxicity focusing on inflammatory and metabolic pathways involved in heart damage Primary heart tumors Metastatic heart tumors Pericardial diseases and intrapericardial chemotherapy for pericardial effusion and more in general all the potential relations between cancer and cardiovascular diseases. The educational purposes of the Association are: To create and promote communication and cooperation between cardiologists and oncologists To create skilled consultants for the evaluation and management of cardiovascular problems in cancer patients To increase awareness of cardiologists and oncologists committees towards the management of cardiotoxicity issue. To promote basic clinical research in the field of cardiac and vascular/endothelial implications caused by oncological treatments. To develop guidelines, which are lacking at the moment, for cardiac monitoring of cancer treatments. There is a need to create and train a new generation of basic scientists and clinicians in the field of Cardioncology, who could build up a “medical synthesis” and a “common sense” and would be able to treat and prevent comorbidities, as well as to remove obstacles from the way to translational medicine.

The International Cardioncology Society promotes training and studies in the fields of: Cardiological and oncological comorbidities Cardiological implications of oncological treatments as: Chemotherapy, medical treatments (such as the use of

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Division of Radiology Massimo BELLOMI, MD Director

STAFF Deputy Directors: Lorenzo Preda, MD, Gaetano Villa, MD, Elvio De Fiori, MD Assistants: Paolo Della Vigna, MD, Lorenzo Monfardini, MD, Giuseppe Petralia, MD, Cristiano Rampinelli, MD, Stefania Rizzo, MD, Luigi Funicelli, MD Registrars: Sarah Brambilla, Stefano Viotti, Federica Lanfranchi, Marina Maniglio, Maurizia Bergamasco, Maddalena Belmonte, Milena Galardo, Stefano Meroni, Marta Gullo, Francesca Priolo Research fellows: Luke Bonello, Moreno Pasin, Paul Eugene Summers Postgraduate Students: Rahali Leila – Sosnovskikh Irina Director’s Secretary: Irene Cleopazzo Head Secretary: Adriana Barioli Secretaries: Barbara Bontempi, Maddalena Ferla, Barbara La Mantia, Sabrina Riboni, Roberta Torre, Clerici Alessandra, Calò Sonia, Lonati Paola Data Manager: Letizia Sirica Secretary, Clinical Studies: Giovanna Ciambrone Administrative Clerk: Anna Palmeri Chief Technician: Giuseppe Bardo Technicians: Emanuele Addonizio, Dario Ardizzone, Nicola Balestreri, Giuseppe Bonfitto, Roberto Di Filippi, Alessandro D’Incecco, Simone Fasulo, Roberto Labruna, Ferdinando Laserra, Manuela Martino, Obregon Valeria, Gabriella Perrone, Ubaldo Piccolo Longo, Filippo Raccosta, Cinzia Resta, Riccardo Simone, Emanuella Veneziano Students, School for Technicians: Michela Cerutti, Fabio Di Bella, Salvatore Savara, Giovanni Schifano, Liana Tina, Vincenzo Caruso, Helena Cipolla, Angela Di Martino, Manuel Salerno Nurses: Claudio Acerbi, Lorenza Ambrosino, Dario Fusè, Nicola Sciancalepore, Pasqualina Sorighe Auxiliaries: Alessandro Napoli, Vincenzo Forcinito, Mariano Garcia, Ylenia Soldati, Sonia Stroppa

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Activities 2009. In 2009 the continuous increasing of clinical activity, observed through the previous years, has been confirmed and a total number of 94.600 diagnostic examinations, visits and interventional procedures were performed. The clinical activity is more and more integrated with clinical and basic research: 7.400 (8%) of the examinations were performed in patients enrolled in clinical trials. The installation of a new digital fluoroscopy completed the renewal of the digital diagnostic fleet, and the PACS (Picture Archive and Communication System) has been implemented with a CAD (Computer Aided Diagnosis) for detection and follow-up of lung nodules. We are co-operating with the company (Median, France) in order to develop a similar system for monitoring volumetric changes that occur during therapy in liver metastases and lynphnodes. The co-operation with industries and with other research Institutes, such as Ist. Mario Negri in Bergamo and Ist. Neurologico Mondino in Pavia, led us to develop and experience new sequences in MRI, also thanks to a research agreement with Siemens, a new software in US imaging and to the co-operation with Esaote. The research activity can be described according to five different topics: non conventional imaging, lung cancer, tumors imaging, breast cancer, biopsy and interventions. Non conventional imaging researches deal with studies on perfusion (both by CT and MR), Diffusion (DW-MRI) and MR- Spectroscopy, aiming to define standard protocols, validate techniques by assessing their reproducibility, and underline the potential of the integration of different techniques. The method to analyze neoplastic tissue perfusion by CT (CTp) was defined, assessing the reproducibility in a high number of examinations and the variability derived from different factors (as the contrast medium injection, choice of arterial input, timing of observation and others). The technical protocol has been approved by consensus in an international meeting organized and published by our team. The clinical impact of the technique was confirmed by demonstrating its accuracy in monitoring the changes induced

by chemotherapy in patients with SCC of the upper aereodigestive tract, and its correlation with the changes in volume. The research on imaging of lung cancer is mainly based on our observational study in a cohort of 6.000 high risk volunteers who are receiving (some from 2000) an yearly low-dose CT for early detection of lung cancer (COSMOS project). We published some preliminary data showing that we detected 212 cancers (72% in stage I) and demonstrated a relatively high incidence (mean 4%), lasting for the 10 years of maximum observation. Five years survival rate of patients with lung cancer detected at screening CT is 63%. Based on the data from this cohort, we studied the reproducibility and accuracy of semi-automatic volume measure-

ments of lung nodules, being the most diffused feature used in diagnostic work-up to determine the nature of screening detected lung nodules. We demonstrated that variation in nodule’s volume smaller than 30% can not be assumed as significant for the diagnosis of malignancy. Another important research was based on the COSMOS study: the analysis of the CT data sets of three subsequent years, led us to demonstrate a significant worsening of emphysema, in terms of 30% increase, in those volunteers who kept on smoking, compared with a 15% increase calculated in those who stopped smoking. This is the first report demonstrating the evolution of emphysema in relation to smoking. Research on the wide field of tumor imaging led us to dem-

83 IEO — Scientific Report 2009 — Ongoing research 2010

onstrate the role of Multidetector CT and PET\CT in diagnosis of peritoneal seeding from ovarian cancer, describing the main features characteristic of the disease and assessing the equivalent accuracy of the two techniques. In another paper we demonstrated as benign splenosis can mimic peritoneal seeding, warning the Radiologists on the characteristic CT features of the two different pathologies. MRI appearance of a rare disease, as cothylenoid dissecting leiomioma of the uterus and MRI imaging of bile ducts tumors, were also described in detail in two other papers. As regards to breast cancer imaging, we described the MRI features of breast primary lymphoma in the widest series of patients reported in literature, demonstrating that this diagnosis should be taken

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into consideration when a large breast enhancing lesion demonstrates a plateau at delayed contrast-enhancement. This will spare delay and unuseful diagnostic work-up, addressing the patient to the proper therapy (chemio or radiotherapy), and undergoing to an histopathologic evaluation rather than a cytological aspiration, for an accurate subclassification of NHL. We also described the important role of Ultrasound guided vacuum assisted breast biopsy (VAAB) in the assessment of C3 breast lesions at Ultrasound guided fine needle aspiration citology: the clinical management of this category of patients is challenging, and no consensus exists in scientific community on the opportunity to address them to surgical biopsy. We demonstrated that VAAB is

feasibility, safety and accuracy of an innovative technique to biopsy laryngo-hypopharyngeal lesions using Ultrasoundguided transcutaneuos tru-cut needle, thus allowing to spare surgical procedures in patients with difficulties in laryngeal intubation due to the tumor, and reducing time, costs and risk to obtain a definitive diagnosis. In 2009 the Radiologists of the Division contributed to the publication of 29 scientific papers, for a total gross IF of 99.539. The Division of Radiology is member of the European Institute of Biomedical Imaging Research, and strict co-operation, in research and medical education, is maintained with the Royal Marsden Hospital in London and Massachusetts General Hospital in Boston. The Division is deeply involved in educational programmes, being part of the teaching activities of the School of Medicine, School of Radiographers, Post-graduate School of Radiology and Master in Senology of the University of Milan and of ESOR (European School of Radiology). In 2009 we organized 7 residential courses, with a total of 62 ECM credits.

very accurate in defining the diagnosis and addressing the patient to the correct therapeutic approach, with a reduction in time and costs compared to surgery. In the field of biopsy and interventional radiology we published the results of two leading clinical researches on Central Venous Catheters (CVC) placement. A randomized trial succeeded in demonstrating that the best insertion site to prevent catheter-related complications, in adult patients who need cancer therapy, is the subclavian vein. A retrospective analysis, on a large series of cases, demonstrated the safety of non-tunneled central venous catheter placement under ultrasound guidance in cancer patients with coagulation disorders. Finally we demonstrated the

85 IEO — Scientific Report 2009 — Ongoing research 2010

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of surgical biopsy. Therefore percutaneous biopsy is a valid alternative because of high accuracy, low costs and less emotional and aesthetic impact for patients. Another study compared imaging between traditional radiotherapy after surgery and intra-operatory radiotherapy (IORT) in patients who underwent conservative breast surgery for breast cancer. Radiological findings were different in the two groups. In particular, IORT is correlated with larger areas of liponecrosis, especially in patient with fatty breasts.

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Unit of Interventional Radiology Franco ORSI, MD Director

STAFF Senior Assistants: Guido Bonomo, MD, Paolo Della Vigna, MD, Lorenzo Monfardini, MD Fellow: Gianluigi Orgera, MD Technicians: Ubaldo Piccolo Longo, Simone Vito Fasulo Secretary: Adriana Barioli Nurses: Claudio Acerbi, Lorenza Ambrosino, Nicola Sciancalepore, Dario Fusè

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Activities 2009.

Interventional Radiology (IR) is a modern branch of medicine, with a very high technology content, which deals with the minimally-invasivemanagement of clinical problems. It represents the union between instrumental diagnostics and clinical-surgical activity, coming from a super-specialized branch of Diagnostic Radiology. The role of Interventional Radiology in Oncology (Interventional Oncology) has rapidly grown both for invasive diagnostics (e.g. imaging-based percutaneous needlebiopsies) and mainly, for loco-regional therapies as therapeutic alternative to traditional surgical and medical treatments. Diagnostic and therapeutic procedures are performed with percutaneous approach (= through the skin and without surgical cuts), guided by instrumental methodologies as ultrasound, CT, MR and fluoroscopy (X rays). Precision and very low invasiveness represent the main features of this clinical discipline. Interventional Radiologist is, therefore, a clinician specialized in imaging methodologies which are employed for guiding very focused procedures Since November 2007 High Intensity Focused Ultrasound (HIFU) has been added to the IR-armamentarium of our Unit. Solid tumors can be ablated from outside the body by using ultrasound energy generated by a dedicated US-guided transducer. Ultrasound waves will focus their power within the target lesion (liver, pancreas, kidney, breast and bone). The Interventional Radiology Unit of the European Institute of Oncology deals with the management of clinical problems, from diagnosis (also by means of biopsy) to the loco-regional treatment of tumors, in multidisciplinary collaboration with surgical and medical departments. Minimally-invasive management of post-surgical complications, such as the control of hemorrhages and drainage of fluid collections is another field where IR is usually involved. As one of the first examples in Europe, the Interventional Radiology Unit in IEO manages also its own beds, which are reserved to the patients who will need an IR treatment.

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Division of Radiotherapy, Brachytherapy Unit and Molecular Imaging Unit Roberto ORECCHIA, MD Director

STAFF Deputy Director: Barbara Alicja Jereczek-Fossa MD PhD, Maria Cristina Leonardi, MD Senior Assistant: Giovanni Battista Ivaldi, MD, Roberta Lazzari, MD Anna Morra, MD, Andrea Vavassori, MD Assistant: Daniela Alterio, MD, Annamaria Ferrari, MD, Gaia Piperno, MD, Dario Zerini, MD Resident: Maria Bonora, MD, Alessandra Cocchi, MD, Anna Cocola, MD, Sara Colangione, MD, Veronica Dell’Acqua, MD, Paola Fanti, MD, Silvia Ferrario, MD, Federica Gherardi, MD, Barbara Vischioni, MD, PhD (until Nov. 2009) Fellow: Luigi De Cicco MD (until Sept. 2009), Alberto Iannalfi, MD, Antonio Laudati, MD (until Sept. 2009), Ilaria Meaglia, MD (until Nov. 2009), Flavia Serafini, MD (until Aug. 2009) Eleonora Preve, Ing. Bioengineering, (until Dec. 2009) Data manager: Cristiana Fodor, MSc MEDICAL Senior Deputy Director (until Sept. 2009): Mario Ciocca, MSc PHYSICS Deputy Director: Federica Cattani, MSc Senior Assistant: Raffaella Cambria, MSc, Cristina Garibaldi, MSc, Elena Rondi, MSc, Sabrina Vigorito, MSc Assistant: Stefania Comi, MSc Fellow: Marco Liotta, MSc Residents: Viviana Carillo, MSc, Rosa Luraschi, MSc TECHNICIANS (RADIOTHERAPY TECHNOLOGISTS, RTT)

Chief Technician: Ignazio Russo Assistant Chief Technician: Massimo Sarra Fiore, Andrea Guido Technician: Jennifer Bona Rivas, Lara Bianchi (until Oct. 2009), Yari Bontà (until Sept. 2009), Enrica Borghetti, Manuela Cannella, Lucia Casanova, Saudia Castagna, Fabiana Castelluccia, Gianluca Cristiano (until Dec. 2009), Guglielmo Gatto, Saverio Greco, Verlie Ann Jones, Olena Kuts, Assuntina Leppa, Francesca Picca, Alberto Rampinelli, Daniela Rozza, Margherita Sglavo, Andrea Vaccari, Ilona Vecchio

NURSES & Nurse: Rodolfo Cendamo, Cosimo Iaconisi, Milena Lucic, AUXILIARIES Livia Mariani (until Sept. 2009) Auxiliary: Barbara Mirrione, Nicola Peconio, Zollino Marinella SECRETARIES Secretary: Alessia Cattaneo, Ida Muraca Secretary, Reception: Maristella Bottalico, Andrea Cucchi, Laura Figgiaconi (until Oct. 2009), Nadia Zanoni

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Activities 2009. The Division of Radiotherapy is an academic department with around 65 employees including a staff of 11 radiation oncologists, 6 physicists and 1 bioengineer committed to the quality care delivery enhanced by research activities and resident and student education. The Division has the convention with the Faculty of Medicine of the University of Milan for postgraduate teaching in radiation oncology. The Division has the latest equipment available for the highprecision radiotherapy like Intensity Modulated Radiotherapy (IMRT, including dynamic arc IMRT using RapidArc technology), Image-Guided Radiotherapy (IGRT), respiratory gating, intraand extra-cranial stereotactic radiotherapy and 3-D conformal radiotherapy. There are 4 treatment planning systems (with image fusion modality), 2 computer tomography units and 3 linear accelerators for external beam radiotherapy. Two mobile linear accelerators are installed in the operating theatres for the intraoperative electron beam radiotherapy (IORT). Each external beam linear accelerator is equipped with one in-room ImageGuided Radiotherapy system (based on ultrasound imaging, computer tomography and X-ray system combined with a robotic 6-degrees of freedom treatment couch, respectively). The Record & Verify system, connecting all treatment planning systems to the 3 linear accelerators, ensures an automatic, fast and safe treatment delivery. Recently, an innovative Accuboost machine has been installed, allowing for mammography-based boost breast irradiation. High precision radiotherapy allows for excellent tumor targeting and maximum sparing of normal tissue. In consequence, several clinical protocols with dose escalation and accelerated hypofractionated schedules (higher dose per fraction, leading to the reduction of the overall treatment time) have been activated. In particular, the FAST project (Frazionamenti Accelerati dello Schema Terapeutico, i.e. Accelerated Fractionation of the Therapeutic Schedule) has been applied to the breast and prostate cancer. Apart from the hypothetical radiobiological advantages, FAST might significantly increase the patient convenience. Molecular Imaging Unit is involved in the research protocols on better definition of biological target volume, allowing for further improvement of radiotherapy precision. Brachytherapy Unit is a full-profile unit equipped with both low-, pulsed- and high dose rate systems. The unit is committed to the integrated approach in

the field of radiotherapy. Several clinical protocols are active with brachytherapy as a boost or exclusive treatment. In particular, prostate cancer patients are treated with exclusive interstitial implant or high dose brachytherapy combined with external beam irradiation, depending on the risk factors. Dedicated planning systems and treatment units allow for image-guided high-precision brachytherapy application. There is an excellent collaboration with other departments within the frame of the disease-specific multidisciplinary teams (see Clinical Research and Management Section). Such multidisciplinary approach allows in many clinical situations for less invasive therapy (organ preservation). Apart from high precision treatment and multidisciplinary approach, a lot of attention is given to the patient’s quality of life issues. An innovative approach to the advanced disease patients has been created (ARPAR, Ambulatorio di Radioterapia Palliativa Rapida, Out-patient Clinic for Fast Palliative Radiotherapy). The patient is examined by radiation oncologist within 96 hours from

the request and, if indicated, the treatment is initiated within 10 days. The Department has access to 10 Day Hospital Beds dedicated to the patients that require intensive supportive care during radiotherapy. The Department collaborates with the National Centre for Oncological Hadrontherapy (CNAO) in Pavia for the definition of the clinical research protocols on the particle therapy in selected cancer patients. There is also an active collaboration with the Department of Experimental Oncology, IEO investigating radiosensitivity of breast cancer stem cells. The Department is involved in several European Projects on improvement in radiotherapy for cancer patients. During 2009 more than 3100 new patients were treated in our Department. The highest proportion of patients has been treated for breast cancer (46%) followed by metastastic disease (22%) and prostate cancer (8%). More than 2200 patients received external beam irradiation, 834 patients - IORT (mainly for breast cancer) and the rest (116 patients) - brachytherapy. Educational activities of the Division include in-department teaching for pre- and postgraduate medicine, physics and biotechnology students and radiology&radiotherapy technicians (University of Milan and Politecnico of Milan). External educational activities include teaching within the programs of the European School of Oncology (ESO), the European Society for Therapeutic Radiation Oncology (ESTRO), the American Society of Therapeutic Radiation Oncology (ASTRO), the Italian Association of Radiation Oncology (AIRO), and the PTCOG (Proton Therapy Co-operative Group) and other national and international societies. Each year the Division hosts numerous visitors from radiotherapy and oncology centers from all over the world (including the fellowship program of the European Agency for Atomic Energy). The Division participates in the establishment of numerous national and international guidelines on cancer treatment. In research activities of the Division the emphasis is placed on breast cancer, prostate tumors and head and neck malignancies. The main aspects include new fractionation protocols, treatment accuracy, side effects and patient’s quality of life, combined modality approach (including organ preservation studies) and new prognostic and predictive factors. Every year the Division publishes about 30 full papers with an overall Impact Factor of over 160.

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Division of Endoscopy Cristiano CROSTA, MD Director

STAFF Co-Director: Giancarla Fiori, MD Senior Assistant: Davide Ravizza, MD Assistant: Cristina Trovato MD, Giuseppe de Roberto MD Data Manager: Darina Tamayo PharmD Secretary: Paola Colli, Elena Degani Head Nurse: Fiorella Zoccatelli Nurse: Irene Colli, Roberta Gilberti, Enza Filippi, Michela Gollo, Claudia Ziviani, Elisabetta Manetti, Maurizio Battaglino, Giuseppe Malacrinò Auxiliary: Dario Matesi, Julio A. Pariona Meneses

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Activities 2009.

The Division is a leading center for Colorectal Cancer Screening Programme. As part of ordinary activity are continuously included new and novel diagnostic-therapeutics technologies in the Digestive Gastroenterology, Biliar-Pancreatic and TracheoBronchial Endoscopy. The Division incorporated the Confocal Endomicroscopy for the “in vivo histology” of gastrointestinal pathologies during ongoing examination. On the other hand, nowadays, the Division offers the new advanced high-definition technologies using virtual chromo-endoscopy. We strongly believe that traditional endoscopy gives the opportunity of removing colonic polyps directly during examination, whereas virtual endoscopy, if polyps are seen or thought to be present, requires a second examination with a new cumbersome preparation. More than 9000 procedures were performed, including 4800 endoscopic operative examinations as polipectomy, mucosectomy and submucosal dissection of early cancer and large adenomas, debulking and stenting of malignancies, treatment of bleeding lesions, endoscopic ultrasonography with fine needle aspiration and management of benign gastrointestinal diseases. A new multicentric, randomised, double-blind study was carried out in order to evaluate a new reduced volume bowel preparation before colonoscopy. Another multicentric, randomised, double-blind chemioprevention study is going on in order to assess the antiproliferative effect and safety of Allopurinol on the adenomatous polyps of the colorectum. Reprocessing of endoscopic devices and patient’s monitoring before, during and after endoscopic procedures are relevant goals of the Division. Clinical, diagnostic and epidemiological studies are closely integrated with the clinical activity and are development in collaboration with IEO Divisions and Health and Research Institutes

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Medical Physics Guido PEDROLI, Dr.Phys Director

STAFF Senior Deputy Director for Physics in Radiotherapy: Mario Ciocca, Dr.Phys Deputy Director for Physics in Radiotherapy: Federica Cattani, Dr.Phys Senior Assistants for Physics in Radiotherapy: Raffaella Cambria, Dr.Phys, Cristina Garibaldi, Dr. Phys, Elena Rondi, Dr.Phys, Sabrina Vigorito, Dr. Phys. Assistant for Physics in Radiotherapy: Stefania Comi Dr.Phys Deputy Director for Physics in Nuclear Medicine: Marta Cremonesi, Dr.Phys Senior Assistant for Physics in Nuclear Medicine: Mahila Ferrari, Dr.Phys Assistant for Physics in Nuclear Medicine: Francesca Botta, Dr.Phys Deputy Director for Physics in Diagnostic Radiology and MR Imaging: Daniela Origgi, Dr.Phys Fellows for Physics in Radiotherapy: Marco Liotta, Dr.Phys, Rosa Luraschi, Dr.Phys, Viviana Carillo Dr. Phys Fellow for Physics in Nuclear Medicine: Amalia Di Dia, Dr.Phys Chief Technician: Annalisa Rossi

Activities 2009. Many diagnostic, therapeutical and research activities performed in the Institute involve the use of sealed and unsealed radioactive substances and of many types of ionising radiation producing equipments (X-ray tubes for diagnostic radiology, conventional and mobile linear accelerators for external radiotherapy, afterremote-loading equipment for brachitherapy with sealed radioactive sources). The contribution of the Medical Physics team is indispensable in order to guarantee the radiation safety of the exposed personnel and of the patients. Moreover, the team regularly and continuously cooperates with the Divisions of Diagnostic Radiology, Nuclear Medicine and Radiotherapy for setting up and optimising protocols for clinical dosimetry, for the development and the introduction into the clinical practice of new and advanced techniques involving the use of ionising and non-ionising radiation sources, for commissioning new equipments and for carrying out a constant quality control on the radiation sources and on the diagnostic imaging systems. In 2009, apart from the radiation protection and quality control procedures, the following routine activities involving the optimisation of diagnostic and therapeutic procedures were performed: - calculation of treatment plans for conventional external radiotherapy, stereotactical radiotherapy, multiple arcs prostate radiotherapy, IORT (Intra Operative Radiation Therapy), conventional brachitherapy and brachitherapy with permanent implant of 125I seeds and TBI (Total Body Irradiation) treatments; - commissioning of a new linear accelerator equipped with RapidArc technique; - internal dosimetry evaluations for systemic and locoregional radionuclide therapies with agents radiolabelled with - emitters, (such as 90Y-avidin-biotin-MoAbs, 90 Y-avidin-biotin and 90Y and 177Lu-peptides); leakage monitoring in perfusion procedures.

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Research activities were directed to: - optimisation of IMRT (Intensity Modulated RadiationTherapy), IGRT (Image Guided Radiation-Therapy) and extra-cranial stereotactical treatments with "deep inspiration breath hold"; - IART (Intraoperative Avidination Radionuclide Therapy); radiobiological models in radionuclide therapies; study of the effect of multi-cycle approach to radionuclide therapy, especially radiopeptide therapy and radioembolization of liver tumours with 90Y-resin microspheres; red marrow dosimetry in radioimmunotherapy; - implementation of a software for the analysis of the activity distribution in scintigraphic images and for the evaluation of dose distribution at the voxel level (voxel dosimetry); analysis of the dose- volume histograms, biological effective dose histograms and Equivalent Uniform Dose; - development of a software for the segmentation of PET

volumes and evaluation of standardized uptake value in 18 F and 68Ga-tracers to facilitate patients’ diagnosis and follow-up assessment; - implementation of Monte Carlo methods (PENELOPE and FLUKA codes) to simulate radiation paths and to calculate absorbed doses in clinical practice (systemic and locoregional therapies); PET image analysis and quantification of 18F- and 68Ga-tracers in the 3D mode vs. the 2D mode; radiation protection evaluations related to patients undergoing therapies with 90Y- and 177Lu-radiopharmaceuticals; - optimization of patient dose in screening and follow up procedures with multislice CT. A new radioluminescent dosimeter, developed by the Department of Materials Science of the Milano-Bicocca University, is being tested with the different radiation sources available in the Institute in order to evaluate its practical use.

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Division of Anaesthesiology and Intensive Care Marco VENTURINO, MD Director

STAFF Codirector: Antonella Tosoni, MD Senior Deputy Director: Giovanni Francesco Manfredi, MD, Marco Tullii, MD Deputy Director: Anna Attanasio, MD, Marilia Bedoni, MD, Roberto Capucci, MD, Laura Della Grazia, MD, Francesca De Lucia, MD, Rita Panzeri, MD, Daniele Sances, MD Assistant: Michela Acciaro, MD, Alessandro Acerbi, MD, Pierantonio Beccalli, MD, Ferdinando Bellotti, MD, Marta Maria Bizzarri, MD, Daniele Boninsegna, MD, Lorenzo D’Acquisto, MD, Davide Galli, MD, Antonio Pinna, MD, Gianluca Spano, MD, Donatella Sparicio, MD, Maria Paola Solinas, MD, Dario Vezzoli, MD Secretary: Maria Rosa Brambilla OPERATING Head Nurse: Laura Ogliari THEATRE Nurses: Paola Agnello, Paola Alghisi, Chiara Arnaboldi, Davide Astolfi, Emanuela Ardau, Danilo Autelitano, Monica Azzolino, Alessandro Banzi, Luca Benatti, Sabrina Bellotto, Maria Grazia Busso, Vincenzo Buscema, Rosario Caruso, Daniela Cataldo, Filiberto Cataldo, Gianna Comandi, Gianluca Cherchi, Suzanna Drakula, Donatella Daniele, Luca De Francesco, Leonardo Del Grosso, Sebastiano De Luca, Giorgio Dentale, Pierpaolo Di Pierro, Antonio Folino, Sabrina Galbiati, Stefania Gentile, Ornella Gioia, Massimiliano Granata, Marina Gritti, Stefania Guerini, Angela Hotea, Andrea Incrocci, Piergiorgio Labò, Silvia Lacchini, Marisa Lamberti, Lucia Latiano, Danuta Lichosik, Emanuela Losio, Federica Macciola, Giorgio Manelli, Mariane Manolova, Laura Mantoan, Manuela Marzocca, Montagna Veronica, Rosetta Murgida, Clara Nadali, Debora Negri, Francesco Perego, Emanuela Pisati, Alma Porta, Maria Rosa Previdi, Luisa Rizzi, Eugenio Romano, Stefano Ronca, Stefania Sacchi, Samira Sallak, Irene Scarlino, Monica Scotti, Fabiana Sechi, Dorota Sobiesak, Carlotta Testa, Renata Trombi, Chiara Varisco, Ettore Vettore, Valentina Zucca Auxiliares: Bonomi Giacomo, Blini Claudia, Chilan Ortiz Francisca, Coppola Gino, Feniello Giuseppina, Massetti Giuseppe, Palmas Marisa, Preutesey Silviya, Rossi Aldo, Russo Anna, Rutolo Cristina, Soranno Rosa Bitzova Jenny, Chilan Ortiz Francisca, Feniello Giuseppina, Palmas Marisa, Preutesey Silviya, Rossi Aldo, Russo Anna, Rutolo Cristina, Tarantino Cinzia, Tenca Cristina, Zollino Marinella Head Nurse: Cristina Simone INTENSIVE Nurses: Alessandro Bracchi, Elio Censori, Adriano Francavilla, CARE Antonino Giacalone, Andrea Gullotta, Antonio Lutzu, Chiara Mauri, Silvia Mauri, Raffaele Pasquariello, Barbara Pilan, Luisella Ruzza, Sandro Sanna, Giovanni Vasaturo Auxiliaries: Laura Arena, Valentina De Marchi, Sabrina Laurello

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Activities 2009.

In 2009 surgical activity at IEO has performed more than 11.000 operations. According to different kind of surgery, techniques of either general or locoregional anaesthesia are used. A computerized monitoring system collects data from all devices connected to patients and to records the anaesthetic procedures. An outpatient’s department is activated for the preoperative assessment of patients that need surgical operations: in 2009 about 61% of the patients submitted to surgical interventions has been checked in this department. In 2009 the robotic surgery has been increased, since we have performed 400 interventions with this technique. According to IEO project called pain-free hospital, specific attention is paid to treatment of postoperative pain. The anesthesiologists is also involved in the safety management of operating room and collects data about adverse events, in order to develop always safer protocols. The activity of the Intensive Care Unit is mainly devoted to post surgical patients. In the 2009 the ICU accepted 633 patients. The ICU is equipped with eight beds provided with complete invasive and non-invasive monitoring and with ventilators able to support different modalities of invasive and non invasive ventilation. An isolated room is also available for patients affected by immunodeficiency. Specific beds are also available to avoid decubitus problems. In addition to usual invasive and non-invasive hemodynamic monitoring systems, new devices are available for monitoring hepatic and hemodynamic functions like PiCCO system and LiMON. Continuous hemodiafiltration is used as part of treatment of patients with acute renal failure, particularly in patients affected by sepsis. Clinical information about ICU patients is collected by a customized database. Special attention and studies are payed about new development about the quality of life of ICU patients and their par-

ents. The functional recovery of critical patients is seeked with the dedicated physiokinesitherapists’ collaboration. The anesthesiological staff is trained to perform Transesophageal Echocardiography both in operating theatre and ICU as well and the Division also organizes an annual teaching event about it. The staff is also trained to perform awake intubation with fiberoscopy and to safely manage difficult intubation with many different devices. In this year we have developed a special formation for

medical staff about the vessels cannulation by echographic support. Anaesthesiologists also support invasive radiological and endoscopic procedures with Monitored Anaesthesia Care or sedation techniques as well as regional or general anaesthesia if required. They also perform central venous catheterization for chemotherapy, plasmapheresis and total parenteral nutrition. In 2009 anesthesiologists were involved in the starting of HIFU activity and into the project and definition of a new day surgery structure.

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Division of Senology Alberto LUINI, MD Director

STAFF Co-Director: Stefano Zurrida, MD Director Molecular Senology Unit: Viviana Galimberti, MD Director Integrated Breast Surgery Unit: Paolo Veronesi, MD Deputy Directors: Mattia Intra, MD, Oreste Gentilini, MD, Annarita Vento, MD Assistants: Simonetta Monti, MD, Paolo Arnone, MD, Fabio Bassi, MD, Piero Caldarella, MD, Gabriel Farante, MD, Giovanna Gatti, MD, Paola Naninato, MD, Gianmatteo Pagani, MD, Antonio Toesca, MD, Francesca Magnoni, MD, Loredana Burgoa, MD, Germana Lissidini, MD Fellows: Paola Baratella, MD, Yellow Helio Rubens De Oliveira, MD, Luciana De Brito Lima, MD, , Denise Mattar, MD, Nicholas Peradze, MD, Paola Andrea Ponzi, MD, Silvia Velpidia Ratini, MD, Andrea Sagona, MD, Manuela Sargenti, MD, Ailyn Vidal Urbinati, MD, Dalila Vidalle, MD, Chifu Camelia, MD,Antonini Cinzia, MD, Soggiu Fiammetta, MD,Baffa Giulia, MD, Maria Milanesi, MD, Gerosa Martino, MD, Conceicao Maria Fraga Guedes, MD, Devasconcellos Golin Paula, MD Secretaries: Patrizia Bonezzi, Manuela Butti, Elena Cassi, Vittoria Rossi Datamanager: Claudia Sangalli Fellow Datamanagers: Simona Musmeci, Francesca Zucca Head Nurse: Luigia Rubio Nurses: Paola Bernasconi, Stefania Bruletti, Federica Chiesa, Salvatore Concadoro, Paola Console, Caterina Cubeddu, Pasquale Di Biase, Rachida Hatzmi, Roberta Malerba, Simone Manera, Francesca Marzocco, Monica Mauri, Lira Milagros, Giuseppina Mulinello, Quinto Nori, Barbara Rossetti, Elena Rocca, Annarita Tarantino, Antonella Tagliente, Katia Venditti, Iwona Wardzinska Auxiliaries: Chiara Agratti, Tiziana De Benedittis, Luana Di Gilio Anna Maria Corapi, Patrizia Frigatti Alessandra Rubio, Rossana Vangelista

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Activities 2009. The Division of Senology consists of two operating units: the Unit of Molecular Senology and the Unit of Integrated Surgery. Both units are concerned with clinical research to develop new surgical techniques to improve the effectiveness of treatments for breast cancer that also preserve the integrity of the woman’s body. The Division of Senology played a major role in the development of sentinel node biopsy for breast cancer, performing pivotal clinical studies demonstrating that this technique is an accurate and minimally invasive method for staging the axilla. Sentinel node biopsy is now a consolidated part of the treatment of breast cancer worldwide, and is indicated for all breast cancer patients, except those in whom axillary metastases are already overt. Treatment of breast cancer needs to be integrated and multisciplinary. The co-operation between surgery, nuclear medicine and radiology led to the development of radio-guided occult lesion localisation (ROLL) and the use of sentinel node biopsy in conjunction with ROLL − a technique called SNOLL. Sentinel node biopsy employs a radioactive tracer which is injected close to the tumour and moves through the lymph ducts to the sentinel node making it visible on scintigraphy and locatable with a radioactivity-detecting probe during surgery. In ROLL, the radiotracer is not mobile and remains where it is injected. The ROLL technique is therefore used to precisely locate non-palpable breast lesions. The radiotracer is injected directly into the lesion under real time radiographic or ultrasonic control. In the operating room, the surgeon can therefore precisely locate the lesion using a hand-held gammadetecting probe, and use this probe as an aid to surgical removal. The SNOLL technique combines ROLL (injection of immobile tracer to localize the primary lesion) with injection of a mobile tracer to localize the sentinel node. The injections are performed separately but both the

impact of micrometastases in the sentinel node. In this study, which is going to be completed in early 2010, patients with micrometastases in the sentinel node are randomized to receive either axillary dissection or no further axillary surgery.

non-palpable lesion and the sentinel node are removed in a single surgical session. If the patient has a prior malignant diagnosis (for example by core biopsy) or malignancy is ascertained by intra-operative histological examination of the ROLL specimen, then the entire surgical treatment (lesion removal, sentinel node biopsy and axillary dissection, if necessary) can be completed in a single surgical session. Moreover in order to further minimize surgical treatment, a prospective randomized trial designed within the International Breast Cancer study Group (IBCGS) is ongoing with the aim of evaluating the prognostic and biological

Intraoperative radiotherapy with electrons (ELIOT) was developed by the Division of Senology in conjunction with the Radiotherapy Division. ELIOT delivers a complete radiotherapy course in a single dose during surgery. It can also be used to give a boost dose to shorten the subsequent course of conventional radiotherapy. The breast area from which the cancer has been removed is targeted using special electron beam-guiding equipment and chest protection techniques. The first single-centre randomized trial on ELIOT was completed in December 2007. For this trial the Division recruited 1306 patients undergoing conservative surgery for breast cancer, and randomized then either to traditional external radiotherapy or ELIOT. Follow-up is ongoing but preliminary results are very encouraging. ELIOT is also being tested in patients with limited ductal intraepithelial neoplasia (DIN) and those undergoing nipple-sparing mastectomy. Nipple-sparing mastectomy is a surgical technique developed in order to spare the nipple-areolar complex in patients requiring mastectomy. ELIOT is used to irradiate the nipple-areola complex to ensure that it can be safely conserved . A further technique under development from the beginning of 2008 in conjunction with the Division of Nuclear Medicine is intraoperative avidination for radionuclide therapy (IART). Avidin is injected intraoperatively in and around the tumour bed after cancer removal performed by an usual quadrantectomy. Later, radiolabelled biotin is injected intravenously. The biotin binds to the avidin in the tumour bed, bringing with it a significant quantity of radionuclide whose radioactive decay contributes to killing of residual tumour cells. In preliminary studies, scintigraphic images demonstrated fast and stable uptake

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of radiolabelled biotin at the site of the operated breast, while the radiation dose released to the breast area was over 5 Gy/GBq, consistent with a boost of 20 Gy. These encouraging results have stimulated a feasibility study for IART. One of the most promising and intriguing new techniques is the use of high intensity focused ultrasound (HIFU) to treat patients with early breast cancer. HIFU is a completely non-invasive method in which ultrasound is used to guide the focusing of high intensity ultrasound energy to a precisely circumscribed area of tissue within the body, resulting in coagulation necrosis within few seconds. We are now using HIFU on a selected and

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limited number of patients prior to surgery. Surgical resection of the treated lesion takes place at least a week later, to evaluate residual viable tumour and extent of necrosis. Preliminary and initial findings, which need to be confirmed on a large basis, indicate that HIFU is a feasible method without major side effects. The Division of Senology collaborates with the Division of Molecular Carcinogenesis and Stem Cell Biology Research in pivotal research on the NUMB protein. NUMB controls the fate of cells during development and differentiation via a mechanism involving inhibition of the activity of plasma membrane receptors of the NOTCH

family. Research at the IEO discovered a new function of human NUMB: it is a regulator of p53 cancer protein, and this finding might have potential therapeutic implications for cancer treatment. To achieve the best cosmetic outcomes of breast surgery, the Senology Division routinely offers plastic reconstruction. When mastectomy is necessary, it can be directly followed by immediate breast reconstruction. In patients undergoing conservative surgery in whom a subsequent asymmetry can be estimated, a bilateral reshaping can be performed to ensure the best possible cosmetic outcome. We collaborate with other research and clinical Divisions of the IEO on a daily basis. This co-operation has proved

very fruitful in research terms, with Senology staff authoring/co-authoring 28 medical/scientific papers in 2008, for a combined impact factor of 125.8. Co-operation has also proved useful for developing clinical techniques that allow each breast cancer patient’s treatment to be personalized. The Division of Senology also remains committed to university and institutional teaching. Division staff teach course for Masters Degrees awarded by the Universities of Milan and Barcelona, and teach various other courses as well. The Division also conducts courses for general practitioners.

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Division of Plastic Surgery Jean Yves PETIT, MD Director

STAFF Co Director: Mario Rietjens, MD Senior Deputy Director: Cristina Garusi, MD Deputy Director: Francesca De Lorenzi, MD Senior assistant: Stefano Martella, MD Assistants: Andrea Manconi, MD, Benedetta Barbieri MD, Valentina Lazzati MD, Giuseppe Cuccia MD Residents: Daniel Barbalho, Yasser Mohmoud Specialty: school of plastic surgery: Hubner Arana Gabriel, Buscarini Alessia Visiting doctors: Giuseppe Lomeo, Visnu Lohsiriwat, Anurag Khare, Jyranki Janne Secretaries: Sonia Boffini, Manuela Lavarone Data managers: Fabio Rossetto Head Nurses: Eleonora Meola Nurses: Irene Barillà, Grazia Basile, Roberta Campari, Desirée Del Grande, Sara Moia, Aldina Pavan, Jlena Pavic, Giulia Valente, Salvatore Lilliu, Najiba Sami, Cristina Di Pasquale, Occhetti Elena, Paola Salvaderi, Paun Michaela Auxiliaries: Carmen Murroni, Addolorata Prete, Silvia Pucci, Girmay Shewit

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Activities 2009.

The Division of Plastic Surgery is dedicated to the improvement of the quality of life of the patients treated for a cancer at the EIO. Most of the reconstructive procedures are well-known and currently applied in our service since many years. However, the recent modification of the cancer protocols such as the irradiation of the thoracic wall in case of extensive involvement of the axilla, led us to question the indications of immediate breast reconstruction. We are studying two stage procedure using the short expansion with an expander introduced at the time of the mastectomy and a replacement by an autologous reconstruction as soon as we are informed of the lymphnode status. Also the reshaping of the conservative surgery (so called oncoplastic surgery) with prosthesis implantation can be done safely now that the protocol of radiotherapy includes more frequently, the intra operative irradiation which decreases the risk of post radiation capsular contracture. The Nipple Sparing Mastectomy protocol is going on rapidly since we gathered up to now more than 1700 cases in 7 years. Four studies will be send for publication this year dedicated to the local recurrences, to the delayed radiotherapy, to the global experience of the IEO and finally to the psychological improvement of the nipple areola preservation. Concerning the technique of reconstruction with latissimus dorsi, a database of 260 flaps has been set up which gave us the opportunity of several national and international presentations and one paper which will be sent for publication in the early 2009. Our database of Tram flaps is made of 712. Our study on prosthesis physical and mechanical modifications after explantation is also going on thanks to the good collaboration with the Istituto Politechnico labs. The first results will be ready in 2010. Since one year we are using a new technique of lipofilling to improve the shape of the reconstructed breast without removing the implant. This technique provides

many opportunities of clinical research, especially concerning the selection of stem cells. At the end of 2009 a database of around 700 lipofillings has been set up. A prospective study concerning lipofilling in case of conservative treatment will be proposed to other international teams to gather a number of case well followed oncologically to prove the safety of the procedure. Plastic surgery is also required after other cancers such as head and neck, thoracic, gynaecologic and soft tissue tumors where the large defects created by the tumour removal should be reconstructed with a large armamentarium of flaps including microsurgery or endoscopic techniques.

Microsurgery at the IEO is developed as a multidisciplinary surgery remaining at the disposal of the different specialties, (head and neck, plastic, thoracic gynaecologic, general surgery and skin and soft tissue surgery. Plastic surgery not only improves the quality of life of cancer patients but also provides a better surgical excision of the tumours by the cancer surgeon who knows that the reconstruction is available immediately in the same time of the cancer treatment. Fifteen articles have been published in 2009 on peerreviewed journals and one in a book on breast surgery.

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Melanoma and soft tissue sarcomas Alessandro TESTORI, MD Surgical oncologist, Director

SURGERY Assistant: Francesco Verrecchia, MD STAFF Assistant: Marco Rastrelli, MD (up to August 2009) Fellow, school of general surgery University of Genova: Giulio Cesare Vitali, MD Fellow, school of general surgery University of Milan: Javier Soteldo, MD ONCOLOGY Deputy Director: Pier Francesco Ferrucci, MD STAFF Assistant: Alessandra Di Pietro, MD Psyco-oncologist: Beatrice Colombo, MD Fellow: Chiara Martinoli, PHD, Biologist DERMATOLOGY Senior Assistants: Federica Baldini, MD, Massimo Mosconi, STAFF MD, Giulio Tosti, MD Fellow: Giuseppe Spadola MD STAFF Secretaries: Semhar Berhane, Monica Burla, Barbara Bottari Data Managers: Francesco Cataldo, Ines Tedeschi Research Nurses: Chiara Pari, Claudia Passoni Foreign annual fellows: Deyana Salazar, MD, Pathologist, Kaline Ferraz, MD, Dermatologist

Activities 2009.

The Division is devoted to the diagnosis and treatment of neoplastic diseases of the skin and of soft tissue. The spectrum of the Unit activity ranges from the dermatologic education of the general population, to the surgical and medical treatments of melanoma and soft tissue sarcomas. Surgical treatment of melanoma and other cutaneous lesions ranges from diagnostic excisional biopsies, to radical excisions and sentinel node biopsies to complete lymph-node dissections in the case of metastatic spread to the nodes, isolated limb perfusion (with Melphalan and TNF when indicated) and electrochemotherapy, both characterized as an interesting approach in the treatment of non operable recurrences. The Melanoma Working Group is currently active with surgical, chemoand immunotherapeutic trials dedicated to each melanoma stage. The most recent and ongoing Melanoma clinical trials are described in the dedicated chapter of the annual report. Concerning soft tissue sarcomas, the standard treatment includes surgical resection and different radiotherapeutic proposals ranging from brachytherapy to intra-operative radiotherapy (IORT) or external beam radiotherapy. The treatment approach is multidisciplinary, mainly involving the divisions of radiotherapy for the intraoperative treatments, and medical oncology for neo-adjuvant chemotherapy. Isolated limb perfusion with TNF and electrochemotherapy have also been implemented in order to offer patients the last surgical technologies in a curative or palliative approach, while the division participates in clinical trials dedicated to the evaluation of the role the most recent therapies proposed in our experimental setting. In 2009 more then 8000 patients were examined in the out patient clinics. The division has a dedicated operating room three days every week for local anaesthesia procedures and once a week for general anaesthesia. The surgical procedures

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conducted on melanoma patients were 305, following a diagnosis of sarcoma 20 patients were operated, 180 for non melanoma skin cancer and 395 related to various cutaneous lesions. The procedures under general anaesthesia were 192 and local anaesthesia 995. During 2009, the Division published 22 articles on peerreviewed journals with a general impact factor of 80.

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Division of General Surgery Bruno ANDREONI, MD Director

STAFF Director Minimally Invasive Unit: Paolo PIetro Bianchi, MD Senior Deputy Director: Antonio Chiappa, MD Assistants: Emilio Bertani, MD, Chiara Ceriani, MD, Residents: Gianmarco Contino, MD; Andrea Locatelli, MD; Pasquale Misitano, MD Medical Students: Carlo Corbellini, Claudia Barsalini, Vittorio Branchi, Fara Uccelli, Andrea Wimer Scientific Secretary: Nordiana Baruzzi Secretary: Paola Italia Data Manager: Rosalba Lembo, Irene Vetrano Secretary of the Lu.V.I. Foundation: Rocco Ditaranto Head Nurse: Liliana Tadini Nurses: Anna Brunoldi, Maura Facchinetti; Daniele Finco, Chiara Foroni, Nicola Fragale, Maryla Guzman, Pierpaolo Iozzia, Marina Mancini, Alessandra Marras, Lorena Murra, Cinzia Pellegrini, Debora Rosa, Iacob Daniel Radu, Gabriela Simion, Antonella Tamborrino, Antonia Tarantino, Auxiliaries: Milena Ladu, Julio Pariona, Cosimo Persichella, Emanuela Rizzi, Maria Rosaria Rizzi

Activities 2009.

The Division of General Surgery started its activities in 1994 through an agreement with the Milan University School of Medicine (Bruno Andreoni has been the Director of the Specialization School in General and Emergency Surgery for the last 6 years). The medical staff of the General and Laparoscopic Surgery has a documented clinical experience in the treatment of upper and lower gastrointestinal tumours (from the esophagus to the anus), including hepato-bilio-pancreatic, renal and adrenal cancers, abdominal sarcomas and neuroendocrine digestive tumours. All clinical activities are performed with particular attention to a multimodal, multidisciplinary approach, involving a close cooperation with medical oncologists, endoscopists, interventional radiologists and radiotherapists within the institutional “Digestive Tumours” Task Force. In 2009, 488 major surgical procedures were performed for: 109 colonic; 71 rectal, 5 oesophageal; 13 gastric and 6 pancreatic cancers. The Division has protocols and trials of preoperative treatments for locally advanced gastric and rectal cancers, and for liver metastases (in collaboration with the Divisions of Radiotherapy and Medical Oncology). In collaboration with the Divisions of Endoscopy and Pathology, the Division is involved in multicentric trials for the screening and treatment of colorectal cancers. In 2009, the Division of General and Laparoscopic Surgery conducted a number of studies, mostly in collaboration with the Division of Abdomino-Pelvic Surgery, namely: a study to evaluate the appropriateness of surgical procedures; a study to evaluate the “Effect of different mechanical bowel preparations in colorectal-cancer surgery”; a study on the “Detection and evaluation of circulating tumours cells (CTC) in patients undergoing curative surgery (open or minimally-invasive) for advanced rectal cancer detected through routine clinical practice”. Within the GISCoR network (Italian Group for Colo-Rectal

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Screening), the Division coordinated some multicentric observational trials on: “Predictive value of Sentinel Nodes in staging early colorectal cancer” ; “Endoscopic and Surgical Treatment of Rectal Cancer”. Enrollment in an observational trial on “Endoscopic Surveillance vs Surgery after complete polypectomy of a malignant polyp” closed in 2009. Other research programmes involve national and international partners in Italy, Europe, USA, Japan and Australia. A programme of international exchanges for postgraduate doctors and research fellows has been established with a number of National and International Institutions. In 2009, the Division published 13 full papers on peerreviewed journals, with an overall IF of about 35. The educational activities promoted by the Division include a number of University Courses (for Surgery Specialisation Schools, Masters, and Undergraduate Courses in Medicine).

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Division of Abdomino-Pelvic Surgery Roberto BIFFI, MD Director

STAFF Senior Deputy Director: Fabrizio Luca, MD Deputy Director: Simonetta Pozzi, MD Senior Assistant: Sabine Cenciarelli, MD Assistants: Manuela Valvo, MD Clinical Researcher (Fondazione IEO): Giuseppina Labagnara, MD (until Dec 2009), Danilo Umana, MD Research Fellow (Fondazione Umberto Veronesi): Tiago Leal Ghezzi,MD Data Manager: Irene Vetrano, MSc Secretary: Benedetta Clementelli Head Nurse: Liliana Tadini

Activities 2009. Clinical activities Established on May 2007, the Division of Abdomino-Pelvic Surgery carried out more than 500 major oncology surgical procedures during 2009, aimed at treatment of the following conditions: oesophageal, gastric, small bowel, colo-rectal, liver and pancreas carcinomas. In addition, staff Physicians have specific expertise and know-how in integrated surgical treatment of trunk and limb-roots sarcomas, gastro-intestinal stromal tumours (GIST), primitive and metastatic tumours located in kidneys and adrenal glands, neuroendocrine tumours of gastrointestinal tract. A significant portion of routine clinical activity involves close cooperation with other clinical Divisions (Gynaecologic Surgery, Thoracic Surgery, Urologic Surgery, Melanoma) in order to provide comprehensive care for oncologic diseases demanding skills and medical knowledge from different specialties (advanced ovarian carcinomas, oesophageal neoplasms extending into the abdomen, highgrade male pelvis tumours, visceral melanoma localizations). The activation in 2009 of the Ovarian Cancer Center for Excellence by the Gynaecologic Oncologic Surgery Division offered the opportunity for an even closer cooperation between gynaecologists and abdominal surgeons, as shown by more than one hundred surgical high-complexity procedures per year, carried out with a multidisciplinary approach. Therapeutic choices are routinely made in agreement with other specialists, such as oncologists, radiotherapists,

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endoscopists and interventional radiologists, by means of team case-discussing within a dedicated task-force. Taking responsabilities for highly complex oncology cases, a strong link with the Anestesiology and Intensive Care Division may be demanded, in order to provide intensive treatments for critically ill surgical patients. Minimally invasive colorectal cancer surgery using a surgical robot started during 2007, and a pilot study on robot-assisted rectal cancer resection using the da Vinci system, a newly developed four-arm robotic device, was concluded. More than 150 patients were so far treated with this technique. A paper, collecting the most relevant clinical series in the world of fully robot-assisted rectal and left colon cancer resection, has been published on Annals of Surgical Oncology-2009. On January 2010 a collaborative paper with US and Italian groups was published, again on Annals of Surgical Oncology, investigating the impact of robotic approach on mesorectal excision for cure of rectal cancer. Extension of this minimally invasive approach to other surgical oncology applications (stomach, adrenal gland, liver, spleen and pancreas) is currently matter of active clinical investigation. Finally, the Division maintained specific expertise on long-term central venous accesses for chemotherapy and total parenteral nutrition administration. A training course for physicians, dealing with diagnosis and treatment of complications associated with central venous access placement and utilization in oncology, was provided. In addition, a randomized three-arm clinical trial aimed at defining the best insertion site to the central venous system in order to perform long-term chemotherapy was concluded. This study, carried out in collaboration with the Medical Oncology, Psycho-Oncology and Interventional Radiology Divisions / Units at IEO, received a biennial research grant from AIRC (Associazione Italiana per la Ricerca sul Cancro). Final results have been recently published in a full paper on Annals of Oncology-2009. A second paper , investigating the impact of long-term central venous accesses on quality of life and anxiety-depression is under evaluation. Dr Biffi was member of the panel of international experts who provided guide-lines for this topic by ESPEN

(European Society of Clinical Nutrition and Metabolism, Clin Nutr 2009). Research Ongoing research activities of 2009 include the following: Surgical oncology of the gastro-intestinal tract: A study evaluating the efficacy of surgical treatment on gastric cancer enrolling 250 patients has been published by the Journal of Surgical Oncology in 2006. Staff Physicians actively cooperated in medical oncology research programs investigating the role and effects of adjuvant and neoadjuvant chemotherapy on colo-rectal primitive tumours and

hepatic metastases. Dr Biffi was Principal Investigator in a multi-center international randomized trial aimed at evaluating the impact of pre-operative docetaxel-based chemotherapy on locally-advanced surgically resectable gastric cancer. This study had the collaboration of the Medical Oncology Division and final data have been recently published on World J Gastroenterol. We concluded that surgery following docetaxel-based chemotherapy was safe and with similar morbidity to immediate surgery in patients with locally-advanced resectable gastric carcinoma. These data support the rationale for using preoperative chemotherapy in locally advanced, operable gastric cancer,

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A study involving the detection of HER2 expression in gastric carcinomas is ongoing, aiming at defining a possible therapeutic role of Trastuzumab in the neoadjuvant setting, after publication of a large international trial demonstrating a benefit from this drug for patients suffering from advanced/metastatic gastric cancer. Full Robot-assisted minimally invasive surgery for colon and rectal cancer: a pilot study was concluded, with the aim to evaluate safety and feasibility of this new system for left colon resection and total mesorectal excision, a recognized standard in rectal resection for cancer. Clinico-pathological data of 55 consecutive patients. who underwent full robotic

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surgery for the treatment of left colon and mid or low rectal cancer, were prospectively collected in a preliminary study. It showed full safety and effectiveness of this minimally invasive procedure, and was matter of a podium presentation at an International Meeting in Toronto and publication of a full paper in Annals of Surgical Oncology-2009. A second collaborative paper with US and Italian groups was published, again on Annals of Surgical Oncology, on January 2010. One hundred forty-three consecutive patients undergoing robotic treatment of rectal cancer in three centers were reviewed. Pathologic data, and postoperative and oncologic outcome measures were prospectively collected and analyzed by an independent researcher. Conversion rate

was 4.9%, mean blood loss was 283 ml, and mean operative time was 297 min. The number of harvested nodes (14.1 +/- 6.5) and margin status compared favorably with those of open series (mean distal margin 2.9 +/- 1.8 cm; negative radial margin in 142 cases). The 3-year overall survival rate was 97%, and no isolated local recurrences were found at mean follow-up of 17.4 months. These very promising data were matter of a podium presentation at the Annual Meetings of the most important international robotic surgery societies in Chicago and San Diego. A phase II trial, investigating the impact of this new approach on genital and urinary functions of patients undergoing this procedure for rectal cancer pretreated with a combination of chemo and radiation therapy is currently run. Totally implantable central venous access devices: a randomized three-arm clinical trial aimed at defining the best insertion site to the central venous system in order to perform long-term chemotherapy was concluded and final results published as a full paper in Annals of Oncology2009. Four hundred and three patients eligible for receiving i.v. chemotherapy for solid tumors were randomly assigned to implantation of a single type of port through a percutaneous landmark access to the internal jugular, a ultrasound (US)-guided access to the subclavian or a surgical cut-down access through the cephalic vein at the deltoid-pectoralis groove. We concluded that central venous insertion modality and sites had no impact on either early or late complication rates, but US-guided subclavian insertion showed the lowest proportion of failures. Further data dealing with psyco-oncologic evaluation and quality of life assessment are expected to be ready soon for publication. Artificial Nutrition in Oncology: Dr Biffi was IEO-appointed investigator in a multi-center Italian trial aimed at evaluating the effects on surgical morbidity of glutamine parenteral administration in oncology patients undergoing major surgical procedures. Trial was closed after reaching the required sample size (428 patients) and an original article was published on Annals of

Surgery -2009, indicating that perioperative glutamine does not affect outcome in well-nourished gastrointestinal cancer patients. In addition, Dr Biffi was Coordinator in a multi-center Italian observational study enrolling more than 200 seriously ill oncology patients undergoing oral omega-3 fatty acids supplementation therapy, to evaluate its effects on nutritional status and quality of life. Currently the Division is participating in a multi-center Italian epidemiological observational study on the prevalence of caloric-proteic malnutrition in the oncology outpatient setting (SCRINIO Project). Preliminary data were published on Supp Care Cancer – 2009. Finally, two randomized trial were concluded in collaboration with Gynecologic Oncologic Surgery Division, and the data were published as full papers in Annals of Surgical Oncology-2009. Early resumption of oral intake was showns feasible and safe in gynecologic oncology patients undergoing intestinal resection as part of a planned surgical procedure. Moreover, significant reduction in length of hospital stay was demonstrated. Venous thromboembolism in surgical oncology: Staff physicians carried out as IEO-appointed investigators a multi-center Italian observational trial, enrolling more then 2000 patients, aimed at defining the prevalence of deep venous thrombosis in surgical oncology patients. They also participated in a multi-center international trial, enrolling more than 25.000 patients, comparing two different strategies for pharmacologic prevention of venous thromboembolism in surgical oncology patients (Fondaparinux vs Dalteparin). Tumor lymphangiogenesis in gastric and colo-rectal cancer: a prospective study in collaboration with the Hemato-Oncology Division to investigate whether the extent of tumour lymphangiogenesis (in intratumour and peritumour tissues/areas) may be related to the risk for lymph node metastasis, distant metastasis and patient survival. Objective of this study is to evaluate the clinical and pathological significance of the tumour lymphangiogenesis in intratumour

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Minimally-Invasive Surgery Unit Paolo Pietro BIANCHI, MD Director

STAFF Senior Assistant: Chiara Ceriani, MD Resident: Andrea Locatelli, MD, Islam Abumalouh, MD

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Activities 2009. Since March 2008 a clinical Unit is dedicated to minimally-invasive surgery. Laparoscopic surgery is commonly applied to the treatment of all digestive tumors, especially to colorectal cancers, adrenal neoplasms and to the staging of advanced malignant diseases. The Resarch activity of the Unit is oriented to develop the technique of sentinel node mapping in colon cancer laparoscopically treated. A muticentre international trial on the prognostic value of micrometastases in sentinel node in colon cancer, is ongoing in cooperation with the McLaren Regional Medical Centre at the Michigan State University and the John Wayne Cancer Centre in Santa Monica (US). Another trial has started on laparoscopic radioguided detection of colon cancer with the use of a portable gamma camera. The aim of this trial is to evaluate the utility of radiotracers in detection of small colon cancer lesions during the minimally-invasive surgery and even to map the lymphatic pathway in order to study sentinel lymphnodes. This study is in cooperation with the Division of nuclear medicine. Another study has been recently closed and the paper is in review for publication on the “evaluation of circulating endothelial progenitors in open versus laparoscopic surgery”, the study has been done in cooperation with the laboratory Unit of Clinical Haematology-Oncology at the IEO. The Unit even participates also in the study “Evaluation of the clinical impact of inflammatory status induced by laparotomic and laparoscopic colorectal cancer surgery”, started in cooperation with IRCCS Istituto Clinico Humanitas. One prospective trial is on going on evaluation of minimally-invasive technique in the treatment of right colon cancer, the study evaluate two different techniques of laparoscopic resection with an intracorporeal anastomosis versus an extracorporeal anastomosis, and is in cooperation with the San Raffaele Hospital of Milano. The robotic surgery is a field of research of great interest in minimally-invasive surgery and many national and international cooperation have been established to

evaluate and promote the new robotic technologies. From January 2008 a prospective data base has been created to evaluate robotic surgery in the treatment of rectal cancer and a preliminary study on 50 patients of robotic versus laparoscopic total mesorectal excision in rectal cancer is closed and is in review for publication. The development of interventional radiology associated to laparoscopic surgery is another field of clinical research and in cooperation with the Unit of Interventional radiology a study on the evaluation of laparoscopic radiofrequency ablation of liver neoplasms was started. The Unit of minimally-invasive surgery is even dedicated to education training inside the IEO Academy program

of laparoscopic and robotic surgery. Training courses of colorectal oncologic laparoscopic surgery are activated with intraoperative training and direct view of the minimally-invasive operations and in the 2010 the courses of the school of robotic surgery will start.

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Division of Head and Neck Surgery Fausto CHIESA, MD Director

STAFF Senior Deputy Director: Mohssen Ansarin, MD Senior Deputy Director: Gioacchino Giugliano, MD Assistants: Roberto Bruschini, MDt, Enrica Grosso, MD, Augusto Cattaneo, MD, Valeria Navach, MD, Stefano Zorzi, MD Director, Oral Unit: Luca Calabrese, MD Director, Prevention: Nicoletta Tradati, MD Deputy Director, Endocrinologist: Bianca Gibelli, MD Consulting Dentist: Filippo Cazzulani, DDS Observers and Fellows: Jan Boucek, MD (Cz Rep), Paula Lorenzon, MD (Brasil), Ahmed Abd El Fattah, MD (Egypt) Zoraida Contreras Rodriguez, MD (Columbia), Akira Saito, MD (Japan), Noriko Saito, MD (Japan) Residents: Laura Mannarini, MD (Pavia University), Giulio Ostanello, MD (Pavia University), Marta Tagliabue, MD (Pavia University) Fellows: Michele Proh, MD, Luigi De Benedetto, MD, Stefano Costa, MD Research Fellow: Angelo Ostuni, DDS, MD Speech therapist: Valeria Zurlo, BS Data managers: Maria Angela Massaro, PhD, Chiara Arrigoni, MSc Secretaries: Paola Maggioni, Gloria Gavioli Head Nurse: Silvana Lacapra Nurses: Giovanni Airaghi, Francesco Anaclerio, Aprile Danila, Elisabetta Basile, Silvia Boasso, Ester Borghi, Lara Buscaini, Cecilia Di Santi, Vito Ditta, Antonio Iuliano, Sabrina Mastrovito, Teresa Zicolella Auxiliaries: Rita Batazzi, Anna Forte, Pietro Grimaldi, Clotilde Sancarlo

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Activities 2009.

The clinical research of the Division is organised on three Units: Laryngology, Oral cavity and Oropharynx, Thyroid and Salivary Glands. They are aimed to improve early cancer diagnosis, new treatment modalities and to develop molecular medicine through a multidisciplinary approach. Main topics are prevention and early detection, mini-invasive surgery, functional reconstruction, and quality of life. The Division established National and International collaboration with many world-wide Institutions and several fellows attend our department for improving their knowledge of Head & Neck Oncology. We are developing organ and function preservation protocols, compartmental surgery of oral cancer; mini-invasive robotic and laser surgery for laryngeal and oropharyngeal malignancies; conservative and video-assisted (MIVAT) thyroid surgery. A Thousand patients were Admitted in the 16 beds of the Division during 2009 (179 in Day Surgery). Among them 320 underwent mini-invasive oral and laryngeal laser surgery, 190 thyroidectomies (20 of them operated with MIVAT), 99 major head and neck operations with free flaps reconstruction, and 25 patients underwent functional robotic surgery for supraglottic and oropharyngeal squamous cell carcinoma. This is an average of about 18 operations a week. Patients usually undergo preoperative staging in out clinic regimen and are admitted the day before or the same day of surgery. Mean patients’ stay in Hospital was 6.8 days. About 13500 patients were checked in the out-patient clinic; 7000 for oral, oropharyngeal, and laryngeal cancers (out of them, 1300 underwent multidisciplinary check together with radiotherapists); 5500 patients (1900 checked together with nuclear MDs and endocrinologist) for a thyroid tumour. Treatment program of 800 patients and possible postoperative therapy of all operated patients were discussed and planned in the weekly multidisciplinary meetings (on Wednesday).

for a period of 6 months. Physicians of the Division are involved in the didactic activities of the school. A similar agreement is on-going also with the ENT and Head and neck surgery Institute of the University of Praha (Cz), and the Camargo Oncological Institute of S Paulo (Brasil): a resident spends one year (respectively) in the IEO Head and Neck department and is involved both in clinical and research activities The Division organised: 1) three Master courses for 5 specialists that spent a week participating at the clinical activities of the Division: a full immersion head and neck surgical oncology programme. 2) a Course of head and neck surgical technique on corpses held in Paris in collaboration with the Institute of Anatomy of the University of Paris and the ENT Clinic of Pavia, Ferrara and Brescia (20 participants and a faculty of 10 tutors from the organising Italian Institutes). 3) A Basic Course on diagnosis of early oral cancer (Oral Test) for 30 dentists and GPs, with an International faculty (JM Huryn USA) 3) a Theoretical and Practical Course on Laser laryngeal surgery for 50 (Theoretical) and 20 (Practical) ENTs with 10 tutors.and International faculty (W Steiner, Germany; R Puxeddu , UK) The Division published 11 papers on peer-reviewed journals, with an overall IF = 27.869. Fausto Chiesa is Editor of Acta Oto-rhino-laryngologica Italica, the official Journal of the Italian ENT – Head & Neck Society. He is President of the Euro-Asian Society of Head and Neck Oncology (EASHNO). The Division is involved in the organization of basic and advanced courses on head and neck and thyroid cancer for ENTs, Dentists and GPs in collaboration with Italian ENT Society. The Division has an agreement with the ENT post-graduate school of the University of Pavia: each resident attends the Division and participates at clinical and research activities

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Division of Thoracic Surgery Lorenzo SPAGGIARI, MD Director

STAFF Co-director: Piergiorgio Solli, MD Director, Unit of Lung Lancer Early Detection: Giulia Veronesi, MD Senior Assistants: Roberto Gasparri, MD, Francesco Petrella, MD, Domenico Galetta, MD Assistants: Alessandro Borri, MD, Monica Casiraghi, MD, Stefano Donghi, MD, Adele Tessitore, MD Fellows: Bernardo Agoglia, MD, Milene Chanquetti Quiterio, MD, Alfredo Monteiro Nogueira, MD, Fabiola Perin, MD, Ernando Vannucci, MD Residents: Juliana Guarize, MD, Alessandro Pardolesi, MD Thesist: Barbara Ciprandi Data Manager: Daniela Brambilla Secretaries: Iliade Federica Lombardi, Laura Cordini, Teresa Drago Head Nurse: Sara Meneghin Nurses: Stefania Avantaggiato, Davide Basso, Claudio Casati, Chiara Esposito, Maria Luisa Ferrari, Nemo Florio, Marzia Madini, Gianni Meloni, Paola Monticelli, Chiara Niccoli, Gigliola Osculati, Michelina Soldano, Ester Spacca, Valentina Tetti, Katarzyna Zal Auxiliries: Franco Chivaschi, Mirella De Montis, Anna Ieronimo, Gilberto Tanzi, Vincenzo Serafino

Activities 2009. The clinical activity involved all fields of thoracic oncology including the treatment of early and advanced stage lung cancers, oesophageal tumors, mediastinal and chest wall diseases. The Division has developed innovative protocols of multimodality strategies for lung and pleural malignancies. Surgery of very extended tumors with main vessels involvement and other demanding procedures are fields of interest and of expertise of the Division together with parenchymal sparing procedures and mini invasive approaches for localised early stage lung or oesophageal cancers. During the past year the introduction in the clinical practice of the rigid bronchoscopy with endotracheal stents and laser treatment allowed to obtain good palliation in cases of bronchial obstruction or ab extrinseco stenosis due to vegentant neoplasms or enlarged lymph nodes. All more advanced staging techniques are routinely followed in the preoperative patient evaluation, including CT-PET and videomediastinoscopy The development of videobronchoscopy with transtrahceal or transbronchial biopsy permitted to obtain diagnosis of neoplastic disease at lymph nodes level in a non invasive manner avoiding often the mediastinoscopy. The use of metal bars has been introduced for stabilitation of the chest wall as an innovative device for reconstruction after resection of lung cancer or other neoplasms with invasion of the chest wall. The use of laser for lung metastasectomy represents a novel technique to perform nodulectomy and lung resections of multiple lesions with minimal sacrifice of healthy parenchyma with reduced air leak. A multicentric trial with induction chemotherapy, pleuropneumonectomy and radiotherapy for pleural mesotelioma has been concluded in collaboration with other Italian Cen-

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tres. The preliminary results are under evaluation. The Division has instituted a program of lung cancer screening with low dose CT scan and biomarkers and developed the minimally invasive approach for the surgery of localised lung cancers and mediastinal tumors including robotic approach and videothoracscopic major lung resections. The research activity is involved in different translational research studies such as pharmacogenomic analysis, molecular biology studies of lung carcinogenesis, lung cancer angiogenesis and stem cell experimentation. The Division has developed collaboration with several research Institutions and is coordinator of different multicenter clinical trials. It is also devoted to educational activity and scientific

meeting organisation. In 2009 the Thoracic Surgery Division performed about 970 surgical procedures. 18 papers have been published on international journals during 2009.

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Division of Gynaecology Angelo MAGGIONI, MD Director

STAFF Co-Directors: Nicoletta Colombo, MD, Mario Sideri, MD Senior Deputy Directors: Fabio Landoni, MD, Luca Bocciolone, MD Deputy Directors: Giovanni Aletti, MD, Dorella Franchi, MD, Gabriella Parma, MD, Vanna Zanagnolo, MD Assistants: Maria Teresa Lapresa, MD, Rosanna Mancari, MD, Eleonora Preti, MD, Research Fellows: Michele Peiretti, MD, Fabio Sanguineti, MD Datamanagers: Maira Biggiogero, ScD, Rosanna Cassano, ScD Datamanager Coordinator: Sara Boveri, ScD Secretaries: Romina Brugnoli, Pina Mariano, Romina Manzini, Anna Steinwurzel, Simona Tognetti Head Nurse: Emanuela D’Anna Research Nurse: Carmen Beltrami Nurses: Paola Amidani, Valentina Andrini, Liberata Anedda, Paola Biffi, Elena Bigoni, Lucia Cantù, Patrizia Capodivento,Michela Cerone, Marika Comensoli, Daniela D’Aronzo, Hanna Gruchala, Chiara Marenghi, Eliana Misurelli, Brigitta Mori, Alessandra Saraca, Auxiliaries: Pasqualina Aliberto, Concetta Cardella, Patrizia Macaluso, Rosa Schiavino

Activities 2009. The Division of Gynaecology provides all services involving the diagnosis, treatment, and follow-up of gynaecologic oncology patients. The Division includes the Unit of Gynaecologic Oncology, mainly dedicated to chemotherapy treatments, and the Unit of Preventive Gynaecology, mainly dedicated to the diagnosis and treatment of genital cancer precursors. Each staff member is a fully-trained gynaecologic oncologist responsible for various activities within the Division, including surgery (minor, major, and minimally invasive: laparoscopic and robotic surgery), chemotherapy treatments, research, clinical trials, and early diagnosis. Clinicians from the Division of Gynaecology are principal

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investigators in several international trials to determine the best treatment for women with ovarian cancer. In co-operation with scientists from the Clinical Trials Unit of the Medical Research Council (MRC), they coordinated the ICON1 (International Collaborative Ovarian Neoplasm) international trial, which established the role of adjuvant chemotherapy in patients with early stage ovarian cancer. The Division of Gynaecology also led the Italian arm of the ICON4 trial, which studied the effect of Paclitaxel plus platinum chemotherapy versus conventional platinum-based chemotherapy in patients with ovarian cancer who, relapsed after a treatment-free period of more than six months. The results indicated that women with relapsed ovarian cancer may live longer when treated with Paclitaxel combined with platinum-based agents. For patients with advanced ovarian cancer, a trial in collaboration with the US National Institute of Health and the International Collaborative Ovarian Neoplasm (ICON) has recently demonstrated that the addition of a third cytotoxic agent to the standard treatment was not associated with improved clinical outcomes. Among the surgical activities particular attention is devoted to fertility preserving surgery in young patients with borderline ovarian tumours and early-stage ovarian and cervical cancer. The division has also the facilities and the experience to perform major surgery, such as extensive cytoreduction in patients with advanced ovarian cancer and pelvic exenteration with IORT (intra-operative radiotherapy) in patients with recurrent cervical, endometrial, and vulvar cancer. A multicenter paper showed the benefits in terms of progression-free survival in patients with ovarian cancer randomized to receive lymph node dissection, compared to no such resection. Overall survival, however was unchanged and the toxicity and morbidity of the operation was the significant factor in time of recovery of patients post-operatively. Another major area of interest is the effort to evaluate less invasive surgical staging modalities in order to reduce morbidity while retaining adequate accuracy.

An observational study conducted in cooperation with other EU centres showed the safety of omitting complete groin dissection in patients affected by early stage vulvar cancer with negative sentinel node. Furthermore, a new trial regarding the efficacy of replacing complete groin dissection with adjuvant radiotherapy will be activated in patients with positive sentinel node(s). Finally, the application of minimally invasive robotic surgery as therapeutic approach to the different gynaecological malignancies, such as endometrial, and cervical cancer (simple and radical hysterectomy plus lymphadenectomy) is a new field of interest. The Unit of Preventive Gynaecology has experience in laser surgery for cervical, vaginal, and vulvar pre-cancerous lesions, operative hysteroscopy, and transvaginal US for ovarian cancer early detection and management. Ongoing studies include HPV genotyping in the follow-up of patients submitted to conization, HPV self-sampling,

evaluation P16 in screening and triage of borderline smears, HPV vaccination in adolescents. The Unit has a central role in the HPV task force, a multidisciplinary group involved in the study of HPV-related genital and non genital cancers (see Virology section). New biomarkers for the early diagnosis of ovarian cancer (HE4 and proteomics) are being evaluated in a prospective ongoing study; the Unit is also involved in a multicentric international study in ultrasonographic discrimination of pelvic masses (IOTAII and III). Particular interest is dedicated to the hormonal conservative treatment of early endometrial cancer in young patients wishing to preserve fertility. In addition to their clinical and research activities, members of the Division have university and institutional teaching responsibilities that mainly involve training residents and fellows. They are also involved in Continuing Medical Education (CME) programs.

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Division of Urology Ottavio de COBELLI, MD Director

STAFF Senior Deputy Directors: Deliu Victor Matei MD, Epifanio Scardino,MD, Fabrizio Verweij, MD Senior Assistants: Gennaro Musi MD, Bernardo Maria Rocco MD Assistants: Giancarlo Albo MD, Carlo Ambruosi MD Fellows: Federica Mazzoleni MD Residents: Sara Melegari MD, Gabriella Mombelli MD, Stefano Zambito MD Secretaries: Elena Collarin, Mariaelisa Ronzino Data Manager: Serena Detti Head Nurse: Eleonora Meola Nurses: Irene Barillà, Grazia Basile, Roberta Campari, Desiree Del Grande, Cristina Di Pasquale, Salvatore Lilliu, Elena Occhetti, Michaela Paun, Aldina Pavan, Jelena Pavic, Paola Salvaderi, Najiba Sami, Giulia Valente Auxiliaries: Shewit Girmay, Carmen Murroni, Addolorata Prete, Silvia Pucci

Activities 2009.

The Division of Urology is concerned with the treatment of all urological tumours, including prostate, bladder, kidney, testis and penis cancer. In 2009, 910 patients were admitted for surgical treatment. Among these we performed both endoscopic, open and robotic surgery. Among open procedures we performed 53 radical retropubic prostatectomies, 40 radical nephrectomies 18 nephron sparing procedures and 28 cystectomies. Of these procedures, 6 were with urinary reconstruction. We had an outstanding increase of robotic surgery, with 221 robotic assisted prostatectomies, nearly double of the last year; we started our robotic experience in other procedures such as kidney surgery (8 robotic radical nephrectomies and 10 nephron sparing procedures) and bladder surgery (3 radical cystectomies). Our experience in urologic oncology was extended in all the items

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such as testis cancer, penis cancer. There were also performed urinary diversions for patients who underwent pelvic exenteration in other divisions (Gynaecology, General Surgery). Many patients underwent endoscopic procedures, like transurethral resection of bladder (206 patients) ureteral stent insertion (57 patients). Accurate follow-up procedures, following international guidelines are strictly observed. The Division of Urology actively collaborates with the Division of Radiotherapy in brachytherapy treatment of prostate carcinoma which is becoming a treatment option for patients with early stage disease. In the last year we had a great development of Robotic surgery, as it was the more frequent surgical treatment for prostate cancer. The oncological results with a medium follow up of 12 months are similar to the open radical prostatectomy; however, the main advantage of this surgical technique is the shorter time required to reach urinary continence and sexual potency, and the better overall outcome for both functional domains, comparing to the open surgery. The tendency of the last year, in favour of robotic surgery, was increased this year and the robotic procedures are becoming the favourite treatment for all the urologic cancers. Plans for research projects in 2010/11 include a further increase of robotic surgery in order to validate these kind of treatments in patients with prostate, kidney and bladder cancer. Moreover, in cooperation with the Department of Medicine, trials for Hormone Refractory Prostate Cancer are ongoing (See specific research chapters on Prostate cancer). The standard treatment for invasive bladder cancer remains radical cystectomy. The indication for orthotopic bladder substitution has greatly increased over the last decade and in suitably selected patients, quality of life is excellent and morbidity is comparable to that with other forms of urinary diversions.

The intestinal bladder substitute should be a low-pressure, capacious and highly compliant reservoir, with a state of fullness that can be appreciated by the patient, allowing him to void at a socially appropriate time. For superficial bladder cancer has been carriyng aninnovative International Multicentric Trial of “Synergo®”.

hardware and real-time software regulates the operation presenting the processed data on the monitor screen.

The Synergo® System, is a computer-embedded intravesical irrigation system combined with an energy-delivering unit. The energy-delivering unit consists of a radio frequency (RF) generator and an antenna. The treatment employs intravesical instillation of a chemotherapeutic agent concomitant with hyperthermia of the bladder wall induced by emission of RF energy, monitored by internal thermocouples. A specially designed combination of

The objective of the study is the comparison of Synergo delivered local hyperthermia combined with intravesical instillation of Mitomycin C versus intravesical instillation of immunotherapy (Bacillus Calmette Guérin) for adjuvant treatment, in patients with intermediate or high risk superficial transitional cell carcinoma of the bladder.

The object of treatment is to heat the bladder wall while instilling the drug solution, thus providing a synergistic antitumor effect.

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Division of Nuclear Medicine Giovanni PAGANELLI, MD Director

STAFF Co-Director: Concetta De Cicco, MD Radiochemistry Unit Director: Marco Chinol Radiochemist Assistant: Luigi Martano, Stefano Papi Fellows: Giovanna Pepe, MD, Stefano Vassallo, MD, Lucia Garaboldi Deputy Directors: Lisa Bodei, MD, Chiara Maria Grana, MD, Giuseppe Trifirò, MD Senior Assistant: Laura Travaini, MD Assistants: Silvia Melania Baio, MD, Marzia Colandrea, MD, Paola Anna Rocca, MD Data managers: Monica Pacifici, Simone Tiberini, Dario Lombardo Chief Technician: Maurizio Fiorenza Technicians: Michele Calabrese, Alfio Severino Cascio, Sebastiano Croce, Riccardo Mei, Domenico Militano, Daniele Paolucci, Gennaro Prisco, Andrea Vertua Scientific Secretary: Deborah Console Secretaries: Laura Brambilla, Annamaria Cazzetta, Karina De Giovanni, Emanuela Giunta, Anna Lucia Tusini Head Nurse: Gianni Bufi Nurses: Boubacar Daou, Monica De Piano, Francesca Fassari, Domenico Oliverio, Riccardo Perego, Alessio Serreli, Sabrina Turin Auxiliaries: Paolo Baldassarre, Vito Nicola Mancini, Valerio Massetti, Maria Claudia Salis Medical physicists to Nuclear Medicine: Marta Cremonesi, Mahila Ferrari, Francesca Botta, Amalia Di Dia

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Activities 2009. The Division of Nuclear Medicine is devoted to the early localisation and treatment of tumours, by means of functional imaging and targeted radionuclide therapy. The Division offers traditional nuclear medicine techniques as well as new diagnostic exams, such as sentinel node lymphoscintigraphy, radioguided occult lesion localisation (ROLL), peptide-guided whole body scans, and PET scans. 18FDG-PET scans are routinely performed in the diagnosis, staging and follow up of various types of cancer. Since July 2008 PET/TC scans with 68Ga-octreotide are performed. The Division is one of the few in Europe having protocols of radionuclide therapy of solid tumours and lymphomas with new radiolabelled molecules that show high affinity for tumour cells, such as monoclonal antibodies, avidin-biotin and radiolabelled peptides, both as systemic and loco-regional approaches. The Nuclear Medicine Division has a special hospitalisation section with 9 beds in rooms set aside for radionuclide therapy. The Division possesses two PET/CT scanners, one double-head gamma-camera and one single head gammacamera. Moreover, the Division is fully equipped for the synthesis of 18FDG and 68Ga-peptides and their quality controls and possesses three hot labs for the preparation of radiopharmaceuticals with different types of emission (gamma, beta+ and beta-), both for diagnosis and therapy. In 2009, 11.230 diagnostic studies were performed, of which 4.301 were PET/CT with 18FDG and 193 with 68Gaoctreotide, and over 609 outpatients were visited. Radionuclide therapies with Yttrium-90 and Lutetium-177 labelled peptides are carried out every week, both as systemic or loco-regional treatments. During 2009, the Division published 26 articles on peerreviewed journals, with an overall 85.8 IF. The Division has an agreement with various Universities in Italy, for the educational activity in the School of Specialisation in Nuclear Medicine, to spread new therapeutic modalities in the field of Radionuclide Therapy. Nuclear Medicine Division is hosting many young fellows from different countries, for pre-clinical and clinical research activities, to foster future collaborations.

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