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Fondazione IRCCS Istituto Nazionale dei Tumori

SCIENTIFIC REPORT 2010

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Fondazione IRCCS Istituto Nazionale dei Tumori

SCIENTIFIC REPORT 2010 TIVE

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FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI

Via G. Venezian 1 20133 Milano, Italy

www.istitutotumori.mi.it

FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI

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Scientific Report 2010

Predictive, Personalized, Preventive, Participatory Cancer Medicine. P4 Medicine is a systems approach fueled by information science, a holistic concept of wellness and disease, emerging technologies to explore new dimensions of patient data space, and new analytical technologies that will decipher the billions of data points associated with each individual. (Leroy Hood, 2004)

Editor Marco A. Pierotti

The Istituto Nazionale dei Tumori adopts this holistic approach to cancer, in particular by placing the ill person at the heart of its philosophy of care and research.

Editorial Committee Silvana Canevari, Aurora Costa, Alessandro M. Gianni, Vincenzo Mazzaferro, Giuseppe Pelosi, Mario Santinami Editorial management and Graphic Design Rosaria Parentela Collaborators Tiziana Camerini, Daniela Majerna Copy editing and Translation Patrick Moore Photographer Massimo Brega (except photographs on pages 89 and 135)

Fondazione IRCCS Istituto Nazionale dei Tumori Via G. Venezian, 1 - 20133 Milan - Italy Scientific Directorate Tel. +39 02 2390 2300 Fax +39 02 2390 3141 direzionescientifica@istitutotumori.mi.it http://www.istitutotumori.mi.it

Printed in June 2011 by Bozzi Multimedia s.r.l. 20026 Novate Milanese (MI)

Copyright Š 2011 Fondazione IRCCS Istituto Nazionale dei Tumori. No part of this communication may be cited, reproduced, stored in a retrieval system, or transmitted by electronic or other means without prior written permission of the Scientific Director and the appropriate investigator.


Fondazione IRCCS Istituto Nazionale dei Tumori

SCIENTIFIC REPORT 2010

FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI


CONTENTS Scientific Director’s Introduction

Clinical Activity Data (an overview)

5

7

Immunotherapy of Human Tumors

84

Tumor Genomics

85

Molecular Targeting

86

Molecular Pharmacology

87

RESEARCH ACTIVITY Prostate Cancer Program

13

Breast Cancer: Outline of Clinical and Preclinical Research

17

Lung Cancer Program

21

Hepato-Oncology: a Multidisciplinary Approach for an Emerging Specialty

27

Melanoma Program

31

Personalized Treatment of Sarcoma

35

Novel Approaches to Determine the Prognosis and Response to Treatment in Mature B-Cell Malignancies

39

Montabone Project for the Development of New Drugs in Medical Oncology

43

Integrated Unit for the Concerted Translational Early Development of New Drugs and/or Therapeutic Approaches in Solid Tumors 47 Development of Radiopharmaceuticals for Tumor Characterization, Molecular Imaging, and Therapy

51

CLINICAL-SCIENTIFIC STRUCTURE Scientific Directorate

57

Descriptive Studies and Health Planning

62

Tumor Registry and Environmental Epidemiology

63

Preventive and Predictive Medicine Department

65

Epidemiology and Prevention

66

Nutritional Epidemiology

67

Evaluative Epidemiology

68

Analytical Epidemiology

69

Medical Genetics

70

Hereditary Digestive Tract Tumors

71

Molecular Basis of Genetic Risk and Genetic Testing

72

Molecular Basis of Genetic Risk, Polygenic Models

73

Experimental Oncology and Molecular Medicine Department

75

Immunobiology of Human Tumors

77

Molecular Therapies

78

Molecular Immunology

79

Biomarkers

80

Chemoprevention

81

Molecular Mechanisms of Cell Cycle Control

82

Molecular Mechanisms

83

Pathology and Laboratory Medicine Department

89

Anatomic Pathology Units 1, 2 &3

90

SIMT, Immunohematology and Transfusion Medicine

93

Laboratory Medicine

94

Surgery Department Gastrointestinal, Hepatopancreatobiliary Surgery and Liver Transplantation Colorectal Surgery

97 98 99

Breast Surgery

100

Melanoma and Sarcoma

101

Diagnostic Endoscopy and Endoscopic Surgery

102

Maxillo-Facial Surgery

103

Gynecologic Oncology

104

Thoracic Surgery

105

Plastic and Reconstructive Surgery

106

Otolaryngology Surgery

107

Urologic Surgery

108

Pediatric Surgery

109

Laser Therapy

110

Medical Oncology Department

113

Hematology and Allogeneic Bone Marrow Transplantation 114 Medical Oncology 1

115

Medical Oncology 2

116

Medical Oncology 3

117

Adult Sarcoma Medical Treatment

118

Head and Neck Cancer Medical Oncology

119

Pediatric Oncology

120

Medical Day Hospital

121

Anesthesia, Intensive Care, Pain Therapy, and Palliative Care Department

123

Clinical Anesthesia

124

Day Surgery

125

Intensive Care

126

Palliative Care, Pain Therapy, and Rehabilitation

127

Supportive Care in Cancer

128

Clinical Nutrition

129


Diagnostic Imaging and Radiotherapy Department Radiology and Diagnostic Imaging 1

131 132

Radiology and Diagnostic Imaging 2

133

Intralesional Treatment

134

Radiology and Diagnostic Imaging 3 and

135

Breast Imaging Unit

135

Diagnostic and Interventional Gastroenterology

135

Nuclear Medicine

137

Clinical PET

138

Nuclear Medicine Therapy and Endocrinology

138

Radiotherapy 1

139

Radiotherapy 2

140

Medical Physics

141

SHARED RESEARCH RESOURCES Cardiology

145

Respiratory Physiopathology

146

Clinical Psycology

147

Medical Statistics, Biometry, and Bioinformatics

148

Clinical Epidemiology and Trial Organization

149

Tissue Bank

150

Functional Genomics Core Facility

151

Cancer Proteomics - Molecular Mechanisms

152

Animal House

153

EDUCATION AND TRAINING

155

PUBLICATIONS

159

INDEPENDENT ETHICS COMMITTEE

182

ONGOING CLINICAL STUDIES

183

ONGOING PROJECTS SUPPORTED BY DIFFERENT ORGANIZATIONS

201


SCIENTIFIC DIRECTOR’S INTRODUCTION

5

SCIENTIFIC DIRECTOR’S INTRODUCTION I am particularly proud to present the accomplishments of the Fondazione IRCCS Istituto Nazionale dei Tumori (INT) in 2010. One hand, the strategic research programs we were able to fund thanks to the the so-called 5‰ have already delivered significant intermediate results, which are detailed in this report, while on the other hand many of the long-term institutional projects and plans started in the past were brought to a satisfying conclusion during the year. First of all, we completed the move of the Experimental Departments to the new premises at the Amadeo Lab on time and with remarkably little disruption of everyday research activities. Thanks to careful planning and to the relentless efforts of all the staff involved, our researchers have been able to avail themselves fully of these new state-of-the art laboratories without major interruptions in their normal activity, which included the design of new scientific projects and applications to all the main funding opportunities. The Amadeo Lab has been fully operating since February 2010 and, since then, it has also hosted numerous scientific seminars and meetings, among which was the workshop “Multidimensional Tumour Characterization”, which was held in June. The objective of the meeting was to discuss the results achieved and solutions to the shortcomings identified in the first two years since the launch of the Integrated Oncology Program (PIO) chaired by INT. All the participants, and in particular the External Units who took part in the event, expressed their appreciation for the high scientific standard of the meeting. Towards the end of 2010, the Amadeo Lab saw the official inauguration of the Biobanca, a tissue bank initially dedicated to colon tumour samples. This initiative, supported by Regione Lombardia and Fondazione Cariplo, as well as the development of a Lombardy virtual tissue bank by ROL, are signs of the deep interest of our Institute in the development of biobanking as a strategic link between clinical and research activities. In the context of this commitment, in 2010 this Scientific Directorate supported the publication of an outstanding document promoted by our Ethics Committee: From the Biobank to the Research Biorepository: Ethical and Legal Recommendations, representing an important step forward in the practical and theoretical clarification of the complex legal and ethical issues associated with biobanking and a benchmark for future discussions. Another initiative that has bore fruits in 2010 is the setting up and activation of the Technology Transfer Office. After a period devoted to a precise update of the existing patent portfolio, this office was finally able to start looking towards the future: not only were a number of new patents submitted, but they were also successfully presented to the investors during important initiatives in the sector, such as BioinItaly. In addition, a crucial collaboration was established with Alintec-Technoscouting, a project (supported by the Regione Lombardia, the Chamber of Commerce, Industry, Craft Trade and Agriculture of Milan, Innovehub and Unioncamere Lombardy) aimed at publicising research results and promoting innovative regional projects with high technological content. Finally, our TTO is also involved in the CERIM, an EC-funded project aimed at improving techno-transfer models in the Central Europe region. The biennial project ROL 2 by the Lombardy Oncology Network (ROL) was completed during 2010. ROL is by now a well-integrated player within the Lombardy oncology community. One of the main results was the development of guidelines for diagnosis, therapy and follow-up for all solid tumours, which are already being used for epidemiologic data analysis on a regional level and the assessment of the appropriateness of the services provided.


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SCIENTIFIC REPORT 2010

The contribution of our Institute as the implementing body and coordinator of ROL activities also led to a new collaboration with Nerviano Medical Sciences (NMS) that resulted in the issuing of ROL/REL 2010 grants. Many Lombardy health structures applied and 15 clinical trials are currently being launched. Moreover, three promising pre-clinical studies have also been selected in order to capitalize on the synergy between INT and NMS, making the best use of the scientific and clinical expertise of our Institute and the experience accumulated by NMS in molecular biology and its infrastructure dedicated to the development of new oncology compounds. International collaboration is more and more essential to the advancement of science and the improvement of standard of care. Almost every Unit at INT is involved in international research projects, and since last year the Institute itself – together with all the best cancer institutes in Europe – has been part of an extensive European project, the EurocanPlatform, both as a partner and as the leader in the Working Group devoted to research in the field of early diagnosis and biomarkers. As my presidency of the European Organisation of Cancer Institutes (OECI) coincided with a growth both in the number of members and in the range of initiatives of this organization, our Institute has also become a partner in the ambitious Worldwide Innovative Networking consortium, WIN. Besides organising a yearly scientific meeting that gathers speakers and an audience from all over the world, in 2010 WIN began to be actively involved in funding clinical trials at an international level. Finally, as I do every year, I would like to comment on one of the possible impact indicators for the scientific output of our Institute. In 2010, our publications achieved an IF of 2,274.62, a result that slightly improves on the 2009 numbers and confirms the overall excellence of our scientific productivity by number of contributions as well as by quality and renown of the scientific journals where several of them have been published. Acknowledgments The research activity at the Institute is possible thanks to the substantial contributions of the Health Ministry, Lombardy Region and European Community, and all our financial supporters, in particular the Italian Association for Cancer Research (AIRC), Fondazione Cariplo, Lega Italiana per la Lotta contro i Tumori, and all other organizations mentioned in this Report. Our special thanks go to the volunteer associations that collaborate with our clinicians, constantly providing help and comfort to our patients and their relatives.

Marco A. Pierotti Scientific Director PUBLICATIONS 426

2010

465

2009

2004 2003 2002 2001

2250

338

1503,55

366

2006 2005

2272,32

415

2008 2007

2274,62

1686,65

293

1559,97

309

1390,49

320 287 275

1349,13 1188,21 1215,17

PUBLISHED PAPERS IMPACT FACTOR


CLINICAL ACTIVITY DATA

7

CLINICAL ACTIVITY DATA (an overview) The Medical Directorate is responsible for various areas: hygiene and health; surveillance and prevention of infectious diseases; quality assurance and clinical risk management; economic-financial organization of access to outpatient services and patient admission. In all these sectors the Medical Directorate is committed to the achievement of institutional objectives, also by defining and implementing new procedures and regulations. Our main effort is the excellence in service and care quality that must be maintained and continuously improved through initiative and personal involvement. The Medical Directorate is consistently seeking to improve its procedures, guided by the ISO 9000 standards, Joint Commission standards, and the guidelines and operational protocols of national and international scientific societies. Safety of treatment is a crucial element of quality and we are actively involved in promoting the safety of hospitalized patients, with specific reference to pharmacological treatments, surgery and anesthesiology pathways, clinical records and informed consent, and management of clinical emergencies. The following graphs briefly summarize clinical activity at INT and are based on: 1) hospital discharge forms for hospitalized patients; 2) budget and control data for ambulatory care activities (involving both outpatients and inpatients). We would like to thank Paola Notti and Paolo Spada for their collaboration in generating these graphs. Gustavo Galmozzi, MD Medical Director

Inpatients by geographical areas (overall 13,706) Soutern Italy 12% Italian Islands 6%

Northwest Italy (except Lombardy) 6% Northeast Italy 5% Outside Italy 1%

Central Italy

Outpatients by geographical areas (overall 9,610) Italian Islands Soutern Italy Northwest Italy 9% (except Lombardy) 3% Central Italy 4% Northeast Italy 3% 3% Outside Italy 1%

5%

Lombardy 65%

Lombardy 77%


SCIENTIFIC REPORT 2010

INPATIENTS OVER THE YEARS (LENGTH OF STAY > 1 DAY) 7500 7000

6735

6945 6347

6500

Number of inpatients

5500 5000

6250

5959

6000

5347

5574

5508

5452

2006

2007

5965 5594

6174

5987

5804 5427

5045

4500 4000

2003

2004

2005 Surgery Surgery

11

2008

2009

2010

Medical Oncology Oncology Medical

INPATIENTS: AVERAGE LENGTH OF STAY (LENGTH OF STAY > 1 DAY)

10 9 8 7 6 5

Average length of stay

8

4 3 2 1

2003

2004

2005 Surgery Surgery

2006

2007

Medical Oncology Overall

2008

2009

Overall Oncology Medical

2010


CLINICAL ACTIVITY DATA

Surgical procedures (overall 7,079) Gastrointestinal and hepatopancreatobiliary surgery & Liver transplantation 6,4% Colorectal surgery 9,3%

Pediatric surgery 6,3% Urologic surgery 7,4%

Cranio-maxillo-facial surgery 4,5%

Senology 16,9%

Melanoma and Sarcoma 14,1%

Otolaryngology surgery 8,7%

Plastic and recontructive surgery 9,4%

Gynecologic surgery 6,5%

1,9% Diagnostic and surgical endoscopy

8,4% Thoracic surgery

CHEMOTHERAPY 2003

2004

2005

2006

2007

2008

2009

2010

Chemotherapy room

15,649

23,118

19,266

19,839

19,276

20,377

21,646

22,707

Ordinary admissions

2,502

2,273

2,524

2,475

2,274

2,310

2,648

2,770

Day Hospital

2,507

1,690

1,415

1,841

1,876

1,327

1,035

1,354

OUTPATIENTS VISITS 2003

2004

2005

2006

2007

2008

2009

2010

Surgery

67,510

64,289

60,602

59,715

61,560

56,217

51,774

52,757

Medical Oncology

43,513

49,481

55,394

61,424

61,983

62,402

90,463

86,060

Diagnostic Imaging & Radiotherapy

18,510

18,685

16,966

17,926

17,537

16,846

14,673

16,702

Anesthesia, Intensive Care, Palliative Care

32,313

32,292

31,141

32,038

33,735

30,929

18,316

25,960

Transfusion Unit

7,456

9,093

7,342

6,997

6,581

6,766

7,163

6,955

Private Patients

8,457

12,937

13,301

14,519

7,932

15,083

14,170

16,201

177,759

186,777

184,746

192,619

189,328

188,243

196,559

204,635

Total

9


RESEARCH ACTIVITY PROSTATE CANCER PROGRAM BREAST CANCER: OUTLINE OF CLINICAL AND PRECLINICAL RESEARCH LUNG CANCER PROGRAM HEPATO-ONCOLOGY: A MULTIDISCIPLINARY APPROACH FOR AN EMERGING SPECIALTY MELANOMA PROGRAM PERSONALIZED TREATMENT OF SARCOMAS NOVEL APPROACHES TO DETERMINE PROGNOSIS AND RESPONSE TO TREATMENT IN MATURE B-CELL MALIGNANCIES MONTABONE PROJECT FOR DEVELOPMENT OF NEW DRUGS IN MEDICAL ONCOLOGY INTEGRATED UNIT FOR THE CONCERTED TRANSLATIONAL EARLY DEVELOPMENT OF NEW DRUGS AND/OR THERAPEUTIC APPROACHES IN SOLID TUMORS DEVELOPMENT OF RADIOPHARMACEUTICALS FOR TUMOR CHARACTERIZATION, MOLECULAR IMAGING, AND THERAPY


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MULTIDISCIPLINARY PROGRAMS

PROSTATE CANCER PROGRAM

Riccardo Valdagni Group Leader Nadia Zaffaroni Preclinical activities and protocols Group Leader PROJECT GROUP

PARTICIPATING UNITS

Tiziana Magnani - Project Manager Assistant Lara Bellardita - Psychologist Simona Donegani - Psychologist Andrea L. Spatuzzi - Psychologist Tiziana Rancati - Expert in radiation modelling, Data Manager Barbara Avuzzi - Fellow in Radiation Oncology Maria Olga Giganti - Fellow in Medical Oncology Antonella Candosin - Secretary Elena Ronchi - Scientific Secretary

Palliative Care, Pain Therapy, and Rehabilitation Supportive Care in Cancer Urologic Surgery Diagnostic Imaging and Radiotherapy Experimental Oncology and Molecular Medicine Medical Oncology Pathology and Laboratory Medicine Preventive and Predictive Medicine Medical Statistics and Biometry Scientific Directorate

Overview The Prostate Cancer (PC) program is a translational multidisciplinary program with expertise in epidemiology, experimental oncology, pathology, imaging, urologic surgery, radiation oncology, medical oncology, palliative care, and psychology. Since 2005, the clinical team has been offering patients with PC a multidisciplinary approach in all stages of disease (in 2010, about 850 multidisciplinary clinical visits were carried out as first examinations, second opinions, follow-ups of patients on active surveillance or watchful waiting). Clinical cases are discussed weekly to share decisions, individualize therapeutic or observational strategies, include patients in trials, and verify adherence to institutional guidelines and quality assurance. Considerable attention is paid to quality of life and psychological issues. Patients and their families can rely on dedicated psychologists in the decision-making phases and throughout the course of the disease. Some of the ongoing research is summarized below.

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Development of novel approaches for the inhibition of cell survival factors in preclinical models of androgenindependent prostate cancer. The effects of several telomeric G-quadruplex (G4) ligands, including anthracene derivatives and other molecules with a naphthalene diimide core bearing side chains composed of reactive chemical species such as the quinone methide, have been assessed in cell lines from PC and other human tumor types. Compounds characterized by a higher binding affinity for G4 inhibited cell proliferation as a consequence of the interference exerted on telomere structure and function, induction of a DNA damage response at the telomere level and the inhibition of the catalytic activity of telomerase. As far as new cyclindependent kinase (CDK) inhibitors are concerned, different classes of nortopsentine derivatives have been evaluated. These compounds were found to significantly reduce tumor cell proliferation as a consequence of a marked inhibition of the catalytic activity of CDK1 and GSK3Ă&#x;, and persistent accumulation of cells in the G2 phase of the cell cycle. miRNAs in PC: expression profiling and functional analysis. We focused on miR-21 due to the evidence that it is over-expressed in different cancers, and that its knockdown counteracts the malignant phenotype of several tumor models. We showed that miR-21 inhibition was insufficient to affect the proliferative and invasive potential or the chemo- and radiosensitivity profiles of PC cell lines, characterized by different miR-21 expression levels and PTEN gene status, or to modulate the expression of PTEN or Pdcd4, which are targeted by miR21 in other tumor types. Additionally, miR-21 was not differently expressed in carcinomas and matched normal tissues obtained from untreated PC patients undergoing surgery. Our data suggest that miR-21 does not play a pivotal role in the onset of PC and that is not a potential therapeutic target in PC, thus highlighting that oncogenic properties of miR-21 are cell/tissue-dependent, and that the potential role of a miRNA as an anti-cancer target should be considered in the specific disease context.

Cells and matricellular proteins as accomplices in PC. Here, the distinct role of SPARC and osteopontin (OPN) produced by either tumor or stroma cells during prostate carcinogenesis is studied in a transgenic adenocarcinoma mouse prostate (TRAMP) model. In particular, TRAMP mice crossed to either SPARC-/- or OPN-/- mice as well as to SPARC-/-OPN-/- double knockout mice are utilized. SPARC-KO TRAMP mice exhibited early, aggressive tumors characterized by the lack of androgen receptor expression and expression of neuroendocrine markers (i.e. synaptophysin) and CD44. A similar phenotype was obtained in TRAMP mice that were rendered deficient for mast cells (MC). MC, classically known as the primary responders in allergic reactions, have recently become known as important players in either cancer promotion or inhibition, depending on the cancer type. We have evidence of such dual role in PC. Within the same human tumor, MC are specifically enriched and degranulated in areas of adenocarcinoma, whereas they are lacking around anaplastic foci. This observation has been confirmed in tumors from TRAMP mice and in two novel tumor cells lines derived from them, with the phenotypes of well and poorly differentiated adenocarcinoma, namely T1525 and T23, respectively. MC promote the growth of the well-differentiated adenocarcinoma T1525 that does not develop when transplanted into MC-deficient mice, or when MC degranulation is pharmacologically inhibited with sodium chromoglycate. MMP-9 protease is necessary for the pro-tumorigenic role of MC; accordingly tumors can develop in MC-deficient mice reconstituted with wt MC, but not in those reconstituted with MC from MMP9ko donor. Surprisingly, pharmacological inhibition or genetic ablation of MC in TRAMP mice results in early development of undifferentiated tumors characterized by a specific neuroendocrine profile. Our data show MC can influence the histotype of tumors arising from the prostate, and that their targeting may alter tumor outcome.


MULTIDISCIPLINARY PROGRAMS

The PRIAS study evaluates active surveillance as an valid alternative to radical therapies in low risk PC. Selected patients are followed up clinically and diagnostically (PSA and biopsy), and offered curative treatment if the PC appears to progress, thus limiting overtreatment. From September 2007 to December 2010, 142 patients entered the study. The hypothesis to be confirmed is that < 5% patients will develop clinical progression by a positive bone scan during their lifetime. An additional investigation is the PROCABIO study (Tailored treatment of PROstate CAncer by BIOmarkers), which will evaluate the most promising PC biomarkers and assess their ability to identify indolent PC and thereby risk-stratify treatment. The INT Prostate Cancer Programme is the only Italian group participating in this project. As of December 2010, 45 patients entered the study. An open label Phase II study of vaccination with survivin peptides in PC patients in biochemical failure (PROVAX study). This trial, started late 2010, is evaluating a novel vaccine combination (survivin peptides and IMP321) in 20 hormone-naïve or refractory patients with biochemical recurrence. Vaccine peptides, restricted for different HLA-I alleles, are emulsified in Montanide® ISA 51 VG and administered weekly for 8 weeks and every 4 weeks thereafter. IMP321 is given prior to every second vaccination at the same site. In patients experiencing clinical benefit at the end of vaccination, the entire vaccine cycle will be repeated. A “safety run-in phase” was included to assess the toxicity of vaccine combination; the first three subjects have been identified, treated and observed for 4 weeks before starting enrolment. No adverse events were observed during the first vaccinations, and new subjects will be screened and enrolled in 2011.

Predictive models of late rectal toxicity after high-dose PC radiotherapy (RT). New RT techniques to treat PC with high doses and a high level of precision are being studied. However, a significant proportion of patients still experience acute and late toxicity, since organs at risk are unavoidably included within the high dose region. Although predicting RT morbidity can prevent further deterioration of quality of life and help introduce treatment corrections to personalize therapy, little attention and inadequate efforts have been devoted to the development of easy-to-use tools that use individual dosimetric, clinical and genetic risk factors and which are able to predict the side-effects of RT. The group involved in the project also participated in two studies (AIROPROS 0101 and AIROPROS 0102) that assessed predictors of rectal toxicity. The results gave important indications about the modeling of rectal bleeding in addition to other acute and late rectal complications. AIROPROS 0102 data were also used to develop nomograms and artificial neural network models to predict acute and late rectal toxicity after RT of PC. These are the first user-friendly tools reported in the literature for the evaluation of individual radio-induced rectal toxicity probability. A pilot study was also designed to identify genetic markers predicting late rectal bleeding. Patients were selected within the AIROPROS 0101 trial, and this pilot study showed that individual dose-volume information coupled to the patient’s genetic profile might help to explain, on the basis of dose-volume histograms the quality and unexpected rectal bleeders, as well as the unpredicted absence of late toxicity in some individuals.

Keywords: translational research, multidisciplinary approach, experimental therapeutics

Publications miR-21: an oncomir on strike in prostate cancer. Folini M, Gandellini P, Longoni N, Profumo V, Callari M, Pennati M, Colecchia M, Supino R, Veneroni S, Salvioni R, Valdagni R, Daidone MG, Zaffaroni N. Mol Cancer. 2010; 9:12-24. Emerging role of microRNAs in prostate cancer: implications for personalized medicine. Gandellini P, Folini M, Zaffaroni N. Discov Med. 2010; 9:212-8. A Neural Network Based Predictive Model for Late Rectal Bleeding after 3DCRT in Prostate Cancer Patients. Tomatis S, Rancati T, Fiorino C, Vavassori V, Fellin G, Monti A, Baccolini M, Bianchi C, Menegotti L, Valdagni R. American Society for Therapeutic Radiology and Oncology (ASTRO). 52th Annual Meeting, San Diego, 31 October - 4 November 2010. Int J Radiat Oncol Biol Phys. 2010; 78:3(S)357.

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MULTIDISCIPLINARY PROGRAMS

BREAST CANCER: OUTLINE OF CLINICAL AND PRECLINICAL RESEARCH

Luca Gianni Group Leader Maria Grazia Daidone Preclinical activity Group Leader PARTICIPATING UNITS

Breast Imaging Experimental Oncology and Molecular Medicine Medical Oncology Pathology Preventive and Predictive Medicine Senology

Overview Major unresolved scientific problems surrounding breast cancer (BC) are related to: increasing incidence, prevention, early diagnosis, disease progression, treatment, and resistance to clinical treatments and their toxicity. The heterogeneity of human BC, in terms of genetic susceptibility, clinical behaviour, molecular profiles, and even histomorphologic features, represents a major obstacle to the solution of more effective therapies. Investigations at the genetic and transcriptional levels have demonstrated shown that such heterogeneity may be explained by: a) varying susceptibility to malignant transformation of different mammary cells; b) progression of breast carcinogenesis that is not necessarily stepwise or linear, from well-differentiated to poorly differentiated tumors, which is also complicated by the finding that; c) no single dominant pathway or histologic presentation has emerged in BC, whereas mutation within a single pathway has a dominant role during progression in virtually all tumor types. High through-put technical approaches for molecular analyses have prompted a new classification of human BC and provided a new paradigm for reducing disease complexity, unraveling biological heterogeneity and thus better identifying those destined to develop BC among atrisk women, and, among patients, those who will develop new disease manifestations for more rational planning of therapeutic strategies. INT has traditionally provided the highest quality and level of innovation in designing and developing new approaches to the multidisciplinary treatment of women with BC. This tradition has led to landmark accomplishments, such as the introduction of new standards of therapy that are now common practice in the field of oncology. Investigations designed and conducted at INT have demonstrated the possibility of limiting the extent of surgical removal of BC, thus avoiding mastectomy in many women with relatively small tumors without compromising the chance of successful eradication of disease. These achievements originate in an approach that merges different disciplines into a common effort for the ultimate benefit of patients. There are several key elements of success, but the most relevant are the creation of a dedicated team of clinical investigators supported by a centralized and unique team for data management and analysis, the establishment of expertise in the development of new drugs against metastatic BC, to rapidly implement new discoveries in the treatment of cases with early BC, and constant exchange among different laboratories of the Department of Experimental Oncology and Molecular Medicine and the Units of the Department of Preventive and Predictive Medicine. In all these respects, the approach to BC at INT has always been translational and multidisciplinary, and this tradition is maintained in the current organization of clinical and experimental services devoted to the treatment and study of BC, also including partnerships with pharmaceutical industry.

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This project represents one of the first efforts to outline the biology underlying the distinct risk situations for BC by applying novel approaches for molecular analysis and target validation to case series recruited at INT in the last decades in the context of epidemiologic or chemoprevention studies and adjuvant/neoadjuvant treatments. Investigations are focused on: a) effects of different metabolic/nutritional factors on relevant biomolecular features; b) effects of lifestyle changes on biomarkers and molecular signatures of proven prognostic relevance; c) interaction between host (including ECM features) and tumor factors; d) new genetic risk factors, including variants of uncertain significance in BRCA genes; e) gene expression fingerprints associated to with distinct new disease manifestations and response to different treatment protocols; f) functional analyses of genes whose expression affects tumor progression and treatment resistance; g) at a preclinical level, effect of novel chemopreventive and/or antitumor therapies. To improve our understanding of BC and to develop clinically-useful strategies, we need better understanding of host factors (including age, diet, life style, metabolic syndrome, environmental factors, polymorphisms and mutations in susceptibility genes), tumor microenvironment (growth factors, infiltrating cells and cytokines), and genomic changes occurring in cancer cells. At INT, we have a unique opportunity to investigate these aspects taking advantage of: a) dedicated infrastructure; b) well-annotated biological samples; c) a wellestablished philosophy for cancer and normal tissue acquisition, storage, and distribution to research Units; d) updated follow-up information and validated dietary questionnaires; e) improvements to overcome intrinsic limitations for genomic studies due to technical artifacts and/or to limited sample size; f) well- trained teams with specific skills in different disciplines.

During 2010, the following areas were investigated. Association of different molecular subtypes of BC with specific etiological pathways identified by hormone and growth factors and metabolic profiles, diet, and anthropometry. The expression of androgen receptors (AR) was investigated in a subset of primary BC from postmenopausal women, and showed a direct association (and co-expression) with AR and patient age and an inverse relation to histologic grade. Interaction between host and tumor factors on BC prognosis. An increased relative risk (RR) of death was associated not only with a high stage at diagnosis, but also with high alcohol intake (RR=3.73, 95%CI=1.708.21), ‘basal-cell-like’ vs. ‘luminal A’ subtype (RR=3.41, 95%CI=1.45-7.99), BMI ≥25 vs. <25 kg/m2 (RR=2.21, 95%CI=1.10-4.44). BMI increased RR and was independent of age, T, N, year of diagnosis, glycemia, and hypertension. There was also a trend towards association between high alcohol intake and unfavorable prognostic factors, such as advanced stage, HER2 overexpression, absence of ER, and PgR. Association between metabolic syndrome and BC risk. Metabolic syndrome is associated with an increased risk of indolent BC (ER+/PgR + and HER2-) in menopause and of aggressive BC (ER-/PgR-and HER2 +) in premenopause. Genetic factors that contribute to the identification of individuals at risk for BC. In collaboration with the group of Georgia Chenevix-Trench, we observed a lack of association between BC risk and SNPs rs17822931 in ABCC11 gene and rs12975333 in miR-125. Genome wide analyses to identify genes/alleles modifiers of risk in carriers of mutations in BRCA1 and BRCA2, carried out in the CIMBA consortium, showed: a) a locus in 19p13, a risk modifier in carriers of BRCA1 mutations


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which is associated with ER- BC; b) genes/alleles modifiers of risk in BRCA2 mutation carriers are similar to those associated with risk in the general population; c) a reduced risk of ovarian cancer even in BRCA1 and BRCA2 mutation carriers of the SNP rs3814113 in the 9p22.2 locus, previously associated with a reduced risk for this BC in the general population; d) the impact of SNPs: rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, rs10941679 in 5p12, with the finding that rs4973768 and rs10941679 are associated with an increased risk in BRCA2 mutation carriers; e) deleterious mutations in BRCAX 12/575, by sequencing the entire coding region of PALB2. Identification of microRNAs differentially expressed in the different BC molecular subtypes (basal, HER2+, and luminal, as defined by the expression of genes ESR1 and ErbB2) and/or associated with distant metastasis in our series of >100 N- BC with long-term follow-up. In the multiclass comparison between basal, luminal and HER2 tumors, 8 modulated microRNAs were identified

Publications Variation in 'standard care' for breast cancer across Europe: a EUROCARE-3 high resolution study. Allemani C, Storm H, Voogd AC, Holli K, Izarzugaza I, Torrella-Ramos A, Bielska-Lasota M, Aareleid T, Ardanaz E, Colonna M, Crocetti E, Danzon A, Federico M, Garau I, Grosclaude P, H茅delin G, MartinezGarcia C, Peignaux K, Plesko I, Primic-Zakelj M, Rachtan J, Tagliabue G, Tumino R, Traina A, Tryggvad贸ttir L, Vercelli M, Sant M. Eur J Cancer. 46:1528, 2010. Gene expression analysis reveals a different transcriptomic landscape in female and male breast cancer. Callari M, Cappelletti V, De Cecco L, Musella V, Miodini P, Veneroni S, Gariboldi M, Pierotti MA, Daidone MG. Breast Cancer Res Treat. 2010 Jul 13. Evaluation of SNPs in miR-146a, miR-196a2 and miR-499 as lowpenetrance alleles in German and Italian familial breast cancer cases. Catucci I, Yang R, Verderio P, Pizzamiglio S, Heesen L, Hemminki K, Sutter C, Wappenschmidt B, Dick M, Arnold N, Bugert P, Niederacher D, Meindl A, Schmutzler RK, Bartram CC, Ficarazzi F, Tizzoni L, Zaffaroni D, Manoukian S, Barile M, Pierotti MA, Radice P, Burwinkel B, Peterlongo P. Hum Mutat. 31:E1052, 2010. 4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells. Tiberio P et al. PLoS One. 5(10):e13362, 2010.

(FDR<15%, FC>1.2), while 14 miRNAs were differentially expressed in a direct comparison between basal and luminal tumors. Mechanisms by which the transcription factor FOXP3 may influence the invasive capacity of cancer cells. Different from regulatory T cells, in BC cells the most represented form consists of a low molecular weight protein (35 kDa), localized in the cytoplasmic fraction, which is not derived from a post-translational modification, as demonstrated by no increase of FOXP3 35kDa in BC cells transfected with wt FOXP3. A synergistic effect of 4-oxo-4-HPR and paclitaxel in two BC cell lines: T47D (ER+) and MDA-MB-231 (triple negative).

Keywords: metabolic syndrome, genetic risk, gene expression profile, microRNA profile, microenvironment

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LUNG CANCER PROGRAM

Ugo Pastorino Group leader Gabriella Sozzi Preclinical activity Group Leader PARTICIPATING UNITS

Thoracic Surgery - Coordinator Cancer Proteomics Immunobiology of Human Tumors Molecular Basis of Genetic Risk, Polygenic Models Molecular Immunology Radiodiagnostics Tumor Genomics

Overview Lung cancer is the most common malignancy in the developed world and an epidemic disease with very high clinical relevance and poor outcome. Cigarette smoking is the main cause. Tobacco use is also a major cause of impairment of lung function. In fact, oxidants in cigarette smoke are responsible for chronic biological damage and injury to DNA, predisposing to chronic obstructive pulmonary disease (COPD), emphysema, and lung carcinogenesis. Susceptibility to smoking-induced tissue damage varies among individuals and results from an interaction between host and environmental factors. Therefore, it is reasonable to investigate whether individual predisposition to develop lung cancer, as well as clinical and pathological features of cancer arising in smokers, differs according to the degree of respiratory failure, pulmonary structural damage, or changes in the circulating protein profile. Experience so far accumulated in the screening of heavy smokers has demonstrated that lowdose spiral CT can detect early lung cancer, with high resectability and improved long-term survival, but its impact on mortality and diagnosis of advanced lung cancer is still undefined. Ongoing randomized studies will hopefully provide a definitive answer concerning the possibility to prevent mortality in heavy smokers by early detection with annual low-dose spiral CT of the chest. Diagnostic performance and screening efficacy would both be improved by focusing on subjects with a higher biological risk of cancer than that defined by standard epidemiological criteria.

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SCREENING AND RANDOMIZED TRIALS The Multicentric Italian Lung Detection (MILD), a randomized study we launched in 2005 combining smoking cessation with early diagnosis and biological assessment of the individual risk of lung cancer, has now entered its 6th year and has recruited more than 4000 subjects in the low-dose spiral CT and control groups. The results at 10 years of the Milan Pilot Study, our first observational trial on early detection by annual singleslice spiral CT, began in 2000 on a cohort of 1035 heavy smokers show that CT screening detects a high proportion of early stage tumors with excellent survival during the first two years, while as the screening progresses, the frequency of late stage tumors increases. These “early advanced” cancers have poor prognosis similar to clinically detected (or symptomatic) advanced cancers. These findings seem to indicate that not all aggressive lung tumors arise from identifiable slowgrowing precursors, and indicate a bipartite biological model of lung cancer, with one indolent and one aggressive type from the earliest stages, rather than a single common initial type that may become aggressive over time. In this respect, the development of molecular markers able to identify tumors in a pre-clinical phase and to track the different aggressiveness of lung tumors, including the early metastatic cancers or even small lesions with aggressive potential, is of paramount importance. BIOMARKERS MicroRNAs (miRNAs) represent a recently identified class of molecules that have the capacity for simultaneous regulation of hundreds of genes and entire networks of biological processes. We have explored microRNA (miRNA) expression profiles of lung tumors, normal lung tissues, and plasma samples from cases with variable prognosis identified in a completed spiral-CT screening trial with extensive followup. miRNA expression patterns significantly distinguished: (i) tumors from normal lung tissues, (ii) tumor histology and growth rate, (iii) clinical outcome, and (iv) year of lung cancer CT detection. Interestingly, miRNA profiles in normal lung tissues also displayed remarkable associations with clinical features, suggesting the influence of a permissive microenvironment for tumor development. miRNAs expression analyses in plasma samples collected 1-2 years before the onset of disease, at the time of CT detection, and in disease-free smokers enrolled in the screening trial, resulted in the identification of miRNA signatures with strong predictive, diagnostic, and prognostic potential (area under the ROC curve ≥0.85). These signatures were validated in an independent cohort from a second randomized spiral-CT trial, and indicate a potential role for miRNAs in lung tissues and plasma as molecular predictors of lung cancer development and aggressiveness that may have both theoretical and clinical implications for lung cancer diagnosis and management.

STEM CELLS The identification of lung tumor-initiating cells and associated markers may be useful for optimization of therapeutic approaches and to provide predictive and prognostic information in lung cancer and melanoma patients. A project on identification and characterization of “Cancer Initiating Cells” in human non-small cell lung cancer is ongoing. In particular, we established in vitro cell systems and in vivo models for studying cancer stem cells in lung tumors that will be useful to identify novel drugs capable of overcoming CSC-induced resistance to conventional cytotoxic compounds. To develop novel preclinical models for analysis of lung cancer initiating cells, we successfully grew 14 tumor grafts in nude mice starting from 31 human lung primary tumors (take rate 45%). Tumor grafts were serially maintained in vivo as tumor lines and were used for biologic and functional studies and for testing combinations of new therapeutic agents. We also set up metabolic imaging of tumor grafts by 18-FDG micro-PET imaging. One observation is that advanced stage tumors were able to engraft and generate tumor grafts more efficiently than early stage tumors. In fact, 10/14 engrafted tumors were Stage>1. In order to use these models for testing novel treatments, we set up tumor graft metabolic imaging in vivo using PET using weekly [18F]FDG-PET and performed coronal and 3D-reconstruction at different days. In six different pairs of primary tumors/tumor grafts, we observed a good correlation between SUV max values of primary tumors and those of its corresponding xenograft in mice, thus suggesting a similar metabolic activity in our “human in mouse” model. The good correlation of metabolic activity between primary tumors and tumor grafts allows us to use these preclinical models for functional studies.


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INFLAMMATION AND CANCER Definition of reliable criteria for the assessment of individual risk of lung cancer in heavy smokers could improve future prevention strategies, diagnostic approaches, and clinical management of this lethal disease and has the potential to influence changes in smoking habits. The recognition of biological, molecular, and genetic risk factors of COPD and lung cancer may characterize the interplay between these two diseases. Information will be gathered on pro-inflammatory mediators and cells in lung tissue by immunohistochemistry and on systemic inflammatory factors by proteomics approaches. Characterization of stromal cell phenotype and gene expression profile will provide a framework for understanding the cross-talk between tissue microenvironment and transformed epithelial cells. Moreover, the setting of reliable animal model of lung cancers where testing tumor promotion by inflammation will allow us to study the cells and molecules responsible for this effect as well as to demonstrate, in mice, the risk factors emerging from human studies. Lung fibroblasts To evaluate the cross-talk between cancer cells and lungderived fibroblasts, we have progressed with the prospective collection of surgical specimens of lung cancer and normal lung tissue and establishment of fibroblast cultures from different areas of the lungs. We have generated 65 different cultures from cancer specimens (Cancer Associated Fibroblasts, CAFs) and 40 cultures from normal lung tissue, including 30 pairs of CAFs/NFs, providing the experimental tools needed for functional analyses. All the cultures tested (n=8) displayed a normal karyotype suggesting that the functional properties of fibroblasts are likely to be the result of epigenetic changes. Immunophenotyping of 18 cultures revealed the frequent presence of alpha smooth actin (Îą-SMA) expressing cells, indicating activation towards a myofibroblastic phenotype. Interestingly, activation properties were also

identified in cultures derived from normal lung tissue indicating changes possibly related to prolonged smoke exposure and concomitant respiratory diseases (COPD and emphysema). These results have been validated by immunofluorescence and immunohistochemistry with high concordance among different techniques. Co-mingling of fibroblasts (NF or CAF) with A549 lung cancer cells generally resulted in increased tumor size after injection in nude mice (n=16) with a stronger effect from CAF cultures (5/8) that also increased tumor take when cancer cells were injected at low doses. Human cells were identified by HLA staining in the stroma of tumors grown after co-injection confirming the contribution of mixed fibroblasts in tumor development. Real-time PCR expression analysis of a panel of extracellular matrix genes (including COL6A3, COL5A2, CTSL, CTSZ, CTSC, MMP2 and SPARC) was carried out in tumors generated by co-injection of cancer cells and fibroblasts. The results indicated that the presence of CAFs or NFs can influence stromal composition, suggesting a possible role in the modulation of invasive and metastatic properties. Furthermore, culture medium conditioned by fibroblasts promoted growth of lung cancer cells or immortalized bronchial epithelial cells. Consistent with their activated phenotype, cultures from normal lung tissue of heavy smokers also displayed protumorigenic activity, indicating that the microenvironment of lungs heavily exposed to damage from carcinogenic substances might already be predisposed to foster the growth of transformed epithelial cells. These results indicate that lung fibroblasts might play a central role in the growth and progression of lung neoplasia. Genome wide analyses We conducted a pilot transcriptome study on RNA extracted from normal lung tissue of patients with clinical stage I lung cancer and lung cancer patients with clinical stage>1. We found that transcriptional profile associated with clinical stage, and the TMEM100 gene showed the best statistical association. These profiles included genes with oncosuppressor potential, since 8 of the 9 validated

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genes also showed downregulation in lung adenocarcinoma tissue compared to normal tissue. We have further conducted a study that identified a specific haplotype in the 5'-region of the CHRNA5 gene that modulated the levels of expression of the CHRNA5 gene in normal lung tissue. Systemic inflammation mediators We have shown that SAA levels are predictive of an elevated risk of lung cancer, supporting the general view that inflammation is implicated in lung cancer development. We demonstrated that SAA levels are also increased in advanced NSCLC patients. A major consequence of the large production of acute phase proteins is the hepatic response determining a decrease of CYP 3A4 activity that, in turn, reduces cytotoxic drug clearance in cancer patients. This is fully concordant with the observation that inflammation-driven IL-6 signaling can cause resistance to drugs that inhibit the epidermal growth factor receptor. In NSCLC, EGFR overexpression has been found in 40% to 80% of cases and soluble form of the receptor has been found in blood. This raises the question of whether ectodomain shedding of transmembrane EGFR (sEGFR) can have a role in diagnosis and therapeutic management. Thus, a comparative analysis of normal lung and NSCLC tissues was performed in an effort to detect differentially expressed, tumor-specific, sEGFR isoforms. We found that soluble EGFR isoforms present in NSCLC biopsies had different isoelectric points than those detected in healthy tissue and plasma (Maramotti et al., submitted). These results support the existence of tumorspecific soluble isoforms that are most likely generated by different glycosylation patterns. At the same time, our observations indicate that the production of these tumorassociated sEGFR molecules requires a highly sensitive and specific quantitative assay that can be applied to a large set of plasma samples. The inflammatory microenvironment of solid tumors is characterized by an excess of cytokines produced and released by cancer cells, infiltrating cells and the reactive stroma that can be shed into the blood. A BioPlex multiplex protein expression analysis has been performed to characterize the inflammatory cytokines present in blood of NSCLC and control subjects. We observed that patients with lung tumor presented with increased monokine induced by interferon- (MIG) plasmatic levels (mean of 1298.6±1052.4 pg/mL) compared to controls (mean of 708.1±393.2 pg/mL), with a p-value of 0.0016 (Vaghi et al.).

Carcinogenesis We carried out an analysis, by immunohistochemistry, of neoplastic tissues from BPCO patients. To this end, we evaluated expression of DNA damage response (DDR) markers. Both normal (alveolar and bronchial tissues) and neoplastic areas of the sections were assessed for expression of the activated (phosphorylated) forms of ATM and CHK-2. It was found that neoplastic tissue often expressed the constitutive forms of ATM and CHK2, with reduced or absent expression of P-ATM and P-CHK2. This is consistent with inactivation of the DDR pathway after neoplastic transformation in the lung. In contrast, the normal epithelial counterpart, adjacent to the lesion, frequently expressed both P-ATM and P-CHK2, consistent with the tissue being under proliferative stress. We also continued flow cytometry analysis of normal tissues (both adjacent and distant from the tumor) and of neoplastic tissues isolated from surgical samples of lung tumors. Preliminary results confirmed the differential expression of regulatory T cells, whose frequency was higher in the neoplastic tissue compared to normal adjacent tissue. We also found an increased fraction of B cells in neoplastic tissue and presence of activated T cells (HLA-DR+, CD69+) in both neoplastic and normal tissues. Experimental models We used p53 +/- mice and replaced their hematopoietic cells with those from p53 wild type Thy 1.1 congenic mice to avoid the prominent lymphoid transformation. The initial idea of promoting lung cancer in such chimeric mice by pulmonary delivery of inflammatory agents was hindered by a high rate of development of osteosarcomas. Lung inflammation was then studied in the context of bleomycin-induced pulmonary fibrosis. We have demonstrated that the matricellular protein SPARC distinctly regulates inflammation and collagen deposition depending on its cellular origin. Reciprocal SPARC-KO and WT bone marrow chimeras revealed that SPARC expression in host fibroblasts is required to induce collagen fibrosis. SPARC-KO>WT chimeras showed exacerbated inflammation and fibrosis due to the inability of SPARC-KO macrophages to down-regulate TNF production because of impaired response to TGFβ1. Keywords: lung cancer, early diagnosis, biomarkers, inflammation


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Publications Lung cancer screening. Pastorino U. Br J Cancer. 2010;102:1681-6. Review. Promoter polymorphisms and transcript levels of nicotinic receptor CHRNA5. Falvella FS, Galvan A, Colombo F, Frullanti E, Pastorino U, Dragani TA. J Natl Cancer Inst. 2010;102:1366-70. Elevated levels of the acute-phase serum amyloid are associated with heightened lung cancer risk. Cremona M, Calabrò E, Randi G, De Bortoli M, Mondellini P, Verri C, Sozzi G, Pierotti MA, La Vecchia C, Pastorino U, Bongarzone I. Cancer. 2010; 116:1326-35.

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HEPATO-ONCOLOGY: A MULTIDISCIPLINARY APPROACH FOR AN EMERGING SPECIALTY

Vincenzo Mazzaferro Group Leader PARTICIPATING UNITS

Hepato-Pancreatic-Biliary (HPB) Oncology and Liver Transplantation - Coordinator Clinical Epidemiology and Trial organization Experimental Oncology and Molecular Medicine Interventional Radiology Nuclear Medicine Therapy and Endocrinology Pathology Rare Tumors Network

Overview Despite enormous advances in the prevention, diagnosis, and therapy of patients with hepatic disease, the burden of patients with liver cancer remains substantial wordwide. Major investments in prevention through anti-hepatitis measures and vaccine policies have produced a progressive decrease in the incidence of hepatocellular carcinoma, while major investments in clinical and laboratory reseach have been endorsed at many levels of society. Liver transplantation, emerging diagnostic technology, and molecular targeted therapies reflect the results of new policies adopted over the last 10 yers and have fostered greater investment in the area. Indeed, primary malignancies of the liver and bile duct were once considered orphan cancers due to the poor avaliability of effective therapeutic alternatives and their lower incidence with respect to “big killers” such as colorectal, prostate, lung, and breast cancer. In the last few years, the picture has changed and hepato-oncology has been repeatedly cited among the fastest growing fields in oncology. Accordingly, it has attracted investments and primed multidiciplinary approaches to diagnosis and treatment, as witnessed by the participation of hepatologists, surgeons, transplant teams, interventional radiologists, and oncologists in decision making. The recognized coupling of liver cancer with chronic liver diseases renders this tumor a unique solid cancer that is potentially cured with organ transplantation. This has opened the field of hepato-oncology to further contributions from regulatory bodies and policy makers devoted to governing resources to be shared among different categories of patients - with or without cancer - competing for the same limited resource of donated organs. The “Hepato-Oncology Group” at INT (INT-HO) has been instituted to promote a true multidisciplinary enviroment dedicated to the diagnosis, treatment, and follow-up of all primary and secondary malignancies of the liver. The project is aimed at improving the suboptimal organization into multidisciplinary professional structures that share information, resources, and professional skills and implement already existing collaborations between surgeons, radiologists, hepatologists, oncologists, and basic scientists toward common goals both in clinical and pre-clinical research. Through the experience of dedicated tumor boards and participation of the INT-HO group in major national and international networks focused on different types of hepatic tumors and on transplantation, any registred advancement (or failure) is considered as a part of very large community effort.

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The “Hepato-Oncology Group” at the National Cancer Institute in Milan promotes a multidisciplinary approach to all primary and secondary malignancies of the liver. Due to the high volume of procedures performed and to the large number of patients referred (Unit 1, for instance, has the highest national output in terms of surgical procedures for treatment of liver tumors), the INTHO group carries out clinical trials on innovative therapeutic approaches for liver cancer and promotes standardized operative procedures (SOP) for tissue/serum banking/biorepository. Through the INT-HO group, health professionals involved in research and treatment of different types of liver tumors find common ground for development of projects devoted to pathophysiological mechanisms, diagnostic aspects, positive prognostic indicators, innovative targets, and/ technical applications. The development of guidelines for diagnosis and treatment is instrumental for a homogeneous approach aimed at enrolling patients in prospective trials. Over the years, our Unit has made significant contributions to clinical and experimental models in hepato-oncology through focused efforts in transplantation, resection, ablation, loco-regional therapies, and more recently, targeted therapies. Clinical endpoints have been coupled with prospective pre-clinical research on molecular classification, models of prognosis, gene profiling, and microRNA investigations. In fact, translational research on liver cancer is a primary objective of the INT-HO Group, which strives to support all activities from basic, translational and clinical Units that are actively partnered with professional organizations focused on novel approaches to cancer.

IMPROVEMENT OF CONVENTIONAL THERAPIES Liver resection and ablative procedures. In November 2010, we were the number 1 recruiting center in the Western nations in terms of enrolment for multicentric randomized trials investigating the efficacy of the targeted drug sorafenib as adjuvant treatment following resection or ablation of hepatocellular carcinoma (HCC). The study enrolled 1100 patients worldwide and followup has just started. Moreover, a collaborative study on

HCC <2 cm undergoing curative resection has been completed within the International Consortium on HCC, which gathers data and experience from the INT-HO, the Hospital Clinic in Barcelona, and Mt. Sinai Hospital in New York. Liver transplantation and downstaging strategies. After final approval by the Institutional Ethical Committee, in 2010 the INT-HO Group initiated the trial “Controlled extension of conventional criteria for liver transplantation in hepatocarcinoma (HCC): a prospective randomized study using downstaging response and metroticket model as predictors of survival (XXL trial)”: the first ever randomized prospective study on liver transplantation for HCC beyond Milan Criteria. This is a pure IIS (investigator initiated study), with a structured eCRF and all regulatory characteristics entirely supported by institutional funds and non-profit organization coordinated by the INT-HO across the Italian major hospitals and transplant centers. Enrolment of patients started in November 2010 and is expected to end in the first half of 2012. Advanced HCC. In January 2010, the follow-up of patients enrolled in the phase II study on "Yttrium-90 radioembolization efficacy for the treatment of advanced HCC" designed and conducted by the INT-HO was completed. The study (publication in preparation) addresses the need for innovative treatments for patients with advanced HCC, with particular reference to portal thrombosis. The results obtained in the phase II study will hopefully give rise to a phase III trial comparing radioembolization with Y-90 to standard care in patients with HCC and portal vein thrombosis. In 2010, the outpatient clinic for advanced HCC has focused on systematic recruitment in clinical trials. This has led to two multicentric studies on new targeted therapies as second line therapy (phase III study on brivanib and phase II study on regorafenib), and other studies are in preparation. New radiological standard for assessment of liver tumor response. The introduction of targeted therapies and radioembolizing agents has challenged conventional criteria as the standard for assessing tumor response. The INT-HO group is actively participating in the


MULTIDISCIPLINARY PROGRAMS

implementation of modified RECIST (mRECIST) criteria through systematic review of our experience and introduction of new standards in any prospective investigation on HCC. Translational research with particular reference to identification of deregulated micro-RNA in HCC. We performed miRNA profiling of 89 HCC samples using a ligation-mediated amplification method. Molecular features specific for each subclass using expression pattern, DNA changes, mutational analysis (CTNNB1), and immunohistochemical (phosphor[p]-Akt, p-IGF-IR, pS6, p-EGFR, β-catenin) techniques were assessed. The roles of selected miRNAs have been investigated in cell lines and in an orthotopic model of HCC. We identified 3 main clusters of HCCs: the Wnt (36%), IFN-related (33%), and proliferation (31%) subclasses. A subset of patients with tumors in the proliferation subclass (9%)

Publications IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY, Solé M, Thung S, Moyano S, Toffanin S, Mínguez B, Cabellos L, Peix J, Schwartz M, Mazzaferro V, Bruix J, Llovet JM. J. Hepatol. 52:550-9, 2010. Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: a proof of principle. Bhoori S, Toffanin S, Sposito C, Germini A, Pellegrinelli A, Lampis A, Mazzaferro V. J. Hepatol. 52:771-5, 2010. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: Available evidence and expert opinion on the use of transarterial chemoembolization. Raoul JL, Sangro B, Forner A, Mazzaferro V, Piscaglia F, Bolondi L, Lencioni R. Cancer Treat Rev. 37(3):212-20, 2011.

overexpressed a family of poorly characterized miRNAs from chr19q13.42. Expression of miR-517a and miR520c (from ch19q13.42) increased proliferation, migration, and invasion of HCC cells in vitro. MiR-517a promoted tumorigenesis and metastatic dissemination in vivo. Considering these results, we proposed a miRNAbased classification of 3 subclasses of HCC. Among the proliferation class, miR-517a is an oncogenic miRNA that promotes tumor progression. There is therefore rationale for developing therapies based on miRNA-517 for patients with HCC. A manuscript summarizing these results has been recently accepted in Gastroenterology. Keywords: hepatocellular carcinoma, liver, transplantation, molecular targeted, loco-regional therapies, neuroendocrine tumors, cholangiocarcinoma

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MELANOMA PROGRAM

Mario Santinami Group leader Licia Rivoltini and Andrea Anichini Preclinical activity and protocols Group Leaders PARTICIPATING UNITS

Melanoma and Sarcoma - Coordinator Immunobiology of Human Tumors Immunotherapy of Human Tumors Medical Oncology Pathology

Overview Malignant melanoma continues to be a considerable medical issue because of the unsatisfactory efficacy and significant toxicities of currently available drugs, and the rising incidence of the disease worldwide, which has doubled in the last 10 years with over 160,000 cases. Currently, over 90% of these patients present with only primary melanoma at the time of first diagnosis. Although resection of the primary tumor is curative in many cases, some 20-30% of the patients will eventually die of their cancer. Patients with distant metastases and/or stage IV disease, have a very poor prognosis with a median survival of 8 months and a 2-year survival rate of 11% [Balch, 2001]. Established in 2000, the Melanoma Program is a multidisciplinary approach involving surgeons, dermatologists, oncologists, pathologists, and experimental scientists, all involved in melanoma patient care and research. This integrated network offers patients the highest standards of care and improves issues related to melanoma diagnosis and therapy by increasing current knowledge about biology, genetics, and interaction with the host environment.

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The projects of this multidisciplinary program: • Offer melanoma patients the most promising therapeutic strategies, based on a careful selection at the individual level of tumor features and disease stage • Perform extensive and coordinated preclinical and clinical studies aimed at understanding the mechanisms of action of novel anti-melanoma therapies and pathways of resistance, with particular attention to immune responses and immunotherapy • Understand the strategies utilized by melanoma cells to restrain tumor immunity from the very early phase of disease and promote disease progression, and to identify pharmacological tools for the recovery of effective immune responses The integrated research projects are ongoing, fostering further understanding of: a) genetic alterations that promote tumor transformation and progression b) the role of altered intracellular signaling pathways in promoting melanoma cell survival, resistance to programmed cell death and escape from immune control c) the role of pro-inflammatory cross-talk between tumor and stroma in promoting tumor growth and progression d) identification of molecular markers of progression e) identification and pharmacological targeting of cancer stem/initiating cells within the tumor population. From a clinical point of view, crucial questions are approached with the goal of developing novel and more effective therapeutic strategies, by combining emerging treatments and drugs (including vaccines) with more conventional therapies, both in experimental models and clinical trials. Novel therapeutic approaches. Phase I-II clinical trials testing the most promising therapeutic strategies have been activated within the multidisciplinary clinical program: patient recruitment is in progress. These include vaccination strategies with tumor antigens as recombinant proteins (MAGE3, PRAME and NY-Eso1,ASCI strategy), immunomodulation of anti-CTLA4 antibodies in combination with chemotherapy (NIBIT trial) and novel BRAF and MEK inhibitors. Studies focused on evaluating the immunological effects occurring in treated patients are performed through dedicated monitoring of tumor T cell immunity, frequency and function of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) and cytokine/chemokine serum profiling. Study of immunoregulatory pathways. The evaluation of the phenotypic and functional features of immunosuppressive cells (such as Tregs and MDSCs), the molecular pathways leading to their accumulation and the impact that these cells may have on the clinical course of melanoma patients has allowed us to gain information about: i) The expression of LAG-3 as marker of activated Treg present at the tumor site, displaying stronger immunosuppressive activity; ii) The role of tumor

exosomes in converting myeloid cells into MDSC, and the immunosuppressive/protumorigenic properties of these cells generated either in vitro or in vivo in melanoma patients; iii) Immunomodulation by drugs, such as cyclophosphamide or proton pump inhibitors (esomeprazole), on Treg and MDSC in vitro or in vivo, of treated patients. Role of melanoma stem cells in disease progression. We have evidence that metastatic melanomas displayed a high frequency of cells forming melanospheres in vitro and growing in SCID mice. These putative stem cells display a heterogonous phenotype with no unidirectional association between tumorigenicity and a given phenotype. We are now focusing on dissecting the interaction between melanoma stem cells and the immune system, evaluating the role of immune-related factors in modulating the behaviour of melanoma stem cells. Molecular studies on melanoma genetics. We have focused on the characterization of genetic pathways and the assessment of sensitivity to targeted therapies in melanoma. Analysis of genetic alterations was carried out by multiplex ligation-dependent probe amplification (MLPA) analysis, which detected changes in copy number of a large number of genes that are often deleted or amplified in several tumor types. Amplifications involving MET, CCND1, CTNNB1 and FGF3 genes were detected and confirmed by qPCR assessing gene copy number. Melanoma cell variants selected for poor sensitivity to PLX4032 (a V600E BRAF-specific inhibitor) inhibited their proliferation, migration and invasive abilities when using a combined treatment with a MET-specific inhibitor. Functional characterization at the tumor site of melanoma patients of CD8+ FOXP3+ "early effector" T cells (EEC). This subset of T lymphocytes, which has not been previously identified in neoplastic tissues from patients with advanced melanoma, represents the earliest stage in the pathway leading to generation of anti-tumor effectors. These cells were antigen experienced, based on an “EM1” phenotype (CCR7- CD45RA- CD28+ CD27+), and exhibited a CD127-, KLRG1-, HLA-DR+, CD38+, T-bet+,


MULTIDISCIPLINARY PROGRAMS

perforin+ PD1-, CD57- “early effector” profile predicted by current models. The EEC to Treg (CD4+ FOXP3+) ratio, in tissues from a panel of melanoma patients, was 1.8±1.6 in primary lesions, 0.3±0.2 in cutaneous metastases and 0.09± 0.07 in tumor-invaded lymph nodes, indicating a progressive reduction of EECs in favor of suppressive T cells, along with tumor progression. At the functional level, EECs expressed Ki-67 upon ex-vivo analysis, indicating competence for proliferation. In vitro, in response to autologous tumor plus cytokines such as IL-2 and IL-15, the EECs proliferated promptly and showed competence for differentiation towards the "short-lived effector cell "(SLEC) fate as indicated by progressive loss of CD27, associated with a gradual up-regulation of T-bet. These results suggest development of early phases of anti-tumor immunity even in advanced melanoma. Moreover, the CD8+ FOXP3+ “early effector” subset may be an invaluable tool for monitoring immunity at tumor site. Biological classification of melanoma based on a phosphoproteomics approach for constitutively active intracellular signaling pathways. This project is being carried out in collaboration with the Istituto Regina Elena (Rome) and the Istituto Superiore di Sanità (Rome). The goal is to define a new classification of human melanoma based on the expression of constitutively-active components of intracellular signaling pathways. Phosphoflow cytometry for detection of phosphorylated components of the MAPK, PI3/AKT and STAT signaling pathways has been applied to 95 short-term melanoma cell lines, all with the already known profile for BRAF or NRAS activating mutations. Keywords: tumor vaccines, immune escape, BRAF/MEK inhibitors, melanoma stem cells

Publications Heterogeneous phenotype of human melanoma cells with in vitro and in vivo features of tumor-initiating cells. Perego M, Tortoreto M, Tragni G, Mariani L, Deho P, Carbone A, Santinami M, Patuzzo R, Mina PD, Villa A, Pratesi G, Cossa G, Perego P, Daidone MG, Alison MR, Parmiani G, Rivoltini L, Castelli C. J Invest Dermatol. 130:1877-86, 2010. pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. De Milito A, Canese R, Marino ML, Borghi M, Iero M, Villa A, Venturi G, Lozupone F, Iessi E, Logozzi M, Della Mina P, Santinami M, Rodolfo M, Podo F, Rivoltini L, Fais S. Int J Cancer. 127:207-19, 2010. Tumor-reactive CD8+ early effector T cells identified at tumor site in primary and metastatic melanoma. Anichini A, Molla A, Vegetti C, Bersani I, Zappasodi R, Arienti F, Ravagnani F, Maurichi A, Patuzzo R, Santinami M, Pircher H, Di Nicola M, Mortarini R. Cancer Res. 70:8378-87, 2010.

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PERSONALIZED TREATMENT OF SARCOMAS

Paolo G. Casali Group Leader PARTICIPATING UNITS

Adult Sarcoma Medical Treatment - Coordinator Biomarkers Clinical PET Evaluative Epidemiology Immunotherapy of Human Tumors Laboratory Medicine Melanoma and Sarcoma Molecular Diagnostic laboratory Palliative Care Molecular Basis of Genetic Risk, Polygenic Models Tumor Genomics

Overview Soft tissue and bone sarcomas, including GISTs, are rare and highly heterogeneous tumors. Heterogeneity is firstly related to their ubiquitous anatomic origin. In this regard, it is well known that applying good surgical principles to all sarcoma primary sites is not feasible. In particular, it is known that retroperitoneal and thoracic sarcomas have a poorer prognosis, primarily for surgical reasons. It is realized that new therapeutic avenues should be explored for these tumors, exploiting all disciplines, from surgery to radiation and medical therapy. Heterogeneity is also related to the pathology of these tumors, as there are dozens of histological subtypes. It is well-known that the natural history of sarcomas differs substantially depending on the histological subtype. In the last few years, it also became clear that histologic subtypes possess distinct cytogenetic and molecular profiles that affect sensitivity to medical therapies, including cytotoxic and targeted agents. These latter have mechanisms of action that are more specifically dependent on the molecular profile of the tumor. This poses new challenges to medical therapy of sarcomas, reinforcing the need to personalize medical treatment, mainly exploiting knowledge of deregulated molecular profiles. In this regard, GISTs constitute a tumor model that the sarcoma medical community has had the privilege to explore, and the model can now be tested in other types of sarcomas. In particular, it is clear that the current approach to sarcomas should be highly personalized, on a highly multidisciplinary basis. GISTs constitute an advanced platform, but other sarcomas are catching up rapidly, as new targeted agents are becoming available at a steady pace. The aim of this project is to strengthen the institutional research platform, aimed at gaining new insights on the antitumor activity of cytotoxics and molecular targeted agents in selected types of sarcoma, including the rarest ones. New insights will also be gained on how to incorporate these medical therapies into multidisciplinary treatment strategies, with insights even in the most challenging clinical presentations of sarcoma. New avenues in the methodology of clinical research will be attempted, so that an additional value of the project will be the assessment of new strategies for clinical research, potentially serving as a model for other rare tumors. The patient populations involved in this project include all patients affected by sarcoma, which for practical reasons are mainly divided into: adult soft tissue sarcoma; GIST; small blue round cell sarcoma; osteosarcoma; chordoma and chondrosarcoma; rare histological types.

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The project intends: • To strengthen the institutional infrastructure for clinical studies on new agents in sarcoma. The aim of the infrastructure is to place the INT in the best position to launch and/or to join phase II and phase III clinical studies on new agents in sarcoma. • To support the institutional infrastructure for translational research related to the targeted use of new molecular agents in sarcoma. The infrastructure will aim to place the INT in the best position to perform translational research on the use of new agents in sarcoma in tailored manner. • To support the sarcoma networking coordinated by this Institute to allow prospective and retrospective studies even on the rarest sarcoma subtypes and presentations. INT coordinates the Italian Network on Rare Tumors, which is a powerful means to perform prospective and retrospective studies on rare presentations, with regards to their natural history and sensitivity to treatments. • To study the clinical utility of new targeted agents for treatment of sarcoma. Targeted agents imply considerable rethinking of clinical methodology (e.g., with regard to tumor response, assessment etc.). However, only centers with a large number of patients can embark on such a project, through systematic clinical observations and studies focusing on treatment strategies. • To develop and to test new methodologies for clinical research in rare tumors. An effort will be made to test new options firsthand at least on the rarest presentations. RELEVANT OUTPUT During the second year of the project, the main effort was to foster a global collaboration among the most important international sarcoma centers to develop new agents. The ESMO International Conference on Sarcoma & GIST was organized by INT on March 2010; during this event an advisory board convened by the global community

together with major pharmaceutical companies took place to identify new drugs for early screening in sarcomas through methodologically innovative studies. Several clinical trials on rare sarcoma subtypes are ongoing: A Phase II trial on nilotinib in pigmented villonodular tenosynovitis. It is a rare condition in which tumor growth is sustained by CSF1R/CSF1 through an autocrineparacrine loop potentially inhibited by nilotinib. Results on the activity of imatinib were presented at ASCO 2010 in collaboration with other European centers. A pooled review on a series from both INT, in collaboration with the Istituto G. Pini-Milan and IOR Bologna, has been published. A Phase II trial on the activity of NGR-TNF, a fusion protein derived from NGR and TNF. We postulated that it would have anti-tumor activity in vascular sarcoma histotypes, such as angiosarcoma, fibrous solitary tumor, and alveolar soft part sarcoma. Five patients had been enrolled to date by the INT. Two Phase II trials in imatinib-pre-treated chordoma: a) lapatinib, an EGFR inhibitor (11 pts enrolled by INT); b) everolimus + imatinib (not yet enrolling). Two Phase II trials on GIST: a) everolimus + imatinib in imatinib-naïve patients with a PDGFRA-D842V mutation; b) regorafenib, a BRAF inhibitor, as third line therapy in s An observational study on the prognostic and predictive role of the mechanisms of immunosuppression in sarcoma and GIST patients treated with targeted therapies. This study will provide new data on the possible effects of immunomodulation by targeted drugs. This information can provide new tools for immunotherapy and vaccination in oncology. With regards to solitary fibrous tumors, we published a paper reporting observations on the translational and


MULTIDISCIPLINARY PROGRAMS

clinical activity of sunitinib, with one observed partial response to an anti-IGF1R agent. This data was confirmed by a US experience. A series of 30 patients treated with sunitinib was updated in a presentation at ESMO 2010. The animal model is under study in order to identify the mechanism of action of the drug. A paper will be submitted for publication. We first presented at ASCO 2010 an update of our data on sunitinib in ASPS, confirming its antitumor activity, that was later published. We also reported that sunitinib is active both by a direct antitumor effect and an antiangiogenic mechanism. We also documented sunitinib activity in a case of clear cell sarcoma, also called "melanoma of soft tissues". During the last ASCO meeting, we presented a retrospective study on a series of 20 cases of CCS, 50% of which were not translocated, showing that the morphology and the molecular profile is the same whether or not translocation has occurred. The results of this study extended to a series of melanoma has been submitted for publication. We established the activity of imatinib in chordoma. A publication on the final analysis of the phase II study on imatinib in advanced chordoma has been finalized. As already mentioned, two new Phase II studies are ongoing in imatinib pre-treated patients. We also reported on the activity of trabected in in myxoid liposarcoma in the advanced setting. The molecular data on the mechanism of action of this drug in myxoid

Publications Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Casali PG, Blay JY; ESMO/CONTICANET/EUROBONET Consensus Panel of Experts. Ann Oncol. 21 Suppl 5:v98-102, 2010. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Casali PG, Blay JY; ESMO/CONTICANET/EUROBONET Consensus Panel of experts. Ann Oncol. May 21 Suppl 5:v198-203, 2010. Extremity soft tissue sarcoma in a series of patients treated at a single institution: the local control directly impacts survival. Gronchi A, Lo Vullo S, Colombo C, Collini P, Stacchiotti S, Mariani L, Fiore M and Casali PG. Ann Surg. Mar 251(3): 506-11, 2010

liposarcoma were studied, and novel models of myxoid liposarcoma xenografts have been published, demonstrating biological and pharmacologic features that mimick human tumors. The results of a recently completed Italian Sarcoma Group Phase II study on neoadjuvant trabectedin were presented at ESMO 2010. An institutional series of extremity soft tissue sarcoma was published, showing improved local control over the two last decades and a direct impact of this treatment on survival. Regarding retroperitoneal sarcomas, a combined analysis from a series at our Institute and from the Gustave-Roussy Institute (Paris) demonstrated that aggressive surgery is safe and is also associated with improved local control. Concerning response criteria evaluation in sarcoma patients, we have attempted to compare RECIST versus Choi criteria, and to correlate these with outcome in a series of patients affected by high-grade limb and superficial soft tissue sarcoma, within the framework of a trial by Spanish and Italian Sarcoma Groups. Data have been submitted to ASCO 2011. Evaluation of response according both to RECIST and Choi criteria was carried out in a series of retroperitoneal sarcoma patients; data were presented at CTOS 2010. Keywords: sarcomas, rare sarcoma subtypes, genetic alterations

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NOVEL APPROACHES TO DETERMINE PROGNOSIS AND RESPONSE TO TREATMENT IN MATURE B-CELL MALIGNANCIES

Paolo Corradini Group Leader PARTICIPATING UNITS

Hematology and Bone Marrow Transplantation - Coordinator Immunobiology of Human Tumor Medical Oncology 3 Medical Statistics and Biometry Pathology Proteomic Laboratories Radiology and Diagnostic Imaging

Overview Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) are mature B-cell cancers with an incidence that increases with age. Despite novel drugs, MM remains incurable for the vast majority of patients, with a highly variable outcome in different prognostic subgroups. The same applies to CLL: the disease is incurable and prognosis is extremely variable depending upon several clinicopathological factors. The selection of the most appropriate treatment (chemo-immunotherapy or stem cell transplantation [SCT]) must include knowledge of the clinical and genetic prognostic factors of the patient. For example, the limited duration of response after autologous SCT for MM patients with t(4;14)(p16;q32), t(14;16)(q32;q23) and 17p13 deletions highlights the need to develop a risk-adapted treatment strategy. The same applies to CLL patients carrying the 17p13 deletion. From an idealistic point of view, treatment strategies should be tailored based on clinical risk determination, adverse genetic prognostic factors, and host features. Although there is some data from gene expression profiling studies, there are no clear and firm conclusions on prognostic relevance and applicability in a clinical setting. While flow cytometry, cytogenetics, and molecular analysis may provide prognostically important information for both MM and CLL, they are not routinely used, and not frequently used together in a prospective fashion. Modern treatment protocols lead to complete remission (CR) in a considerable proportion of patients with MM and CLL. However, many patients will ultimately relapse, implying that the achievement of a clinical CR is compatible with a significant amount of residual malignant cells. For these reasons, a comprehensive approach prospectively integrating clinical and laboratory data is required for better stratification of patients, which will in turn translate into better allocation of healthcare resources.

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Our major objective is to analyze the pre-treatment clinical and biological features of patients to determine their value in predicting disease response and survival. In particular, focus is placed on four main research areas: i) the genetic features of the tumor (cytogenetics and FISH studies of MM cells, detection of MM stem cells, validation of the 17-gene expression-based riskstratification model, identification of circulating MM specific miRNAs, the use of a proteomic strategy on both leukemic cells and plasma specimens to identify novel proteins as biologic indicators of prognosis and response to treatment for CLL); ii) the immunological evaluation of the host and tumor interaction (evaluation of the T cell, natural killer cell and myeloid derived suppressor cell compartment); iii) monitoring of minimal residual disease (multiparameter flow cytometry and molecular methods); iv) assessment of bone lesions using a novel imaging method [whole body magnetic resonance imaging (DWMRI)]. A fundamental goal of this project is to find a panel of biomarkers that can be easily and routinely used in a clinical setting. RELEVANT OUTPUT Promising results have been obtained during the last year of activity. In particular, we have demonstrated that: • Preliminary analyses with diffusion weighted MRI (DW-MRI) on 50 patients showed that the number of lesions revealed by DW-MRI is significantly higher than that revealed using standard radiological examinations. There was a significant difference in the number of lesions detected in patients with symptomatic MM compared to patients in follow-up. Complex image analysis defined a diffusion coefficient (ADC, apparent diffusion coefficient) that is inversely correlated with tumor cellularity. In particular, most patients with MM had lesions characterized by a median ADC of 0.7, with a

narrow standard deviation. The ADC value increases with response to treatment. The monitoring of the ADC value allows functional and morphological evaluation of bone lesions, indicating the enormous potential of applying DW-MRI for evaluation of MM. • Circulating miRNAs can be detected and analyzed by quantitative RT-PCR in peripheral blood plasma samples of MM patients. We have characterized a specific circulating miRNA signature that differentiates MM patients from healthy subjects. The altered MM-related miRNA signature in this subset of patients is characterized by increased expression of miR-124, -19b, -135b, -380, and -548a.3p, and decreased expression miR-187. Targets of overexpressed miRNAs include tumor suppressor genes as well as genes encoding proteins acting as negative regulators of cell proliferation, survival, and osteogenesis. In addition, it was possible to identify a correlation between the levels of specific circulating miRNAs and prognostic factors defined by the ISS and cytogenetics. Further studies are aimed at identifying the role of differentially-expressed miRNAs in the plasma of myeloma patients. Nonetheless, these preliminary results indicate that miRNAs present in the peripheral blood could be used for disease monitoring in MM patients. • Elevated levels of serum amyloid A (SAA) protein in the plasma of CLL patients were identified using a proteomic strategy. To detect new plasma biomarkers in CLL patients, surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF) mass spectrometry was applied. The analysis revealed statistically significant differences in SAA expression between the plasma of LLC patients and healthy subjects (P=0.002). In addition, SAA levels are elevated in the plasma of patients with an unfavorable cytogenetic profile (try12; del17 del11) compared to patients with normal or other cytogenetic


MULTIDISCIPLINARY PROGRAMS

status (P=0.02). In CLL patients, SAA plasma levels also positively correlated with a peripheral lymphocyte doubling times of less than one year (P=0.009). Although preliminary, these data suggest that elevated SAA levels are associated with unfavorable prognostic markers and support the view that inflammation is implicated in development of CLL. â&#x20AC;˘ Clonogenic MM cells can be stained using the Hoechst side population and Aldefluor assays. Each assay identified CD138neg cells, suggesting a high drug efflux capacity and intracellular drug detoxification activity. We also found that these cells express the CD56

Publications Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Lancet. 376(9758):2075-85, 2010. Pretransplantation [18-F]fluorodeoxyglucose positron emission tomography scan predicts outcome in patients with recurrent Hodgkin lymphoma or aggressive non-Hodgkin lymphoma undergoing reducedintensity conditioning followed by allogeneic stem cell transplantation. Dodero A, Crocchiolo R, Patriarca F, Miceli R, Castagna L, Ciceri F, Bramanti S, Frungillo N, Milani R, Crippa F, Fallanca F, Englaro E, Corradini P. Cancer. 116(21):5001-11, 2010. Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Sarina B, Castagna L, Farina L, Patriarca F, Benedetti F, Carella AM, Falda M, Guidi S, Ciceri F, Bonini A, Ferrari S, Malagola M, Morello E, Milone G, Bruno B, Mordini N, Viviani S, Levis A, Giordano L, Santoro A, Corradini P; Gruppo Italiano Trapianto di Midollo Osseo. Blood. 115(18):3671-7, 2010.

marker. Our results complement those recently obtained by other groups. The combined use of surface phenotype with flow cytometricâ&#x20AC;&#x201C;based functional stem cell properties facilitates identification of these circulating cells in MM patients. Therefore, it is possible to use these methods quantify MM stem cells for use as a surrogate marker for clinical response during therapy. Keywords: multiple myeloma; response to therapy; biomarkers; chronic lymphocytic leukemia

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MONTABONE PROJECT FOR DEVELOPMENT OF NEW DRUGS IN MEDICAL ONCOLOGY

Luca Gianni Group Leader PROJECT LEADERS

Cristiana Sessa and Giuseppe Capri PROJECT GROUP

Sara Cresta, Gianluca Del Conte, Angelica Fasolo, Antonella Perotti, Alberta Locatelli, Lucia Viganò, Giovanni Brambilla, Mauro Desogus

Overview The Montabone Project was started in 2001 and is one of the strategic projects of the Science Directorate. It major aim is develop new drugs, chemotherapies, and molecular targets for the treatment of solid tumors in Phase I and early Phase II studies. It also includes assessments of pharmacokinetics, including translational research with pharmacodynamic endpoints. Another goal is to enrich these studies with pharmacogenetic evaluations with the objective of increasing safety and efficacy based on individual genetic profiles. The final ambition is the creation of a research Unit that can independently provide planning of studies in Phases I and Ib, which also comprises clinical management of patients through collaboration with the Laboratory of Clinical Pharmacology and the support of two researchers. It is also our intention to train nurses in the administration of novel therapies and techniques of pharmacokinetic and pharmacodynamic sampling. Lastly, as part of the same project, clinical data will be evaluated together with biological data, all of which is managed through collaboration with a dedicated data manager. Screening of patients takes place using a team of physicians in two walk-in clinics, one of which is open on a daily basis, and the other two days per week. External visits are followed by a clinical report that is sent to the referring physician. In 2010, there were a total of 204 visits. In addition, a system of active patient recruitment has been established, in addition to pre-existing programs: 51 were treated with chemotherapy combined with targeted drugs; 26 patients were treated with new agents combined with traditional chemotherapy or new chemotherapeutic agents; lastly, 17 patients received an innovative molecularly targeted drug. All patients were also subjected to pharmacokinetic assessment, and the majority was also evaluated with pharmacodynamics and pharmacogenetics. Continuous collaboration was seen with other departments with constant case referral; together with the Diagnostic Imaging Department several individual cases were also reevaluated. A total of 204 visits were carried out as part of the Montabone Project considering patients potentially eligible for phase I studies. Most visits were for breast, gynecological, gastroenteric, and head and neck cancers.

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The main objective of the Montabone Project was to actively participate in patient enrolment for two interesting clinical trials. The first involves the combination of two drugs with antiangiogenic and antivascular activity (bevacizumab and ombrabulin, respectively) with endpoints of pharmacodynamic radiologic evaluation using DCE-US, in addition to assessment of pharmacokinetic interactions. The project relies on collaboration with the Cardiology Unit for realtime evaluation of cardiac function with Holter monitoring, echocardiography, and clinical assessment following drug infusion. The second trial will use a new generation anti-EGFR monoclonal antibody, with should be active even in patients with a Fc-gamma genetic profile that is typically not responsive to traditional therapy with currentlyemployed anti-EGFR monoclonal antibodies. Pharmacokinetic, pharmacodynamic, and pharmacogenetic studies will also be carried out in this trial. The camptothecin analog namitecan (ST1968). The new inhibitor of topoisomerase I that is being investigated as part of a phase I study with the objective of establishing safety and dose during a 3-day schedule every 21 days. Currently in pre-clinical studies, namitecan has shown signs of activity in ovarian, head and neck, and uterine cancers. The study is being carried out together with two centers in Switzerland. In 2010 at our institute, 15 patients have been treated with namitecan, all of whom were also subjected to pharmacokinetic evaluation. The drug showed good activity and acceptable hematological toxicity. Definition of the optimal dose is still in progress.

Monoclonal antibody anti-TA-MUC1 (Pankomab). The humanized antibody, defucosylated, is directed against TA-MUC-1, and can be determined using immunohistochemical analysis in a centralized laboratory in Germany. The drug is “first in human”, and dose escalation studies are in progress in three centers (INT, IOSI, and Tumorzentrum in Hamburg). In 2010, 12 patients received the drug after showing positivity for the target, with good tolerability and some evidence of control of disease. Pharmacokinetic, pharmacodynamic, and pharmacogenetic studies were carried out on all patients enrolled. Taxol combined with lenalidomide. The phase Ib study is carried out at the IOSI and INT and all doses have been completed such that the optimal dose can be defined in association. The expansion phase is in progress. Studies involving pharmacokinetics and pharmacodynamics are aimed at investigating eventual kinetic interferences between the two drugs in combination, and evaluating the impact of immunomodulating therapy and the tumoral microenvironmental level. Nine patients have received the treatment with preliminary evidence of limited collateral effects, especially hematological toxicity. Keywords: phase I study, antivascular drugs, monoclonal antibodies

Publications Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine. Perotti A, Locatelli A, Sessa C, Hess D, Viganò L, Capri G, Maur M, Cerny T, Cresta S, Rojo F, Albanell J, Marsoni S, Corradino I, Berk L, Rivera VM, Haluska F, Gianni L. J Clin Oncol. 28(30):4554-61, 2010. Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573;MK-8669) with weekly paclitaxel. Sessa C, Tosi D, Viganò L, Albanell J, Hess D, Maur M, Cresta S, Locatelli A, Angst R, Rojo F, Coceani N, Rivera VM, Berk L, Haluska F, Gianni L. Ann Oncol. 21:1315-22, 2010.


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INTEGRATED UNIT FOR THE CONCERTED TRANSLATIONAL EARLY DEVELOPMENT OF NEW DRUGS AND/OR THERAPEUTIC APPROACHES IN SOLID TUMORS

Luca Gianni and Angela Moliterni Group Leaders PARTICIPATING UNITS

Montabone Project Biomarkers Molecular Pharmacology Radiology and Diagnostic Imaging Michelangelo Foundation

Overview The project will develop and implement an integrated functional model of human resources and institutional logistics for Phase I and II studies in solid tumors. This will entail integration of the knowledge and resources of several collaborative Units on specific projects at the IRCCS Foundation - INT. Once established, this project will permit the identification of new agents and/or novel uses for already known compounds. At a later phase, such a model can be applied to other research projects at the Foundation. The creation of a Consortium for the Development of Innovative Therapies in Oncology, coordinated by Unit 1 of the present program, will manage clinical and translational studies for the development of new drugs and therapeutic approaches in solid tumors. The collaboration will allow for independent clinical research and will establish a partnership with pharmaceutical industry.

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The multidisciplinary program intends: • Develop innovative therapies for solid tumors through Phase I and II studies. The major objective is to carry out pharmacokinetic and pharmacodynamic investigations with the support of the Labatory of Clinical Pharmacology within Unit 1. • Identify new inhibitors of Hsp90 (by molecular modeling approaches) to determine in silico the possibility that compounds belonging to public collections (NCI) can inhibit Hsp90 by interacting with the ATP binding pocket or by acting as an allosteric inhibitor. A major objective is to study non-conventional pharmacological targets to evaluate the antiproliferative activity of stabilizers of guanine quartets at DNA telomeres. Optimization of animal models of human breast cancer that can spontaneously generate metastases following xenotransplantation in nude mice. • Develop focused animal models for optimization of targeted therapy and their combination with cytotoxic drugs using methodology available at the Genomics Core Facility of the INT. • Carry out centralized multidisciplinary revision of radiologic images from subjects included in Phase I and II trials. Evaluate the possibility to carry out rapid biopsies for diagnosis and/or research. • Activation and management of a consortium for clinical and translational studies for the development of new drugs and/or therapeutic approaches in solid tumors - Consorzio per la Ricerca Oncologica Lombarda sul Territorio (CROLT) - with the collaboration of the Michelangelo Foundation. Relevant output In 2010 two clinincal studies were initiated, one with a new monoclonal antibody and the other investigating the combination of two drugs with a molecular vascular target. Patients are being actively recruited, in addition to those already participating: 51 patients have been treated with combined chemotherapy with targeted drugs; 26 patients have been treated with a new combination and traditional chemotherapy or with new chemotherapeutic agents; 17 patients have been treated with an innovative drug with a molecular target. In all patients pharamacokinetic assessment was carried out, and in the majority of cases pharmacodynamic and pharmacogenetic evaluation was also performed. A selected panel of human breast cancer cell lines was evaluated to determine the relative sensitivity to targeted drugs. In addition to cytotoxicity, the biochemical interactions and relevant pathways were also examined. In the case of pharmacological associations, the type of interaction with the drug was determined using an appropriate mathematical model (combination index,

isobolograms). Interestingly, interaction between a HDAC inhibitor and an inhibitor of mTOR was seen, which in some lines had an additive/synergistic effect. Nine molecules are under study in terms of their ability to interact with recombinant Hsp90 in vitro and deregulate Hsp90 client proteins in cells exposed to drugs. It has been observed that guanine stabilizers lead to inhibition of cellular proliferation through induction of replicative senescence following destabilization of telomeres (after release of proteins TRF2 and POT1) and inhibition of telomerase activity. Animal models of human breast carcinoma have been optimized that are able to spontaneously generate metastases following xenotransplantation in nude mice. Based on in vitro analyses, the MDA-MB231 line appears to be an interesting model to study the antitumoral and antimetastatic activity of drugs and drug combinations. The molecular alterations associated with resistance to platinum has been investigated using a panel of cell lines (3 parent lines and 5 resistant lines), and a “signature” of 77 transcripts and 11 microRNA that are differentiallyexpressed has been identified. An analysis of gene and miRNA expression has been carried out using software that is based on an anti-correlation approach, which allows for integration of the available predictions on-line for interactions between miRNA and the target gene. From this analysis, several interactions have been found that will be validated experimentally. Study of rational pharmacological combinations in also in progress using cellular models of ovarian carcinoma. A reduction in the levels of mRNA and proteins belonging to the DUSP family (which dephosphorylates ERK1/2), in IGROV-1/OHP and in other resistant variants with respect to the parental lines has been found. Since p53 can bind to the DUSP5 and DUSP6 promoter regions, mutations in IGROV-1/OHP cells could bring about down-regulation of DUSP5 and DUSP6. Additionally, targeting of the MAPK pathway could increase the sensitivity of ovarian carcinoma cells to platinum compounds, and a better understanding of the molecular interactions that favor a synergic action could potentially provide the basis for the


MULTIDISCIPLINARY PROGRAMS

design of rational drug combinations. Moreover, the combination of histone deacetylase inhibitors and proteosome inhibitors has been studied in models of ovarian cancer with p53 mutations and resistance to platinum compounds, and a synergistic interaction has been observed The Unit has provided a valuable contribution to the overall collaboration in accordance with the project proposal. The support of the Michelangelo Foundation has permitted the activation of the CROLT study and contributed to the design of the study protocols in

Publications Modulation of cell sensitivity to antitumor agents by targeting survival pathways. Perego P., Cossa G., Zuco V., Zunino F. Biochem. Pharmacol. 80:1459-65, 2010. Clinical pharmacokinetics of the new oral camptothecin gimatecan: the interpatient variability is related to alpha1-acid glycoprotein plasma levels. Frapolli R., Zucchetti M., Sessa C., Marsoni S., Viganò L., Locatelli A., Rulli E., Compagnoni A., Bello E., Pisano C., Carminati P., D'Incalci M. Eur J Cancer. 46:505-516, 2010. Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine. Perotti A., Locatelli A., Sessa C., Hess D., Viganò L., Capri G., Maur M., Cerny T., Cresta S., Rojo F., Albanell J., Marsoni S., Corradino I., Berk L., Rivera V.M., Haluska F., Gianni L. J Clin Oncol. 28:4554-4561, 2010. Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel. Sessa C., Tosi D., Viganò L., Albanell J., Hess D., Maur M., Cresta S., Locatelli A., Angst R., Rojo F., Coceani N., Rivera V.M., Berk L., Haluska F., Gianni L. Ann Oncol. 21:1315-1322, 2010.

accordance with GCP standards, statistical considerations and data analysis. For the first trial (CROLT1), the Michelangelo Foundation has provided electronic a Case Report Form (e-CRF) using compatible systems and procedures. The study was granted approval from the relevant Ethics Committees and will initiate in 2011. Concerning the second study (CROLT2), the relative e-CRF is being prepared. The protocol will be subjected to the approval of the Ethics Committees from participating centers in the first quarter of 2011, and will initiate as soon as approved. Keywords: innovative therapies, targeted therapy, mechanisms of drug resistance

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MULTIDISCIPLINARY PROGRAMS

DEVELOPMENT OF RADIOPHARMACEUTICALS FOR TUMOR CHARACTERIZATION, MOLECULAR IMAGING, AND THERAPY

Emilio Bombardieri Group Leader PARTICIPATING UNITS

Nuclear Medicine - Coordinator Molecular Therapies Medical Oncology Prostate Program Molecular Immunology

Overview The use of Nuclear Medicine tracers for tumor imaging offers the advantage of providing not only morphological data, but also information on the biology of tumor tissue, describing several parameters such as aggressiveness, proliferative activity, hypoxia, and amino acid uptake. All these features can be considered prognostic and may be useful when selecting the most effective treatment. The use of metabolic tracers in monitoring treatment effectiveness can also overcome the intrinsic limitations of morphological assessment of tumor response. In addition to metabolic tracers, new tracers based on specific recognition and binding to tumor targets can be exploited as diagnostic radiopharmaceuticals. Furthermore, the same radiopharmaceuticals proposed for tumor imaging, when labeled with high activity radioisotopes, might be able to deliver a sufficient amount of radiation to kill cancer cells. In this regard, it is essential to: choose a specific target on cancer cells; select a metabolic â&#x20AC;&#x2DC;bulletâ&#x20AC;&#x2122; that can bind the target with high affinity; radiolabel this tracer in order to localize the disease, taking into account the physicochemical characteristics of the radionuclide (positron, beta or gamma emitters). In the case of thyroid cancer, which is already treated with radioisotopes, the optimization of dosimetry and better knowledge of its biology could greatly improve treatment strategies. This project is focused on the development of: a) 3'deoxy-3' 18F-fluorothymidine as a radiopharmaceutical for PET imaging; b) radiolabeled somatostatin analogues for radioreceptor therapy of neuroendocrine tumors (NET); c) a radiolabeled monoclonal antibody fragment directed to the prostatic specific membrane antigen (PSMA) as a diagnostic tracer and therapeutic agent for prostate cancer; d) novel techniques for radiopharmaceutical and nuclear medicine, and to provide biological insights to optimize therapy of thyroid cancer.

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The projects of this multidisciplinary program have as: • The first objective to provide a new prognostic marker for PET imaging that is able to differentiate malignant from normal tissues and to measure cancer cell proliferation. The tracer under investigation is 18Ffluorothymidine (18F-FLT) that can be used for diagnosis and monitoring the effectiveness of anticancer treatments. In particular, the tracer will be assessed in both preclinical and clinical studies in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. • The second objective to design a new radioreceptor therapy for NETs. The radiolabeling of somatostatin analogues with lanthanides or lanthanides-like radiometals has already been optimized using beta emitters such as 90Y and 177Lu, and with 68Ga for PET. Here, the objective is to evaluate whether combined treatment with 177Lu-DOTA-TATE and 90Y-DOTA-TATE can exploit the different emission energy of the two radionuclides to improve the killing effects on both microand macro-metastases. • The third objective the development of immunological probes against PSMA, a transmembrane protein overexpressed in prostatic cancer. The anti-PSMA single chain Fv, after radiolabeling, can detect prostate cancer cells better than traditional anti-PSA antibodies due to its binding to the cell surface. Both positron and electron emitting radioisotopes are considered for radiolabeling since the reliable tracers used for diagnostic imaging can potentially be utilized for therapy when conjugated with 131I, 90Y, or 177Lu. • The last objective to develop new approaches for treatment of thyroid cancer. The first step will be to investigate the expression of IGFBP7 and TIMP3, rearrangement of the oncogenes RET/PTC, and the mechanism of tumor response to combined treatment with gimatecam and HSP90 or MEK-CI-1040 inhibitors. When 131I is used, pre-treatment dosimetry is essential to establish the optimal activity and to maximize the dose of irradiation.

An original method for 18F-FLT synthesis that allows easy production of 18F-FDG has been patented. The radiopharmaceutical fulfills the requirements of the Pharmacopea (sterility, pyrogenicity, pH, chemical and radiochemical purity, analysis of residual reagents). Animal models bearing breast cancer tumors have been studied to compare the uptake of 18F-FLT with 18F-FDG and to determine 18F-FLT uptake and behavior, and in particular its relationship with the biology of cancer tissue (cell proliferation, necrosis, prognostic markers). Studies using micro-PET have confirmed the feasibility of an in vivo approach. A clinical protocol has been approved by an Independent Ethics Committee, which entails evaluation of early response to primary chemotherapy (AT+CMF) in patients with locally advanced breast cancer, stage T2-4,N0-3,M0. A PET evaluation with 18FFLT is planned at the beginning of treatment, after the first cycle, and at the end of the treatment prior to surgery. The uptake of 18F-FLT uptake will be compared with pathological response, prognostic parameters, and other modalities of diagnostic imaging. This ongoing study aims to validate the use of 18F-FLT PET as an early predictor of response to chemotherapy. The study of radioreceptor therapy of NETs has been continued with tyr(3)-octreotate (TATE) bound to DOTA with 90Y or 177Lu radioisotopes. Because these radionuclides have different emission energies, combined treatment is associated with optimal irradiation of tumor lesions with different sizes. The protocol adopted (repeated cycles with 5.5 GBq of 177Lu DOTA-TATE and 2.6 GBq of 90Y DOTA-TATE) resulted in an objective response in 21 of 26 cases (80.1%), and included 8 partial responses (30.1%), 1 complete response (3.8%), and 12 stable disease (46.1%). Side effects were limited to transient leucopenia in a few cases; no renal toxicity was described. On the basis of these results, it is planned to increase the activity of the radiopharmaceuticals injected (7.4 GBq for 177Lu and 3.7 GBq for 90Y) to further improve clinical response in patients with advanced disease that is refractory to traditional approaches. The murine monoclonal anti-PSMA engineered fragment (D2B) has been radiolabeled with different radionuclides that are suitable for diagnostic imaging (111In) and therapy (131I and 90Y). The conditions for radiolabeling have been studied along with the stability of the fragment and its affinity, all with satisfactory results. Animal models based on cell lines having different expression of the antigen of interest (PC3-PSMA, cells transfected with PSMA, and PC3-WT, the same line not expressing the antigen) have been prepared. Initial data have shown that the biokinetics of the D2B fragment is better than the intact antibody, and tumor visualization is very clear within 6 hours after injection (vs 48-72 hours), and the tumor/background ratio is more favorable. In addition, the specificity of D2B uptake was very high with the fragment, which detects only lesions expressing PSMA. Successive studies will involve the use of this


MULTIDISCIPLINARY PROGRAMS

radiopharmaceutical in animal models for diagnostic imaging of prostate cancer and treatment of metastases. The biological characterization of thyroid cancer and the study of new therapeutic approaches are being carried out. In particular, the genetic mechanisms in thyroid cancer have been studied (BRAF mutations, RET/PTC and TRK oncogenes in papillary cancer, and PAX8/PPARgamma rearrangements and RAS mutations in follicular cancer). The development of new anticancer drugs is being investigated by identifying the role of the RET/PC (TPC-1) translocation, the BRAF V600E (BCPAP and NIM1) mutation, and the double lesions BRAF V600E/PI3K E54K (K1). The antiproliferative activity of gimatecan, a topoisomerase inhibitor, and several agents that influence the transduction pathway such as the

HSP90 inhibitor 17-AAG and the MEK 1/2 inhibitor CI1040 have been investigated. Considering radiometabolic treatment of thyroid cancer, individualized dosimetry has been developed which demonstrates that there is a need to optimize the activity of 131iodine according to the characteristics of tumor lesions. A multicenter Italian study was also coordinated to calculate the dose of irradiation of bone marrow and blood in patients treated with activities ranging from 3.7 to 12 GBq. The mean dose to bone marrow per unit was 0.074 Gy/GBq, and to blood was 0.102 Gy/GBq. This implies that the activities currently used in these types of treatment can be increased. Keywords: molecular imaging, radiopharmaceutical development, radiometabolic therapy

Publications Treatment with tandem 90YDOTA-TATE and 177LuDOTA-TATE of NETs refractory to conventional therapy: preliminary results. Seregni E, Maccauro M, Coliva A, Castellani MR, Chiesa C, Bombardieri E. Q J Nucl Med Mol Imaging. 54:84-91, 2010. 111In-pentetreotide scintigraphy:procedure guidelines for tumour imaging. Bombardieri E, Ambrosini V, Aktoloun C, Baum RP, Bishof-Delaloye A, del Vecchio S, Maffioli L, Mortelsman L, Oyen W, Pepe G, Chiti A Eur J Nucl Med Mol imaging. 37:1441-8. 2010. Imaging of NETs with gamma-emitting radiopharmaceuticals. Bombardeiri E, Coliva A, Maccauro M, Seregni E, Orunesu E, Chiti A, Lucognani G. Q J Nucl Med Mol Imaging. 37:2436-46, 2010.

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CLINICAL SCIENTIFIC STRUCTURE SCIENTIFIC DIRECTORATE PREVENTIVE AND PREDICTIVE MEDICINE EXPERIMENTAL ONCOLOGY & MOLECULAR MEDICINE PATHOLOGY AND LABORATORY MEDICINE SURGERY MEDICAL ONCOLOGY ANESTHESIA, INTENSIVE CARE, PAIN THERAPY AND PALLIATIVE CARE DIAGNOSTIC IMAGING AND RADIOTHERAPY


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SCIENTIFIC DIRECTORATE

SCIENTIFIC DIRECTOR

Marco A. Pierotti, PhD +39 02 2390 2300 marco.pierotti@istitutotumori.mi.it STAFF MEMBERS

Tiziana Camerini, Maths D Aurora Costa, Biol Sci D Cecilia Melani, MD, PhD SECRETARIAT

Laura Ballariano Rossi Lucia De Zorzi INTERNATIONAL RELATIONS AND LINGUISTIC CONSULTANT

Daniela Majerna, B Phil GRANT OFFICE

Valeria Anselmi, B Litt Marco Asioli Sabrina Braghieri, BA Claudia Casoli Stefania Didonè Cristina Mazzadi

The responsibilities of the Scientific Directorate traditionally include: the co-ordination of research and education activities, planning of scientific policy and evaluation of scientific projects (Committee of the Scientific Directorate); management of the institutional relationships with key Health authorities at a regional and national level; supporting researchers seeking public and private funding (Grant Office); giving access to information resources in support of ongoing research programs (Biomedical Library); the enhancement of communication and collaboration among all cancer-related institutions in Lombardy (Lombardy Oncologic Network); the supervision of the Institute scientific communication, the promotion of effective health communication with the larger public and the development of patients education materials (Office of Communication). Thanks to the tight cooperation with the TTO, the Scientific Directorate also facilitates the transfer of inventions and knowledge from INT labs to the public. Every year the Scientific Directorate organizes a Research Day: the 2010 edition was held on November 16th at INT. The meeting offered an opportunity to look back to the scientific accomplishments achieved during the year, and to look forward to the future of research by recognizing three young scientists. In 2010 we had to say goodbye to a dear colleague and friend, Angela Codonesu, aged 56, who died on 29 September at our Institute, where she had spent her entire working life. Her expertise as a bibliographic assistant at the Library as well as her profound kindness will be greatly missed.

LOMBARDY ONCOLOGIC NETWORK (ROL)

Rosaria Bufalino Elisa Ferri, B Eng Marco Tricomi, B Eng INFORMATION TO PATIENTS

Antonio Florita, B Litt BIOMEDICAL LIBRARY

Rossella Ballarini Marina Calderisi Angela Codonesu EDITORIAL OFFICE

Rosaria Parentela TUMORI - EDITORIAL ASSISTANT

Elena Morittu

Committee of the Scientific Directorate Marco A. Pierotti, Scientific Director Alessandro M. Gianni, Deputy Scientific Director Vincenzo Mazzaferro, Deputy Scientific Director Mario Santinami, Deputy Scientific Director Franco Berrino Emilio Bombardieri

Paolo Corradini Maria Grazia Daidone Martin Langer Ugo Pastorino Giuseppe Pelosi Francesco Reitano, Chief Medical Officer Gustavo Galmozzi, Medical Director

This Committee is the Institutional Reviewer Board (IRB) and assists the Scientific Director in defining the Strategic Scientific Program and the contents of the correlated educational activities. Its main objectives are: • definition of research areas at INT • approval of multidisciplinary research projects • approval of the development of the research projects at a scientific and administrative level


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• evaluation of scientific quality and feasibility of newly proposed clinical studies prior to their submission to the Independent Ethics Committee • evaluation of the educational programs for residential and non-resident courses, approval of applications by physicians and researchers of the INT to spend training periods in other countries, and applications by foreign researchers to spend training periods in INT. The IRB says farewell to Patricia Crollari, and welcomes Francesco Reitano in the board.

Grant Office The Grant Office (G.O.) has the mission to support research activities within the Institute, facilitating access to external financing, national and international, by looking for relevant information in the appropriate media, making direct contact with public and private funding agencies, and swiftly providing information to potentially interested researchers. Announcements regarding funding possibilities are constantly updated in the “Calls for Application” section of the Institute Intranet website, on the Scientific Directorate web page. It is the G.O.’s duty to help investigators in preparing and submitting grants applications, promoting collaborations among the researchers working at INT and in other public services, helping them to collaborate on research projects. Other goals of the G.O. are: • To stimulate and constantly support researchers, giving methodological guidelines and meeting organizational needs, particularly in the conduction of multidisciplinary research activities. • To assist researchers, from the funding request to the completion of the task, monitoring their results, and adherence and achievement of the defined objectives. The monitoring activity also includes administrative supervision. At the Scientific Directorate office, a database has been created and is continuously updated according to emerging new needs. The database stores information regarding research projects from submission to conclusion. To monitor scientific productivity, a database of all publications from the Institute has been created: it is thus possible to know in real time the number of publications and their Impact Factor. These tools allow a more efficient collaboration with the Administration in the evaluation of scientific productivity of each individual Department and of the Institute as a whole. The G.O. office keeps in contact with the officers in charge of research at the Ministry of Health and at the Health Management offices of the Lombardy Region. The G.O.’s activities include the management of ongoing Institutional Projects and the design of calls aimed at distributing the funding coming from the 5‰ tax donation. In 2009, the G.O. supported INT researchers in: 36 applications for public funding (Ministry of Health and the Lombardy Region); 52 applications to private funding agencies (AIRC and CARIPLO) and 28 international funding bodies. With regards to ongoing research, in 2009 the G.O. presented a new scientific and financial document illustrating the 3-year activity within the 6 research areas funded by the Ministry of Health.

Lombardy Oncologic Network (ROL) The regional Lombardy government is establishing an innovative model for delivering healthcare to cancer patients, based on clinical cooperation and exchange of information, as well as sharing and integration of existing cancer facilities throughout the regional network of organizations and professionals. The Lombardy Cancer Network (ROL) was started in 2006 and is a major effort of the Lombardy government, aimed at creating “an integrated network of health and social services devoted to cancer patients” to provide a framework for facilitating the exchange of information, capacity, and expertise and, as consequence, to offer a more accurate diagnosis, treatment, and control of cancer. INT, with the coordination of Scientific Directorate, has been the implementing body of ROL since its start-up. ROL is consistent and integrated with the Lombardy CRS-SISS Project, as one of its advanced evolutions. ROL is testing innovative solutions for distance sharing of health data pertaining to a regional population of nearly 10 million by introducing a structured hospital discharge program focused on a unified “in/out-patient clinical discharge report”. Its semantics were defined so as to design a cancer-oriented “minimum clinical data set” that can


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spare physicians any data input in excess of what they are ordinarily required for clinical purposes. Reports can be shared over the network among centers treating the same patient. In addition, teleconsultation facilities, asking for second opinions as well as to refer patients from one center to another, will be implemented by using the same master document. The main goal of ROL is to improve the quality of care focusing on the cost/efficacy ratio to reduce healthcare costs. ROL is also developing a more rational approach to the cancer patients referral system in Lombardy by creating specific applications that have gradually established a network that achieves concrete results even at an early stage. The implementation of ROL was aimed to design evidence-based clinical practice guidelines for all solid tumors developed through a consensus process among the oncology community to make a comprehensive impact on clinical oncologic practice. This is primarily cultural, but it is also finalized to evaluate appropriateness of treatment by extensive use of integrated ICT tools. A link between patient report and guidelines will allow rapid assessment of the consistency between guidelines and clinical treatment in each patient. This process will allow a populationbased assessment of medical appropriateness. At the end of 2010, guidelines are available for practically all solid tumors and each guideline is updated yearly by a dedicated regional working group. INT also provides the Coordination Office of ROL, active since 2006 to coordinate the regional activities of ROL and enable the functionality of the Coordination ROL (C-ROL), a board with an operational role constituted by representatives from several ROL communities and representatives of Lombardy Government; it works in relation to the decisions of the Regional Government and the Regional Oncologic Committee. Starting in 2009, in 2010 ROL has expanded its field of activity to clinical and translational research and has contributed to the creation of a virtual tissue bank, and in particular in the definition of homogenous criteria for the storage of biological samples to be adopted by all participating centers, with the network information system as an added value. The collaboration with Nerviano Medical Sciences started in 2010 was crucial; this joint effort is organizing studies for clinical drug development by research groups in the ROL/REL (Lombardy hematologic network) area. In 2010, a call for support of independent clinical research has been issued by the Scientific Director of INT, and 15 study proposals have been selected to be supported for their scientific organization in collaboration with the Department of Clinical Development of NMS. Furthermore, in 2010 meetings with representatives of the Ethics Committees of the institutions related to ROL were organized to facilitate harmonization of criteria for future work. One focus was informed consent and protection of sensitive data in the creation of tissue banks.

Patient Information The Scientific Directorate actively participates in the organization of an innovative model of providing information to cancer patients in Italy by establishment of a National Service of Information in Oncology through ongoing multicentric projects in collaboration with the Istituto Superiore di SanitĂ , the oncology IRCCS, and the main Italian Associations of Volunteers, sponsored by Alliance Against Cancer and the Ministry of Health. These projects aim to reduce barriers to treatment and to achieve better therapeutic results and better acceptance of treatment by the patient. The main goal is to create a comprehensive cancer care model offering the most advanced diagnosis and treatment techniques and information support with the best quality available, improving doctor-patient communication and patient empowerment. This will assure better treatment compliance, thereby allowing patients to fully participate in the decision making process in cancer care. The INT Information Point (since 2005) supports patients and their families, by meeting their informational needs, was implemented in 2010. Our IP is part of the Italian IP network, a community based on shared strategies, guidelines, tools and aims to establish a qualified and formally recognized service for information in oncology.

Biomedical Library The INT Library is affiliated to European Association for Health Information and Libraries. It offers a large collection of basic science journals and reference books, and electronic access to full text journals, database and books. The INT Library, specializing in oncology, has the mission to meet the ongoing needs of physicians, investigators and students, resident and non-resident, allowing the quick retrieval of information necessary for professional activity and formation.


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The Library’s electronic resources give access to over 9,000 titles (including current subscriptions and journals obtained through the consortia SBBL and Bibliosan) can be consulted through “A to Z”, an online virtual catalogue that collects and updates the links to publisher’s web sites. The Library’s collection is supplemented by interlibrary loan services with access to the following catalogs: • GIDIF-RBM: a consortium of key biomedical libraries in Italy (over 5,000 titles from 51 biomedical libraries); • SBBL: the Network of Lombardy Biomedical Libraries (6,200 titles from 16 libraries); online scientific journals and data banks: Embase, CODIFA. The library offers access to specialized reference data banks, such as Medline and Toxnet. • BIBLIOSAN: a system which groups 50 Italian Research Institutions with over 4,100 active titles. The project is supported by the Ministry of Health. From 2009, we also have the access to ISI Web of Knowledge and Journal Citation Reports, which offer an objective means to evaluate the world's leading journals, with statistical information based on citation data. The library is also a member of ANCP, the National Archival Collection of Periodicals, and is thus linked to over 2,300 Libraries in Italy and over 110,000 journals. The Italian framework Nilde (Network for Inter-Library Document Exchange) allows libraries to request and supply documents via the web. Library customers can also access RefWorks, personal bibliographic management software designed to help researchers gather, manage and store information, as well as generate citations and bibliographies. The library staff aims at informing the public about about all services offered. In addition to disseminating information via the constantly updated Intranet Library web page, various courses were held in order to help researchers gather information more easily. Lastly, two important courses were held: • Impact Factor, analysis of citations and H-index: online evaluation of research activities with bibliometric indicators. Speaker: Alain Frey • Best practice by BMJ. An innovative evidence-based instrument and available online. Speaker: Jenny Lewis The Library manages an house database and updates the collection of publications of INT investigators, and calculates their Impact Factor to respond to periodic queries from the Management Control and Ministry of Health.

Editorial Office The Editorial Office coordinates and manages all activities relative to the production of materials that describe the clinical and scientific activities of the Institute. This comprises organization of content and collection of material for publication, in addition to graphic layout. The end result is a ready-to-publish, high-quality document (either printed or in electronic form) to which many individuals have contributed, including individual authors, editors, and specialized persons whom are all dedicated producing a high-quality document. In addition, the editorial office oversees the publication of the annual Scientific Report and Brochure, and provides support to individual departments in the preparation of more specific materials such as brochures and meeting reports. The editorial office has a dedicated workstation for graphic design and all stages of editing using the most up-to-date software.

Editorial Board of Tumori In 2010, the Editorial Board of Tumori received 610 manuscripts for publication. In the same year, 6 issues containing 178 reviews, original articles, and case reports were published. Five thousand copies per issue were printed.

Awards & Recognitions • In 2010, our Institute has been recognized as a Center of Excellence for the diagnosis and treatment of Neuroendocrine Tumors by ENETS (European Neuroendocrine Tumor Society). • The Comitato Ospedaledonna of the Osservatorio Nazionale sulla salute della Donna (O.N.Da) awarded the Fondazione IRCCS Istituto Nazionale dei Tumori with 3 Bollino Rosa prizes for its care in the research and treatment of female diseases and its attention to the specific needs of women patients.


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• The Intensive Care Unit has been chosen as Italian party leader in the Clean Care Project of the World Health Organization (WHO) finalized to optimize patient safety in the hospital. • Vincenzo Mazzaferro, Head of the Gastrointestinal and Hepatopancreatobiliary Surgery and Liver Transplantation Unit, received CIRSE (Cardiovascular and Interventional Radiological Society of Europe) Award. Honorary Lecture at the 2nd European Conference on Interventional Oncology (ECIO) 2010. • Franco Berrino, Head of the Preventive and Predictive Medicine Department, was conferred the International Award for Cancer Prevention, VI Edition, by Lega Italiana per la Lotta contro i Tumori. • Emilio Bombardieri, Head of the Diagnostic Imaging and Radiotherapy Department, was awarded the "Una vita per la ricerca" prize by ABO Foundation and has been appointed President Elect of the European Association of Nuclear Medicine (EANM) Congress 2012. • Lisa Licitra, Head of the Head and Neck Cancer Medical Oncology Unit, was conferred the FIRC Guido Venosta prize. • Augusto T. Caraceni, Head of the Palliative Care, Pain Therapy and Rehabilitation Unit, was conferred Professorate in Palliative Medicine at the University of Science and Technology in Trondheim, Norway. • Lucio Bertario Head of the Hereditary Digestive Tract Tumors Unit is the President elect of AIFEG (Associazione Italiana per lo Studio della Familiarità ed Ereditarietà dei Tumori Gastrointestinali). • Andrea Necchi of the Urology Unit was conferred the “Giovani Ricercatori” award of the Fondazione IRCCS Istituto Nazionale dei Tumori. • Antonella Galvan of the Molecular Basis of Genetic risk, Polygenic Models was conferred the “Giovani Ricercatori” award of the Fondazione IRCCS Istituto Nazionale dei Tumori. • Sabina Sangaletti of the Molecular Immunology Unit was conferred the “Giovani Ricercatori” award of the Fondazione IRCCS Istituto Nazionale dei Tumori. • Silvia Piconese of the Molecular Immunology Unit was conferred the “Giovani Ricercatori Cecilia Cioffrese” prize of the Fondazione Carlo Erba and the Fondazione Guido Berlucchi’s prize. • Mauro Carrara of the Medical Physics Unit was conferred the Young Scientist Award-Travel Grant for his participation at the 16th Solid State Dosimetry Conference in Sydney. • Marzia Pennati of the Molecular Pharmacology Unit was conferred research fellowship by Fondazione Pezcoller-Ferruccio ed Elena Bernardi. • Giovanna De Vecchi of the Molecular Basis of Genetic Risk and Genetic Testing Unit was conferred ‘Doniselli’ fellowship by the Soroptimist International d’Italia. • Giulia Bertolini of the Tumor Genomics Unit won a FIRC-AIRC three year fellowship. • Maria Grazia Vizioli of the Molecular Mechanisms Unit was conferred the Graziella Persico award for best poster presented at the 52th Meeting of the Società Italiana di Cancerologia (SIC). • The American Journal of Roentgenology (AJR) society recognized the article “Percutaneous radiofrequency interstitial thermal ablation in the treatment of hepatic cancer” published by the staff of the Intralesional Treatment Unit as one of the most influential articles published in the AJR's first 100 years. • The project "New antibody-based reagents for imaging and treatment of prostate cancer" of the Molecular Therapies Unit was selected by the Regione Lombardia sponsored program Technoscouting as one of the 3 best projects to be presented to the investors. • The European Community within the framework of the 7th international program, has granted financial support to a member of the Hematology and Allogeneic Bone Marrow Transplantation Unit for a project aimed at the better understanding of the role of Jak and STAT signaling in immunologic processes occurring after allogeneic hematopoietic stem cell transplant (allo-HSCT) and to develop new strategies to overcome graft versus host disease (GVHD).


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DESCRIPTIVE STUDIES & HEALTH PLANNING

HEAD

Andrea Micheli, Sociologist, PhD STAFF MEMBERS

Paolo Baili, Statistician, PhD Elisabetta Meneghini, Physic, PhD Roberta Ciampichini, Statistician Francesca Di Salvo, Statistician Ilaria Casella, Economist Camilla Amati, BA Stefania Saltarelli, BA Mirko Esposito, Technician Agatina A. Cifalà, Administrative

The Descriptive Studies & Health Planning Unit (DSHP) carries out cancer research in the field of public health and promotes studies for planning cancer control. In 2010, a number of projects were run by DSHP at the international and national level. EUROCHIP-3 Project. During 2010: a) articles on the status of cervical cancer screening in Lithuania, Latvia, Estonia, and Bulgaria were published in Tumori; b) a study on the availability status of cancer indicators in the EU cancer registries was presented at the Annual International Cancer Registry Association meeting; c) a list of cancer rehabilitation indicators was discussed; d) a discussion was started on strategies for the reduction of cancer cost (at unvaried outcomes) for breast cancer and acute lymphoblastic leukaemia. All activities are described in the report available on the project web-site: http://www.tumori.net/eurochip/material/Report/EUROCHIP3_Report_M24.pdf The EUROCHIP group was directly involved in the preparation of the European Commission Joint Action “European Partnership Action Against Cancer- EPPAC” (2011-2013) for a EU program on cancer control. CAREMORE Project. During 2010, the involved CRs concluded collection of clinical data and improved the collection of rehabilitation data. An interim analysis was presented by DSHP at the Annual Italian Epidemiology Association meeting. ROL Project. During 2010, at DSHP we analyzed data collected through the Lombardy Oncologic Network showing that hospital records compiled by clinicians for ROL are useful for patients (text fields in the report are positively used by clinicians), while they cannot be used yet for epidemiological analysis (coded field use is not yet widespread among clinicians) New project phases were designed and started: third phase of STUDIO API FALCONARA and new phase of “I TUMORI IN ITALIA” Keywords: cancer control, breast cancer aetiology, cancer networks

2010 RELEVANT NOTES Collaborations

Publications

EUROCHIP-3 (subsidized by the European Commission-EC). The project was designed to improve information and knowledge on cancer control in the European Union in various fields.

Barriers in cervical cancer screening programs in new European Union member states. Tumori. 2010; 96: 515-516.

DYNAMO-HIA on the development of a dynamic modelling tool to assess health impact of health policies (project subsidized by EC and coordinated by Erasmus University in Rotterdam). EUROCARE on cancer survival comparison across Europe. DSHP works on life tables estimations and on the related demographic studies. CAREMORE (subsidized by Italian Welfare Ministry) is a population-based study aimed to identify the rehabilitation services used by cancer prevalent cases based on cancer registry (CR) databases. I TUMORI IN ITALIA (subsidized by Centro Controllo Malattie, Italian Welfare Ministry) for constantly updates two web-sites on cancer epidemiology and on relation between diet and health. STUDIO API FALCONARA (subsidized by ARPAm-Marche Region). This population-based case-control study investigated the association between residential petrochemical exposure and leukaemia-lymphoma mortality risk in Falconara Marittima in collaboration with the Epidemiology Unit of the Marche Region. ROL (subsidized by Lombardy Region) for descriptive analysis of data collected by the Lombardy Oncologic Network. HORMONES and BREAST CANCER (BC) performing statistical analysis in studies on BC aetiology and participating in international collaborative studies. IF (subsidized by AIRC) is aimed to study national and international performance in cancer research using bibliometric measures.

Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol. 2010; 11: 530-542.

Contributions Micheli A. is in the editorial board in Tumori and Epidemiologia & Prevenzione Micheli A and Baili P are referees for Tumori Micheli A is referee for European Journal of Public Health, Annals of Oncology, Journal of Clinical Oncology


SCIENTIFIC DIRECTORATE

63

CANCER REGISTRY AND ENVIRONMENTAL EPIDEMIOLOGY

HEAD

Paolo Crosignani, DSc, MD, PhD STAFF MEMBERS

Martina Bertoldi, DSc Paolo Contiero, DSc, PhD Enrica Costa, DSc Daniela Del Sette Lauria Di Grazia, DSc Rosaria Fissi, DSc Emanuela Frassoldi, DSc Daniela Gada, DSc Mariarosa Ruzza, DSc Giovanna Tagliabue, MD, PhD TECHNICIANS

Tittarelli Andrea MSc Scaburri Alessandra, DSc Sabrina Fabiano, DSc

Cancer Registry: data collection and processing for Varese Province incidence data for 20052006. In-depth anaysis for survival and quality of care for the most frequent tumors. Tutorship for six cancer registries in Lombardy region. Screening: analysis for effectiveness for breast (female) and colorectal cancer Congenital Malformations Registry: data collection for four Lombardy provinces and data quality control. Occupational Cancer: Managing the Occupational Cancer Monitoring system in collaboration with the Italian National Institute of Occupational Health and with five Italian regions. Cases likely of occupational origin are referred for compensation and firms are examined for the presence of carcinogenic hazards. Environment and Cancer: study and valildation of air pollution indicators of exposure. Air pollution was found to be a determinant of childhood leukemia. Keywords: cancer registry, survival, outcome, occupation, environment

FELLOWS

Alessandro Borgini, DSc Edoardo Bai, MD PhD Enrico Oddone, MD PhD Milena Calati, MSc Lucia Preto Eugenia Sanoja, DSc ADMINISTRATIVES

Tiziana Codazzi, Imma Favia, Anna Maghini, Clotilde Viganò

2010 RELEVANT NOTES Collaborations Six Lombardy cancer registries adopted the structure and information system of our cancer registries and are run under our procedures. Lombardy, Campania, Umbria, and Lazio regions are followed for occupational cancer monitoring, by collaborating with the local Occupational Health Unit. This activity is enforced by Italian law. The Spanish government requested for a similar system and a feasibility analysis is under way.

Publications How valid are the rates of Down syndrome internationally? Findings from the International Clearinghouse for Birth Defects Surveillance and Research. Am J Med Genet A. 2010;152A(7):1670-80. Confounders and Confusion: Dealing with Cancer Cases of Occupational Origin. Am J Ind Med. 2010; 53:1002-5.

Contributions Paolo Crosignani is member of Editorial Board of Epidemiologia e Prevenzione and of the Giornale Italiano di Medicina del Lavoro ed Ergonomia


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PREVENTIVE AND PREDICTIVE MEDICINE DEPARTMENT

PREVENTIVE AND PREDICTIVE MEDICINE DEPARTMENT

DIRECTOR OF DEPARTMENT Franco Berrino phone number: +39 02 2390 3515 franco.berrino@istitutotumori.mi.it

UNITS EPIDEMIOLOGY AND PREVENTION Franco Berrino NUTRITIONAL EPIDEMIOLOGY Vittorio Krogh EVALUATIVE EPIDEMIOLOGY Gemma Gatta ANALYTICAL EPIDEMIOLOGY Milena Sant MEDICAL GENETICS Siranoush Manoukian HEREDITARY DIGESTIVE TRACT TUMORS Lucio Bertario MOLECULAR BASIS OF GENETIC RISK AND GENETIC TESTING Paolo Radice MOLECULAR BASIS OF GENETIC RISK, POLYGENIC MODELS Tommaso Dragani

This Department focuses primarily on epidemiological and translational research. This comprises knowledge of lifestyle and genetic risk factors in order to take preventive action (i.e. from prediction to prevention), and knowledge of inequalities in cancer treatment for carrying out corrective actions. This research relies on extensive interaction between researchers in the fields of basic experimental science, epidemiology, genetics, and clinical medicine. The priorities of the Department are: • promotion of healthy diet and lifestyle: to proceed from large cohort studies in which the INT has been actively involved for more than 20 years, to dietary intervention studies targeting the general population, high-risk subgroups and cancer patients to minimize the risk of recurrence • environmental and occupational risk factors: this research is moving from standard epidemiological designs to the systematic monitoring of occupational risk through the linkage of cancer registry data and occupational history files, in addition to forming stronger collaborations with the public agencies that are responsible for occupational and environmental surveillance in order to establish specific preventive actions • hereditary cancer prevention in high-risk families: to go beyond clinical surveillance and prophylactic surgery, and promote research on environmental and lifestyle factors as well as genetic characteristics that may affect the penetrance of hereditary cancer genes • in the field of low penetrance cancer genes and polygenic inheritance: to classify the complex genetics of risk and prognosis of lung and breast cancer • inequalities in survival and cure rates of cancer patients: from the systematic description of cancer incidence, prevalence and survival, to research on the interpretation of survival differences between and within countries, and advance actions to minimize such inequalities.

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66

SCIENTIFIC REPORT 2010

EPIDEMIOLOGY AND PREVENTION

HEAD

Franco Berrino, MD STAFF MEMBERS

Giorgio Secreto, MD Maria Gaetana Di Mauro, MD RESEARCH MEMBERS

Patrizia Pasanisi, MD, MSc; Anna Villarini, Biol Sci; Elisabetta Venturelli, Biol Sci; Giuliana Gargano, Biol Sci; Eleonora Bruno, MSc ; Milena Rraimondi, Psycologist; Manuela Bellegotti, Dietician TECHNICIANS

Adalberto Cavalleri Daniela Del Sette Cerulli ADMINISTRATIVES

Paola Consorti, Curtosi Patrizia, Maria Grazia Guerrini, Maria Larossa

The Unit has two main research activities: 1) dietary and life-style intervention trials aimed at the prevention of breast cancer (BC) and of BC recurrences, and 2) observational studies on the relationship between metabolic and endocrine parameters and the incidence of BC and BC recurrences. The main ongoing study is the DIANA (DIet and ANdrogens)-5 project: randomized controlled trial to test the efficacy of dietary change and physical activity to prevent or delay the development of recurrences in BC patients estimated to be at high risk based on their hormonal or metabolic milieu. Study design: a) recruitment 2000 patients aged 35-70, operated for BC in the last 5 years, without recurrences, but with high serum levels of testosterone or insulin, in 8 collaborative centres in different Italian regions (Lombardy, Piedmont, Emilia, Abruzzo, Campania, Basilicata, and Sicily); b) randomisation in a control group that receives only general lifestyle recommendations for cancer prevention and in an intervention group that is helped to change through periodic meeting, kitchen and fitness courses, common meals, with decreasing intensity schedules over 5 years; c) follow-up the cohort for 5 years; analysis by intention to treat and by compliance score. By December 2010 1,200 patients were randomised. Further studies include: • A prospective study on several thousand BC patients admitted to INT for primary surgical treatment to test the prognostic role of androgens in BC progression. A biological bank of fasting blood samples collected at the time of diagnosis is available for BC researches. • A pilot trial of metformin and diet for the prevention of breast cancer in 400 peri-or postmenopausal women with anthropometric or metabolic traits of metabolic syndrome. Factorial design: metformin versus placebo (double blind) and dietary intervention with kitchen courses and common meals versus dietary recommendations only. Keywords: diet, breast cancer, metformin, intervention trial

2010 RELEVANT NOTES Publications Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol. 2010; 11: 530-542. Urinary 6-Sulphatoxymelatonin levels and risk of breast cancer in premenopausal women: the ORDET cohort. Cancer Epidemiol Biomarkers Prev. 2010; 19: 729-737.

Contributions Pasanisi Patrizia, Masteri in Nutrition, Università Politecnica delle Marche Eleonora Bruno, Master in Epidemiology, University of Turin


PREVENTIVE AND PREDICTIVE MEDICINE DEPARTMENT

67

NUTRITIONAL EPIDEMIOLOGY

HEAD

Vittorio Krogh, MD MS STAFF MEMBERS

Alberto Evangelista, Follow-up and Database Manager, BSc RESEARCH MEMBERS

Claudia Agnoli, Nutrition Tech, ScD, MSc Sara Grioni, Nutrition Tech, BSc Maria Valeria Pala, Agronomy D, PhD Sabina Sieri, Biol Sci D, PhD ADMINISTRATIVE

Gloria Bosco

The Nutritional Epidemiology Unit is involved in large prospective studies on the association between diet, hormones, nutrition, lifestyle, genetic factors and cancer risk. 1. The EPIC study (http://epic.iarc.fr) was designed to investigate the relationships between diet, nutritional status, lifestyle and environmental factors and the incidence of cancer and chronic diseases. EPIC has recruited over 500,000 individuals in 10 European countries. The major published results during 2010 include: i) higher plasma levels of vitamins B2 and B6 are associated with a lower risk of colorectal cancer; ii) an increased risk of endometrial cancer with estrogen-only hormone therapy (HT) and a weaker association with combined HT; iii) obesity is an important modifiable risk factor for epithelial ovarian cancer; iv) serum levels of vitamin B6 and methionine are inversely associated with an increased risk of lung cancer; v) a genome-wide association study in pancreatic cancer identified loci associated with increased susceptibility on chromosomes 13q22.1, 1q32.1, and 5p15.33; vi) tobacco smoke (both active and passive) is associated with an increased risk of pancreatic cancer. 2. The ORDET study, one of the first prospective European studies on the role of hORmones and DiET in the aetiology of cancer, was organized within the Epidemiology Units of the INT. During 2010, the main results from ORDET were: i) metabolic syndrome is an important risk factor for breast cancer in postmenopausal women; ii) there is a positive association between aMT6s and the risk of breast cancer in premenopausal women. 3. The ORDET study is participating in the â&#x20AC;&#x153;Pooling Project of Prospective Studies of Diet and Cancerâ&#x20AC;? (http://www.hsph.harvard.edu/poolingproject/about.html). This collaborative project involves major European and North American cohort studies (at present 28). The main results in 2010 were: i) a modest inverse association between folate, vitamin C and E intake and colon cancer; ii) drinking coffee or sugar-sweetened carbonated soft drinks was not associated with an increased risk of colon cancer. Keywords: prospective study, diet, hormones

2010 RELEVANT NOTES Collaborations Epidemiology of endometrial cancer consortium (E2C2) The Pooling Project of Prospective Studies of Diet and Cancer Endogenous Hormones and Breast Cancer Collaborative Group International Lung Cancer Consortium IDEFICS Consortium IMMIDIET Consortium

Publications A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010;42:224-8. Serum B vitamin levels and risk of lung cancer. JAMA. 2010;303:237785.


68

SCIENTIFIC REPORT 2010

EVALUATIVE EPIDEMIOLOGY

HEAD

Gemma Gatta, MD RESEARCH MEMBERS

Roberto Foschi, Statistician Annalisa Trama, MD Giulia Zigon, Statistician TECHNICIANS

Rossana Berruti Samba Sowe

The Unit is currently estimating the incidence, mortality and prevalence for several common tumors. In Italy, the burden of cancer is known only in areas covered by cancer registries. However, with the application of appropriate statistical models the basic indicators at the national and regional level can be estimated. The Unit also has a principal role in assessing the burden of cancer in populations, focusing on rare tumors. Along these lines, the project “Surveillance of rare cancers in Europe” (RARECARE) will estimate the burden of rare cancers for which no estimates were previously available. The project takes advantage of a large database of cancer cases collected from population-based cancer registries in 21 countries. Based on the RARECARE definition (incidence <6/100,000/year), the annual incidence of all rare cancers in Europe was about 97 per 100,000, corresponding to 488,000 new diagnoses annually or 19% of all cancer diagnoses (www.rarecare.eu). The study of cancer survival among children, adolescents and young adults (AYA) can determine whether differences found in EUROCARE for adults were also present in AYA. Despite the higher cancer incidence in the 15-30 age group compared to children, with only modest survival improvement, no specific consideration is given to the treatment of AYA patients with respect to their elderly counterparts. The unit collaborates with the CONCORD (World Comparison of Cancer Patient Survival) study, which investigates differences in Europe, North America, Australia and Japan. The major objective of 2010 was to interpret variations between Europe and the US for colorectal, prostate, and breast cancers. The AIRC funded project “Prostate cancer survival patients in Italy” will study variabilities in Italy by applying cure survival models that will separately estimate the proportion of cured patients and the life expectancy of cases who die of disease. Keywords: rare cancers, cancer in adolescents and young adults, burden of cancer

2010 RELEVANT NOTES Collaborations Tropical Medicine, LSHTM, London, UK Center for Disease Control and Prevention, CDC, Atlanta, USA Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil

Publications Patterns of care for European colorectal cancer patients diagnosed 19961998: a EUROCARE high resolution study. Acta Oncol. 2010; 49:776-83. The burden of rare cancers in Europe. Adv Exp Med Biol. 2010; 686:285303. Review

Contributions Referee for several journals (G. Gatta) during 2010 for papers submitted to CMAJ, Ann Oncol, Eur J Cancer, Int J Cancer, Br J Cancer, Orphanet Journal G. Gatta, Member of the EUCERD (European Commission of Experts on Rare Diseases)


PREVENTIVE AND PREDICTIVE MEDICINE DEPARTMENT

69

ANALYTICAL EPIDEMIOLOGY

HEAD

Milena Sant, MD RESEARCH MEMBERS

Claudia Allemani, Biostatistician, PhD Pamela Minicozzi, Mathematics D, MSc Carmen Tereanu, MD, MSc ADMINISTRATIVE

Chiara Margutti

The main activity of the unit consists in the analysis of cancer survival data and in the interpretation of differences across countries over time, within the framework of EUROCARE (European CAncer REgistry based project on survival and care of cancer patients). EUROCARE started in the 1990s and has produced 4 monographs (cases diagnosed in 1978-84, 198589, 1990-94,1995-99) and numerous scientific publications. EUROCARE-5, relative to patients diagnosed after 2002, is in progress. The unit is responsible for the EUROCARE scientific secretary and, in collaboration with the Istituto Superiore di Sanità, Rome, contributes to data management and statistical analyses. The unit is responsible for data collection and analyses of the EUROCARE high resolution (HR) studies, designed to understand survival differences across regions and over time. The cancer registries participating in EUROCARE HR collect detailed clinical information on tumor stage, diagnostic exams, tumor gene expression, treatment, follow-up, and comorbidities that influence survival. The HR studies describe, compare and monitor patterns of cancer care across European countries/regions, developing indicators of best practice and analyzing the effect of innovative diagnostic procedures and treatment in current clinical practice. Presently, studies are in course on breast, colorectal and lung cancer, as well as lymphoma and melanoma. The Unit is responsible for HAEMACARE, a project aimed to investigate epidemiological and clinical indicators for hematological neoplasms in Europe. The unit also collaborates with the CONCORD project (a worldwide study on cancer survival) that is led by Prof. MP Coleman, LSHTM, London (UK). Dr. Milena Sant is project leader of the Work Package 4 (Health information) of the European Partnership Against Cancer. In addition to population-based analyses, the unit carries out studies on clinical cohorts of patients to investigate the prognostic role of tumor characteristics and metabolic factors. Keywords: survival, prognosis, population cancer registries, patterns of care, public health

2010 RELEVANT NOTES Collaborations

Publications

Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità, Rome

Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010; 116 3724-34.

IARC, International Agency for Research on Cancer LSHTM, London School of Hygiene and Tropical Medicine

Variation in 'standard care' for breast cancer across Europe: a EUROCARE-3 high resolution study. Eur J Cancer. 2010; 46:1528-36.

AIRTUM, Italian Association of TUMor Registries

Contributions

FRANCIM, FRANce Cancer Incidence et Mortalité

Manual for coding and reporting haematological malignancies. Tumori 96: i-A32. (M. Sant, co-editor)

ENCR, European Network of Cancer Registries ICBP, International Cancer Benchmark Project, UK EUROCOURSE, EUROpe against Cancer: Optimisation of the Use of Registries for Scientific Excellence in research EUROCHIP, EUROpean Cancer Health Indicator Project


70

SCIENTIFIC REPORT 2010

MEDICAL GENETICS

HEAD

Siranoush Manoukian, MD, PhD STAFF MEMBER

Bernard Peissel, MD, PhD RESEARCH MEMBERS

Gaia Roversi, MD, PhD Daniela Zaffaroni, Biol Sci D, PhD Marilena Morganti, Graduate Nurse RESIDENT

Elisa Cattaneo, MD ADMINISTRATIVE

Caterina Spina

The consolidated activity of the Medical Genetics Unit offers genetic counselling for several hereditary predispositions to cancer syndromes. The main focus of the Unit is the study of hereditary breast and ovarian cancer syndrome (HBOC), in addition to other inherited predispositions to cancer such as Li-Fraumeni syndrome and familial melanoma. The principal goal of the Unit is to identify individuals at genetically increased risk of cancer in order to offer targeted clinical management by providing an integrated and multidisciplinary healthcare service. More than 6,550 individuals belonging to about 3,150 different HBOC families have been identified and characterized. When available, all relevant data has been collected in the Medical Genetics HBOC database (including more than 870 BRCA1 and BRCA2 gene carriers from over 470 families). Moreover, about 550 healthy and 450 affected women are regularly followed in collaboration with other INT Units. All clinical, genetic, and molecular data of individuals belonging to HBOC families is constantly updated. For all patients treated at INT and followed by the Medical Genetics Unit, tumor specimens and blood samples are routinely collected. The availability of familial, molecular, clinical and pathological data, as well as biological specimens, is essential for the following studies: • genetic characterization of HBOC: gene penetrance, survival, disease features, as well as environmental risk factor modifiers and tumor characteristics • long-term efficacy, health and psychological impact of clinical and instrumental surveillance, risk-reducing options and treatment in HBOC individuals • biological and clinical significance of BRCA gene mutations of unknown risk • genomic and transcriptomic analyses for the identification of modifiable risk factors and new genes involved in genetic predisposition to HBOC Keywords: hereditary breast and ovarian cancer, cancer predisposition syndrome, familial and hereditary cancer

2010 RELEVANT NOTES Collaborations Breast Cancer Consortium (BCAC) Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) Medical Genetics, Department of Medicine, Surgery and Dentistry, University of Milan Hereditary Breast Cancer Clinical Study Group Department of Oncology, Sacco Hospital and Fatebenefratelli Hospital (Project: Development of a model for the identification and management of women at high genetic risk for breast cancer, PI: S. Manoukian)

Publications Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics. Breast Cancer Res Treat. 2010; 124:251-8. Is there a specific magnetic resonance phenotype characteristic of hereditary breast cancer? Tumori. 2010; 96:363-84.

Contributions S. Manoukian, Member of the Scientific Committee of the National Italian Network for the Surveillance of the high genetic risk women (Ministry of Health and Istituto Superiore Sanità, Rome) S. Manoukian, Member of Italian Society of Human Genetics (S.I.G.U.) and of SIGU-Oncological Medical Genetics group


PREVENTIVE AND PREDICTIVE MEDICINE DEPARTMENT

71

HEREDITARY DIGESTIVE TRACT TUMORS

HEAD

Lucio Bertario, MD STAFF MEMBERS

Paola Sala, Biol Sci D RESEARCH MEMBER

Stefano Signoroni, Biol Sci D ADMINISTRATIVES

Mariangela Di Ceglie Ornella Galuppo

The Unit of Hereditary Digestive Tract Tumors is devoted to the counselling, molecular testing, and clinical management of individuals with genetic predisposition to the major hereditary syndromes of gastrointestinal cancer. These include Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP) and its phenotypic variant attenuated FAP, Peutz-Jeghers Syndrome, and hereditary gastric cancer. Individuals with evidence of hereditary susceptibility to cancer are counseled and informed about personal risk and that of their relatives. Depending of the fulfillment of defined criteria, individuals who receive genetic counseling are offered the possibility to undergo molecular testing for identification of specific genetic alteration(s) that may be associated with the increased risk of cancer in their families. These criteria include personal and family history of cancer, presence of specific clinical phenotypes, and tumor characteristics. The genes presently screened on a routine basis include: MLH1, MSH2, MSH6, and PMS2, cumulatively referred to as DNA mismatch repair (MMR) genes (HNPCC); APC and MUTYH (FAP and attenuated FAP); LKB1 (Peutz-Jeghers Syndrome) and CDK1 (gastric cancer). All tests are performed at the diagnostic laboratory located at IFOM (FIRC Institute of Molecular Oncology) in collaboration with the DNA Sequencing Unit of the Cogentech Consortium at the IFOM-IEO campus. During 2010, more than 500 individuals were screened for germline mutations in cancer predisposing genes. This diagnostic activity is integrated by several research programs (LILT, Rome; PIO, Bari). At the preclinical level, they are focused on the identification of genetic markers responsible for familial aggregations that test negative by the above described molecular screenings or that influence cancer risk in mutation carriers. Keywords: colorectal cancer, familial adenomatous polyposis (FAP), Lynch syndrome (HNPCC), Peutz-Jeghers syndrome, hereditary gastric cancer

2010 RELEVANT NOTES Collaborations Mallorca Europen Group for the Hereditary Colorectal Cancer InTEF (Network Nazionale Italiano Tumori Eredo-Famigliari)

Publications Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010; 59:975-86. Biomarkers in familial adenomatous polyposis: role and significance. Front Biosci (Schol Ed). 2010; 2:413-21. Review

Contributions L. Bertario, coordinator of the collaborative group for the elaboration of guidelines for clinical management of familial adematous polyposis, Lombardy Region


72

SCIENTIFIC REPORT 2010

MOLECULAR BASIS OF GENETIC RISK AND GENETIC TESTING

HEAD

Paolo Radice, MD STAFF MEMBER

Daniela Perotti, PhD RESEARCH MEMBERS

Mara Colombo, PhD Antonio Fiorino, Biol Sci D Claudia Foglia, Biol Sci D Paolo Peterlongo, PhD* Carla B. Ripamonti, MD POSTDOCTORAL FELLOW

Laura Caleca, PhD FELLOWS

Irene Catucci, Med Biotech D* Giovanna De Vecchi, Biol Sci D Beatrice Gamba, Med Biotech D Carmela Nici, Biol Sci D* TECHNICIAN

Patrizia Mondini ADMINISTRATIVE

Silvia Grassi *c/o FIRC Institute of Molecular Oncology Foundation (IFOM)

This Unit is primarily involved in the identification and characterization of genetic elements associated with predisposition to development of cancer and its progression. Our research aims to improve current strategies for the identification of individuals at increased risk of cancer or who are more likely to experience recurrence, due to predisposing alleles and/or somatically acquired genetic alterations. Our studies are mainly focused on breast and colorectal carcinomas, and Wilms' tumor (WT). The major achievements during 2010 are as follows. 1. The identification of an indel polymorphism in the promoter of the CASP8 gene (rs3834129) as a modifier of breast cancer risk in carriers of BRCA1 mutations, particularly class I mutations (loss-of-function). 2. In cancer patients with double heterozygosity (DH) for mutations in both BRCA1 and BRCA2 genes, the age of disease onset was found to be comparable to that of carriers of single BRCA gene mutations; tumour development appears to be driven mainly by BRCA1 mutations. 3. The development of a procedure for the classification (in relation to cancer risk) of previously unclassified variants at splicing regions of BRCA genes, integrating in vitro and in silico analyses. 4. The identification, through reanalysis of the data from a previously performed whole-genome single nucleotide polymorphism array analysis of 77 WTs using recently developed bioinformatic tools, of different chromosomal regions associated with relapse, age at diagnosis and disease stage, as well as of focal anomalies at five regions involved in tumorigenesis and/or cancer development. 5. The identification, using transcriptome and ChIPchip arrays, of direct targets of RPF-1, a transcription factor encoded by the WT-related POU6F2 gene, and the observation that the expression of a subset of these genes, whose promoters are enriched in degenerate POU-based octamers, is directly modulated by RPF-1. Keywords: cancer genetics, familial breast cancer, hereditary colorectal cancer, Wilms’ tumor

2010 RELEVANT NOTES Network Italiano Tumori Eredo-Famigliari (INTEF) - P. Radice, co-coordinator

IRCCS: Istituto Europeo di Oncologia and Istituto Clinico Humanitas, Milan; Istituto Nazionale dei Tumori, Fondazione Pascale, Naples and Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG)

CONsorzio degli Studi ITaliani sul Tumore Ereditario alla Mammella (CONSIT TEAM) - P. Radice, coordinator

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), P. Radice, steering committee member

Consorzio per lo studio degli alleli MMR e dei loro modificatori (CONSAMM) P. Radice, co-coordinator

Breast Cancer Consortium (BCAC)

Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) - D. Perotti, Wilms’ tumor working group steering committee member

COlorectal cancer GENeTics (COGENT)

Collaborations

Fondazione Istituto FIRC di Oncologia Molecolare, Milan

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) University of Heidelberg and University of Cologne Centro Nacional de Investigaciones Oncologicas, Madrid and Institut Catala de Oncologia, Barcelona University of Texas M.D. Anderson Cancer Center, Houston, Texas Queensland Institute of Medical Research, Brisbane, Queensland

Publications Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological and family characteristics. Breast Cancer Res Treat. 2010;124:251–58. The CASP8 rs3834129 polymorphism and breast cancer risk in BRCA1 mutation carriers. Breast Cancer Res Treat. 2010. [Epub ahead of print]


PREVENTIVE AND PREDICTIVE MEDICINE DEPARTMENT

73

MOLECULAR BASIS OF GENETIC RISK, POLYGENIC MODELS

HEAD

Tommaso A. Dragani, Pharm Sci D, PhD STAFF MEMBER

Giacomo Manenti, Pharm Chem D, PhD POSTDOCTORAL FELLOW

Antonella Galvan, Biotech D FELLOWS

Francesca Colombo, Biotech D Elisa Frullanti, Biotech D TECHNICIANS

Felicia S. Falvella, Biol Sci D Angela Pettinicchio

This Unit carries out studies on the genetic epidemiology of lung cancer in humans, and is also characterizing the link between genetic susceptibility to inflammation and lung tumorigenesis in animal models. In humans, we have identified a functional haplotype in the 5'-region of the cholinergic receptor nicotinic alpha5 (CHRNA5), on chromosomal locus 15q25, which is implicated in an increased risk of lung cancer and nicotine dependence. The functional haplotype is responsible for the modulation of the transcriptional levels of the CHRNA5 gene. We have also carried out a revision of the literature of available genome-wide association studies, showing that the identified loci exert a very small effect on the phenotype, and that most heritability remains unexplained. We have proposed that genetic heterogeneity might be involved in the complex genetics of cancer, thus implicating hundreds of genetic variants in determining cancer risk. We have also characterized the MFSD2A (major facilitator superfamily domain containing 2) gene, which maps to chromosome 1p34 within a linkage disequilibrium block containing genetic elements associated with progression of lung cancer. We found that MFSD2A expression is strongly down-regulated in lung cancer, and that exogenous expression of MFSD2A in lung cancer cells induced a G1 block, impaired adhesion and migration in vitro, and a significantly reduced tumour colony number in vitro. Overall, our data suggest that MFSD2A is a novel tumor suppressor gene in lung cancer that regulates cell cycle progression and matrix attachment. We have also carried a genome-wide linkage analysis in pedigrees of mice differing in the extent of acute inflammatory response (AIRmax or AIRmin), and determined their genetic susceptibility to lung tumorigenesis. We mapped the major inflammatory response modulator 1 locus on chromosome 7, linked to the number of infiltrating cells through the production of IL-1beta. Keywords: genetic predisposition, SNPs, genome-wide association studies, lung cancer

2010 RELEVANT NOTES Collaborations Istituto Butantan, Sao Paulo Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX Center for Genetic Epidemiology and Modeling, Tufts Medical Center and Tufts University School of Medicine, Boston, MA Stazione Zoologica Anton Dohrn, Naples

Publications Promoter polymorphisms and transcript levels of nicotinic receptor CHRNA5. J Natl Cancer Inst. 2010; 102:1366-70. Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer. Trends Genet. 2010; 26:132-41.


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EXPERIMENTAL ONCOLOGY & MOLECULAR MEDICINE DEPARTMENT

EXPERIMENTAL ONCOLOGY & MOLECULAR MEDICINE DEPARTMENT

DIRECTOR OF DEPARTMENT Maria Grazia Daidone phone: +39 02 2390 2238 mariagrazia.daidone@istitutotumori.mi.it

UNITS IMMUNOBIOLOGY OF HUMAN TUMORS Andrea Anichini MOLECULAR THERAPIES Silvana Canevari MOLECULAR IMMUNOLOGY Mario P. Colombo BIOMARKERS Maria Grazia Daidone CHEMOPREVENTION Maria Grazia Daidone MOLECULAR MECHANISMS OF CELL CYCLE CONTROL Domenico Delia MOLECULAR MECHANISMS Angela Greco IMMUNOTHERAPY OF HUMAN TUMORS Licia Rivoltini TUMOR GENOMICS Gabriella Sozzi MOLECULAR TARGETING Elda Tagliabue MOLECULAR PHARMACOLOGY Nadia Zaffaroni

The Department of Experimental Oncology and Molecular Medicine includes 11 Research Units dedicated to experimental research. In 2010, the redevelopment of a new building, fully dedicated to preclinical research and located closed to the historical INT site, was completed. Eight of the 11 research Units of the Department moved to this new building, in which 3,650 m2 are available for laboratories and meeting rooms, with 600 m2 for open space-laboratories, 14 sterile rooms, a dedicated area for radioactive manipulations, a cryogenic area of 220 m2, and areas for advanced technologies. The primary goal of the Department is to serve as an important conduit through which new discoveries are applied to cancer diagnosis, prognosis, and treatment. This is fostered by a strong collaboration and interaction among physicians and preclinical investigators working in different disciplines. The Department provides several shared research resources, which support investigators with well-equipped facilities and trained specialists. The following resources are available. • Immunohistochemistry (Technical Specialist: Lorena Ventura and Lucia Gioiosa): the histopathology facility assists investigators in research projects that require histological and cytological processing, including tissue microarrays. In addition to routine processing of tissue and cells, the service assists researchers with a full range of histological techniques, immunohistochemistry, in situ hybridization, and autoradiography. • Cell imaging facility (Technical Specialist: Patrizia Casalini, Biol Sci D): the laboratory is equipped with a BioRad Radiance 2000 laser confocal microscope (Nikon Diaphot Inverted) with a 15 mW krypton/argon laser source allowing for a wide range of fluorescent dye use (488, 569 and 647 nm excitation wavelengths). Sequential and simultaneous three channel image collection is possible along with bright field imaging. Live cell

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imaging is possible due to the incubation chamber with temperature and CO2 regulation. • Flow cytometry and cell sorting (Technical Specialist: Gabriella Abolafio; Research Fellow: Andrea Vecchi, Biol Sci D): this facility uses state-of-the-art flow cytometric instrumentation, technical expertise, training, and software analysis. • Microbiology (Technical Specialist: Maria Teresa Radice): this facility takes careof: a) preparation of competent bacteria, media, agar plates, and other reagents; b) bacterial transformation and miniprep analysis; c) medium and large scale plasmid DNA preparation; d) BAC and YAC DNA preparation; e) culture and induction of bacteria for the purification of recombinant proteins and oversees freezing and storage of recombinant plasmids and transformed bacteria and management of the relative database. • DNA sequencing (Technical Specialist: Donata Penso): this facility provides the Units of this Department as well as Units of other Departments with computer-readable sequences and fragment analysis of DNA templates, processing samples on ABI 3100 and 3130 capillary genetic analyzers. • Functional genomics (see a detailed description on page 151) • Proteomics/mass spectrometry laboratory (see a detailed description on page 152) • Tissue and cell repository (see a detailed description on page 150) • Laboratory animal facility (see a detailed description on page 153) Administrative team: Grazia Barp, Grazia Convertino, Simona Galluzzi, Ester Grande, Silvia Grassi, Laura Mameli, Silvia Portincasa, Luisa Rivetta, Daniela Silva, Laura Zanesi, Cristina Zanini This team facilitates the activity of the Department by providing administrative support to research unit leaders and core facilities, coordinating the activities of graduate students and fellows, handling purchasing requests for laboratory consumables, and finance administration. Laboratory Management Team: Enrico Ronchi, Domenico Di Fazio, Angelo Labori, Salvatore Venturino This team plays an essential role in the support of research units within the Department for maintenance of instrumentation , and management and supervision of areas for cryopreservation of stored tissues/cells/cell extracts and reagents. In addition, the team – in association with the administrative team - also oversees a cost-effective and efficient centralized system of ordering and stock control for the most widely used items. Support Personnel: Antonietta Calcagno, Linda Cimaglia, Antonio Illuminato, Agata Mancuso, Luisa Mona, David Penni, Gisella Rivadossi, Pasquale Russo, Claudio Santagostini


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77

IMMUNOBIOLOGY OF HUMAN TUMORS

HEAD Andrea Anichini, Biol Sci D STAFF MEMBERS

Roberta Mortarini, Biol Sci D Marialuisa Sensi, Biol Sci D FELLOW

Valentina E. Perotti POSTDOCTORAL FELLOW

Elena Tassi TECHNICIANS

Paola L. Baldassari, Ilaria Bersani, Alessandra Molla, Gabriella Nicolini, Claudia Vegetti

The main goals of the research Unit are to understand the regulation of immunity in human tumors, to identify new molecular targets to overcome tumor resistance to cell death, and to dissect the role of the tumor-host interaction in promoting cancer development and progression. The main projects during 2010 have focused on: a) mechanisms of adaptive immunity in human tumors with emphasis on cutaneous melanoma, pediatric solid tumors, non-Hodgkin lymphomas, thyroid tumors, and lung cancer b) mechanisms of inflammation-associated cancer development c) role of transcription factors and signaling receptors in tumor progression, and in tumormicroenvironment interactions d) strategies to overcome tumor resistance to programmed cell death induced by pro-apoptotic drugs and target-specific inhibitors e) the role of phosphoproteomics in tumor classification in melanoma. The Unit also contributes to the identification of new biological markers of response in the context of clinical studies of biochemotherapy or target-specific therapy in collaboration with INT Clinical Units. The main results in 2010 included: a) identification of a new subset of CD8+ T lymphocytes in neoplastic tissues of advanced melanoma patients expressing FOXP3 and representing the earliest stage of differentiation to anti-tumor effectors; b) evidence that a biochemotherapy approach based on administration of bevacizumab plus fotemustine can inhibit not only angiogenic, but lymphangiogenic factors in metastatic melanoma patients, c) identification of a subset of MITF- AXL+ human melanomas whose migratory and invasive activity can be suppressed by AXL inhibitors. Keywords: melanoma, tumor immunity, microenvironment, biomarkers.

2010 RELEVANT NOTES Collaborations Riccardo Dolcetti, Cancer Bio-Immunotherapy Unit, Centro di Ricerca Oncologica - IRCCS - Aviano (PN) Ruggero De Maria, Director of the Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome Rita Falcioni (Department of Experimental Oncology) and Dr. Michele Milella (Division of Medical Oncology A), Istituto Regina Elena - IRCCS - Rome Bruno Venerando, Department of Chemistry, Biochemistry and Biotechnologies for Medicine, University of Milan Ennio Carbone, Laboratory of Tumor Immunology, Department of Experimental and Clinical Medicine, University “Magna Graecia” of Catanzaro Paola Allavena, Department of Immunology and Inflammation, Istituto Clinico Humanitas -IRCCS - Rozzano (MI) Pier Francesco Ferrucci, Chief of the Clinical Translational Research Program, Melanoma and Muscle-Cutaneous Sarcomas Division, Istituto Europeo di Oncologia - IRCCS - Milan Giancarlo Avanzi, Department of Clinical and Experimental Medicine, Università “Amedeo Avogadro” del Piemonte Orientale, Novara Soldano Ferrone, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

Publications Tumor-reactive CD8+ early effector T cells identified at tumor site in primary and metastatic melanoma. Cancer Res. 2010;70:8378-87. Bevacizumab plus fotemustine as first-line treatment in metastatic melanoma patients: clinical activity and modulation of angiogenesis and lymphangiogenesis factors. Clin Cancer Res. 2010;16:5862-72.

Contributions Andrea Anichini is member of the editorial board of the following journals: Cancer Immunology Immunotherapy, The International Journal of Biological Markers, Tumori.


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MOLECULAR THERAPIES

HEAD Silvana Canevari, Biol Sci D STAFF MEMBERS

Mariangela Figini, Biol Sci D Delia Mezzanzanica, Biol Sci D Antonella Tomassetti, Pharmacol Sci D RESEARCH MEMBERS

Marina Bagnoli, Biol Sci D Alberto Zacchetti, Vet D FELLOWS

Chiara Alberti, Biol Sci D Davide Bernareggi, Biotechnol Sci D Ileana Bortolomai, Biol Sci D Barbara Frigerio, Biol Sci D Anna Granata, Biol Sci D Patrizia Pinciroli, Biol Sci D TECHNICIANS

Paola Alberti, Renata Ferri, Elena Luison

The aims of the Unit, using a multidisciplinary approach and integration between functional and analytical methodologies, are: to gain insight into the molecular events involved in tumor progression and identify new targets; to identify and validate new prognostic/predictive markers for ovarian carcinoma; to develop and validate new diagnostic/therapeutic strategies targeting ovarian and prostate carcinoma. The majority of the projects of the Unit are pursued in collaboration with other experimental and Clinical Units of the INT, and in particular interactions in the area of translational research are active among Molecular Therapies and other Units of the Department, Gynecological Oncology, Prostate Program, Nuclear Medicine, and Anatomic Pathology. Furthermore, the research group is involved in numerous national and international collaborations. Major results in 2010: In the area of characterization of molecular events involved in the development/progression of cancer we: established the basis for critical evaluation of tumor initiating cells in cervical cancer; demonstrated the added value of combining bioinformatics and biological approaches in the validation of the role of the autocrine TGFA/EGFR loop in thyroid cancer; identified a subgroup of tumors characterized by a proinflammatory secretome, whose key molecules are IL-6 and PAI-1, due to the activation of the EGFR/ERK/NFkB pathway. In the area of new prognostic/predictive markers for ovarian carcinoma we: defined that the reduction/absence of a Xq27.3 located cluster of miRNAs is predictive of poor response to platinum-based first-line treatment; contributed to the identification of the lack of biological activity of IL-18 in patient fluids as a possible mechanism of tumor-escape; actively participated in the characterization of two in vivo preclinical models as a basis for further development of non-invasive clinical magnetic resonance approaches. Keywords: ovarian cancer, translational medicine, molecular mechanisms of tumor progression, molecular profiling, antibody-based therapy

2010 RELEVANT NOTES Collaborations Silvano Ferrini - IST, IRCCS. Genova Marco Colombatti - University of Verona Franca Podo and Dr Egidio Iorio - ISS. Rome Sandro Pignata on behalf of MITO group - Istituto Pascale, IRCCS. Naples Massimo Libra - University of Catania Gustavo Baldassarre - CRO, IRCCS. Aviano Teresa Pellegrino, CNR Lecce and ITT. Genova Nathalie Jacobs - CNR. Liege (B) Sophia Karagiannis and Dr. Hannah Gould - Kingâ&#x20AC;&#x2122;s College - London (UK) Zaver Bhujwalla - Johns Hopkins University, Baltimore (USA) Daniel Powell - University of Pennsylvania (USA)

Publications Tumor initiating cells: development and critical characterization of a model derived from the A431 carcinoma cell line forming spheres in suspension. Cell Cycle. 2010;9:1194-1206. Integrated ligand-receptor bioinformatic and in vitro functional analysis identifies active TGFA/EGFR signaling loop in papillary thyroid carcinomas. PLoS One 2010;5(9):e12701.

Contributions Patent: PCT/IB2009005326, Isolated monoclonal antibody or fragment there of binding prostate specific membrane antigen, conjugates and uses thereof Silvana Canevari is on the editorial board of Cancer Immunology Immunotherapy


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79

MOLECULAR IMMUNOLOGY

HEAD Mario P. Colombo, Biol Sci D, PhD STAFF MEMBERS

Claudia Chiodoni, Biol Sci D, PhD Silvia Miotti, Biol Sci D RESEARCH MEMBER

Sabina Sangaletti, Biol Sci D, PhD POSTDOCTORAL FELLOWS

Barbara Comuzzi, Biol Sci D, PhD Giorgio Mauri, Med Biotech D, PhD Silvia Piconese, Med Biotech D, PhD Paola Pittoni, Med Biotech D, PhD Caterina Vitali, Ind Pharm Biotech D,PhD PHD STUDENTS

Alessia Burocchi, Biol Sci D Alfonso Passafaro, Biol Sci D Alessandra Santangelo, Biol Sci D TECHNICIANS

Ivano Arioli, Barbara Cappetti, Ileana Facetti, Mariella Parenza, Chiara Ratti

We aim to dissect the complex relationships between cells of the immune system, extracellular matrix, and transforming tissues. The main goals in 2010 focused on the following. 1) We have investigated the impact of the inflammatory cytokine TNF on the natural history of spontaneous mammary cancer in the HER-2/neuT (NeuT) transgenic mouse model. Bonemarrow transplantation from TNF knock-out mice into NeuT recipients impaired tumor growth, indicating that the source of TNF fostering tumor development originated from bone marrow. The absence of leukocyte-derived TNF disarranged tumor vasculature, impaired pericyte coverage, and structural integrity, leading to diffuse vascular hemorrhage and stromal necrosis. In addition, tumor-associated Tie-2-expressing monocytes were reduced and cytokine expression skewed from Th2 to Th1 type. Treatment with anti-TNF antibody phenocopied the effect of TNF-deficiency, providing a strong pre-clinical rationale for the introduction of TNF antagonists in the treatment of human breast cancer, including basal-like type for which consolidated targeted therapies do not exist. 2) Regulatory T cells (Treg) are believed to inhibit a variety of immune responses including an antitumor response. After showing inactivation of Treg activity via stimulation of OX40, we uncovered a novel role of OX40 in sustaining Treg competitive fitness in vivo, during repopulation of lymphopenic hosts. OX40-mediated Treg fitness spanned beyond lymphopenic environments, as endogenous Treg in OX40-null hosts showed decreased accumulation during thymic development and enhanced susceptibility to antibody-mediated depletion. OX40deficient Treg were found to be hyporesponsive to IL-2, in terms of Stat5 phosphorylation, according to elevated SOCS1 content and reduced miR155 expression. Therefore, OX40 is a key factor in shaping Treg sensitivity to IL-2 and promoting their proliferation and survival, toward accurate immune regulation. Keywords: regulatory T cells, OX40, TNF, tumor stroma

2010 RELEVANT NOTES Collaborations Claudio Tripodo, University of Palermo Katia Scotlandi, Istituto Ortopedico Rizzoli - IRCCS - Bologna Alessandra Carè, Istituto Superiore di Sanità, Rome Giorgio Trinchieri, NCI, NIH.

Publications Oncogene-driven intrinsic inflammation induces leukocyte production of tumor necrosis factor that critically contributes to mammary carcinogenesis Cancer Res. 2010;70:7764-5. A non-redundant role for OX40 in the competitive fitness of Treg in response to IL-2. Eur J Immunol. 2010;40:2902–13.

Contributions Mario P. Colombo is Senior Editor, of Cancer Research and Associate Editor of Cancer Immunology Immunotherapy


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BIOMARKERS

HEAD Maria Grazia Daidone, Biol Sci D, PhD STAFF MEMBERS

Vera Cappelletti, Biol Sci D Silvia Veneroni, Biol Sci D Raffaella Villa, Biol Sci D POSTDOCTORAL FELLOWS

Graziella Cimino Reale, Biol Sci D, PhD Nicola Orlotti, Biol Sci D, PhD Daniela Sia, Med BiotechD, PhD FELLOWS

Maurizio Callari, Med Biotech D Eleonora Di Buduo, Med Biotech D Emanuela Fina, Biol Sci D Valeria Musella, Med Biotech D Guido Santilli, Biol Sci D Sara Toffanin, Med Biotech D Lorenza Venturini, Biol, Sci D TECHNICIANS

Cinzia De Marco, Lucia Gioiosa, Patrizia Miodini, Biol Sci D, Rosita Motta

Research in this Unit is focused on identification and validation of cancer-related molecular targets, and extends from therapeutically-oriented studies, addressed to design innovative approaches, to optimization of their use in experimental models and testing new drug delivery systems, to more clinically-oriented studies on the role of the relevant targets on cancer progression. During 2010, our interest focused on characterization of gene and miRNA expression profiles of breast cancer specimens (node-negative primary breast cancer developing distant metastases within 5 years from local regional treatment or free of metastases for 5-10 years and matched for age, tumor size, and ER status) and breast cancer initiating cells, derived from clinical tumors and established cell lines. In clinical tumors, up-regulation of IFN- and immune response-related gene clusters was associated with the development of metastases, with a site–related pattern. In this series of tumors, we also identified a set of miRNAs that were modulated as a function of the molecular subtype, 14 miRNA differentially expressed between the basal and luminal subtypes, and 6 miRNA associated with the development of distant metastasis. Tumor-related gene expression variability was dissected from time-related variability taking advantage of our matched series of primary tumors (PT) and synchronous (18 cases) or metachronous bilateral breast tumors (MBT, 11 cases) and local recurrences (LR, 10 cases). Intraclass correlation coefficients (ICC) were compared for each type of tumor pair demonstrating that time-related and tumor-related variability may be separated using specific gene lists, such as the intrinsic and stromal-related ones. The lowest ICCs were observed for MBT, where variability due to distinct genetic background adds to time-related variability, thus supporting their independence from the PT, while LRs share a genetic background with the PT. Keywords: breast cancer, biomolecular profiles, cancer stem cells

2010 RELEVANT NOTES Collaborations

Contributions

Stefano Piccolo, University of Padua, Italy

M.G. Daidone, Scientific Secretariat ABO (Associazione Biomarcatori in Oncologia) Project

Josep M. Llovet, Hospital Clinic (Barcelona, Spain) and Mount Sinai School of Medicine (New York, USA), within the frame of the HCC Consortium EATRIS Consortium, European Community funded project to foster translational research and IATRIS Consortium, Italian initiative for translational studies coordinated by ISS, the Italian Health Institute

M.G. Daidone is Member of the Technical-Scientific Committee of AIRC, the Italian Association for Cancer Research and Member of the Scientific Committee of the Italian School of Senology (SIS)

Ileana Zucchi (ITB-CNR), within the framework of the NOBEL project supported by CARIPLO

M.G. Daidone is Chairperson of the PathoBiology Group of the EORTC (European Organization for Research and Treatment of Cancer) and Member of the Translational Research Division of EORTC

Pier Giuseppe Pelicci (IEO), within the framework of a research project supported by ACC, the Italian Alliance against Cancer

M.G. Daidone is Co-editor of the International Journal of Biological Markers and Member of the Editorial Board of BMC Cancer

Maurizio D’Incalci (IRFMN, Milan), within the framework of the project NEPENTE, financed by the Lombardy Region Gaio Paradossi, University of Tor Vergata, Rome, Italy European Collaborative Project “SIGHT - Systems for in situ theranostic using of micro-particles triggered by ultra-sound”, FP6 HEALTH European Collaborative Project “3 MICRON - Three modality contrast imaging using multi-functionalised microballoons”, FP7 HEALTH Genomnia (s.r.l.): Next generation sequencing on single cell samples

Publications Gene expression analysis reveals a different transcriptomic landscape in female and male breast cancer. Breast Cancer Res Treat. 2010 Jul 13. A MicroRNA targeting dicer for metastasis control. Cell. 2010;141:1195-1207.


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81

CHEMOPREVENTION

HEAD Maria Grazia Daidone, Biol Sci D, PhD RESEARCH MEMBER

Valentina Appierto, Biol Sci D, PhD POSTDOCTORAL FELLOW

Paola Tiberio, Biol, Sci D, PhD TECHNICIANS

Elena Cavadini, Loredana Cleris

Molecular mechanisms involved in 4-oxo-4-HPR anticancer activity. 4-oxo-4-HPR is a a synthetic retinoid that has emerged as a promising candidate for cancer chemoprevention, and is also a polar metabolite of N-(4-hydroxyphenyl)retinamide or fenretinide (4-HPR). 4-oxo-4-HPR induces inhibition of cell growth and apoptosis in various cancer cells more efficiently than 4-HPR, is also effective in 4-HPR-resistant cells, and when combined with 4-HPR has a profound synergistic effect. We found that the anticancer activity of 4-oxo-4-HPR is due to at least two independent mechanisms: the retinoid acts as an antimicrotubule agent and induces apoptosis through a signaling cascade starting from ROS generation and involving endoplasmic reticulum stress response, Jun N-terminal kinase activation, and upregulation of the proapoptotic placental bone morphogenetic protein. The results have provided an explanation of the ability of 4-oxo-4-HPR to be more potent than the parent drug and to also be effective in 4-HPR-resistant cell lines. In addition, the dual mechanism of action may allow 4-oxo-4-HPR to efficiently target tumor cells and to eventually counteract the development of drug resistance. Plasma microRNAs as prognostic markers for breast cancer. MicroRNAs (miRNAs) present altered expression in different tumor types and are also detectable in body fluids. As an complimentary investigation of the Fenretinide Breast Cancer Prevention Trial carried out at our Institute, we will analyze miRNA plasma profiles associated with breast cancer recurrence to assess their potential for early detection. One prerequisite for analysis of the prognostic role of plasma miRNAs is the reliability to measure their levels with high sensitivity and precision. We tested and compared different RNA extraction protocols as well as different high-throughput platforms for miRNA micro-arrays, selecting the optimal experimental methods. Keywords: 4-oxo-4-HPR, miRNA, breast cancer

2010 RELEVANT NOTES Publications 4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells. PLoS One. 2010;5:e13362. Relationship among pharmacokinetics and pharmacodynamics of fenretinide and plasma retinol reduction in neuroblastoma patients. Cancer Chemother Pharmacol. 2010;66:993-8.


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MOLECULAR MECHANISMS OF CELL CYCLE CONTROL

HEAD Domenico Delia, Biol Sci D POSTDOCTORAL FELLOWS

Giacomo Buscemi, PhD Laura Zannini, PhD RESEARCH MEMBERS

Luigi Carlessi, Biol Sci D Daniele Lecis, Biol Sci D Federica Morelli, Biol Sci D TECHNICIAN

Enrico Fontanella

The focus of this Research Unit is centered on two projects, the first on the ATM-Chk2 dependent DNA damage response, the other on tumor-sensitizing pro-apoptotic molecules. Concerning the former, we have fully characterized its activity and characterized a regulatory circuit involving the ser/thr protein phosphatases, which, in undamaged cells, maintains Chk2 in an unphosphorylated status. Regarding studies on apoptotic molecules, we have generated several small monomeric and dimeric SMAC-mimetic compounds that specifically target the BIR2 and BIR3 domains of XIAP through rational design and crystallography structures in collaboration with Martino Bolognesi and Pierfausto Seneci at the University of Milan. In vitro, these SMAC-mimetics stimulate tumor cell cytotoxicity (eg: melanomas, CLL) at submicromolar concentrations, also in combination with TRAIL and Bortezomid. Importantly, one of these molecules exhibits potent antitumor activity in mouse xenografts. Keywords: DNA damage, cell cycle checkpoints, apoptosis

2010 RELEVANT NOTES Collaborations Martino Bolognesi and Pierfausto Seneci, University of Milan Henning Walczak, Imperial College, London

Publications A protein phosphatase feedback mechanism regulates the basal phosphorylation of Chk2 kinase in the absence of DNA damage. Biochim Biophys Acta. 2010;1803:1213-23. Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib. Br J Cancer. 2010;102:1707-16.


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83

MOLECULAR MECHANISMS

HEAD Angela Greco, Biol Sci D STAFF MEMBER

Maria Grazia Borrello, Biol Sci D RESEARCH MEMBERS

Debora Degl’Innocenti, Biol Sci D Claudia Miranda, Biol Sci D PHD STUDENTS

Maria Chiara Anania, Biol Sci D Massimo Moro, Biol Sci D Maria Grazia Vizioli, Med Biotech D POSTDOCTORAL FELLOW

Veronica Catalano TECHNICIANS

Sonia Pagliardini, Maria Grazia Rizzetti

This Unit is involved in studies on the molecular mechanisms of thyroid carcinogenesis, with particular interest to papillary thyroid carcinoma (PTC), the most frequent thyroid neoplasia. The goal of ongoing studies is the identification of markers for early detection, prognosis, and follow-up, as well as novel therapeutic targets. The Unit employs several different experimental approaches including: generation of in vitro models of thyroid carcinogenesis using tumorderived cell lines and human primary thyrocytes; analysis of the role of selected pathways and molecules; mRNA and microRNA expression analysis; characterization of a thyroid tumor case collection, used both for discovery and validation studies. The major results achieved during 2010 were related to: • Dissection of the oncosuppressor role of TIMP3 gene, frequently downregulated in PTC, by demonstrating its ability to modulate cell adhesion and migration, and in vivo tumorigenicity • Demonstration of the relevance in thyroid carcinogenesis of oncogene-induced senescence (OIS), a novel mechanism proposed as a barrier to cancer. The expression of OIS markers (IGFBP7, p16, p21) was shown to be lost during tumor progression • Identification of miRNAs modulated by RET/PTC1, and demonstration that RET/PTC1 may up-regulate MET expression through miR199a • Relevance of an active TGFA/EGFR signaling loop in PTC • Relationships among oncogenes, thyroiditis and thyroid cancer • Demonstration of the oncogenic potential of the RET-K666E mutation detected in the germ line of an MTC patient • Identification of genetic determinants controlling the progression of medullary thyroid carcinoma by using a mouse model (in collaboration with Polygenic Inheritance Unit) Keywords: thyroid carcinoma, oncogenes, oncogene-induced senescence, inflammation, miRNAs

2010 RELEVANT NOTES Collaborations Laura Fugazzola. Endocrine Unit, Fondazione IRCCS Ca’ Granda, University of Milan Paola Allavena. Department of Immunology and Inflammation, Humanitas Clinical Institute, IRCCS. Rozzano, Milan Enrico Radaelli. Department of Veterinary Pathology, University of Milan Erminio Giavini, Prof. Elena Menegola. Functional and Reproductive Biology. Department of Biology - University of Milan Clara V. Alvarez. IDIS, Neoplasia and Endocrine Differentiation, Department of Physiology, CIMUS, School of Medicine, University of Santiago de Compostela USC, Spain Daniel Peeper. Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Publications IGFBP7: an oncosuppressor gene in thyroid carcinogenesis. Oncogene. 2010;29:3835-44. Integrated Ligand-Receptor bioinformatic and in vitro functional analysis identifies active TGFA/EGFR sgnaling loop in papillary thyroid carcinomas. PLoS One. 2010;22;5(9):e12701.


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IMMUNOTHERAPY OF HUMAN TUMORS

HEAD Licia Rivoltini, MD STAFF MEMBERS

Chiara Castelli, Biol Sci D Monica Rodolfo, Biol Sci D RESEARCH MEMBER

Veronica B Huber, MD CLINICAL RESEARCH MEMBERS

Maria Carmela Careri, MD Marco Asioli, Data Manager Paola Frati, Data Manager FELLOWS

Chiara Camisaschi,PhD Student Michela Perego, PhD Student Marcella Tazzari, PhD student Elisabetta Vergani, PhD Student POSTDOCTORAL FELLOWS

Annamaria De Filippo, Biol Sci D Paola Filipazzi, Biol Sci D Viviana Vallacchi, Biol Sci D TECHNICIANS

Valeria Beretta, Agata Cova, Paola Deho, Simona Frigerio, Francesca Rini, Paola Squarcina RESEARCH NURSES

Felicetta Giardino, Gianluigi Rigamonti

Thanks to the presence of scientists with specific clinical and research expertises, the Unit has the possibility to focus on three different research fields in a human setting: clinical development of novel therapeutic strategies for melanoma and prostate carcinoma patients, including the ex-vivo study of treatment-related immune effects; study of immune regulatory pathways in cancer patients, with specific focus on pharmacological tools to overcome cancerrelated immune suppression; and biological and genetic studies on melanoma and melanoma initiating cells, including sensitivity to novel target-therapies and mechanisms of resistance. Specifically: Experimental clinical trials: activation (in collaboration with the Units of Melanoma and Saecoma and the Medical Oncology) of Phase I-II trials addressing the clinical efficacy of the most promising therapeutical strategies for melanoma and prostate carcinoma patients, including anti-CTLA4 Ab in combination with chemotherapy (NIBIT trial), cancer vaccines based on recombinant tumor Ag (PRAME and NY-Eso1, ASCI trials) and tumor peptides (Prostavax), and BRAF/MEK inhibitors. Immunological monitoring: we are involved in monitoring tumor T cell immunity and immunoregulatory pathways (including MDSC, Treg, cytokine/chemokine profiling) in melanoma, prostate carcinoma and sarcoma patients undergoing different anticancer treatments, such as vaccines, small-molecules, kinase inhibitors, and immunomodulating antibodies. Study of the immunoescape mechanisms: identification of crucial tumor pathways leading to the accumulation in cancer patients of MDSC and Treg, effector mechanisms mediating T cell suppression, protumorigenic and pro-angiogenic properties; characterization of the role of tumor exosomes in MDSC and Treg differentiation and function, and molecular factors involved; assessment of tumor acidity in T cell anergy and tumor immunosuppression, and effect of proton pump inhibitors (esomeprazole) on MDSC. Keywords: immunotherapy, cancer vaccines, melanoma genetics, myeloid-derived suppressor cells, exosomes

2010 RELEVANT NOTES Collaborations

Publications

Italian Network for Tumor Bio-Immunotherapy (NIBIT)

Exploiting liver immunity for the prevention of hepatic metastases. J Hepatol. 2010;53:596-8.

Italian Melanoma Intergroup (IMI) International Melanoma Working Group (IMWG) International Society for Biological and Cellular Therapy (ISBTC) Istituto Superiore di Sanità (Dr S. Fais) University of Siena (M. Maio) University of Milan (L. Guerrini) University of Genoa (G. Bianchi Scarrà) Istituto Pascale, IRCCS. Naples (P. Ascierto) University of Heidelberg (V. Umansky) National Cancer Institute, Bethesda (F. Marincola) University of Charleston (M. Nishimura) University of Tokyo (Y. Kawakami) Karolinska Institute, Stockholm (S. Caramuta, A. De Milito) Faculté de Pharmacie of Chatenay-Malabry, Université Paris-Sud (F. Triebel) Université Catholique de Louvain (S. Lukas) Ludwig Cancer Institute, Brussels (P. Coulie)

LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol. 2010;184:6545-51.

Contributions Patent on the Immunomodulating use of PPI Masters on Melanoma (IMI), Masters on Tumor Biotherapy (NIBIT) Editorial Board of Journal of Immunotherapy National Guidelines on Immunomonitoring (NIBIT) National Guidelines in Melanoma Treatment (contribution)


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TUMOR GENOMICS

HEAD Gabriella Sozzi, PhD STAFF MEMBER

Luca Roz, Pharm Sci D POSTDOCTORAL FELLOWS

Francesca Andriani, Pharm Sci D Patrizaia Gasparini, Biol Sci D Massimo Moro, PhD Carla Verri, Biol Sci D PHD STUDENTS

Giulia Bertolini, Med. Biotech. D. Mattia Boeri, Biotech D. TECHNICIANS

Roberto Caserini, Davide Conte, Federica Facchinetti

The main field of interest of the Tumor Genomics Unit is biological and molecular characterization of lung cancer, the identification of genetic signatures in tissues and biological fluids that are useful for early detection of lung cancer, and to establish novel therapeutic approaches. Recent scientific interests include the study of lung cancer initiating cells and the characterization of miRNA expression in lung tissues and plasma samples to assess their functional role in lung carcinogenesis and to evaluate their potential as diagnostic markers, predictors of outcome, and as the basis for therapeutic strategies. During 2010, we have mainly progressed in the project concerning the identification and the characterization of cancer initiating cells in human non-small cell lung cancer. The purpose of this study is to detect phenotypically distinct subpopulations of cells in lung tumors endowed with the ability of self-renewal and the capacity to initiate tumorigenesis. These cells are being studied at the biological, molecular, and pharmacological level to characterize their profile in terms of resistance/sensitivity to chemotherapy treatments and to identify molecular targets for novel therapies. In particular, since little was known about the genomic characterization and genetic stability of cancer stem cells, we have carried out detailed molecular cytogenetic characterization using spectral karyotyping and fluorescent in situ hybridization of sphere-growing stem-like cell lines of different solid tumors, including lung cancer. Our findings indicate increased cytogenetic complexity in sphere-growing stem-like cells, suggesting the existence within cell-lines of heterogeneous and genetically unstable subpopulations of cells endowed with stem-like features. Moreover, we established in vitro cell systems and in vivo models, including PET imaging, for studying lung cancer stem cells and testing new therapeutic agents. Keywords: lung cancer, molecular changes, cancer stem cells

2010 RELEVANT NOTES Collaborations PET Unit (F. Fazio, R. Moresco) San Raffaele Scientific Institute, IRCCS. Milan CERMS, A.O.U. San Giovanni Battista, Turin (R. Ferracini) Francesco Pezzella, Oxford University, UK Carlo M. Croce, OSUMC, Columbus, OH, USA Chemores consortium (FP6, European Community)

Publications Molecular cytogenetic characterization of stem-like cancer cells isolated from established cell lines. Cancer Lett. 2010;296:206-15 The “stem” of chemoresistance. Cell Cycle. 2010;9:628-9

Contributions Gabriella Sozzi takes part in the Scientific Committee “Fondazione Edo Tempia”, Biella and Società Italiana di Cancerologia (SIC); Scientific Advisory Board American-Italian Cancer Foundation (AICF); Selection Committee Pezcoller-AACR Award 2011; Steering Committee of the European project “Chemores” (VI shared-cost RTD action)


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MOLECULAR TARGETING

HEAD Elda Tagliabue, Biol Sci D STAFF MEMBERS

Manuela Campiglio, Biol Sci D Rosaria Orlandi, Biol Sci D Serenella M. Pupa, Biol Sci D TECHNICIANS

Pierangela Aiello, Patrizia Casalini (Responsible for DOSMM imaging facility), Cristina A. Ghirelli RESEARCH FELLOWS

Valentina Ciravolo, Biotech Sci D Gaia C. Ghedini, Biotech Sci Alessandra Meini, Biol Sci D Ilaria Plantamura, Biol Sci D Manuela Ratti, Biol Sci D Francesca Ripamonti, Biotech Sci D Tiziana Triulzi, Biotech Sci D (AIRC) PHD STUDENTS

Francesca Bianchi, Biotech Sci D (AIRC) Marilena V. Iorio, Biotech Sci D Marianna Sasso, Biol Sci D CONSULTANTS

Sylvie MĂŠnard, Biol Sci D Marco Sandri, Stat Sci D

During 2010, we focused on identification of new cancer-related antigens and investigated pathways driving development and progression of breast carcinoma. Concentrating our efforts on triple negative breast cancer (TNBC), we observed that these undifferentiated tumors present an endothelial-like phenotype. This property appears to be related to FGFR2, PDGFR- , and c-Kit. Inhibition of these receptors abrogated the in vivo growth of TNBC cell lines, indicating that these pathways might represent a specific therapeutic target. Investigating the role of microRNA in a model of TNBC, our results indicate that miR-205 has a strong suppressive function, inhibiting migration, cell proliferation, colony forming ability, and in vivo growth. In HER2+ breast carcinomas, we found that a HER2 splice variant lacking exon 16 (delta16HER2), which forms covalent cysteine bonds generating constitutively active homodimers on cell membrane, is constitutively expressed in human breast carcinomas in a proportion (about 9%) of WT HER2. Additionally, delta16HER2-expressing transfectants have increased transforming potency compared to WT HER2-expressing transfectants, and it was also found that only mice transgenic for the delta16HER2 isoform develop multiple spontaneous mammary carcinomas, demonstrating that delta16HER2 is a candidate for the transforming form of the HER2 oncoprotein. With the aim to identify HER2+ patients likely to benefit from trastuzumab therapy, we critically reassessed emerging data from clinical studies. The MAb appeared to act through multiple mechanisms, according to stage of the disease and treatment protocol. ADCC appears to be predominant when trastuzumab is used as monotherapy in neoadjuvant and metastatic settings; inhibition of DNA repair predominates in neoadjuvant and adjuvant settings involving concomitant trastuzumab and chemotherapy; whereas in sequential protocols, the monoclonal antibody appears to act primarily through cytostatic activity. Keywords: breast carcinoma, targeted therapy, HER2

2010 RELEVANT NOTES Collaborations Augusto Amici, Department of Molecular, Cellular and Animal Biology, University of Camerino (generation of delta16HER2 transgenic mice) Carlo M. Croce, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus OH (analysis of microRNA involved in the progression of triple negative breast carcinoma)

Publications Triple-negative breast cancer: Present challenges and new perspectives. Mol Oncol. 2010;4:209-29.


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MOLECULAR PHARMACOLOGY

HEAD Nadia Zaffaroni, Biol Sci D, PhD STAFF MEMBERS

Marco Folini, Biol Sci D, PhD Cinzia Lanzi, Biol Sci D Paola M.C. Perego, Biol Sci D, PhD Rosanna Supino, Biol Sci D TECHNICIANS

Nives Carenini, Elisabetta Corna, Laura Dal Bo, Enrica M. Favini, Maria Stella Tinelli, Monica Tortoreto RESEARCH MEMBERS

Giovanni L. Beretta, Biol Sci D, PhD Giuliana Cassinelli, Pharm D; PhD Michelandrea De Cesare, Vet D Laura Gatti, Biol Sci D, PhD Chiara Giommarelli, Pharm D Marzia Pennati, Biol Sc D, PhD Giovanna Petrangolini, Biol Sci D Valentina M. Zuco, Biol Sci D FELLOWS

Raffaella Cincinelli, Chemistry D Giacomo Cossa, Biotech Sci D Paolo Gandellini, Biotech Sci D Valentina Nicolini, Pharm D Valentina Profumo, Biotech Sci D CONSULTANT

Franco Zunino, Biol Sci D

The research activity of the Unit is focused on: Identification and validation of novel therapeutic targets. It has been demonstrated that telomeric G-quadruplexes (G4) represent a valuable target since following exposure to a bisantrene derivative, the G4 ligand was able to induce a DNA damage response at the telomeric level, which was followed by decline of cell proliferation and appearance of cell senescence in human tumor cell lines independently of the telomere maintenance mechanism. In addition, heparanase has been validated as a new therapeutic target in a panel of pediatric sarcomas with different histotypes. Mechanisms of drug resistance. The molecular characterization of ovarian carcinoma cell acquired resistance to conventional cytotoxic drugs has revealed that the resistant phenotype is associated with increased levels of glycosylation-defective transporters of the ABC family. Rational development of new drug combinations. When testing combinations of modulators of acetylation, it was found that acetyl-L-carnitine was effective in sensitizing wild-type p53 tumor cells to cisplatin. A synergistic interaction was observed when new histone deacetylase inhibitors were combined with atypical retinoids, proteasome inhibitors, or taxanes. Preclinical development of new anticancer agents. We demonstrated that novel bis-platinum complexes, endowed with an improved pharmacological profile, were capable of overcoming resistance mediated by DNA mismatch repair defects in different cellular models and retained marked antitumor efficacy in cisplatin-refractory tumor xenografts. Recently, the Unit has extended its interests to the role of miRNAs in the response of cancer cells to anticancer agents. In this context, the functional analysis of miRNAs downregulated in prostate cancer (i.e., miR-205), has highlighted the possibility to positively modulate drug sensitivity following their reconstitution in prostate cancer models. Keywords: therapeutic targets, drug resistance, preclinical drug development

2010 RELEVANT NOTES Collaborations Eugenio Scanziani, University of Milan Mauro Magnani, University of Urbino Manlio Palumbo, University of Padua Laura Fugazzola, Fondazione Policlinico IRCCS, Milan Israel Vlodavsky, The Bruce Rappaport Faculty of Medicine, Haifa (Israel) Roger R. Reddel, Childrenâ&#x20AC;&#x2122;s Medical Research Institute, Sydney (Australia) Frank Caruso, University of Melbourne (Australia) Nicolas W. Keith, University of Glasgow (UK) Stephen B. Howell, University of San Diego (CA) Dario A. Altieri, The Wistar Institute Cancer Centre, Philadelphia (PA)

Publications The ABC of glycosylation. Nat Rev Cancer. 2010;10:523. miR-21: an oncomir on strike in prostate cancer. Mol Cancer. 2010;9:12.

Contributions Editorial board: Critical Reviews in Oncology/Hematology, European Journal of Cancer, BMC Cancer, Journal of Chemotherapy, Apoptosis (Nadia Zaffaroni) International Journal of Oncology (Paola Perego) Anti-Cancer Agents in Medicinal Chemistry, ISRN Oncology (Marco Folini)


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PATHOLOGY AND LABORATORY MEDICINE DEPARTMENT

PATHOLOGY AND LABORATORY MEDICINE DEPARTMENT

DIRECTOR OF DEPARTMENT Giuseppe Pelosi Professor of Pathology University of Milan +39 02 2390 3017 giuseppe.pelosi@istitutotumori.mi.it

UNITS ANATOMIC PATHOLOGY 1 Maria Luisa Carcangiu ANATOMIC PATHOLOGY 2 AND 3 Giuseppe Pelosi EXPERIMENTAL MOLECULAR PATHOLOGY LABORATORY (part of Anatomic Pathology 3) Silvana Pilotti SIMT - IMMUNOHEMATOLOGY AND TRANSFUSION MEDICINE Fernando Ravagnani LABORATORY MEDICINE Daniele Morelli

The mission of the Department is to provide accurate diagnoses and information of prognostic and therapeutic value to clinicians. The activities of Surgical Pathology, Diagnostic Molecular Pathology, Cytopathology, and Autopsy Pathology are carried out in the three Anatomic Pathology Units, while biological tests/microbiological investigations and blood collection, screening, processing, storage, and distribution are carried out at the Laboratory Medicine Unit and SIMT-Hematological Transfusion Service, respectively. The activities are performed using conventional and state-of-theart techniques, and all the laboratories are quality certified (ISO9001; 2000, confirmed in 2008 until 2011). The Pathology Department is also involved in two Institutional activities: Human frozen tumor tissue bank (see Shared Research Resources page 150) The frozen tumor tissue bank of INT is a systematic collection that looks much like a project-driven collection, but is not restricted to a specific organ or disease type. Telepathology In order to acquire uniform high quality in pathologic diagnostics and to rapidly spread knowledge related to cancer research, a Virtual Pathology group is being developed in Italy. It is composed of pathologists working in the seven Italian Cancer Institutes within the national ACC project. The programs of the ACC Virtual Pathology Institution include consensus sessions, quality control, educational activities, second opinion, and research.

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ANATOMIC PATHOLOGY UNITS 1, 2 & 3

HEADS

Maria Luisa Carcangiu, MD: Anatomic Pathology Unit 1 Giuseppe Pelosi, MD: Anatomic Pathology Units 2 & 3 Silvana Pilotti, MD: Experimental Molecular Pathology Laboratory (part of Anatomic Pathology 3) STAFF MEMBERS

Marta Barisella, MD, Antonello D. Cabras, MD, Paola Collini, MD, Maurizio Colecchia, MD, Alessandra Fabbri, MD, Flavia Melotti, MD, Massimo Milione, MD, Biagio Paolini, MD, Alessandro Pellegrinelli, MD, Pasquale Quattrone, MD, Gabrina Tragni, MD, Barbara Valeri, MD, Antonella Aiello, Biol Sci D, Annunziata Gloghini, Biol Sci D, Federica Perrone, Biol Sci D, Carla Riva, Biol Sci D (Coordinator of Cytopathology), Mario Ruggeri, Biol Sci D, Elena Tamborini, Biol Sci D, Adele Testi, Biol Sci D FELLOWS

Nicoletta Di Mari, MD; Valentina Galimberti, Biol Sci D; Ambra Gualemi, Biol Sci D; Zaka Zheni, Technician; Mariangela Girotti, Administrative POSTDOCTORAL FELLOW

In 2010, the clinical activity of Anatomic Pathology Units 1, 2 & 3, devoted to provide accurate, exhaustive and timely diagnoses, included more than 20,000 histological and more than 20,000 cytological pathology reports, all carried out according to internationally shared classification schemes. An autopsy service is also available for precisely identifying causes of death in patients admitted to the hospital. The spectrum of the diverse tumor types has comprises skin tumors (including melanomas), lymphoproliferative disorders, male genitourinary tract tumors, non-neuroendocrine gastrointestinal tumors, thoracic and mediastinal lesions, endocrine tumors (including thyroid, adrenal glands, gastroenteropancreatic tract and lung), soft tissue tumors, head and neck tumors, pediatric malignancies, gynecologic and breast tumors, and malignancies from unknown primary sites. Most diagnoses in 2010 were rendered within 7 days of admission.The details of histological diagnoses on surgical pathology specimens included cases seen in consultation for second opinion, frozen section examinations, sentinel lymph nodes, and biopsy samples, as well as cytological diagnoses on fine needle aspiration biopsies or extravaginal cytology samples and PAP tests, half of which came from screening programs as a part of routine preventive healthcare for gynecological cancers.

Elena De Paoli, Biol Sci D RESIDENTS

Chiara Volpi, Biol Sci D STAFF TECHNICIANS

Claudia Alphandery (Cytotechnologist), Maria Grazia Bonora, Renata Borchini, Rita A. Carminati, Alessandra Chinosi, Marilena Colantuono, Silvia Colombo (Cytotechnologist), Daniela De Bari, Francesca Dominoni (Chief-Technician and Department Coordinator), Alessandra Elli, Maria Grazia Facciorusso, Elena Fomiatti, Angelo Gaito, Daniela Galbiati, Morena Gobbo, Rosangela Intorre, Teresa Labella, Matteo Marcuzzo, Alessia Mietta, Marzia Mietta, Loretta Missiato, Maria Luisa Moiraghi, Margherita Mondini, Paola Murè, Marta Orsenigo, Desirè Parimbelli, Katia Ponzoni (Cytotechnologist), Silvia Redaelli, Gianni Roncato (Photographer), Carla Scalia, Manuela Scuro, Consiglia Sgura STAFF ADMINISTRATIVES

Patrizia Cangioli, Margherita Cariglia, Maria Teresa Codecasa, Maria Cristina Di Bartolomeo, Roberto Ferrari, Maria Morelli, Alda Tosi HEALTHCARE ASSISTANTS

Paolo Castioni, Cosima Ciccarese, Massimo Festa, Paola Tonielli, Anna Urbano RESEARCH MEMBERS (EXPERIMENTAL MOLECULAR PATHOLOGY LABORATORY)

Fabio Bozzi, Biol Sci D, Tiziana Negri, Biol Sci D FELLOWS (EXPERIMENTAL MOLECULAR PATHOLOGY LABORATORY)

Claudia Bertan, Biol Sci D, Silvia Brich, Biol Sci D, Elisa Ciulla, Biol Sci student (since October 2010), Elena Conca, Biol Sci D, Barbara Cortelazzi, Biol Sci D, Genny Jocollè, Biol Sci D (until October 2010), Andrea Lampis, Biol Sci D, Valentina Mauro, Biol Sci D, Eva Tarantino, Biol Sci D

DIAGNOSTIC ACTIVITY OF ANATOMIC PATHOLOGY UNITS 1,2 & 3 IN 2010

Type of Report

Number

Histological (total 21,387)

Surgical pathology specimens Biopsy samples Frozen section examinations Sentinel lymph nodes Consultation for second opinion

11,467 7,114 2,544 657 2,797

Cytological (total 21,890)

Fine needle aspiration biopsy or extravaginal cytology samples Conventional PAP tests PAP tests from screening programs

3,266 9,452 9,172

Most pathological reports were supplied with extensive pheno-genotyping for diagnosis, indicating predictive and/or prognostic factors and personalization of the best care according to criteria of so-called therapeutic pathology. About 50,000 immunohistochemical reactions, over 5,000 special stains, and 2898 genetic reports were carried out in 2010 for characterization of malignancies, with particular reference to lymphoproliferative disorders and pediatric, thoracic, soft tissue, neuroendocrine, head and neck, breast and gynecologic tumors, including the immunohistochemical evaluation of estrogen and progesterone receptors and Her-2/neu in breast cancer, the assessment of the status of several genes for tailored therapy (such as, Her-2/neu, EGFR, CD117, PDGFRA/B, VEGFR, ALK or TP53) or characterization of malignancies from unknown primary sites.


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There is also a Laboratory of Molecular Pathology hosted under Anatomic pathology Unit 3, whose aim is extensive molecular testing both at diagnostic and experimental levels. DIAGNOSTIC ACTIVITY OF THE MOLECULAR PATHOLOGY LABORATORY IN 2010

Type of Analysis

Number

Mutational analysis (EGFR, K-ras, PDGFRA/B, c-kit, TP53, RET, beta-catenin, and BRAF) 701 FISH 776 CISH 318 Clonality tests 115 Cytogenetic assessments 249 Total 2,159

The experimental activity of the Molecular Pathology Laboratory has focused on: a) characterization of tumor profiles for identifying therapeutic targets; b) identification of the basis of response/resistance to target therapies by using pre- and post-treatment tumor patient samples; and c) validation of the consistency and reproducibility of molecular markers in clinical settings. Specifically, the following projects are in progress: a) characterization of the activation profile of RTKs and their signalling (MAPK, AKT, mTOR) in diverse na誰ve tumors and sarcomas, including peritoneal mesothelioma, chordoma, and myxoid liposarcoma, also with mice xenograft models; b) biological basis of response/resistance to target treatments in solitary fibrous tumor and dermatofibrosarcoma protuberans-derived fibrosarcoma; c) demonstration of impaired response to neoadjuvant cisplatin and fluorouracil chemotherapy in TP53 mutated squamous cell carcinoma of the oral cavity. Furthermore, we have reported on a significant association between Her-2/neu gene amplification and beclin1 gene loss in breast cancer samples. Keywords: diagnosis, tumor grading, staging, therapeutic pathology, immunohistochemistry, cytology, molecular assay


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SCIENTIFIC REPORT 2010

2010 RELEVANT NOTES Collaborations Marta Barisella: Italian Sarcoma Group (ISG) Maurizio Colecchia: Italian Socity of Urology (SIU); Hospital Urologist Association (AURO); Project on “Sorveglianza attiva del carcinoma della prostata”, Italian Society of Urology (SIURO); Italian Group of Uropathology (SIAPEC, Italy) (Coordinator) Paola Collini: Italian Group of Oncologic Pediatric Pathology (GIPOP); Pediatric Oncology International Society (SIOP); Italian Sarcoma Group (ISG) Alessandro Pellegrinelli: Integrative genomic analysis of human intrahepatic cholangiocarcinoma (PI: Llovet JM, Barcelona, Spain; Senior advisor: Mazzaferro V; Project Coordinator: Sia D, Spain) Giuseppe Pelosi: Italian Group of Pleuropulmonary pathology (GIPP); Pathologist Panel Member of the International Academy for the Study of Lung Cancer (IASLC); International Association of Cytology (IAC) Member (MIAC), USA; Pulmonary Pathology Society (PPS) Member, USA Silvana Pilotti: Sabrina Pricl, Molecular Simulation Engineering Laboratory, DI3, University of Trieste; Maurizio D’Incalci, Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri, Milan. Annunziata Gloghini: Amedeo Avogadro East Piemonte University (G. Gaidano, D. Capello); CRO – Aviano (A. Carbone, V. De Re, D. Aldinucci); Oncology Institute of Southern Switzerland (IOSI) (F. Bertoni); Conway Institute for Biomolecular and Biomedical Research, Conway Institute for Biomolecular and Biomedical Research, University College Dublin (G. Elia) Elena Tamborini: G. Kroemer and Zitvogel, INSERM Paris (expression of SNPs in GIST); J Trent, MD Anderson, Houston Texas (gene copy number evaluation in GIST)

Publications Lynch syndrome—related endometrial carcinomas show a high frequency of nonendometrioid types and of high FIGO grade endometrioid types. Int J Surg Pathol. 2010;18:21-6.

Teratoma With Somatic-Type Malignant Components in Germ Cell Tumors of the Testis: A Clinicopathologic Analysis of 40 Cases With Outcome Correlation. Int J Surg Pathol. 2010 Dec 6. [Epub ahead of print] Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer. 2010;17:977-87. Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors. PLoS One. 2010;5(12):e16010. Functional mapping of receptor tyrosine kinases in myxoid liposarcoma. Clin Cancer Res. 2010;16:3581-93. B-cell lymphomas with features intermediate between distinct pathologic entities. From pathogenesis to pathology. Human Pathol. 2010; 41:621-31 Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas. Neuro Oncol. 2010;12:776-89

Contributions Antonello D. Cabras for: Peritoneal Tumors (primary lesions and metastases) and Lymphoproliferative disorders, Santa Chiara Hospital, Trento Maria Luisa Carcangiu: Editorial Board, International Journal of Gynecological Pathology Marurizio Colecchia: Guidelines on urinary bladder (Puppo et al, BJU Int. 2010;106:168-79) and penis tumors (edited by the Italian Society of Urology); Editorial Board, Pathologica Giuseppe Pelosi: Associate Editor, International Journal of Surgical Pathology; Editorial Board, Virchows Archiv; Editorial Board, Pathologica Annunziata Gloghini: Recommendations on minimal requirements, reporting criteria, and methods on Her-2/neu assessement in breast cancer (AIOMSIAPEC cooperative group on molecular therapy of tumors (http://www.aiom.it/Attivit%E0+Scientifica/Documenti+AIOM/Position+pap er/Raccomdandazioni+per+la+determinazione+dello+stato+di+HER2+nel+c arcinoma+mammario/1,4296,0,)


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SIMT, IMMUNOHEMATOLOGY AND TRANSFUSION MEDICINE

Orietta C. Polisena, Elide Spinelli, Giovanni Veronese, Maria C. Zanetti

Involved in blood collection, screening, processing, storage, and distribution of blood components and laboratory activities. Immunohematology, serological and molecular virology, HLA typing of patients and related/unrelated donors, and therapeutic apheresis are also performed. Clinical work and laboratory testing are always in accordance with European and American technologies and standards. Therapeutic apheresis is focused on peripheral blood stem cell harvesting for autologous and allogeneic stem cell transplantation. The Apheresis Group has recently implemented the procedure of extracorporeal photopheresis (ECP), which is mainly used for the treatment of dermatologic diseases, autoimmune diseases, lymphoma, and treatment of acute and chronic graft versus host disease (GVHD). In 2010, we also implemented the production of platelet gel, a blood component used for local application with an important role in wound healing. Three patients have been successfully treated. In collaboration with the Virology Department at the University of Milan, a study on occult infection with HBV in donor blood samples is ongoing. A preliminary analysis shows very interesting data.

TECHNICIANS

Keywords: immunohematology, transfusion medicine, virology

HEAD Fernando Ravagnani, MD STAFF MEMBERS

Flavio Arienti, MD Annalisa Birolini, MD Paola Coluccia, MD Caudia Lombardo, Biol Sci D Arabella MazzocchiI, Biol Sci D Laura R. M. Terranova, MD FELLOWS

Francesca Taverna, Biol Sci D Veronica Salvatori, Biol Sci D ADMINISTRATIVES

Antonella Atzeni, Maria A. Somma, Mario Avella, Cinzia L. Biasuz, Alvaro Bompadre, Laura M. Bonizzoni, Antonella Falanga, Daniela Ferrari, Marina Galbiati, Annamaria Gorla, Silvia Larghi, Roberto Losa, Antonia Morleo, Ernestina Pigliafreddo, Lara Pusterla, Roberta Serpi, Lorena Sfreddo, Carmela Gizzi, Barbara Strada, Maria Tamburriello, Tiziano P. Tattanelli, Ornella Zanaboni NURSES

Donata Bertolesi, Roberta Colombo, Marisa Dentella, Filomena Fedele, Rita Fiorito, Cristina I. Lasala, Monica Pedretti, Carmela Santolla

2010 RELEVANT NOTES Collaborations European Institute of Oncology, L. Sacco Hospital, Fondazione IRCCS Istituto Neurologico Besta, University of Milan, Virology Department

Publications Single-nucleotide polymorphism inside microRNA target sites influence tumor susceptibility. Cancer Res. 2010;70(7):2789-98


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SCIENTIFIC REPORT 2010

LABORATORY MEDICINE

HEAD Daniele Morelli, Biol Sci D STAFF MEMBERS

Mariachiara Bonini, Biol Sci D Eutilia Conte, Biol Sci D Antonio Mastroianni , Biol Sci D Roberta Rossi , Biol Sci D Loredana Simoni, MD Giovanna Viola , Biol Sci D TECHNICIANS

Giuseppina Ballabio, Rosella Bonfanti, Chiara Brusati, Maria Rosa Carati, Maria Rosa Cattaneo, Maria V. Corengia, Teresa Fontana, Carlo Maggi, Roberta Marchetti, Valerio Motta, Giuseppa Perrucci, Pia S. M. Picco, Marco Ranzani, Nicola Salvatore, Federica Sozzani

Laboratory Medicine performs biological tests and microbiological investigations that contribute to the diagnosis, prognosis, and monitoring of oncologic patients submitted to conventional and experimental therapies. In 2010, about 1,700,000 examinations were performed, an increase of almost 5% over the previous year. The reliability of the results is guaranteed by maintaining high quality standards, which are constantly monitored by national and international External Quality Assessment (EQA). Much attention has been paid to the choice of appropriate technologies and to the continuous improvement of technical and scientific knowledge of the medical and scientific staff. Moreover, the Unit tests new technologies and analytical methodologies and transfers scientific know-how relative to the clinical laboratory to professionals and students. The Unit is also involved in evaluation of the diagnostic potential of new tests and technologies and in the search for innovative organizational solutions. The Unit is engaged in support activity for several clinical trials conducted at the INT and is involved in the project â&#x20AC;&#x153;Personalized Treatment of Sarcomasâ&#x20AC;?. Keywords: clinical chemistry, hematology, microbiology

ADMINISTRATIVE

Santa Zingone

2010 RELEVANT NOTES Publications Colorectal cancer detection by means of optical fluoroscopy. A study on 494 subjects. Front Biosci (Elite Ed). 2010;2:694-700.


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SURGERY DEPARTMENT

SURGERY DEPARTMENT

DIRECTOR OF DEPARTMENT Ugo Pastorino +39 02 2390 2906 ugo.pastorino@istitutotumori.mi.it

UNITS GASTROINTESTINAL, HEPATOPANCREATOBILIARY SURGERY AND LIVER TRANSPLANTATION Vincenzo Mazzaferro COLORECTAL SURGERY Ermanno Leo BREAST SURGERY Robrto Agresti MELANOMA AND SARCOMA Mario Santinami DIAGNOSTIC ENDOSCOPY AND ENDOSCOPIC SURGERY Emanuele Meroni MAXILLO-FACIAL SURGERY Giulio Cant첫 and Gabriele Scaramellini (from September 14th) GYNECOLOGIC ONCOLOGY Francesco Raspagliesi THORACIC SURGERY Ugo Pastorino PLASTIC AND RECONSTRUCTIVE SURGERY Maurizio B. Nava OTOLARYNGOLOGY SURGERY Gabriele Scaramellini UROLOGIC SURGERY Roberto Salvioni PEDIATRIC SURGERY Luigi Piva LASER THERAPY Anna Colombetti

The Department consists of 11 surgical divisions and 2 Units under the responsibility of the Director of the Department (Pediatric Surgery and Laser Therapy); there are 240 inpatient beds and 14 outpatient beds. Routine clinical activity ensures a high standard of care for all surgically-treated patients, providing conservative surgery (organ/function preserving or minimally invasive) for early stage disease and combined treatment modalities for advanced disease. Furthermore, all surgeons of the Department continue in their specific research activity in order to achieve an outstanding quality of results. Through frequent meetings the Department optimizes its resources and plans clinical activities in collaboration with the Medical Office.

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GASTROINTESTINAL, HEPATOPANCREATOBILIARY SURGERY AND LIVER TRANSPLANTATION HEAD Vincenzo Mazzaferro, MD STAFF MEMBERS

Carlo Battiston, MD, Sherrie Bhoori (hepato-gastoenterologist), Jorgelina C. Coppa, MD (HPB-surgery coordination), Christian Cotsoglou, MD, Alessandro Germini, MD, Andrea Pulvirenti, MD, Enrico Regalia, MD (transplant activity coordination), Raffaele Romito, MD, Marcello Schiavo, MD (video-assisted surgery coordination) FELLOWS

Carlo Ferruccio Sposito, MD, Maria Flores Reyes, MD RESIDENTS

Concetta Blundo, MD, Marco Bongini, MD, Cristina Garcia, MD ADMINISTRATIVES Daniela Guarneri (Scientific Secretariat) Nela C. Zito (Scientific Assistant) Francesco Roncacci (Unit Secretariat) Simona G. Marchesi (Data manager) NURSES

Salvatore Bonafede, Annateresa Bugada, Milda Di Giacomo, Francesca Maiorano, Giuseppe Marena, Antonella Masiello, Laura Morsenti, Nadia Nicoletti, Patrizia Perottoghi, Patrizia Rota, Aurelio Scarabelli, Paola Serafin (Head Nurse), Rossella Sitta, Cristina Stracquadaimi, Carmela Tomasicchio, Patrizia Valentini, Luigi Zarella HEALTHCARE ASSISTANTS

Rossella De Felice, Nicoletta Damiani, Annamaria Pancari, Enza Spina, Anna Vecchio

The activity of this Unit is focused on improving the standard of care and clinical research on primary and secondary tumors of the upper gastrointestinal tract affecting the liver, biliary system, stomach, pancreas, and small bowel. This is a comprehensive surgical and medical facility dedicated to all forms of upper gastrointestinal cancer. A Liver Transplant program mainly focused on oncological indications is incorporated in the Unit. In clinical activities, trials and technical procedures are applied far beyond conventional indications as daily practice involves a multidisciplinary approach. In the setting of hepato-oncology, laparoscopic surgery, resection, and transplantation are part of integrated therapeutic programs including radiofrequency ablation, trans-arterial chemoembolization, radioembolization, and use of molecular targeted therapies. More than 60% of patients are offered therapies within prospective clinical trials. In addition, new clinical technologies are routinely used in the management of patients, and recent updated devices are offered to patients admitted to the Unit. These include: a) Myrian: a program to calculate liver volume for the evaluation of the remnant liver (and liver to be removed) in case of large resections; b) Limon: a monitoring system for non–invasive measurement of the global liver function based on the elimination of the diagnostic drug ICG pulsion injected intravenously and eliminated exclusively by the liver; c) bipolar sealing devices: designed to seal blood vessels and reduce blood loss and transfusion; d) latest generation of ultrasound technologies with or without contrast agents is employed on a routine basis for targeting liver lesion in association with; e) ablation devices: using either radiofrequency or microwaves. Patient care and support are the highest standard for the over 800 admissions and 400 major surgical procedures/year, among which treatment of colorectal and liver metastases represent the majority. The Unit has the highest complexity within the INT and is part of the International Consortium on Liver Cancer, within a transplational research program that received the AARC Innovation Award 2009 (with Barcelona Clinic and Mt. Sinai University in New York). Clinical research programs are part of FP7 Project and transplantion trials on extended criteria are led by this Unit. Interventional experimental devices, decision-making analysis, and criteria that focus on patient benefit are part of novel programs on pancreatic and biliary tract cancers. Research projects that focus on positive prognostic markers through biobank implemetation are ongoing for gastric and esophageal-gastric junction cancers as well as for GEP-NET. Teaching-training activities attract a large number of specialists to this Unit every year. Keywords: liver cancer, pancreatic cancer, liver metastases, liver transplantation, neuroendocrine tumors (gastrointestinal tract)

2010 RELEVANT NOTES Collaborations Barcelona Clinic Liver Cancer Group, Barcelona, Spain Liver Unit of the Mt. Sinai School of Medicine , New York USA Harvard Broad and Dana-Farber Institute, Boston, USA University of Geneva, Switzerland University of Milan, Gastroenterology and Surgery Nord-Italia Transplant (NITp), Milan

Publications Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: a proof of principle. J Hepatol. 2010; 52:771-5. Partial hepatectomy versus radiofrequency ablation for hepatocellular carcinoma: confirming the trial that will never be, and some comments on the indications for liver resection. Hepatology (Editorial). 2010;51:1116-8. IGF activation in a molecular subclass of HCC and pre-clinical efficacy of IGF1R blockage. J Hepatol. 2010;52:550-9.

V. Mazzaferro: “Organization and management of primary care” Course Doctorate at SDA Bocconi Economic University, Milan

Contributions

V. Mazzaferro:Associate Editor of Journal of Hepatology and part of the Editorial Board of Lancet Oncology, Liver Transplantation

V. Mazzaferro: Good Clinical Practice Guidelines – Ashford and St. Peter’s Hospitals NHS Trust Certificate

V. Mazzaferro: Expert for EASL (European Association for the Study of the Liver): EASL-EORTC Clinical Giudelines of Hepatocellular Carcinoma 2011


SURGERY DEPARTMENT

99

COLORECTAL SURGERY

HEAD Ermanno Leo, MD STAFF MEMBERS

Luigi Battaglia, MD Filiberto Belli, MD Giuliano Bonfanti, MD Gianfrancesco Gallino, MD Elia Poiasina, MD Alberto Vannelli, MD Marco Vitellaro, MD FELLOW

Mario Rampa, MD ADMINISTRATIVE

Roberta Aceto NURSES

Rosalia Aloe, Jose M. M. Alonso, Maria P. Augello, Placida Battaglia, Fabiana Bettoni, Lucia Caracciolo, Rut Cittadin, Angela V. Colamonaco, Nagore N. Lecuona, Vittorio Mauro, Maria F. Palma, Raffaella Rossi, Giovanni Santalucia, Riccardo Vacca TECHNICIANS

Nunzia Di Perna, Santina Domingo, Fabio Lizzano, Maria Petrosino

At present, the Unit has 28 beds and its activity is devoted to the study, treatment, and clinical research of colorectal cancer. The objective of the Colorectal Unit, in Italy and abroad, is to realize and promote surgical studies, in particular colorectal oncology, whose target is the treatment of tumor while respecting the life quality. To fulfill this aim, many novel approaches are used, which include the promotion and organization of courses for surgical teaching, meetings, conferences, workshops, seminars, and debates. The Unit is affiliated with the General Surgery Residency Programs of the Universities of Milan Bicocca and Pavia. Clinical activity involves diagnosis and treatment of colorectal cancer with specific interest in the use and development of sphincter saving procedures for tumors located in the lower rectum. Overall, a median of 400-500 major operations are performed yearly. Preclinical research is conducted in collaboration with the Units of Pathology and Immunotherapy of Human Tumors. The main area of research in 2010 was: evaluation of rational surgical strategies for the treatment of pelvic relapses in rectal cancer patients. In collaboration of the Department of Medical Oncology, we have continued a program aimed at defining a rational surgical and medical approach in these cases. We are also performing clinical studies of active immunotherapy in rectal cancer patients, and in particular, on the possible role of the native fluorescence of blood plasma in the management of colorectal cancer and its feasibility as a new tumor marker. The role of tissue resonance interaction method (TRIMprobe) electromagnetic detector (Galileo Avionica, Turin), which consists of a nonlinear oscillator as rectal cancer screening, is also being assessed. Keywords: rectal cancer, conservative sphincter surgery, colorectal screening

2010 RELEVANT NOTES Collaborations ENETS GEP-NET Center

Publications Diagnosis of rectal cancer by Tissue Resonance Interaction Method. BMC Gastroenterol. 2010;10:45-50. Colorectal cancer detection by means of optical fluoroscopy. A study on 494 subjects. Front Biosci (Elite Ed). 2010;2:694-700.

Contributions Alberto Vannelli, Commission on the regional guidelines in Lombardy: study group for modification of current hospital tariffs in oncology


100

SCIENTIFIC REPORT 2010

BREAST SURGERY

HEAD Roberto Agresti, MD STAFF MEMBERS

Silvia Bohm, MD Alberto Rudy Conti, MD Cristina Ferraris, MD Domenico Galluzzo, MD Massimiliano Gennaro, MD Maria Ilaria Grosso, MD Gabriele Martelli, MD Cristina Pellitteri, MD Domenico Piromalli, MD POSTDOCTORAL FELLOWS

Elisa Giustarini, MD Ilaria Maugeri, MD ADMINISTRATIVE

Angela Allegri NURSES

Irene Alessandrini, Giovanni Cavaliere, Myriam Paola Conti, Stefano Licata, Bruna Nuscis, Maria Carla Puddu, Michele Rossello, Gelsomina Sasso, Francesco Antonio Spagnolo, Liliane Venafra HEALTHCARE ASSISTENTS

Maria Caterina Fadda, Luigi Magnifico, Caterina Pianu

The clinical activity of the Unit includes all the aspects of breast cancer treatment: diagnosis, primary and adjuvant therapy, and follow up. Treatment is performed by multidisciplinary teams involving several other Units and Departments. A randomized clinical trial aiming at the development of integrated therapeutic strategies to reduce surgical morbidity in the treatment of T1N0 breast cancer has been continued. Another randomized clinical trial compared axillary dissection to observation in patients aged >65 years with T1N0 breast cancer. Follow-up is ongoing to assess long-term results. A prospective non-randomized trial comparing axillary clearance with observation in elderly breast cancer patients without axillary palpable nodes was recently published. Moreover, in the same case series we are investigating whether biological markers may predict axillary relapse and breast cancer mortality. A pilot study is in progress, that compares FDG-PET with sentinel lymph node biopsy for staging of regional lymph nodes, followed a previous experience in the use of PET in preoperative evaluation of axillary lymph nodes. Enhanced understanding of the pathogenesis of breast cancer coupled with growing interest in improved esthetic results led to investigate skin-sparing and nipple-sparing mastectomy as a potential modification to conventional mastectomy. In the last two years, we performed over 200 NAC sparing mastectomies. In a joint study with the MRI unit, we are evaluating the ability of MRI to show the extent and location of the tumor in a breast surgical specimen by â&#x20AC;&#x153;ex vivoâ&#x20AC;? MRI. In cooperation with the Medical Genetics Unit, an approach tailored for women at high genetic risk has been developed. During genetic counselling, a genetic risk estimation is performed to allow a personalized program including available preventive options and treatments. Furthermore, patient risk stratification allows classification of patients and definition of different classes of clinical and instrumental surveillance. Keywords: breast cancer, surgical treatment, axillary management

2010 RELEVANT NOTES Publications Axillary dissection versus no axillary dissection in elderly patients with breast cancer and no palpable axillary nodes: results after 15 years of follow up. Ann. Surg. Oncol. 2011;18:125-33. Recurrence and mortality according to estrogen receptor status for breast cancer patients undergoing conservative surgery. Ipsilateral breast tumour recurrence dynamics provides clues for tumour biology within the residual breast. BMC Cancer. 2010;10:656-64.


SURGERY DEPARTMENT

101

MELANOMA AND SARCOMA

HEAD Mario Santinami, MD STAFF MEMBERS

Dario Baratti, MD Marcello Deraco, MD Marco Fiore, MD Alessandro Gronchi, MD Andrea Maurichi, MD Daniele Moglia, MD Roberto Patuzzo, MD Roberta Ruggeri, MD RESEARCH MEMBERS

Chiara Colombo, MD Federica Crippa, MD Elena Tolomio, MD

During 2010, more than 550 melanoma patients underwent major surgery. More than 15,000 patients were seen in the outpatient clinic, and 1,000 were subjected to minor surgery; a Unit database, containing more than 3,000 patients over the last 10 years, has been managed. Our Unit is a referral center for soft tissue sarcomas of the extremities and trunk, as well as retroperitoneal sarcomas, GIST, and axial bone sarcomas. We carried out 316 major operations for new patients and 27 operations for patients presenting with a loco-regional recurrence. We saw 770 new patients in consultation and performed routine follow-up visit for over 3,000 cases. We also chaired the surgical section of the Italian Network on Rare Tumors, performing a weekly second opinion through the network. We run an institutional database containing over 6,000 patients affected by sarcoma treated in the last 30 years. Part of this institutional database has been linked to CONTICABASE, a virtual data base connected with tissue banks shared among the partners of CONTICANET, a European network on rare cancers. We also treated 25 patients for peritoneal neoplasms.

RESIDENTS

Nikolas Peradze Pierpaolo Prestianni Stefano Radaelli

Keywords: melanoma, sarcoma, peritoneal cancer 2010 RELEVANT NOTES

Contributions

Antonella Vescera

Collaborations

DATA MANAGER

Tor Vergata University, Rome

Mario Santinami, Deputy President of SICO (SocietĂ Italiana Chirurgia Oncologica)

Annabella Di Florio

Istituto Clinico Humanitas, IRCCS and European Institute of Oncology, IRCCS, Milan

ADMINISTRATIVE

NURSES

Nicola Abatangelo, Annamaria Biondo, Annarita Carluccio, Mario Castronovo, Alessio Cremonesi, Esther Reinoso Crespo, Nello Curatolo, Floarea Dorca, Giovanna Lomartire (Head Nurse), Loridana Marino, Silvana Mirante, Erika Panigada, Giuseppina Pede, Consolata Romeo, Claudia Maria Sonzogni, Monica Ullio, Elisabetta Velluti, Addolarata Volpe

Manerbio Hospital, Brescia

Mario Santinami, Editorial board and reviewer: Dermatology Research and Practice; European Journal Surgical Oncology; Journal Investigative Dermatology; World Journal Surgical Oncology; Tumori

Institute of Oncology, Ljubljana

Alessandro Gronchi Associate Editor of Sarcoma Journal

Universitatea de Medicina si Farmacie (UMF), Targu Mures, Romania

Alessandro Gronchi, Editor for Sarcoma Section in Annals of Surgical Oncology

Publications Phase III trial comparing adjuvant treatment with pegylated interferon Alfa-2b versus observation: prognostic significance of autoantibodies - EORTC 18991. J Clin Oncol. 2010;28:2460-6.

Participation in the following groups: Sarcoma Task Force, European Society for Medical Oncology (ESMO) Scientific Directorate, Connective Tissue Oncology Society (CTOS)

Pure desmoplastic melanoma: a melanoma with distinctive clinical behavior. Ann Surg. 2010;252:1052-7.

International Committee, Society of Surgical Oncology (SSO)

Aggressive surgery in retroperitoneal soft tissue sarcoma carried out at high-volume centers is safe and is associated with improved local control. Ann Surg Oncol. 2010; 17:1507-14.

Secretary of EORTC Soft Tissue and Bone Sarcoma Group

Extremity soft tissue sarcoma in a series of patients treated at a single institution: local control directly impacts survival. Ann Surg. 2010;251:506-11.

Secretary of SITILO (Italian Society for Locoregional Therapies in Oncology)

A novel tumor-node-metastasis (TNM) staging system of diffuse malignant peritoneal mesothelioma using outcome analysis of a multi-institutional database. Cancer. Epub 2010 Nov 18. Receptor tyrosine kinase and downstream signaling analysis in diffuse malignant peritoneal mesothelioma. Eur J Cancer. 2010;46:2837-48.

Chairman of Italian Sarcoma Group (ISG) Soft Tissue Sarcoma committee

Member of Business Committee of PSOGI (Peritoneal Surface Oncology Group International) ROL guidelines on Melanoma Contribution to drafting the guidelines of bone and soft tissue sarcoma published in Annals of Oncology Participation to the scientific group processing the Scientific Bases for Guidelines Definition on Regional Cancer Therapies (SITILO and Alleanza Contro il Cancro)


102

SCIENTIFIC REPORT 2010

DIAGNOSTIC ENDOSCOPY AND ENDOSCOPIC SURGERY

HEAD Emanuele Meroni, MD STAFF MEMBERS

Giovanni Ballardini, MD Giuseppe M, Calarco, MD Gianfranco Di Felice, MD Massimo Falsitta, MD Andrea Mancini, MD ADMINISTRATIVES

Concetta A. Di Quattro Annamaria Mercuri NURSES

Francesco P. Bottani, Raffaele Calò, Roberto Fiocco, Francesca La Monica, Daniele M. Lo Curcio, Maria Francesca Mannai, Vittorio Mauro (Head Nurse), Raffaele Quagliuolo, Giovanni Sammartino TECHNICIANS

Silvia Cara, Rosanna Loi, Salvatore Morfeo

The activities of multidisciplinary endoscopy Unit consist of both diagnostic and therapeutic procedures of the gastrointestinal, biliopancreatic, respiratory, and urinary tracts. Among conventional diagnostic procedures, special effort is dedicated to the Regional Colorectal Cancer Screening Program. In cooperation with the Hereditary Digestive Tract Tumors Units, patients affected with familial adenomatous polyposis (FAP) or Lynch syndrome are thoroughly studied with top-to-tail examinations including wireless capsule endoscopy for detection of small intestinal lesions. Endoscopic ultrasonography (EUS) is also routinely performed for diagnosis and staging of tumors, equipment for endoscopic radiofrequency ablation (RFA) of Barrett’s esophagus is available for treatment of this precancerous lesion when low-grade or high-grade dysplasia are demonstrated. The special commitment given to innovation in endotherapy has led to treatment of precancerous lesions using mucosectomy, radiofrequency ablation, Argon plasma electrocoagulation, and laser photocoagulation. A fruitful collaboration with the Fondazione IRCCS Istituto Neurologico Carlo Besta is ongoing for treatment of symptoms related to neurological disorders (neurologic dysphagia, Parkinson’s disease). Tracheobronchial, esophageal, duodenal, and colorectal stenting are performed for palliation of advanced cancer. Keywords: diagnostic endoscopy, therapeutic endoscopy, cancer prevention, early cancer diagnosis, advanced cancer palliation

2010 RELEVANT NOTES Collaborations Clinical research in the field of endomicroscopy is ongoing using a prototype of endocytoscope in collaboration with the IRCCS Istituto Nazionale Tumori (IST), Genoa.

Publications Prevalence of nonpolypoid colorectal neoplasia: an Italian multicenter observational study. Endoscopy 2010;42:279-85.

Contributions Emanuele Meroni is on the review board of Gastrointestinal Endoscopy and the editorial board of the World Journal of Gastrointestinal Endoscopy; Guidelines for Regional Oncological Network


SURGERY DEPARTMENT

103

MAXILLO-FACIAL SURGERY

HEAD Giulio Cantù, MD Gabriele Scaramellini, MD (from September 14th) STAFF MEMBERS

Gabriella Bimbi, MD Sarah Colombo, MD Madia Pompilio, MD Stefano Riccio, MD Paolo Formillo, PF ADMINISTRATIVE

Anna Mazza NURSES

Elena Omati, Roberta Albasini, Cinzia Cocca, Elena Cotelessa, Angela Michaela Farcas, Patrizia Galantin, Erminia Nardo, Vincenza Natola, Luca Ostion, Samanta Palmisano, Maria Stefania Selva, Stefania Sperandio, Luigi Tamburrino, G. Nicola Virgilio, Peny Vargas TECHNICIANS

Fabrizio D’amico, Rocio De La Cruz, Virginia Marini, Nicolina Paola

In our Unit, state-of-the-art surgical treatment for patients with head and neck tumors is guaranteed by experts from across disciplines: head and neck surgeons, neurosurgeons, plastic surgeon, and dentists. This team of specialists treats patients with tumors of the skull base, paranasal sinus, oral cavity, pharynx, larynx, thyroid gland, salivary glands, melanomas, non-melanoma skin cancers, sarcomas of the soft tissue and bone, and orbital and ocular adnexal malignancies. Our surgical team works together with medical oncologists and radiation oncologists to optimize functional outcome and provide the highest level of care. In particular, we have extensive experience in management of skull base and paranasal sinus tumors and in complex reconstruction of surgical defects of head and neck, using free microvascular flaps, having the largest series in Italy for both. In 2010, we have introduced some innovations: • the use of customized stereolithographic models in bone reconstruction; this method is used to obtain the most effective cosmetic and functional long-term results • ozone-therapy followed by conservative surgery for the treatment of BRONJ (clinical study phase I-II 01/01/2007 in progress) • intraoperative rehabilitation after resection of the maxilla by using a prefabricated dental obturator • development of techniques for endoscopic sinus surgery. Flexible fiberoptic endoscopes, flexible fiberoptic endoscopes with working channels for videoassisted biopsy, development of rigid endoscopy, ozone-therapy, stereolithographic models were also used. During the year, we also carried on the study about the possible role of polymorphisms in xenobiotic metabolizing enzymes as a determinant for the degree of susceptibility to intestinal type adenocarcinomas (FRAC), and we participated in the development of Regional Guidelines for the management of thyroid tumors. Keywords: head and neck cancer, reconstructive surgery, multidisciplinary approach, skull base, paranasal sinus

2010 RELEVANT NOTES Collaborations The Unit actively cooperates with the Neurosurgery Unit of the Fondazione IRCCS Istituto Neurologico C. Besta in Milan and with the Maxillo-Facial Surgery Unit of the S. Anna Hospital in Como.

Publications Surgery for malignant maxillary tumors involving the middle cranial fossa. Skull Base. 2010;20:55-60. Intestinal type adenocarcinoma of the ethmoid sinus in wood and leather workers: A retrospective study of 153 cases. Head Neck. 2011;33:535-42.


104

SCIENTIFIC REPORT 2010

GYNECOLOGIC ONCOLOGY

HEAD Francesco Raspagliesi, MD STAFF MEMBERS

Antonino Ditto, MD Rosanna Fontanelli, MD Barbara Grijuela, MD Francesco Hanozet, MD Marina Merola, MD Eugenio Solima, MD Gianbattista Spatti, MD Bernardina Stefanon, MD Flavia Zanaboni, MD FELLOW

Massimo Gabbanini, MD Valentina Guadalupi, MD ADMINISTRATIVES

Cinzia Marretta Rosella Zennoni NURSES

Concetta Brugaletta, Lorenzina Greco, Eva Guitti, Marianela P. Maienza, Agnese Manganoni, Marianna Miranda, Rosanna P. Penasa, Maria R. T. Pichardo, Ylenia Ponti, Giuseppa M. Serravillo, Patrizia A. Valente, Viviana Villa, Stefania Labori TECHNICIANS

Michele Iannelli, Simona Tuiu, Rosa Farro, Laura Somma

The Unit deals mainly with primary and secondary tumors of the female genital tract. The activities of staff members are dedicated to clinical practice, research, and teaching (3 Tumor Boards weekly, International meetings; 3 surgical master courses yearly) Gynecologic Oncology is mainly focused on: first entry gynecological oncological evaluation; familial cancer; abnormal pap and 1st and 2nd level colposcopy; HPV multidisciplinary office; 1st and 2nd level US; hysteroscopy; follow-up. All surgical and medical treatments are coordinated on a weekly basis meeting by a multidisciplinary team involving surgeons, medical oncologists, pathologists, and radiotherapists. The research activity of the group concerns clinical studies from basic science to clinical research. In collaboration with the Experimental Oncology Department and Molecular Medicine, we carried out several studies on gene expression, folate receptor levels, and apoptosis in ovarian carcinoma. Studies on the detection of stem cells in normal ovaries and ovarian cancer to preserve the endocrine potential in ovarian cancer patients by selecting new drugs against these cells are ongoing. Clinical research aimed to evaluate the efficacy of chemotherapeutic agents in ovarian cancer was also carried out, and active collaboration in international and national multicenter controlled clinical studies in both medical and surgical protocols are ongoing. To improve the prognosis of early stage cancer, several studies are ongoing on the efficacy and safety of laparoscopic techniques in gynecological oncology. We extended the concept of mini-invasiveness to laparotomy to reduce the complications of radical hysterectomy. Surgical research includes: • Nerve-sparing radical surgery • Debulking surgery • Laparoscopic surgery in diagnosis, staging and treatment of early gynecological tumors • Sentinel node detection in endometrial cancer • Development of fertility-sparing surgery (cervix, ovary) • Surgery in advanced cases and/or recurrences from all origins • Photodynamic treatment of recurrent Paget’s disease of the vulva • Vulvar, vaginal and uterine melanoma surgery • Reconstructive surgery in collaboration with Plastic Surgery Unit We perform about 1,200 procedures per year in ambulatory surgery. 560 major surgical procedures are currently carried out yearly.


SURGERY DEPARTMENT

105

THORACIC SURGERY

HEAD Ugo Pastorino, MD STAFF MEMBERS

Barbara Conti, MD Vincenzo Delledonne, MD Francesco Leo, MD Paolo Scanagatta, MD Luca D. Tavecchio, MD FELLOWS

Elisa Calabrò, MD Leonardo Duranti, MD Simone Furia, MD Emiia Polimeno, MD RESIDENTS

Sara Badiali, MD Stefano Redaelli, MD ADMINISTRATIVES

Elena Bertocchi Tiziana Negri NURSES

Federica Pirovano, Francesco Auletta, Marcella Bernardo, Laura De Porras Payà, Yesica Del Rio Mendez, Maria Della Croce, Margherita Fersurella, Hilda A. Martinez, Daniele Marino, Maria L. Quitadamo, Anna M. Panareo, Antonio Pantano, Antonella Prete, Antonino Proto TECHNICIANS

Nekpen Eguavoen, Beatrice Fais, Antonietta G. Fantilli, Annunziata Rugolo, Pamela K. Soto Fernandez

The clinical activity of the Unit covers all aspects of thoracic oncologic surgery: surgical management of primary and secondary lung cancer, mediastinal, chest wall, pleural and esophageal tumors, and pulmonary metastases. All cases are discussed during multidisciplinary meetings on a weekly basis. Minimally invasive approaches are used to limit the functional consequences of surgery and muscle-sparing approaches are utilized in all cases. In the management of lung cancer, our standards of care reproduce international guidelines in terms of extent of resection, nodal dissection and postoperative care. In case of of extended disease, we have developed original techniques of combined resection and reconstruction of the bronchus and/or pulmonary artery to avoid pneumonectomy, whenever feasible. Three-dimensional chest wall reconstruction is performed by the use of an innovative technique developed at the INT. In the surgical management of malignant pleural mesothelioma, pleuropneumonectomy has been improved by the use of autologous rotated flap of the latissimus dorsi muscle instead of prosthetic material, reducing operating time and risk of infection. The Unit provides excellent standards of care for cancer of the esophagus, with limited morbidity and mortality, also due to continuous collaboration with the Units of Diagnostic and Surgical Endoscopy, Otolaryngology, Gastrointestinal, Hepatopancreatobiliary Surgery and Liver Transplantation. In the field of lung metastasectomy, the Unit has gained extensive experience in systematic salvage surgery thanks to our ongoing collaboration with various Units of the INT, in particular the Pediatric Oncology and the Melanoma and Sarcoma Units. As a result of our committment in thoracic oncology, the perioperative morbidity, mortality and postoperative hospital stay in our Unit are excellent compared to the international standards for thoracic surgery. Keywords: lung cancer, pulmonary metastases, mediastinum

2010 RELEVANT NOTES Collaborations San Raffaele, Humanitas, Milan; San Gerardo, Monza; Istituto di Ricerche Farmacologiche Mario Negri, Milan; Istituto Superiore di Sanità, Regina Elena, Rome; Università degli Studi, Politecnico, Milan; University of Oxford - UK; IARC, Lyon

Publications Anterior diaphragmatic plication in mediastinal surgery: the “reefing the mainsail” technique. Ann Thorac Surg. 2010;90:2065-7. Lung cancer screening. Br J Cancer. 2010;102:1681-6.

Contributions Ugo Pastorino is scientific reviewer: Annals of Oncology, Annals of Thoracic Surgery, British Journal of Cancer, European Journal of Cancer, International Journal of Cancer, Lung Cancer, Respiration, Thorax, Tumori, European Journal of Cardio-Thoracic Surgery; Associate Editor: Journal of the National Cancer Institute.


106

SCIENTIFIC REPORT 2010

PLASTIC AND RECONSTRUCTIVE SURGERY

HEAD Maurizio B. Nava, MD STAFF MEMBERS

Umberto Cortinovis, MD Joseph Ottolenghi, MD Angela E. Pennati, MD Egidio Riggio, MD Andrea Spano, MD Novella Bruno, MD Manuela Forti, MD Valentina Visintini Cividin, MD ADMINISTRATIVES

Luciana Bagnara, Maria A. Ceccarini, Luisa Morandi NURSES

Samantha F. Castelli, Cinzia Gentilini, Giusppe Lâ&#x20AC;&#x2122;Abbate, Marisa Labò, Barbara Malaspina, Giovanna Melia, Serafina Micalizzi, Francesco Nicotera, Caterina Pireddu, Irene Rossi, Maria Saracino (Head), Rosanna Scarpa, Raffaella Tupputi

Reconstructive surgical procedures are related to demolitive breast and head and neck surgery, soft-tissue tumors, chest-wall surgery, and other types of aggressive oncologic surgeries, as well as surgical treatment and repair of skin cancer. Oncoplastic surgery represents a new standard for reconstructive procedures after tumor excision. Plastic procedures related to breast cancer surgery account for the main workload, and fat and implant hybrid breast reconstruction is planned and started concurrently with breast ablation. Fat cell transplantation allows implant-based reconstruction in some cases even after tissue damages by radiotherapy. In patients who are not candidates for hybrid breast implant insertion, reconstruction is carried out with flaps. Diep and free flaps have been used for delayed or immediate breast reconstruction, after ablation of large soft tissue tumors, and in reconstruction after head and neck demolitions. Cohesive gel breast implants together with fat cell transplantation and microsurgery rapresent the highest standard in reconstructive surgery. Fat tissue transplantation using fat cells together with adipose-derived fat cells and platelet-rich plasma allow us to regenerate damaged tissue. Oncoplastic surgery is actually the main activity of the unit and the core of its clinical and experimental investigations. Keywords: plastic, oncoplastic, surgery, microsurgery, fat cell transplanatation

TECHNICIANS

Raffaella Cagnazzo, Nadia Casati, Beatrice Fais, Provvidenza Peci, Esther N. Ybazeta Ramos

2010 RELEVANT NOTES Collaborations We continue collaboration with the Department of Experimental Oncology and Molecular Medicine to evaluate the stem cell activity of injected fat cells. We extended our collaboration in clinical investigations with Israel and Argentina.

Publications Simultaneous augmentation and periareolar mastopexy: selecting the correct implant. Aesthetic Plast Surg. 2010;34:33-9.

Contributions In 2010, enrollment for clinical trials is continuing and new clinical studies and experimental investigations have been started. The collaboration with the Politecnico University is still active and new studies have been set including that with the Unit of Cell Factory of the Policlinico.


SURGERY DEPARTMENT

107

OTOLARYNGOLOGY SURGERY

HEAD Gabriele Scaramellini, MD STAFF MEMBERS

Roberto Bianchi, MD Letizia M. C. Ferraro, MD Marco Guzzo, MD Walter Fontanella, MD Tullio M. Ibba, MD, PhD Franco Mattavelli, MD Natalia R. E. Pizzi, MD ADMINISTRATIVE

Sabrina Zazzera NURSES

Giovanna V. Bello, Petronilla D’agostino, Giorgio Fumi, Giorgio Inverni, Vincenzo Mandurino, Laura Ongari, Daniele Pezzera, Francesca Pisano, Federica Prudenzano, Raffaella Repetto, Maura Rimoldi, Serena Togni, Vincenzo Spanò TECHNICIANS

Dalila Cajahuarinea, Pablita Endaya, Erick Papa, Immacolata Pedico

The Unit is among the most dynamic and busiest in Italy, with both local and national referral patterns. Yearly, more than 650 operations are performed. The Unit is highly specialized in the treatment of benign and malignant tumors of the head and neck area, including thyroid and salivary gland tumors, focusing considerably on quality-of-life issues such as retaining the ability to speak and swallow, maintaining a normal appearance, and optimizing the functional outcome of radiation and surgical treatments. We have developed a multidisciplinary team including specialists in surgery, radiation oncology, medical oncology, endocrinology, radiology, pathology, plastic and reconstructive surgery, dental and maxillofacial prosthetics, nutrition, and pain management. Weekly staff meetings ensure that each patient receives the state-of-the-art treatment, as well as rehabilitation and prevention services tailored to his or her needs. Preclinical research is conducted in collaborations with medical oncologists, pathologists, and molecular biologists on prognostic features and molecular targets of head and neck cancer. In collaboration with qualified experts of other Italian hospitals, we are developing guidelines for the management of head and neck tumors. Our outpatient oral precancerous lesions unit has been increasing its activity in the diagnosis and conservative treatment of these lesions, and our attention is focusing on HPV-related lesions and the cancerogenetic role of this virus. Flexible and rigid fiberoptic endoscopes, flexible fiberoptic endoscopes with working channel for video-assisted biopsy, laser-assisted surgery of larynx and oral cavity were also used. Keywords: head and neck cancer, reconstructive surgery, organ preservation, multidisciplinary approach, quality of life, precancerous lesions, HPV-related lesions

2010 RELEVANT NOTES Collaborations The Unit actively cooperates with the Otorhinolaryngologic School of Specialization of the State University of Milan, hosting residents for hands-on training, and organizes several lessons and courses. In cooperation with “Miguel Hernandez de Elche” State University of Alicante (Spain), the Unit organizes a theoretical and hands-on head and neck dissection course for young surgeons

Publications Open organ preservation surgery of the larynx: Experience of Istituto Nazionale Tumori of Milan. Head Neck. 2011;33:673-8. Salivary gland carcinomas in children and adolescents: A population-based study, with comparison to adult cases. Head Neck. 2010 Nov 10. [Epub ahead of print]


108

SCIENTIFIC REPORT 2010

UROLOGIC SURGERY

HEAD Roberto Salvioni, MD STAFF MEMBERS

Davide Biasoni, MD Mario A. Catanzaro, MD Angelo Milani, MD Nicola Nicolai, MD (Head, Testicular Cancer Surgery Unit)

Luigi Piva, MD (Head, Pediatric Surgery Unit)

Silvia Stagni, MD Tullio Torelli, MD RESEARCH MEMBER Andrea Necchi, MD (Department of Medicine) NURSES

Graziella Russo (Coordinator), Antonino Amodei, Maria L. Cennamo, Anna M. Cercaci, Zino Ferro, Maria R. Leo, Francesca Marelli, Giovanni Mazzilli, Lucia Mesiano, Arturo Monetta, Filippo Monno, Maria Riflesso, Veronica P. Rojas, Malgorzata Slomiany ADMINISTRATIVE

Maria G. Bodini HEALTHCARE ASSISTANTS

Antonio Bonelli, Elena Cristiani, Maria Rosa Forte, Isabella Vurchio

In 2010, new trials have been initiated for urothelial cancers and germ-cell cancers. Urothelial Cancer An Institutional Phase II trial have been started with the multikinase inhibitor pazopanib for pre-treated metastatic patients. Very promising interim results have been presented (Necchi A, LBA23, ESMO 2010). Furthermore, an Institutional Phase II translational trial of chemotherapy (cisplatin-gemcitabine) combined with a targeted therapy (sorafenib) in neoadjuvant setting began enrolling patients in Q3 2010. Also, we will participate in a multicenter, randomized Phase II trial of first-line vinflunine-carboplatin compared with vinflunine-gemcitabine for patients unfit for platinum-based therapies. We desinged a new, comprehensive web-based database for bladder cancer at INT. Testicular Cancer We started a Phase III, non-randomized trial comparing open and laparoscopic retroperitoneal lymphadenectomy in clinical stage I non-seminoma and a 2nd-line Phase II trial of tandem high-dose chemotherapy in relapsed germ cell tumors. We contributed to the final analysis of an international study on prognostic factors in relapsed or refractory male patients with germ cell tumors. We also designed a new comprehensive web-based database for this disease. Penile Cancer We designed a Phase II EORTC trial with the combination of TPF chemotherapy with anti-EGFR targeted therapy as neoadjuvant treatment for locally advanced squamous cell penile carcinoma. Renal Cancer We broadened our prospective case-series of surgery combined with targeted therapy for locally advanced disease and with cryotherapy for small renal tumors. We extended the indications for conservative laparoscopic surgery. Supportive care We started a multicenter Phase I/II trial investigating a new orally available thrombopoetin-receptor agonist (eltrombopag) for patients candidates to chemotherapy. Rare Genito-Urinary Tumors We pursued consultations within the Italian Rare Tumors Network (RTR). Prostate Cancer See Prostate Program page 13. Technical approaches other than conventional surgery are: Laparoscopic surgical devices (dedicated high-technology operating room); Laser-therapy outpatient facilities for early-stage penile cancer; Cryotherapy for early renal cell neoplasms (in collaboration with the Interventional Radiology Unit). Keywords: multidisciplinary oncology, genito-urinary oncology, rare tumors

2010 RELEVANT NOTES Collaborations European Organisation for the Research and Treatment of Cancer (EORTC)

Publications Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol. 2010;28:4906-11 Retroperitoneal lymph node dissection with no adjuvant chemotherapy in clinical stage i nonseminomatous germ cell tumours: long-term outcome and analysis of risk factors of recurrence. Eur Urol. 2010;58:912-8

Contributions ROL (Rete Oncologica Lombarda). Guidelines on adult male germ-cell tumors


SURGERY DEPARTMENT

109

PEDIATRIC SURGERY

HEAD

Luigi Piva, MD

The Unit collaborates with pediatric oncologists and provides a high standard of treatment for the most frequent solid tumors observed in children and adolescents. The role of surgery is established according to ongoing European treatment protocols. During the 2010 the following surgical interventions were carried out. Wilmsâ&#x20AC;&#x2122; tumor. 8 surgeries on patients enrolled in the TW 2003 AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) study were performed. In the management of 1 bilateral tumor, aggressive surgical resection was avoided to preserve long-term renal function. Neuroblastoma. 7 surgeries. Germ cell tumors and gynecological tumors. 2 and 4 surgical procedures were performed, respectively; 3 other retroperitoneal lymphoadenectomies were carried out. In addition, 4 reconstructive surgeries were performed. Soft tissue sarcomas and rare tumors. Surgery on soft tissue sarcomas was performed in collaboration with the Melanoma and Sarcoma Unit: 18 soft tissue tumors and 8 cutaneous lesions. Cranio-maxillofacial tumors. In this type of tumor, patient eligibility for surgery is discussed in cooperation with the ORL Division: 7 thyroidectomies and 9 facial surgeries. Lung metastases. The eligibility of patients is discussed in collaboration with the Thoracic Surgery Unit: 12 metastasectomies. In collaboration with the Colorectal Unit, 5 colectomies through laparoscopy were perfomed. Liver Surgery was also performed with the devoted Unit with one partial resection and two ortothopic liver transplantations. Finally, 14 surgical biopsies were necessary for 3 sarcoma, 9 lymphoadenopathies, and 2 hepatic lesions. Keywords: renal tumors, pediatric sarcoma, multidisciplinary teams

2010 RELEVANT NOTES Publications Renal cell carcinoma in children and adolescents. Expert Rev Anticancer Ther. 2010;10:1967-78.

Contributions START: Wilmsâ&#x20AC;&#x2122; tumor

Collaborations SIOP and AIEOP pediatric renal tumor groups


110

SCIENTIFIC REPORT 2010

LASER THERAPY

HEAD Anna Colombetti, MD RESEARCH MEMBER

Roberto M. Grillo, MD ADMINISTRATIVE

M. Rosaria Aceto NURSE

Emilia Dâ&#x20AC;&#x2122;Arrigo HEALTHCARE ASSISTANT

Domenica Loprete

The Unit is dedicated to diseases where laser therapy is the first or only treatment choice and the Unit features high quality instrumentation: 4 lasers for a total of 20 wavelengths. This allows both conservative and ablative therapies. Selective photothermolysis laser treatment is performed for keloids, pigmented and vascular lesions, and the laser ablation technique is used for mucosal and skin cancers lesions requiring histological evaluation. Treated lesions can be conveniently classified into 5 groups: Vascular lesions: flat-type congenital capillary angiodysplasia, angiomas, and venouslymphatic angiodysplasia Tumor lesions: melanoma in-transit metastases, cutaneous and mucosal localizations of Kaposiâ&#x20AC;&#x2122;s sarcoma, skin carcinomas, precancerous lesions such as actinic keratosis Nevi: giant melanocytic nevi Traumatic and post-burn hypertrophic scars and keloids Cutaneous localizations originating from complex syndromes, such as adenomas in tuberous sclerosis, angiodysplasias related to Sturge-Weber syndrome, neurofibromas, and cafe-au-lait spots in neurofibromatosis (with the INT serving as national referral center for this disease). Compared with previous years, an increasing rate of tumoral and vascular diseases and complex syndromes was observed. Laser procedures were performed in collaboration with the Melanoma and Sarcoma Unit for the treatment of melanoma in-transit metastases, and in collaboration with the Radiology Unit congenital and acquired vascular lesions are diagnosed and followed. The general clinical management of patients affected by neurofibromatosis is ensured by the Medical Genetic Unit of the Fondazione IRCCS Policlinico of Milan. In collaboration with the Department of Anesthesiology, 88 pediatric patients affected by giant nevi, post-burn scars, hemangiomas and congenital vascular pathologies were treated with laser procedures under general anesthesia. During 2010, 2,800 patients were treated with laser therapy; 1,900 of these procedures were in an ambulatory setting. Keywords: laser therapy, Q-Switch laser, CO2 laser, skin cancer, giant nevi, angiodysplasia, keloid


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MEDICAL ONCOLOGY DEPARTMENT

MEDICAL ONCOLOGY DEPARTMENT

DIRECTOR OF DEPARTMENT Paolo Corradini Professor of Hematology University of Milan +39 02 2390 2950 paolo.corradini@istitutotumori.mi.it

UNITS HEMATOLOGY AND ALLOGENEIC BONE MARROW TRANSPLANTATION (ETMO) Paolo Corradini MEDICAL ONCOLOGY 1 Luca Gianni MEDICAL ONCOLOGY 2 Emilio Bajetta (until 9/2010) Roberto Buzzoni (from 10/2010) MEDICAL ONCOLOGY 3 A. Massimo Gianni ADULT SARCOMA MEDICAL TREATMENT Paolo G. Casali HEAD AND NECK CANCER MEDICAL ONCOLOGY Lisa Licitra PEDIATRIC ONCOLOGY Maura Massimino MEDICAL DAY HOSPITAL Maria C. Brambilla (until 9/2010) Roberto Buzzoni (from 10/2010)

The Department consists of five 5 clinical divisions (81 beds), one centralized day hospital (28 beds), 22 outpatient rooms, and a laboratory area for clinical cell manipulation, flow cytometry, clinical pharmacology, and molecular biology. Routine clinical activity is focused on the treatment of adult and pediatric patients with solid tumors and hematological malignancies. Several clinical programs are active, which range from conventional chemotherapy to Phase I studies to the transplantation of hematopoietic cells. The Department is organized in Units which are involved in different aspects of cancer research and treatment. • Medical Oncology 1: breast cancer treatment and development of new drugs • Medical Oncology 2: gastrointestinal, lung, renal, and prostate cancer, melanoma, and neuroendocrine tumors • Medical Oncology 3: preclinical and clinical activities mainly in the field of non-Hodgkin and Hodgkin lymphomas, multiple myeloma, and selected patients with high-risk germ cell testicular tumors • Head & Neck Cancer Unit • Adult Sarcoma Medical Treatment Unit • Pediatric Oncology: pediatric patients with solid cancers • Hematology and Allogeneic Bone Marrow Transplantation: treatment of hematological malignancies and allogeneic transplantation • The Medical Day Hospital treats adult patients referred by the clinical Units of the Department.

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SCIENTIFIC REPORT 2010

HEMATOLOGY AND ALLOGENEIC BONE MARROW TRANSPLANTATION (ETMO) HEAD Paolo Corradini, MD STAFF MEMBERS

Cristiana Carniti, PhD Anna Dodero, MD Lucia Farina, MD Jacopo Mariotti, MD Raffaella Milani, MD Vittorio Montefusco, MD FELLOWS

Serena Dalto, MD Mara Morelli, MD Cecilia Olivares, MD Luisa Roncari, MD Barbara Scimeca, MD PHD STUDENTS

Anisa Bermema, Biol Sci D, Francesco Spina, MD Antonio Vendramin, Biol Sci D Liana Bevilacqua, data manager Elena Maggioni, data manager ADMINISTRATIVE

Marialuisa Longhi NURSES

Giorgia Gobbi, Rosa Abate, Sonia Citro, Letteria Consolo, Riccardo De Stefano, David Guiote Pertierra, Donatella Luongo, Simona Mazzella, Elisabetta Martinelli, Francesco Murana, Rita Russo, Leonardo Orsini, Rita Sciancalepore, Serafina Tomasicchio, Giuseppe Torregrossa, Anna Vernone

The ETMO Unit coordinates and participates in several clinical trials investigating new combinations of drugs and monoclonal antibodies for the treatment of lymphoid and myeloid malignancies with the aim of enhancing anti-tumor activity and reducing the toxicity. The Unit has focused on implementing a program to determine the therapeutic benefit of bendamustine combined with ofatumumab in patients with relapsed or refractory B-cell chronic lymphocytic leukemia. In addition, an intensified program including bendamustine, high-dose therapy and autograft has just been initiated in patients affected by relapsed or refractory non-Hodgkin lymphoma. A Phase I/II prospective multicenter trial is ongoing to evaluate the combination of pomalidomide with cyclophosphamide and prednisone in patients with multiple myeloma (MM) that has relapsed and/or refractory to lenalidomide. The Unit has designed and will coordinate a Phase III trial for MM patients at first relapse aiming at comparing the activity of a regimen including bortezomib or lenalinomide to cyclophosphamide and dexamethasone. This trial includes also biological evaluation of biomarkers based on FISH, flow cytometry, and molecular monitoring that might be useful to predict long term response in the relapse setting. We are also exploring the possibility that the quantitation of MM progenitor cells may be used as a surrogate marker for clinical response to a given drug combination. Circulating microRNAs are currently being evaluated as possible biomarkers of disease and response to therapy in patients with MM. Other research projects include: i) the phenotypic, functional, and molecular characterization of post-transplant T-cell and B-cell recovery to elucidate the kinetics of the immune recovery after stem cell transplantation; ii) prospective analysis of the plasma miRNA profile of allografted patients to identify markers predictive of acute GVHD onset. Keywords: b-cell chronic lymphocytic leukemia, multiple myeloma, graft versus host disease

HEALTHCARE ASSISTANTS

Nunzio Bovello, Carmelo Fede, Evelina Palella

2010 RELEVANT NOTES Publications Allogeneic transplantation improves the overall and progressionfree survival of Hodgkinâ&#x20AC;&#x2122;s lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood. 2010;115:3671-7. Pretransplantation [18-F] fluorodeoxyglucose positron emission tomography scan predicts outcome in patients with relapsed Hodgkin lymphoma or aggressive non-Hodgkin lymphoma undergoing reduced-intensity conditioning followed by allogeneic stem cell transplantation. Cancer 2010;116:5001-11.


MEDICAL ONCOLOGY DEPARTMENT

115

MEDICAL ONCOLOGY 1

HEAD Luca Gianni, MD STAFF MEMBERS

Giulia Bianchi, MD Giuseppe Capri, MD Sara Cresta, MD Gabriella Mariani, MD Angela Moliterni, MD Antonella Perotti, MD Milvia Zambetti, MD CONSULTANT

Cristiana Sessa, MD RESEARCH MEMBERS

Giampaolo Bianchini, MD Gianluca Del Conte, MD Angelica Fasolo, MD Silvia Damian, MD Elena De Benedictis, MD Paola Mariani, MD Alberta Locatelli, Biol Sci D FELLOWS

Maria Chiara Dazzani, MD Silvia Grecchi, MD Maria Chiara Parati, MD Lorenzo Sica, MD Anna Tessari, MD

This Unit is dedicated to planning and carrying out medical and/or multidisciplinary clinical trials in breast cancer, and is also responsible for a strategic project (Montabone Project) in clinical trials involving all types of solid tumors (Phase I and early Phase II studies). The activity of Medical Oncology 1 (MO1) is organized in small groups of staff members and fellows-intraining who are responsible for the coordinated conduction of clinical assistance and research. Each group provides care to a pre-determined number of patients and is in charge of specific research programs with coordinated access to all facilities. The Unit leads an outpatient daily clinic in which all new patients referred to the INT, who have a confirmed diagnosis of invasive breast cancer, are seen by a multidisciplinary team (medical oncologists, surgeons, pathologists, and radiotherapists when needed) that provides prompt staging and planning of treatment for new cases of breast cancer, allows uniform information and communication to patients, and streamlines the application of specific procedures, tailoring intervention to individual patient needs. Available facilities in MO1 include 11 in-hospital beds, day-hospital areas, out-patient rooms, and a research laboratory for pharmacokinetic and pharmacodynamic evaluation of new treatments. The core of the clinical activity is conducted as outpatient care in 6 daily clinics (one exclusively dedicated to Phase I studies). In 2010, there were about 500 admissions for in-hospital beds, of which more than 150 for patients enrolled in clinical trials. The Unit carried out around 30,000 clinical visits (100 per day), 1,200 consultations to patients at their first access, including cases of second and further opinion, and 1,200 multidisciplinary consultations to patients surgically treated in the Institute for breast cancer Keywords: breast cancer, targeted therapies, new drugs (Phase I and II studies)

RESIDENT

Daniele Raggi, MD ADMINISTRATIVE

Gaia Missaglia LABORATORY TECHNICIAN

Lucia Viganò, Biol Sci D RESEARCH NURSES

Giovanni Brambilla, Mauro Desogus Technicians, Nurses and Healthcare Assistants are shared with the Medical Oncology Unit 2

2010 RELEVANT NOTES Collaborations MO1 is leading the clinical and scientific coordination of the Breast Cancer Working Group of the Michelangelo Foundation, has a long-standing collaboration with the Southern Europe New Drugs Organization, and coordinates Italian and European collaborative groups focused on Phase I-II trials in operable breast cancer.

Publications Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377-84. Open-Label, Phase II, Multicenter, Randomized Study of the Efficacy and Safety of Two Dose Levels of Pertuzumab, a Human Epidermal Growth Factor Receptor 2 Dimerization Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2010;28:1131-7.

Contributions Luca Gianni is a member of the Editorial Boards of: Clinical Cancer Research, Clinical Breast Cancer; European Journal of Cancer; Nature Practice Clinical Oncology (currently renamed Nature Reviews Clinical Oncology). He is also Consulting Editor of the Journal of Clinical Investigation, and is a member of the Scientific and Ethical Committee of the Fondazione Piemontese per la Ricerca sul Cancro (Istituto di Candiolo) and the Breast Cancer Scientific Program Committee of the American Society of Clinical Oncology (ASCO).


116

SCIENTIFIC REPORT 2010

MEDICAL ONCOLOGY 2

HEAD Emilio Bajetta, MD until 9/2010 Roberto Buzzoni, MD from 10/2010 STAFF MEMBERS

Luigi Celio, MD Michele Del Vecchio, MD Maria Di Bartolomeo, MD Giuseppe Procopio, MD Nicoletta Zilembo, MD RESEARCH MEMBER

Antonia A. Martinetti, Biol Sci D Marco Platania, MD POSTDOCTORAL FELLOWS

Lorenza A. Di Guardo, MD Katia F. Dotti, MD Lucia E. Franceschelli, MD Sara Pusceddu, MD Elena Verzoni, MD FELLOW

Milena Vitali, MD RESIDENTS

Francesco Agustoni, MD Pamela Biondani, MD Valentina Colonna, MD Francesco Gelsomino, MD Filippo Pietrantonio, MD Isabella Testa, MD

The goals of Medical Oncology 2 (MO2) are to promote cancer research and, in particular, the development of new avenues for early detection of malignant processes and novel therapeutic approaches. The research programs at MO2 are at the forefront of cancer research in the development of treatment schedules, and most of the ongoing programs utilize biological agents such as inhibitors of the EGFR, VEGFR, Raf kinase, and mTOR signaling pathways. Furthermore, the Unit is part of the â&#x20AC;&#x153;Centro di Riferimento per lo Studio e la Cura dei Carcinoidi e dei Tumori Neuroendocrini (Ce.Ri.Ca.)â&#x20AC;? which applies a multidisciplinary approach to the treatment of rare neuroendocrine tumors. All new patients receive tailored treatment recommendations, whether just visiting for a consultation or considering transfer of care. Pathology slides and imaging studies are carefully reviewed as part of initial evaluation. Appointments can generally be scheduled within one week, or sooner, if clinically indicated. We offer our patients the opportunity to participate in clinical research studies sponsored by our institution and pharmaceutical industry, including many studies with novel targeted biological agents, as well as new chemotherapy regimens. Study selections are tailored for the individual patient, taking into consideration many factors such as the type of cancer, previous treatment history, and general health conditions. In 2010, the clinical hospitalization activity (the ward has 14 beds for inpatients) had about 650 admissions; the outpatient activity (four consulting rooms, one of which dedicated to consultations and first-admittance visits) provided 33,185 visits. Keywords: chemotharapy, targeted therapy, multidisciplinary approach

ADMINISTRATIVES

Barbara Formisano, Giuseppa Iannaci Technicians, Nurses and Healthcare Assistants are shared with the Medical Oncology Unit 1

2010 RELEVANT NOTES Publications Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28:2144-50. Bevacizumab plus fotemustine as first-line treatment in metastatic melanoma patients: clinical activity and modulation of angiogenesis and lymphangiogenesis factors. Clin Cancer Res. 2010;16:5862-72.

Contributions The Unit, together with other important members of the multidisciplinary team on neuroendocrine tumors, was asked by the ROL (Rete Oncologica Lombarda) to update national guidelines for neuroendocrine tumors.


MEDICAL ONCOLOGY DEPARTMENT

117

MEDICAL ONCOLOGY 3

HEAD Massimo A. Gianni, MD STAFF MEMBERS

Carmelo Carlo-Stella, MD Liliana F. Devizzi, MD Massimo A. Di Nicola, MD Anna Guidetti, MD Michele Magni, MD Paola Matteucci, MD Simonetta Viviani, MD RESEARCH MEMBERS

Alessandra Canavè, PhD, Arianna Giacomini, PhD Silvia Locatelli, PhD Roberta Zappasodi, PhD ADMINISTRATIVE

Anabela Di Giovanni NURSES

Lucia Saracino (head nurse) Maria G. Abbruzzi, Gaetano Bellotti, Stefania Bevacqua, Matteo Biondelli, Rita Boffa, Michele Capobianco, Chiara Paternoster, Salvatore Capuano, Dario Longo, Fabio Pagliaro, Santina Marafioti, Immacolata Navarra, Giuseppina Tomassini, Daniela Trentin HEALTHCARE ASSISTANTS

Loredana Costa, Antonella Di Perna, Agnese Lasala, Antonietta M. Maglione, Mauro L. Pedretti TECHNICIANS

The Unit carries out both preclinical and clinical translational research in different areas, including hematopoietic stem cells, immunotherapy, cell and gene therapy, high-dose sequential chemotherapy (HDS), autologous stem cell transplantation (ASCT), and targeted therapies. The facilities available at Medical Oncology 3 (MO3) include a 10 bed in-patient ward, a day hospital facility, three consulting rooms for outpatients, and a cell processing laboratory. In 2010, 100 patients were treated as in-patients, with a total of about 600 admissions; 35 patients received ASCT. A total of 1,500 treatments were administered on an outpatient basis. An average of 300 new outpatients requested clinical visits. The activity of the cell processing laboratory consisted in 1,100 CD34+ cell monitoring assays and 220 stem cell cryopreservations. Several randomized Phase III clinical studies comparing standard-dose and high-dose chemotherapy were conducted in aggressive non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia. A randomized Phase III trial in advanced stage Hodgkin’s lymphoma (HL) patients receiving ABVD or BEACOPP as first-line chemotherapy has been concluded and the data is currently being analyzed. A Phase III study comparing rituximab-supplemented ABVD (R-ABVD) and ABVD followed by involved-field radiotherapy (ABVD-RT) has been started in early-stage HL patients. In addition, a randomized, double-blind, placebo-controlled Phase III study of SGN-35 (brentuximab vedotin) and best supportive care (BSC) versus placebo and BSC in the treatment of high risk HL patients following high-dose chemotherapy and autologous stem cell transplant has been initiated. A Phase II trial evaluating the DOT regimen (ofatumumab, bendamustine, dexamethasone) has been started in elderly patients with mantle cell lymphoma at diagnosis. Several Phase II trials investigating the efficacy and safety of epigenetic (histone deacetylase inhibitor ITF2357 in combination with meclorethamine) and targeted therapies (sorafenib, perifosine) in relapsed/refractor.

Paolo D. Longoni, Marco Milanesi

Keywords: lymphoproliferative disease, stem cell transplantation, immunotherapy

2010 RELEVANT NOTES Collaborations Istituto Superiore di Sanità, Rome

Publications Human CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature. Blood. 2010;115:2231-40. Improved clinical outcome in indolent B-cell lymphoma patients vaccinated with autologous tumor cells experiencing immunogenic death. Cancer Res. 2010;70:9062-72.


118

SCIENTIFIC REPORT 2010

ADULT SARCOMA MEDICAL TREATMENT

HEAD Paolo G. Casali, MD STAFF MEMBERS

Rossella Bertulli, MD Paola Coco, MD Elena Fumagalli, MD Elena Palassini, MD Roberta Sanfilippo, MD Silvia Stacchiotti, MD RESIDENTS

Elisa Puma, MD Mauro Rossitto, MD Camilla Cassani, PhD - pt data manager Stefania Cimbari, PhD - pt data administrative Anabela Di Giovanni, PhD - pt data administrative Paola Esposti - pt administrative Cinzia Molendini, PhD - pt data manager

The Unit is devoted to the medical treatment of sarcomas in adults and works within the institutional Multidisciplinary Sarcoma Group, providing organizational support, in addition to serving as the medical oncology facility to the group. This activity is carried out within a special clinical-translational institutional project on sarcomas. In 2010, the Unit had more than 450 in-patient admissions and over 5,000 outpatient visits, with more than 1,000 new sarcoma patients seen. About 550 new sarcoma patients were clinically shared with other Italian centers mainly through the Italian Network on Rare Cancers (RTR). RTR, coordinated by the Unit, has performed retrospective analysis on rare tumors in Italy. The interest in distant clinical collaboration led the Unit to coordinate a workpackage in the ROL3 Project (see Scientific Directorate, page 57), aimed at the creation of a regional virtual center on mesenchymal neoplasms in collaboration with RTR. Research activities include worldwide collaborations and prospective trials with 72 patients enrolled in 2010. Clinical studies are active on imatinib-sunitinib resistant GIST (regorafenib) and imatinib resistantchordoma (imatinib + everolimus/lapatinib). The antitumor activity of sunitinib in alveolar soft-part sarcomas and clear cell sarcoma, and the role of sunitinib and figitumumab in solitary fibrous tumor treatment have been documented. Retrospective analyses on the role of imatinib in fibrosarcoma-dermatofibrosarcoma, dacarbazine in uterine leyomiosarcoma, and trabectedine in myxoid liposarcoma were conducted. In addition a randomized trial on neoadjuvant chemotherapy in localized STS was reported at ASCO in 2010. Lastly, a trial on the activity of histotype-tailored neoadjuvant chemotherapy is ongoing. Keywords: adult sarcoma, italian network on rare tumors, GIST

2010 RELEVANT NOTES Collaborations Paolo G. Casali is: Project Responsible, Italian Network on Rare Tumors Secretary, Italian Sarcoma Group Full member, EORTC Soft Tissue and Bone Sarcoma Group Expert of the Italian Ministry of Health for the Continuous Medical Education Programme

Publications Trabectedin therapy for sarcomas. Curr Opin Oncol. 2010;22:342-6. Sunitinib malate and figitumumab in solitary fibrous tumor: patterns and molecular bases of tumor response. Mol Cancer Ther. 2010;9:1286-97.

Contributions Paolo G. Casali is: -Member of the Board of Directors and Executive Committee, serving as Treasurer, of the European Society for Medical Oncology (ESMO) Member of the Cancer Education Committee (Sarcoma/Bone and Soft Tissue Cancers Track Team Leader for ASCO 2009) of the American Society of Clinical Oncology (ASCO) Editor, START - State-of-the-Art Oncology in Europe Member of the Editorial Board of Cancer Treatment Reviews Faculty coordinator for sarcoma of the European Society for Medical Oncology (ESMO) The Unit has been involved in driving the update of the ESMO Clinical Guidelines on STS and GIST and the Clinical Guidelines on Sarcomas and Rare Tumors within the Regional Cancer Network


MEDICAL ONCOLOGY DEPARTMENT

119

HEAD AND NECK CANCER MEDICAL ONCOLOGY

HEAD Lisa Licitra, MD STAFF MEMBERS

Cristiana Bergamini, MD Paolo Bossi, MD Laura Locati, MD Aurora Mirabile, MD RESIDENTS

Roberta Granata, MD Carlo Resteghini, MD Data managers and administative staff are shared with the Adult Sarcoma Medical Treatment Unit

The Unit performed the following clinical activities in 2010: 454 in-patient admissions, 72 day hospital admissions and 4,243 outpatient visits. In 2010, the following clinical trials were conducted: four studies on squamous head and neck cancer were opened with 20 patients enrolled; 3 trials on thyroid cancer were active and 22 patients were enrolled, treated, and followed; two studies were dedicated to supportive care with 18 patients enrolled; one study was dedicated to salivary gland tumors with 12 patients included. The Unit was also involved in the establishment of the oncological network of Lombardy (ROL) for head and neck cancers. Keywords: head and neck cancer, medical oncology, clinical research

2010 RELEVANT NOTES Collaborations Lisa Licitra is a member of the board of of the EORTC and chairelect of the Head & Neck EORTC group The Unit coordinates the START project.

Publications Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann Oncol. 2011;22:1078-87. Squamous cell carcinoma of the head and neck: EHNS-ESMOESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v184-6.

Contributions Lisa Licitra is: Associate Editor, Annals of Oncology Chair Head and Neck faculty for ESMO The Unit is responsible for the production and updating of guidelines for head and neck cancer.


120

SCIENTIFIC REPORT 2010

PEDIATRIC ONCOLOGY

HEAD Maura Massimino, MD STAFF MEMBERS

Michela Casanova, MD Graziella S. Cefalo, MD Andrea Ferrari, MD Roberto Luksch, MD Daniela Polastri, MD Filippo Spreafico, MD Monica Terenziani, MD RESEARCH MEMBERS

Veronica Biassoni, MD Serena Catania, MD Cristina Meazza, MD Marta Podda, MD Elisabetta Schiavello, MD Carlo A. Clerici, MD psychologist Barbara Giacon, psychologist Fabio Simonetti, MD RESIDENT

Francesca Favini, MD Patrizia Giannatempo, MD ADMINISTRATIVES

Paola Gorgoglione, Daniela Migliorini, Gabriella Vighi Luna Boschetti, data manager Chiara Secco, data manager

The Unit is involved in the following clinical-research projects in pediatric cancers. Brain tumors: national coordination of trials in localized medulloblastoma; coordination for the second national study on ependymoma with a total of 112 patients; a pilot study with concomitant radiotherapy, anti-EGFR nimotuzumab and vinorelbine has enrolled 12 patients with brain stem glioma and is demonstrating a statistically significant difference compared to previous results in EFS. Neuroblastoma: national coordination of the pan-European protocol for high-risk neuroblastoma with 310 Italian patients enrolled to date. Wilms’ tumor: chair of the AIEOP WT Working Group and coordination ofnational clinical and biological studies; chair of the relapse program in SIOP. Soft-tissue sarcomas: enrollment for the EpSSG trials is ongoing; 1556 patients have been registered from 14 countries, and enrollment is highest from our center (156 patients); coordination of the EpSSG NRSTS 2005 protocol. Bone tumors: coordination of a new protocol for high risk Ewing’s sarcoma. Germ-cell malignancies: national coordination for this trial. Rare childhood tumors: coordination of a national cooperative project for uncommon pediatric cancers (600 patients have been enrolled with one-third from our center). New drugs: the center is one of 34 members of the ITCC Consortium with specific expertise in early drug development/clinical trials. Late effects: the Unit has been admitted to PanCare, a European network to ensure that every European survivor of childhood and adolescent cancer receives optimal long-term care. In 2010, 265 newly diagnosed patients have been admitted. Keywords: international trials, new drugs, adolescents, multidisciplinary care

TECHNICIANS

Elena Barzanò, Giovanni Malatacca, Giovanna Casiraghi, social worker, Michela Rapetti, social worker, TEACHERS

Stefania Benedetti, Franca Bertola, Cinzia Cassanelli, EDUCATORS

Antonia Biasi, Greta Bulbarelli, Maria Cremona, Andrea Gazzi, Angelo Prati

2010 RELEVANT NOTES Collaborations AIEOP (Italian Association of Pediatric Oncology): the Unit leads a new Working Group on adolescents with cancer Cooperation with the International Working Group on Adolescents is ongoing. SIOP (International Society for Pediatric Oncology)

NURSES

COG (Children Oncology Group)

Mariangela Armiraglio, head nurse Cecilia Alberti, Giulia Antonacci, Iris Baranella, Morena Berti, Daniela Bruno, Cristina Comelli, Patrizia Conti, Domenica Costeri, Lucia Curelli, Ruggero Fauro, Marta Ferrante, Carmelo Fiorello, Giuseppe Forzini, Marinella Gaidolfi, Rossana Ghezzi, Laura Lottaroli, Simone Macchi, Rossana Marra, Manuela Oriani, Elisa Procopio, Silvana Saverino

ISG (Italian Sarcoma Group)

HEALTHCARE ASSISTANTS

Annamaria Bilanzuoli, Gisella Cancedda, Rita Carulli, Silvana Celauro, Rita Marina Tamburo, Stella Uzzardi

Publications Comparison of the prognostic value of assessing tumor diameter versus tumor volume at diagnosis or in response to initial chemotherapy in rhabdomyosarcoma. J Clin Oncol. 2010;28:1322-8.

Teratoma with a malignant somatic component in pediatric patients: the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience. Pediatr Blood Cancer. 2010;54:532-7.

Contributions START chapters on neuroblastoma, Wilms’ tumors, medulloblastoma; MIUR guidelines for diagnosis and treatment of Ewing sarcoma Andrea Ferrari was guest editor for a special issue of the Journal of Clinical Oncology on adolescents and young adults (November 2010) Maura Massimino has acted as guest editor for Pediatric Blood and Cancer for a special issue on high-dose chemotherapy in brain tumors (January 2010)


MEDICAL ONCOLOGY DEPARTMENT

121

MEDICAL DAY HOSPITAL

HEAD Maria C. Brambilla, MD until 9/2010 Roberto Buzzoni, MD from 10/2010 STAFF MEMBER

Laura A. M. Ferrari CLINICAL FELLOW

Fabio G. Rossi, M.D. ADMINISTRATIVES

Anna R. Cabiddu, Antonella Bifano NURSES

Zordan Deborah (head nurse) Chiara Bernasconi, Domenica Comberiati, Laura Di Vico, Claudia Facchinetti, Carmela Fallacara, Anna Frisario,Lucia Giordano, Francesca Maffione, Santina Marafioti, Elena Nuti, Maria S. Paolillo, Maria N. Pisanu, Stefania Russo, Laura Sala, Pietrina Sanna, Davide Voinovich, Lucia D’Agnessa (Pharmacy), Elena Sala (Pharmacy)

The Medical Day Hospital (MDH) treats adult patients referred by different clinical Units of the Department. The administration of oncologic medical treatments has become increasingly complex. In fact, new molecules are now available, numerous patients are enrolled in medical trials which frequently need defined procedures during one day hospitalization, and all cases require close observation during treatment. Treatments are prepared by specialized nurses, who dilute therapeutic agents in a protected area equipped with two air flow cabinets and administer them under the supervision of MDH physicians. A separate section is dedicated to short duration regimens or biologic therapies by infusion pump systems and management of central venous catheters. Patients enrolled in research protocols are also evaluated during their stay in the MDH by physicians of the Medical Oncology Units. Special care is given to management and prevention of acute drug reactions, particularly allergic reactions, emesis, diarrhea, and extravasation of cytotoxic drugs. In 2010, the activities of the MDH consisted of approximately 21,000 procedures (monthly average activity of 1,750) [57% short therapies (treatments carried out in the outpatient area), 38 % long therapies (treatments administered in MDH but prescribed as “File F”), and MDH therapies (treatments requiring admission)]. The cancer types treated were breast cancer (35%), gastrointestinal cancer (29%), lymphoma and hematologic malignancies (22.5%), melanoma (4%), lung cancer (5%), head and neck cancer (2%), sarcomas (1%), and other tumors (1.5%). Keywords: chemotherapy, biologic therapy, supportive care, medical procedure

HEALTHCARE ASSISTANTS

Maria L. Cipolletti, Claudia Cocciolo, Fabio Di Bortolo, Lucia A. Di Murro, Anna M. Meloni, Maria R. Moscatiello, Diego Putzu, Rita E. Trovato, Filomena Libori

2010 RELEVANT NOTES Collaborations Regional Pharmacovigilance survey of ADR ( FARMA-ONCO)


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ANESTHESIA, INTENSIVE CARE, PAIN THERAPY, AND PALLIATIVE CARE DEPARTMENT

ANESTHESIA, INTENSIVE CARE, PAIN THERAPY, AND PALLIATIVE CARE DEPARTMENT

DIRECTOR OF DEPARTMENT Martin Langer Professor of Anesthesiology University of Milan +39 02 2390 2139 martin.langer@istitutotumori.mi.it

UNITS CLINICAL ANESTHESIA Martin Langer DAY SURGERY Aldo E. Bono INTENSIVE CARE Myriam Favaro PALLIATIVE CARE, PAIN THERAPY, AND REHABILITATION Augusto T. Caraceni SUPPORTIVE CARE IN CANCER Carla I. Ripamonti CLINICAL NUTRITION Cecilia Gavazzi

The Department has 4 main missions: 1) perioperative medicine; 2) treatment of chronic pain and supportive care in cancer patients; 3) palliative care/terminal support in the hospice or in home care for patients with advanced cancer when active treatments failed; 4) safety in the hospital. The cooperation among anesthesiologists and intensive care specialists, cardiologists and pneumologists, guarantees an adequate extensive preoperative evaluation and postoperative treatment of complex clinical situations. This perioperative team also contributed to the outstanding results obtained in the liver transplant program chaired by Vincenzo Mazzaferro. In collaboration with the Hospital management the Intensive Care Unit team develops also training programs for resuscitation from in-hospital cardiac arrest (BLS-D courses) as well as for other emergencies like fire and/or other major failures in the system. The Day Surgery Unit is devoted to surgical procedures performed in ambulatory and day hospital settings. Particular attention in our Department is devoted to the treatment of acute pain in postoperative patients, managed mainly by the anesthetists and a comprehensive multidisciplinary program to control pain and symptoms in patients with advanced and terminal cancer leaded by the palliative care physicians. Palliative care and admission to the Hospice is not exclusively restricted to end-of-life patients, but also allows, in selected cases, a better titration of palliative medication. The homecare service provides care for very severely or terminally ill patients and is deeply involved in the care network of Milan. An important international collaboration with the University of Trondheim, Norway, is ongoing. The Clinical Nutrition Unit treats patients suffering from any form of malnutrition and offers a comprehensive nutrition program. This Unit is a major referral centre for home artificial nutrition in Lombardy Region.

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SCIENTIFIC REPORT 2010

CLINICAL ANESTHESIA

HEAD Martin Langer MD STAFF MEMBERS

Mario Ammatuna, MD, Matteo Antoniazzi, MD, Maria Grazia Bonalumi, MD, Anna Cardani, MD, Pasqualina Costanzo, MD, Ilaria Donati, MD, Luca Fumagalli, MD, Edward A. Haeusler, MD, Antonio Maucione, MD, Silvana Migliavacca, MD, Lucia Miradoli, MD, Federico Piccioni, MD, Andrea Poli, MD, Giacomino Rebuffoni, MD, Giuseppe Rigillo, MD, Mara G. Roberto, MD, Emiliano Tognoli, MD, Alessandro Zanon, MD RESIDENTS

Lucia Bogno, MD, Valentina Colosio, MD, Paolo Proto, MD, Giuliana Motta, MD, Giada Donà, MD, Camilla L’Acqua, MD, Marco Carbonara, MD, Simona Marescotti, MD, Raffaella Di Pasquale, MD ADMINISTRATIVES

Stefania Bettinardi, Fiorina Cantisani NURSES

Romano Castellari RN (Head Nurse) Teresina Altana RN, Elisabetta Anchora RN, Stefania S Andreoli RN, Laura E. Anselmi RN, Marina Balbi RN, Marco Balconi RN, Silvana Bertoli RN, Gabriella Bianchessi RN, Renata Bordonali RN, Rossella Brambilla RN, Debora Buenaventura Boada RN, Julia D.Burgos Baena RN, Claudia Calderara RN, Antonella Chiesa RN, Hipolito V.Condorcuya Otani RN, Liviu D Corbu RN, Maria B. Corbu RN, Matrona De Felice RN, Maria Della Croce RN, Simonetta Delrio RN, Andrea Dibiase RN, Maria A.DiTano RN, Marina Djokic RN, Luca G Falcone RN, Federica Fiorini RN, Claudio Gasparro NR, Angelo Giannuzzi RN, Rosanna Giumbo RN, Marcella Gozzo RN, Cinzia Locatelli RN, Mara G Longo RN, Ezio Luzzi RN, Margherita A Marzo RN, Anna Rita Mazzotta RN, Annamaria Morricella RN, Antonella Nieddu RN,Cosmina V Noti RN, Barbara Ottonello RN, Lucia Orru RN, Maria R Pezone RN, Cecilia Pifarotti RN, Flavia F C Ravasi RN, Manuela Riva RN, Stefania Ronca RN, Maria A Jolanda Rosso RN, Massimo Sanseverino RN, Salvatore Santucciu RN, Sara Sciamanna RN, Paola Striglia RN, Ioan Marius Tere RN, George F Titi RN, Adriana Valentini RN, Filippo Venezia RN, Mirella A. Zaninelli RN, Silvia Zanotto RN.

The Fondazione IRCCS at the Istituto dei Tumori runs a very intense surgical program. The Anesthesia Team also participates in challenging surgical procedures such as liver transplantation, major liver resection, peritonectomy, and resection of tumors in the thorax or retroperitoneum. The hospital is also a referral center for pediatric solid tumors and anesthesiologists are involved not only in the operating room (OR), but is also involved in many other procedures including catheter placement, diagnostics, and radiotherapy. In June 2010, the new part of the Surgical Department with five ORs became available for clinical use and allowed for substantial improvement of safety standards and to increase the available OR time. Unfortunately, the number of nurses, anesthesiologists, and surgeons has not varied, and therefore the overall activity remained essentially the same with more than 7,000 major surgical procedures. In the second part of the year, 73 hours in nine ORs are available daily for surgical programs of the ten Surgical Services. The ORs are fully utilized. Quality improvement programs during 2010 were focused on patient safety (check list and TIME-OUT procedure) and care for acute, postoperative pain. Patientcontrolled analgesia is needed in about 40–50% of patients undergoing major surgery, epidural analgesia with elastomeric pumps accounts for 20–25%, while continuous intravenous opioid infusion by an elastomeric pump is the treatment chosen for the remaining 30–40% of patients. The pain team visits patients for 3-4 days after surgery and tailors treatment as necessary. Our training program for residents of the Anesthesia and Intensive Care Program of the University of Milan is well established and allows yearly 5–7 young physicians to become trained in clinical anesthesia and pain therapy. Emiliano Tognoli is running a randomized, blinded, placebo-controlled trial on the possible opioid sparing effects of ketamine and methadone after surgery. Keywords: anesthesia, acute pain therapy, operating room

HEALTHCARE ASSISTANTS

Rosa M. Benvenuto, Pierangela Carrino, Denise de Bastiani, Annuccia Delrio, Miriam Faccini, Antonio Labori, Anna Lorenti, Maria Maestri, Stefania Massella, Monica Mastrogiovanni, Maria C Pirrotta, Maria C Pisasale, Elisabetta Saccaggi, Elena Scotti, Carmelo Scrofani, Rosa Selvati, Rosa M Tirone TECHNICIANS

Maria I. Cipolletta, Giovanni Di Bari, Gerardo Gizzi, Gianbattista Grazioli, Monica Mastrogiacomo, Luca Pedone

2010 RELEVANT NOTES Publications Thoracic paravertebral anaesthesia for awake video-assisted thoracoscopic surgery daily. Anaesthesia 2010; 65:1221-4. Daily monitoring of biomarkers of sepsis in complicated long-term ICUpatients: can it support treatment decisions? Minerva Anestesiol. 2010; 76: 814-23.


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DAY SURGERY

HEAD Aldo E. Bono, MD ADMINISTRATIVES

Maria R. Bignamini, Anna Corella, Loredana Orezzi NURSES

Giovanna R. Colaci RN, Mariangela Lena RN, Mara D. Luisoni MD, Pina P. Mele RN, Anna Picciallo RN, Marina Zocchi RN HEALTHCARE ASSISTANTS

Guglielmina Riccio, Franca Atzeni, Antonella Bordoni

The Day Surgery Unit is devoted to surgical procedures performed in ambulatory and Day Hospital settings. The Unit includes 10 beds, 2 operating rooms for various surgical activities , and one operating room for laser surgery. The permanent staff includes one physician, 9 nurses trained in the management of ambulatory surgical patients, and 3 secretaries. The clinical activity covers many aspects of oncologic surgery, and in particular involves different lesions involving skin, soft tissues, and breast, as well lesions in gynecological, urological, and head and neck areas. This activity involves physicians of the Department of Surgery, sometimes working in cooperation. During 2010, 4,866 surgical procedures were performed. Of these, 3,028 were performed in a Day Hospital setting, whereas 1,838 patients underwent outpatient surgery. 4,350 operations were performed under local anesthesia, while 516 were performed under sedo-analgesia or general anesthesia. In addition to normal surgical activity, other procedures were performed such as electrochemotherapy of secondary skin tumors (in collaboration with Melanoma and Sarcoma Unit) and fat injection or lipostructure with the Coleman technique to lessen local skin and subcutaneous damage (in collaboration with Plastic and Reconstructive Unit). Clinical research activity is, at present, mainly performed in collaboration with the Melanoma and Sarcoma Unit. The aim of this activity is to better define the initial clinical features of early melanoma for curative surgery (see Multidisciplinary Project â&#x20AC;&#x153;Melanoma Programâ&#x20AC;? page 31). A prospective study concerning narrower surgical margins (0.5 cm) for horizontal growth phase melanoma has been concluded, and the results will be soon published. A study on the clinical and dermoscopic features of small nodular melanoma of the skin has also been concluded and published. Keywords: day-surgery, ambulatory surgery, early melanoma


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INTENSIVE CARE

HEAD Myriam Favaro, MD

Staff Members Valerio Costagli, MD Fortunato D’Elia, MD Marco Faustini, MD Renato Manzi, MD Laura Persiani, MD Maurillia Rizzi, MD Roberta Casirani, MD Nurses M. Savioli (Head Nurse), M. Gasparini, R. Di Nino, A. Simonetti, F. Filippazzo, S. Alcamo, A. Casali, S. Sirigu, S. Romero Lemos, E. Lonetti, M. Zoanni, M. Boccola, A. Cofone, L. Morsenti, D. Violi, A. Ferraresi Health Care Assistants G. Montecalvo, E. Zedda, R. Zicconi, C. Garzon

Monitoring and surveillance of high-risk surgical patients in the immediate postoperative period and intensive treatment of patients with life-threatening postoperative complications or organ failure are the mission of this Intensive Care Unit (ICU). The Unit is equipped with 6 ICU beds and in 2010 admitted 602 patients (76% after scheduled surgery) for 1,587 treatment days. Two physicians during the day and one in the night are available, together with the nurses of the ICU, for emergencies in the INT, counseling for critically-ill patients in the different wards and blood gas and point-of-care analyses for all patients. 431 central venous catheters, both as elective and as emergency procedures, have been placed by ICU physicians; we also started a program for the long-term catheter positioning (12 Groshong catheters). Liver function was investigated in 91 patients, mainly preoperatively, before major liver resections. Percutaneous tracheotomy (“Griggs”) was performed in 20 patients on prolonged mechanical ventilation. We continue to treat patients with failing liver function and hyperbilirubinemia with extracorporeal “plasma-adsorption-perfusion”. We continued activities in the surgical day hospital: sedo-analgesia in patients scheduled for limited resections of breast cancer (153 patients ) and we adopt sedo-analgesia even for patients with metastatic melanoma, in plastic surgery (30 patients), in radiology and endoscopy non-surgical procedures (646 patients). We took part in a new national study (ALBIOS ) on the efficacy of albumin administration for volume replacement in patients with severe sepsis or septic shock, and from 2008 we collaborated with the Italian GiViTI Network in the MARGHERITA project, which aims to improve the quality of ICU care through the analysis of epidemiological data. Keywords: intensive care; emergency in hospital; anesthesia for day surgery

2010 RELEVANT NOTES Technologies This ICU has been chosen as Italian lead in the Clean Care Project of the WHO to optimize patients safety in the hospital.

Collaborations The unit is part of the Italian GiViTI (Gruppo Italiano Valutazione Interventi in Terapia Intensiva) network


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PALLIATIVE CARE, PAIN THERAPY, AND REHABILITATION

HEAD Augusto T. Caraceni, MD STAFF MEMBERS

Augusta Balzarini, MD Fulvia A. Gariboldi, MD Cinzia A. Martini, MD Luigi Saita, MD Ernesto Zecca, MD RESEARCH MEMBERS

Paola Bracchi, MD Cinzia Brunelli, ScD Tiziana Campa, MD Laura Campanello, PhyD Marco Carminati Gianluigi Cislaghi Daniela G.M. Ermolli, MD Elena Fagnoni, MD Nausika Gusella, PsyD Andrea Magni, MD Alessandra Pigni, MD Carmela P. Sigari, MD Fabio Simonetti, MD ADMINISTRATIVES

Emanuela Brusati, Loredana D’Urso, Loredana R. Illuminato PHYSICAL THERAPISTS

Livia I. E. Bedodi, Maria G. Blandini, Chiara Bottani, Simona Breggiè, Paola Campanini, Lucia M. Cavallin, Anna B. Cotza, Liviana Craba, Heike Feddersen, Cinzia A. Ficcarelli, Donato F. Ficchì, Alida M. E. Grossi, Chiara Piazza, Patrizia Placucci, Raffaella Sensi, Beatrice Simoncini NURSES

Barbara Acquisto, Maria C. Allemano, Giuseppe Baiguini, Claudio Baratella, Barbara Benegiamo, Sara Bianchi, Giuseppina Bottigliero, Rosa A. Candigliota, Angela Carugati, Olmina Di Florio, Massimo Di Francesco, Floriana Dimo, Vincenzina Ferraro, Elsa R. Lovo, Anna M. Mazzucchelli, Rosa Olivieri, Nives Porta, Edoardo Rossetti, Arianna Rossi, Elisabetta Volpato HEALTHCARE ASSISTANTS

Raffaela Diaferio, Maria Rosaria Lia, Nataliya Maksymova, Cristina Marras, Anna Mastroianni, Teresa Natali, Teresa Pace, Nicola Paternoster TECHNICIANS

Maria L. Cipolletti, Martinelli Brunella

The clinical and research programs reflect the two-fold mission of the unit: palliative care/pain and rehabilitation. This program is characterized by a multidisciplinary and multi-professional approach encompassing control of physical symptoms, psychological and social support, and the alleviation of spiritual/existential suffering with early integration of all antineoplastic interventions according to the “simultaneous care” model. Cancer rehabilitation includes interventions that are appropriate for the recovery of acute and chronic consequences of surgery, radiotherapy, and medical treatments as well as to support the complications of advanced cancer. In 2010, the following results highlight the widespread clinical activities: 221 inpatient unit (Hospice) admissions, 2,357 day-hospital admissions, 30,513 outpatient clinic calls, 11,798 inpatient consults, and 163 home care (hospital at home) admissions. The research program in 2010 continued building on multicenter, international collaborations together with individual and national projects. The status of the Unit within the European Palliative Care Research Center (PRC) was formally acknowledged in a contract between the INT and the University of Science and Technology in Trondheim (Norway) and a number of projects were concluded and/or continued: • Cancer pain assessment and classification, international consensus, systematic reviews and empirical research • Cancer pain opiod guidelines in collaboration with the European Association for Palliative Care • Translational research on opioid pharmacogenomics • A multicenter national trial on control of cancer pain with different opioids in collaboration with the Mario Negri Institute. • A phase II trial on methylnaltrexone for opioid induced constipation • Systematic review on hydration and nutrition within OPCARE (FP7) • National cluster randomized trial on the Liverpool Care Pathway Keywords: palliative care, cancer pain, rehabilitation, end-of-life care

2010 RELEVANT NOTES Collaborations Istituto di Ricerche Farmacologiche Mario Negri, Milano Department of Cancer and Molecular Biology, Norwegian University of Science and Technology. Trondheim Istituto Nazionale Tumori (IST) IRCCS, Genova

Publications Assessment and classification of cancer breakthrough pain: a systematic literature review. Pain 2010;149: 476-82. The validity of average 8-h pain intensity assessment in cancer patients. Eur J Pain 2010; 4: 441-5.

Contributions Editorial board of Journal of Pain and Symptom Management, Minerva Anestesiologica


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SCIENTIFIC REPORT 2010

SUPPORTIVE CARE IN CANCER

HEAD Carla I. Ripamonti, MD PhD STAFF MEMBER

Maria A. Pessi, MD PhD NURSES

Chiarina Pireddu, Maria Albertina Sorgato, Pietro Toma VOLUNTEERS

Italian League Against Cancer (Milan section)

The Supportive Care in Cancer Unit at the INT (out-patient and Day Hospital settings) cares for patients sent from all INT Units starting from the diagnosis of cancer throughout the period of active oncological therapies with the aim to prevent and treat all symptoms caused by therapies according to MASCC guidelines (www.mascc.org). We work in integration with all hospital Units and administer the following therapies: hydration, transfusions, antiviral agents, antibiotics, analgesic drugs, IV nutrition (not TPN), and IV bisphosphonates. Moreover, we carry out prevention and treatment of osteonecrosis of the jaw in collaboration with Dental Team. All patients are regularly assessed for the presence and the intensity of physical and psychological symptoms and spiritual and social needs. They have visit from the chaplain and/or social worker and/or psychologists during the infusion of drugs in the Supportive Care Unit. All patients are on active oncological therapies, and thanks to the supportive care their physical and emotional conditions improve and can undergo to chemotherapy or radiotherapy under better conditions. The clinical activity in 2010 included 2,493 clinical visits, 1,189 in Day Hospital, 1,435 infusions in an out-patient regimen, 390 transfusions,and 503 administrations of bisphosphonates (zoledronic acid). Keywords: supportive care, patients on oncological treatments, bone health

2010 RELEVANT NOTES

Contributions

Collaborations

Updated Guidelines on the Use of Bisphosphonates in Bone Metastases (coordinator Daniele Santini) for the Associazione Italiana di Oncologia Medica (AIOM)

Department of Oncology, Hematology and Respiratory Diseases, Azienda Ospedaliera Universitaria, University of Modena and Reggio Emilia Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti) Psychology Unit, Center for Oncological Rehabilitation-CERION of Florence Clinical Epidemiology Unit, ISPO-Institute for the Study and Prevention of Cancer, Florence; Department of Psychology University of Milan Bicocca CeVEAS, WHO Collaborating Center, Modena Liguria Regional Coordination of Palliative Care, (IST), Genova Palliative Care Unit ASL Bi- Biella Campus Biomedico Rome University of Verona (Specialties of Internal Medicine-Reumatology-Oncology) Istituto Scientifico Romagnolo University of Torino (Specialization in oncology) World Health Organization for cancer pain relief (WHO) European Society Medical Oncology (ESMO) for Palliative Care Working Group Multinational Association Supportive Care in Cancer ( MASCC) for psychosocial and spiritual working group

Publications Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid policy initiative. Ann Oncol. 2010;21:615-26. Impact of setting of care on pain management in patients with cancer: a multicentre cross-sectional study. Ann Oncol. 2010;21:2088-93. System of belief inventory (SBI-15R): a validation study in Italian cancer patients on oncological, rehabilitation, psychological and supportive care settings. Tumori. 2010;96:1016-21.

Adviser in the working group for the preparation and the development of the WHO Guidelines for pharmacological treatment of persisting pain in children with medical illnesses Re-elected as Italian Member of the Palliative Care Working Group of the European Society Medical Oncology (ESMO PCWG) Re-elected as Italian Member of Directors of the International Association Hospice Palliative Care (IAHPC) Invited as ESMO Media Ambassador for Pain Therapy and Supportive Care topics


ANESTHESIA, INTENSIVE CARE, PAIN THERAPY, AND PALLIATIVE CARE DEPARTMENT

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CLINICAL NUTRITION

HEAD Cecilia Gavazzi, MD STAFF MEMBER

Alessandro Sironi, MD RESIDENT

Valerio Barbieri, MD NURSES

Annaluigia Armonti, Franca Filincieri, Carmen Maiorana, Lorena Riva TECHNICIAN

Colatruglio Silvi

The prevention and the treatment of malnutrition are the major goals of this Unit. Malnutrition is a well known negative prognostic factor in the final prognosis of cancer patients, and it reduces tolerance to oncological treatment, increases morbidity and mortality, and worsens the quality of life; nutritional intervention should be considered throughout all different oncologic phases, from diagnosis, during surgery, to chemotherapy and radiotherapy. In accordance with the European Society of Clinical Nutrition, nutritional screening is carried out in all patients with a high risk of malnutrition, i.e. patients affected by gastrointestinal cancer, candidates for major surgery and patients affected by head and neck cancer and candidate for combined chemotherapy and radiotherapy. Patients affected by any form of malnutrition are included in a comprehensive nutrition program that consists in nutritional status monitoring and personalized nutrition therapy, mainly with artificial nutrition, enteral and parenteral, nutritional couseling, and diet therapy. For those patients who need a prolonged period of artificial nutrition, specific training is performed by specialized nurses, logistic procedure are organized, and patients are discharged on home artificial nutrition. In 2010, 406 inpatients were included in a nutrition program and 2,723 days of nutrition therapy were administered; 81 patients were discharged on home artificial nutrition. Keywords: malnutrition, nutrition therapy, gastrointestinal cancer

2010 RELEVANT NOTES Collaborations Italian Society for Artificial Nutrition and Metabolism (SINPE)

Contributions AIOM Guidelines on Prevention and Treatment of Cancer Cachexia


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DIAGNOSTIC IMAGING AND RADIOTHERAPY DEPARTMENT

DIAGNOSTIC IMAGING AND RADIOTHERAPY DEPARTMENT

DIRECTOR OF DEPARTMENT Emilio Bombardieri +39 02 2390 2220 emilio.bombardieri@istitutotumori.mi.it

UNITS RADIOLOGY AND DIAGNOSTIC IMAGING 1 Daniele Vergnaghi RADIOLOGY AND DIAGNOSTIC IMAGING 2 Alfonso V. Marchianò INTRALESIONAL TREATMENT Francesco Garbagnati RADIOLOGY AND DIAGNOSTIC IMAGING 3 AND BREAST IMAGING UNIT Silvana Bergonzi DIAGNOSTIC AND INTERVENTIONAL GASTROENTEROLOGY Guido Cozzi NUCLEAR MEDICINE Emilio Bombardieri CLINICAL PET Flavio Crippa NUCLEAR MEDICINE THERAPY AND ENDOCRINOLOGY Ettore Seregni RADIOTHERAPY 1 Patrizia Olmi (retired 30 Sept 2010) Emilio Bombardieri (present) RADIOTHERAPY 2 Carlo Fallai MEDICAL PHYSICS Giancarlo Zonca

The Department includes: three Radiology and Diagnostic Imaging Units: RD1 carries out conventional radiologic examinations and magnetic resonance imaging (MRI); RD2 is specialized in mammographic examinations, breast US, diagnostic, interventional radiology, and US for gastroenterology; it is considered the intralesional treatment unit. For diagnostic and interventional activities in 2010, more than 90,000 conventional radiologic examinations, 11,000 MRI scans, and 4,000 interventional procedures were performed. The Nuclear Medicine Unit performs functional imaging by positron emission tomograhy (PET), nuclear medicine therapy, and has a radioisotope laboratory and endocrinology outpatient clinic. Overall, the clinical activity in 2010 involved more than 3,900 PET examinations, 5,900 diagnostic imaging tests, 84,000 in vitro tests, and 3,200 medical examinations. Two Radiotherapy Units: RT1 performs external radiation therapy, while RT2 carries out inpatient radiation therapy. In 2010, 1,600 outpatients and 367 inpatients were treated. One Medical Physics Unit.

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SCIENTIFIC REPORT 2010

RADIOLOGY AND DIAGNOSTIC IMAGING 1

HEAD

Daniele Vergnaghi, MD STAFF MEMBERS

Alberto Laffranchi, MD Antonella Messina, MD Paolo Potepan, MD Davide Scaramuzza, MD Giovanna Trecate, MD ADMINISTRATIVES

Angelina Laganà, Sonia Leone, Giulia Melis TECHNICIANS

Cinzia Fossaceca, Annunziata Gaetano, Antonella Laturra, Tina Mastrostefano, Luca Musumeci, Carmelina Pannone, Nicola Pulerà, Valeria Tosi, Maurizio Zattoni NURSE

Loredana Palella

Magnetic Resonance Imaging (MRI) continues to play an essential role in diagnosis and staging of primary cancers, monitoring treatment response, and follow-up. Over the past year, two emerging functional techniques, namely DCE-MRI and diffusion weighted imaging (DWI), have established their importance in clinical management. These techniques have been widely used in our investigations to distinguish tumor from non-tumoral tissue, assessing treatment response, and prediction of treatment outcome. Another emerging technology, endorectal magnetic resonance imaging and magnetic resonance spectroscopic imaging (endoMRI/MRSI), has been developed in our Department to improve staging of prostate cancer. Significant efforts have been also directed toward development of breast MRI, for early detection, diagnosis, and treatment planning of breast cancers with particular attention to cases suspect for multifocality (780 breast MRI performed in 2010). Functional imaging increased its role over morphokinetic aspects of breast lesions. The Unit also participates in a multicentric surveillance study of women at high genetic risk for breast cancer aimed at improving the accuracy of MRI in cancer detection, and collaborates with Milan Polytechnic to develop new software for computer-aided diagnosis and follow-up using whole body and head and neck MRI examinations. Whole-body MRI and whole-body DWI have also been developed as new staging methods, and have been demonstrated to be reliable in detection of skeletal metastases and evaluate the extent of bone diseases. Whole-body MRI also provides additional tumor-related information in lymphomas, especially that related to early response to therapy and surrounding soft tissue and parenchymal status. MRSI and DWI have been utilized for diagnosis and follow up of pediatric brain tumors, an expanding field of clinical commitment and research. Keywords: MRI, functional imaging, perfusion, diffusion imaging, total body examination

2010 RELEVANT NOTES Collaborations Istituto Superiore di Sanità, Rome Department of Biomedical Engeneering of Polytechnic of Milan Imaging Science and Biomedical Engineering (ISBE) Research Group. Medical School, Faculty of Medical and Human Sciences, University of Manchester

Publications Multicenter Surveillance of Women at High Genetic Breast Cancer Risk Using Mammography, Ultrasonography, and Contrast-Enhanced Magnetic Resonance Imaging (the High Breast Cancer Risk Italian 1 Study): Final Results. Invest Radiol. 2011;46:94-105.

Contributions European Guidelines & Protocols for Diagnosis and Follow-up of Pediatric Brain Tumors by MRI (in collaboration with SIOP and Pediatric Oncology Unit) European Guidelines & Protocols to assess early response on Head & Neck Cancer by DCE-DWI MRI (in collaboration with EORTC)


DIAGNOSTIC IMAGING AND RADIOTHERAPY DEPARTMENT

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RADIOLOGY AND DIAGNOSTIC IMAGING 2

HEAD Alfonso V. Marchianò, MD STAFF MEMBERS

Enrico M. Civelli, MD Giuseppe Di Tolla, MD Laura F. Frigerio, MD Francesco Garbagnati, MD Rodolfo Lanocita, MD Carlo Morosi, MD Carlo Spreafico, MD ADMINISTRATIVES

Giovanni Capone, Giuliana Manzoni, Ornella Venegoni TECHNICIANS

Marilena Barbiero, Pietro Basile, Maria Ferrarello, Roberto Gallo, Giuseppina Gentile, Roberto Nioi, Geremia Porcelli, Salvatore Romaniello, Luciana G. Tanzini, Vanni Tirella NURSES

Pietro Ciccarese, Laura Fagnani, Roberta S. Populin, Marinella Porceddu

Diagnostic oncology and interventional-oriented radiology represent the core activity of the Unit. Inpatients and outpatients undergo a diagnostic work-up that includes the different steps of patient management: primary cancer diagnosis, staging, follow-up and monitoring after surgery, chemotherapy, and radiotherapy. The lung cancer screening program (MILD) with “low-dose” spiral CT continued in 2010. We performed over 2,000 low-dose spiral CT, and we are currently testing a system of computer-aided detection (CAD) of pulmonary nodules. Interventional radiology activities include long-term venous central catheter placement, embolization, and chemoembolization for regional cancer treatment. Intralesional radiofrequency ablation based-methods, such as the chemo-interventional procedures consisting in local-regional drug delivery for malignancies of the liver, head and neck, pelvis, and limbs, have been successfully performed. An international multicentric study on the treatment of inoperable hepatocellular carcinoma with intra-arterial injection of yttrium-90 radiolabeled microspheres is ongoing in collaboration with Units of Nuclear Medicine and Gastrointestinal and Hepatopancreatobiliary Surgery and Liver Transplantation. The Unit has also developed an original experience of percutaneous cryoblation in selected patients with small renal tumors. During 2010, over 1,000 vascular diagnostic procedures, 500 vascular and non-vascular interventional procedures, over 550 long-term venous central catheters, and 600 percutaneous biopsies in various body districts were performed. Keywords: image-guided therapies, ultrasonography, computed tomography, multifunctional fluoroscopy, digital angiography

2010 RELEVANT NOTES Publications Lung function predicts lung cancer risk in smokers: a tool for targeting screening programs. Eur Respir J. 2010;35:146-51. Comparison of the prognostic value of assessing tumor diameter versus tumor volume at diagnosis or in response to initial chemotherapy in rhabdomyosarcoma. J Clin Oncol. 2010;28:1322-8.


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SCIENTIFIC REPORT 2010

INTRALESIONAL TREATMENT

HEAD Francesco Garbagnati, MD

Beginning in 1988, a procedure was developed to evaluate the possibility of utilizing a percutaneous mini-invasive approach in non-operable parenchymal tumors using intralesional thermal ablation. Overall, more than 900 patients with non-operable hepatic tumors, and kidney, lung, and bone neoplasms have been treated without major complications. The Intralesional Treatment Unit takes advantage of the experience of interventional radiology staff to organize tumor treatment in collaboration with the clinical and surgical units. The results of intralesional thermal ablation can be optimized with the addition of a radiological intralesional approach, with guidance procedures as ultrasound, CT, MR, and angiography. During 2010, we treated 80 patients with percutaneous intralesional radiofrequency, most of whom had non-operable HCC with a diameter of about 3.5 cm. When the diameter was larger than 3.5 cm, we combined radiofrequency with temporary arterial stop-flow during selective hepatic angiography. The combination of radiofrequency and arterial stop-flow can lead to the destruction of very large liver tumors, with only one insertion of the radiofrequency electrode in mini-invasive approach and only one day of hospitalization. We have also treated kidney neoplasms, primary and secondary lung tumors, soft tissue and suprarenal gland tumors. In some cases, we have employed microwaves and laser intralesional treatment techniques. Keywords: thermal ablation, interventional oncological radiology

2010 RELEVANT NOTES Collaborations Fondazione IRCCS Policlinico San Matteo, Pavia Azienda Ospedaliera, Ospedale di Circolo di Melegnano, Milan University of Milan The Royal Marsden, NHS Foundation Trust, London

Publications Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: a long-term cohort study. Hepatology, September 2010

Contributions Our RF stop-flow combination technique for treatment of large HCC was inserted in the Italian National Radiological Society guidelines for Interventional Radiology In international guidelines for treatment of HCC, a percutaneous approach with RF thermal ablation of HCC up to 3.5 cm diameter was considered as a definitive mini-invasive therapy.


DIAGNOSTIC IMAGING AND RADIOTHERAPY DEPARTMENT

135

RADIOLOGY AND DIAGNOSTIC IMAGING 3

HEAD Silvana Bergonzi, MD

This Diagnostic Radiology is composed of two Units: the Breast Imaging Unit and the Diagnostic and Interventional Gastroenterology Unit. The two Units share technicians, while staff members have specific duties in each Unit.

STAFF MEMBERS

Guido Cozzi, MD Claudio Ferranti, MD Monica Marchesini, MD Marco Milella, MD Monica Salvetti, MD Gianfranco Scaperrotta, MD Laura Suman, MD TECHNICIANS

Cristina Folini (coordinator) Luisa Colombo, Luciana Dedei, Enrico Depedri, Luca Lanzilotti, Maria Pia Mannella, Stefania Sala, Anna Tavola NURSES

Mauro Addolorato, Ferruccio Mirella ADMINISTRATIVES

Marzia Gaffo, Lucia Nardin, Giuseppa Pacicca, Francesca Vescera

BREAST IMAGING UNIT (Head: Silvana Bergonzi) The aims of diagnostic work up and breast biopsy are to localize primary or recurrent breast cancer in the preclinical phase and/or validate clinical findings with the intent to reduce unnecessary surgery. The biopsies performed in non-palpable breast lesions are also a basic element of a multidisciplinary approach to provide the histological parameters needed for surgical planning. Breast imaging consists mostly in clinical mammography and breast ultrasound studies on symptomatic or treated patients and on asymptomatic women for screening and prevention, with specific regard to women with known genetic predisposition and/or family history for breast cancer. In 2010, 13,300 mammographic examinations and 9,000 breast ultrasound studies were performed, in addition to 400 second opinion consultations. Moreover, 830 conventional radiodiagnostic procedures on inpatients were performed. A total of 1,600 interventional procedures (6% increase vs 2009) were carried out in 2010 on patients with suspicious imaging findings in INT or other diagnostic centers (650 preoperative targeting of non-palpable breast lesions and 950 breast biopsies [ultrasound and stereotacticguided, particularly vacuum-assisted]). During 2010, a new breast lesion excision system able to provide a single sample with intact architecture was tested that will be compared to other vacuum-assisted devices. Keywords: breast, diagnostic imaging, breast biopsy

DIAGNOSTIC AND INTERVENTIONAL GASTROENTEROLOGY (Head: Guido Cozzi) The clinical activity of the Unit deals with diagnostic and interventional radiology of the digestive and biliary tracts, and diagnostic and interventional ultrasound (US), the latter primarily in thyroid and neck pathologies. Thyroid diseases (6,104 US examinations) still represent a prominent area of interest. In cooperation with the multidisciplinary outpatient service of thyroid diseases, 2,446 neck US examinations for diagnosis and monitoring of thyroid nodules were performed. A total of 654 diagnostic examinations of functional disorders of the digestive tract were performed.


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SCIENTIFIC REPORT 2010

Compared to 2009, a small decrease in diagnostic radiologic examinations was offset by a considerable increase (12%) in interventional procedures (IP) that may allow resolution of surgical complications without reintervention. IP represent, both in the biliary and gastrointestinal areas, the most clinically relevant activity of the Unit that has become a point of reference for many institutions. In the biliary field, definitive jaundice palliation with drainages or stents, curative dilatation of cicatricial stenoses, drainage of fistulas, transluminal biopsies, and other less common maneuvers are routinely performed. In the gastrointestinal field, in addition to treatment of complications (transluminal drainage of fluid collections, dilatation of cicatricial stenoses), IP plays a basic role in nutritional support (percutaneous gastrostomy, positioning of feeding tubes, stenting of inoperable stenoses). The majority of these procedures are urgent, which requires significant organizational capacity. In 2010, the first non-covered, self-expandable, biodegradable stent was positioned with success in a patient with a benign esophageal stricture. This IP is expected to have an important role in the treatment of benign stenoses of the digestive tract (included biliary), since it provides long-term dilation and self-removal. Keywords: interventional biliary radiology, interventional gastroenteric radiology, thyroid biopsy

2010 RELEVANT NOTES Contributions Guido Cozzi was reviewer for Cardiovascular and Interventional Radiology Journal

Publications Is there a specific magnetic resonance phenotype characteristic of hereditary breast cancer? Tumori. 2010; 96:363-84


DIAGNOSTIC IMAGING AND RADIOTHERAPY DEPARTMENT

137

NUCLEAR MEDICINE

POST-DOCTORAL FELLOWS

This Unit includes different groups and is involved in various clinical and experimental activities. Given the multidisciplinary clinical and research activities, a variety of expertise ranging from nuclear medicine, endocrinology, chemistry, engineering, biology, and physics are present. Major clinical activities include a diagnostic unit for tomographic scintigraphy (SPECT); PET unit; several radiochemistry laboratories for both gamma and beta radiopharmaceuticals; radioisotope laboratory for radioimmunometric tests; protective ward for radiometabolic treatments. The research involves several topics: measurement of biochemical markers of neoplasia and evaluation of bone metabolism parameters in patients with bone metastases; studies on clinical PET and validation of PET applications; development of new radipharmaceuticals for PET and therapy; new approaches for the radioisotopic therapy of thyroid cancer, neuroblastoma and lymphoma; dosimetry studies to optimize the activity to be administered to increase the efficacy of treatment. In particular, new radiopharmaceuticals have been synthesized such as 18Ffluorodeoxithymdine (18F-FLT), which is being investigated in experimental and clinical studies in both animal models (with MicroPET) and humans (breast cancer patients). Novel approaches for the treatment of neuroendocrine tumors with tandem radiolabeled somatostatin analogues (177Lu/ and 90Y DOTA-TATE) are being studied. Dosimetric studies on thyroid cancer treatment and HCC therapy with microspheres have been carried out to administer the optimal activity.

Barbara Padovano, MD Federica Pallotti, MD

Keywords: molecular imaging, radiopharmaceutical development, radioisotope therapy

HEAD Emilio Bombardieri MD STAFF MEMBERS

Alessandra Alessi, MD Gianluca Aliberti, MD Anna Bogni, Biol Sci Maria R. Castellani, MD Carlo Chiesa,Physicist Flavio Crippa, MD Vinicio De Sanctis, Engineer Marco Maccauro, MD Eva Orunesu, MD Claudio Pascali, Radiochemist Gianluca Serafini, MD Ettore Seregni, MD RESEARCH MEMBERS

Angela Coliva, Chemist Claudio Cucchi, Chemist Luca Laera, Chemist Greta Maiocchi, Chemist

ADMINISTRATIVES

Annaluisa De Simone Sorrentino (Coordinator), Isabella Flauto, Valentina Fracchiolla, Rosangela Ghilardi, Patrizia Gobbi TECHNICIANS

2010 RELEVANT NOTES

Contributions

Collaborations

GUIDELINES

Monica Testoni (Coordinator), Grazia Aprigliano, Danilo Baratella, Davide Bassani, Sergio Bavusi, Gianenrico Cucchetti, Maria Di Francesco, Pietro Di Nuzzi, Martino Faedui, Rita Filieri, Deborah Mansi, Giovanni Nido, Rossana Pavesi, Biagio Perrone, Matteo Regazzoni, Lidia Spano, Roberto Segreti

International Agency Atomic Energy (IAEA), Vienna Edition of Technical books on PET Application and Development

NURSES

Publications

Rita Sicari (Coordinator), Mirella Ferruccio, Gaetano Naso, Calogero Oliveri, Loredana Palella

Associazione Italiana di Medicina Nucleare (AIMN) Multicentric study on dosimetry of radioiodine treatment of advanced thyroid cancer International Society of Pediatric Neuroblastoma (SIOPEN) Group), Multicentric study on the treatment of advanced neuroblastoma

Imaging of NETs with gamma-emitting radiopharmaceuticals. Q J Nucl Med Mol Imaging. 2010;54: 3-15. 131I-MIBG treatment of pheochromopcitoma: low versus intermediate activity regimens of therapy. Q J Nucl Med Mol Imaging. 2010;54:100-13.

Bombardieri E, Ambrosini V, Aktolun C, Baum RP, BishofDelaloye A, Del vecchio S, Maffioli L. 111In-pentetreotide scintigraphy: procedure guidelines for tumour Imaging. Eur J Nucl Med Mol Imaging. 2010;37:1441-8. Bombardieri E, Gianmarile F, Aktolun C, Baum RP, BishofDelaloye A, Maffioli L. 131I/123I mIBG scintigraphy; procedure guidelines for tumor imaging. Eur J Nucl Med Mol Imaging. 2010;37:2436-46. EDITORIAL BOARD European Journal of Nuclear Medicine and Molecular Imaging - Springer (Heidelberg, Germany) Quarterly Journal of Nuclear Medicine and Molecular Imaging - Minerva Medica (Turin, Italy)


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SCIENTIFIC REPORT 2010

CLINICAL PET (Head: Flavio Crippa) Clinical activities are focused on PET scans for staging, therapy monitoring, and follow-up of almost all types of human malignancies. The most investigated malignancies were lymphoma, breast cancer, colorectal cancer, lung cancer, melanoma, soft tissue sarcomas, ovarian cancer, head and neck cancers, and gliomas. Ongoing clinical research programs are based on the use of FDG-PET: in combination with CT for the follow-up of asymptomatic melanoma patients with a high risk of metastases for early detection of tumor progression and potentially curable with surgical treatment; monitoring the efficacy of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer and pazopanib monotherapy in patients with relapsed/refractory urothelial cancer (INT70/09, NCT01031875); early evaluation of chemosensitivity in lymphoma patients; providing imaging support to several clinical research programs carried out by the Sarcoma Group of INT with particular reference to GISTs and chordomas. Furthermore, 11C-methionine PET is under investigation to study brain tumors, and in particular low-grade gliomas, where FDG-PET lacks sensitivity as an imaging modality. A small animal PET imaging facility (microPET) has been installed, and research has been focused on training a multidisciplinary staff who will perform experiments investigating the biodistribution of PET tracers, such as FDG and 18F-FLT, in selected cancer animal models. Keywords: PET/CT in tumor staging, metabolic imaging, therapy monitoring, 18F-FDG, PET radiopharmaceuticals

2010 RELEVANT NOTES Collaborations Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan Azienda Ospedaliero-Universitaria Molinette San Giovanni Battista, Turin

Publications Pretransplantation [18F]fluorodeoxyglucose positron emission tomography scan predicts outcome in patients with recurrent Hodgkin lymphoma or aggressive non-Hodgkin lymphoma undergoing reduced-intensity conditioning followed by allogeneic stem cell transplantation. Cancer 2010;116: 5001-11. Treatment with tandem [(90)Y]DOTATATE and [(177)Lu] DOTA-TATE of neuroendocrine tumors refractory to conventional therapy: preliminary results. Q J Nucl Med Mol Imaging. 2010;54:84-91.

NUCLEAR MEDICINE THERAPY AND ENDOCRINOLOGY (Head: Ettore Seregni) The activities of the Unit cover three main areas involved in routine and experimental procedures: nuclear medicine therapy, radioisotope laboratory, and an endocrinology outpatient clinic. The main therapeutic areas are thyroid cancer, neuroendocrine tumors and endocrine therapy. In 2010, two protocols of experimental therapies were active: Efficacy of tandem treatment of neuroendocrine tumors refractory to conventional therapies with the somatostatin analogs 90Y-DOTA-TATE and 177Lu-DOTA-TATE. The protocol prescribes 4 therapeutic cycles alternating [177Lu]DOTA-TATE (5.55 GBq) and [90Y]DOTA-TATE (2.6 GBq). Dosimetric evaluation after administration of [177Lu]DOTA-TATE allows calculation of the absorbed doses in healthy organs. Toxicity was evaluated considering hematological parameters and glomerular filtration rate (GFR), while efficacy was measured with RECIST criteria. In 2010, 10 patients were enrolled and completed all cycles of treatment. In general, treatment was well tolerated and no adverse events were registered. No damage to healthy organs was revealed in accordance with the calculated absorbed doses. Considering the 26 patients treated since the start of accrual, 1 complete response, 9 partial responses, and 12 stabilizations of disease were recorded at 6 months after the last treatment. Efficacy of endoarterial treatment with 90Y-TheraSphere microspheres in hepatocellular carcinoma. To date, more than 90 patients with unresectable hepatocellular carcinoma have been evaluated after 90Y radioembolization. Fifty-six patients entered the study and were treated with standard lobar activity of 90Y TheraSpheres. The therapeutic activity was calculated so that a fixed absorbed dose of 120 Gy to the target lobe was reached. Median follow-up was 10 months, and complete or partial responses were obtained in 27.5-33.3% of patients, depending on the criteria used for evaluation. Keywords: peptide receptor radiotherapy, trans arterialhery radioembolization, pediatric endocrinology


DIAGNOSTIC IMAGING AND RADIOTHERAPY DEPARTMENT

139

RADIOTHERAPY 1

HEAD Patrizia Olmi, MD (retired 30 Sept 2010) Emilio Bombardieri, MD (present) STAFF MEMBERS

Nice Bedini, MD Anna Di Russo, MD Lorenza Gandola, MD Laura Lozza, MD Ester Orlandi, MD Claudia Sangalli, MD Fulvia Soncini, MD Silvia Tana, MD Francesca Valvo, MD Sergio Villa, MD

The research activity of the Unit is devoted to clinical multidisciplinary trials and projects mainly in the field of pediatric tumors, head and neck cancer, soft tissue sarcomas, and prostate cancer. Clinical activities also involve validation of new technologies (i.e. Rapid Arc) in specific clinical settings and quality assurance surveys. Overall, in 2010, treatment plans were delivered using the following techniques: 926 treatments with 3D conformal radiation therapy, 179 with IMRT, 225 with Rapid Arc, and 573 with 2D conventional radiotherapy, for a total of 1903 treatment plans (>1/patient). Rival plans are often required for optimal assessment of treatment. All treatments were delivered on an outpatient basis. Nearly 80% of patients were treated with curative intent. Keywords: radiotherapy, rapid arc technology, quality assurance

ADMINISTRATIVES

Donatella Orlandi, Patrizia Riva NURSES

Carla Viscardi, Pasquale Brunacci HEALTHCARE ASSISTANTS

Grazia Arpaia, Sebastiano Sicilia, Cristina Terenghi TECHNICIANS

Ciro Pintaudi (Coordinator), Cosimo Attolino, Arianna Bianchini,Claudio Boccadamo, Giuseppina Bonanno, Alberto Buzzetti, Carmelo Campolo, Gabriele Carabelli, Pasquale Contessa, Paolo D’Agnese, Carmelo Di Marco, Lucio Donatone, Rosa Fortunato, Sarah Frasca, Piera Fusar Poli, Franca Gaetano, Emanuela Gatti, Manuela Guerra, Daniela Pierograndi, Antonio Spartano, Francesca Spartano, Carla Valenti, Luca Zappa

2010 RELEVANT NOTES Collaborations Lorenza Gandola: Coordinator of “Radiotherapy Working Group” of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) and CoChairman Brain Tumor Group of the International Society of Paediatric Oncology (SIOP) Ester Orlandi: Co-investigator for the EORTC 24061 study: Randomized phase II feasibility study of Cetuximab combined with 4 cycles of TPF followed by platinum based chemo-radiation strategies and Member of the EORTC Head and Neck Group Silvia Tana: Member of Italian Germ Cell Cancer Group (IGG), Member of EAU Board for Guidelines on penis carcinoma Nice Bedini, Sergio Villa: clinicians in charge of Prostate Cancer Research International, active surveillance (PRIAS)

Publications Radiobiological basis and clinical results of the simultaneous integrated boost (SIB) in intensity modulated radiotherapy (IMRT) for head and neck cancer: A review. Crit Rev Oncol Hematol. 2010;73:111-25.


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SCIENTIFIC REPORT 2010

RADIOTHERAPY 2

HEAD Carlo Fallai, MD STAFF MEMBER

Annamaria Cerrotta, MD POSTDOCTORAL FELLOWS

Monica Alicia Garcia, MD NURSES

Pier Giulio Pezzaglia, Head Nurse Rosa Attolino, Marisa De Carli, Alessandra Licata, Emanuela Visentin, Antonio Micello , Antonella Causio, Francesco Tartaglione, Carmen Cuesta Garcia, Carmelina Minio, Luigia Cerra, Antonio Floresta, Antonio Lucenti HEALTHCARE ASSISTANTS

Angela Abatangelo, Brenilda M. Fuentes Delgado, Giuseppe Gaglio, Concetta Rugolo, Dario Tonelli, Claudia Soave ADMINISTRATIVE

Emilia Mausoli

Radiotherapy 2 (RT2) is the inpatient section of the Department of Diagnostic Imaging and Radiotherapy; its facilities include 8 beds in 4 shielded rooms, one operating room, and 1 office for inpatient preparatory procedures and for outpatient follow-up. In 2010, the mean hospital stay for inpatients was 7.7 days. Its principal aim is care of patients affected with any form of cancer undergoing inpatient radiation therapy. RT2 also cooperates with Radiotherapy 1(RT1) in the planning and delivery of external beam radiation treatments in outpatients, mainly for gynecologic and head and neck cancers, and in a metastatic/palliative setting. In addition to external beam radiotherapy, the activities of RT2 consist in administering high dose rate brachytherapy (HDR-BT). BT is generally administered on an outpatient basis: as endocavitary treatment in uterine cancers; as endoluminal treatment in biliary tract cancers; as interstitial treatment in breast cancer. During 2010, 65 patients were treated with 171 fractions and 167 treatment plans. Prostate cancer HDR-BT, as monotherapy, was activated in December 2010, consisting in 2 treatment sessions of 14 Gy each performed in low risk patients. RT2 collaborates with the Radiology Diagnostic Units for care of patients undergoing chemoembolization, intra-arterial chemotherapy, and other oncologically targeted interventional procedures requiring hospitalization. Combination chemoradiotherapy treatments were also performed, mainly in gynecologic, anorectal, and head and neck cancers. A total of 204 cycles of chemotherapy were administered in 2010. Supportive care for acute and, more infrequently, late radiotherapy-related complications is also provided. Keywords: head and neck cancer, gynecologic cancer, HDR brachytherapy, geriatric Oncology

2010 RELEVANT NOTES Collaborations MARCH Collaborative Group, Villejuif Cedex Gynecologic Cancer InterGroup (GCIG), Kingston, Ontario Associazione Italiana Radioterapia Oncologica (AIRO) and Scientific Secretariat of AIRO Annual Congress Regional Group of Lumbardy. Associazione Italiana di Radiobiologia (AIRB) European Society Therapeutic Radiation Oncology (ESTRO) American Society Therapeutic Radiation Oncology (ASTRO) SocietĂ Internazionale Oncologia Geriatrica (SIOG) Alleanza Contro il Cancro (ACC) (Project WP4 - Program 1)

Publications Fricke gel-layer dosimetry in high dose-rate brachytherapy. Appl Radiat Isot. 2010;68:722-5. Hyperfractionated or accelerated radiotherapy for head and neck cancer. Cochrane Database Syst Rev. 2010;12:CD002026.


DIAGNOSTIC IMAGING AND RADIOTHERAPY DEPARTMENT

141

MEDICAL PHYSICS

HEAD Giancarlo Zonca, Physics D STAFF MEMBERS Marta R. Borroni, Physics D Mauro Carrara, Physics D Valeria Mongioj, Physics D Emanuele Pignoli, Physics D Stefano Tomatis, Physics D RESEARCH MEMBERS Manuela Lualdi, Physics D TECHNICIANS

Vito Cosentino, Elena Fraigola, Luca C. Marrone, Ester Mazzarella, Dario Postè, Claudio G. Stucchi HEALTHCARE ASSISTANT

Giuseppina Esposito

The Unit is engaged in investigating high conformal treatments for the irradiation of different anatomical regions, and to achieve dose distribution optimization. Since many linac parameters can vary during patient irradiation, phantom dosimetric verification of treatment plans are also performed to evaluate the accuracy of the calculated dosimetric distribution on different planes. The accordance obtained between calculated and measured dose distribution in phantom was within the values reported in literature. Furthermore, in 2010 relevant support to the clinical application of image guided radiotherapy (IGRT) was provided. In collaboration with Radiotherapy 1 and the Department of Anaesthesiology, the Unit contributed to the adoption and optimization of an innovative facility for high dose rate brachytherapy (HDR-BT) for prostate cancer under real-time ultrasound guidance. Dosimetric calculations were performed for all patients recruited in HDR-BT study. The application of fluorescence intensity in patients with hereditary colorectal cancer (HCRC) is under investigation in collaboration with the Laboratory Medicine Unit. Promising preliminary data indicate that the intensity of the fluorescence emission peak around 615-635 nm is significantly different between patients with HCRC and control subjects. Keywords: dosimetry, radiotherapy, treatment planning

2010 RELEVANT NOTES Collaborations Physics Department of the University of Milan and the National Institute of Nuclear Physics.

Publications Feasibility study of a dosimeter for in vivo measurements of the absolute dose delivered in high dose rate brachytherapy. Il Nuovo Cimento. 125B(2010),667-73.


SHARED RESEARCH RESOURCES CARDIOLOGY RESPIRATORY PHYSIOPATHOLOGY CLINICAL PSYCHOLOGY MEDICAL STATISTICS, BIOMETRY AND BIOINFORMATICS CLINICAL EPIDEMIOLOGY AND TRIAL ORGANIZATION TISSUE BANK FUNCTIONAL GENOMICS CORE FACILITY CANCER PROTEOMICS-MOLECULAR MECHANISMS ANIMAL HOUSE


SHARED RESEARCH RESOURCES

145

CARDIOLOGY

HEAD

Patrizia Piotti, MD STAFF MEMBERS

Carlo Mterazzo, MD Enzo Viggiano, MD Costanza Mantovani, MD POSTDOCTORAL FELLOW

Ivan Moschetti, MD NURSES

Sabrina Barrotta, Graziella Borlenghi, Rosella Murru, Luisa Sala, Maria Nunziata Depetro ADMINISTRATIVES

The Cardiology Unit mainly carries out activities related to preoperative evaluation of surgical patients, tightly collaborating with anesthetists and thoracic and abdominal surgeons to reduce pre- and peri-operative risk and to manage complications. Evaluation and consultation is also carried out for patients of Fondazione IRCCS Istituto Neurologico C. Besta. The Cardiology Unit, among its main obligations, performs general cardiac evaluation of all candidates for chemo-radiotherapy treatment, with the aim of monitoring potential cardiovascular toxicity related to antineoplastic treatments. Several Phase II and Phase III clinical studies have been followed-up during 2010, with routine, mandatory, cardiologic surveillance for the possible cardiotoxicity of new experimental drugs. Keywords: preoperative evaluation, cardiotoxicity, experimental drugs surveillance

Maria Grazia Marchetti, Rosanna Villani

2010 RELEVANT NOTES Publications The Incremental Prognostic Value of Echocardiography in Asymptomatic Stage. A Heart Failure. J Amer Soc Echocardiography 2010;23:1025-34.

Contributions Patrizia Piotti and Carlo Materazzo participate in a multicenter study organized by the Italian Society of Cardiovascular Echography


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SCIENTIFIC REPORT 2010

RESPIRATORY PHYSIOPATHOLOGY

STAFF MEMBERS

Roberto Boffi, MD Alessandra Busia, MD NURSES

Maria A. Chiricosta, Elena Munarini, Ario A. Ruprecht HEALTHCARE ASSISTANT

Sara F. Santoro TECHNICIANS

Simona Montalti, Vito F. Valente CONSULTANT

Giovanni Invernizzi

The Respiratory Physiopathology Unit ensures functional pulmonary evaluation to patients who are candidate for thoracotomy, lung resection or abdominal surgery to assess individual risk of postoperative pulmonary complications and provide monitoring of pulmonary function. Lung function is also tested in patients who undergo radiotherapy and chemotherapy regimens known to be associated with the risk of pulmonary toxicity. Specifically, various examinations can be carried out such as: spirometry, 2D-Doppler echocardiography at rest, cardiopulmonary exercise test on cycloergometer and determination of cardiac output by a non-invasive method. Moreover, diagnostic and clinical assistance is provided to oncologic outpatients and patients referred by GPs and external medical consultants. Our activity focuses on the diagnosis and treatment of chronic obstructive pulmonary disease, asthma, interstitial pneumonia, and respiratory failure. Finally, the Unit is engaged in three main branches of tobacco control activity: clinical (smoking cessation), educational, and environmental tobacco smoke (ETS) research. In collaboration with the Thoracic Surgery Unit, we continue the evaluation of preoperative pulmonary function and risk factors in thoracic surgery patients. Conventional preoperative evaluation of thoracic surgery for lung cancer includes spirometry, determination of lung transfer factor for CO, arterial blood gas measurement, estimate of postoperative function calculated from radioisotopic studies, and exercise testing. Tobacco Control Unit (TCU) In collaboration with: Respiratory Unit, Brompton Hospital, London; South Western University, Los Angeles, California; Cornell University, New York; Tobacco Free Research Institute Dublin; National Environmental Research Institute, Roskilde; Department of Epidemiology for Cancer Prevention Victor Segalen Bordeaux University; UnitĂ Operativa di Epidemiologia ambientale e occupazionale, Istituto per lo Studio e la Prevenzione Oncologica (ISPO), Florence; Dipartimento di Prevenzione Regione Veneto. The TCU develops and organizes smoking cessation programs; in about 10 years of activity, TCU has enrolled more than 1,900 smokers, with an average cessation or reduction of 40%, in agreement with data from guidelines. A significant portion of clinical activity is devoted to passive smokersâ&#x20AC;&#x2122; health, with first diagnoses of obstructive lung disease in non-smokers complaining of respiratory symptoms associated with passive smoke. In 2005, we started a comprehensive project aimed to offer advice and a SC program to all INT smoker patients. Educational activities of TCU aim to enhance the awareness of nosmoking policies at the workplace, to supply schools with educational programs, and to lobby against tobacco smoke. TCU provided numerous local schools with educational antismoking programs for students and teachers. From 2003, we are holding courses on smoking cessation and tobacco marketing at the University of Milan School for Nurses. Because of the educational importance of explaining the environmental health risks linked to tobacco smoke, a research laboratory section for the study of ETS was implemented in 2001. The laboratory carries out several innovative research programs and scientific articles are published in collaboration with various national and international research institutions.


SHARED RESEARCH RESOURCES

147

CLINICAL PSYCHOLOGY

HEAD

Claudia Borreani, MD STAFF MEMBERS

Marco Bosisio, Psychologist Laura Gangeri, Psychopedagogist CONSULTANTS

Margherita Greco, Psychologist Luciana Murru, Psychologist Patrizia Trimigno, Psychologist Micaela Lina, Psychologist Cinzia Brunelli, Statistician FELLOW

Elisabetta Bianchi, Psychologist ADMINISTRATIVE

Maria Teresa Cariglia SOCIAL ASSISTANT

Silvia Bettega

The Unit is involved in clinical psychology, research, and education in oncology. The mission of the Unit is to support adult patients and families who are living with a life-threatening illness. The goals are to enhance quality of life and well-being, and to relieve suffering in all its dimensions throughout illness, survivorship, and bereavement. This is accomplished by providing expert clinical intervention such as individual psychological counseling, short psychotherapies, verbal and psycho-bodily groups, psycho-educational groups, and family therapies. Multidisciplinary clinical projects are carried out in collaboration with Medical and Surgical Units of the INT. The Unit aims also to improve knowledge about the psychological experience of cancer through its research activities. The following research projects were in progress during 2010: - Psychological impact of prevention programs in BRCA1-2 carriers. - Individual end-of-life preferences: impact and usefulness of the ELPI Interview. - The role of religious practices/beliefs and of spirituality in the search for meaning during the psychological adjustment process of cancer patients. - Participants' perspective on information aid for newly-diagnosed MS patients: a qualitative study within the SIMS-Trial (SIMS-Qual) The Clinical Psychology Unit actively took part in the constitution of multidisciplinary work groups such as the Conflicts Mediation Group and the Work Related Stress Group. During 2010, the Unit planned educational trainings for healthcare professionals and administrative front line workers. The purpose was to upgrade their communication skills in relationships with cancer patients and their families. Keywords: psychosocial care, communication, quality of life

2010 RELEVANT NOTES Collaborations FACIT Measurement System; University of Milan - Bicocca; ISPO Florence; Istituto Nazionale per la Ricerca sul Cancro (IST), Genoa; Istituto Regina Elena IRCCS, Rome; Fondazione IRCCS Istituto Neurologico C. Besta, Milan

Publications SIMS-Trial group. An information aid for newly diagnosed multiple sclerosis patients improves disease knowledge and satisfaction with care. Mult Scler. 2010;16:1393-405 What "best practice" could be in Palliative Care: an analysis of statements on practice and ethics expressed by the main Health Organizations. BMC Palliat Care. 2010;9:1

Contributions National Commission: SIPO Psiconcogen North Italian Transplant - Technical review of the psychological aspects of transplantation


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SCIENTIFIC REPORT 2010

MEDICAL STATISTICS, BIOMETRY, AND BIOINFORMATICS

HEAD

Adriano Decarli, PhD STAFF MEMBERS

Elia Biganzoli, PhD Paolo Verderio, Biol Sci D, PhD FELLOWS

Ilaria Ardoino, PhD Chiara Maura Ciniselli, MSC Matteo Malvezzi, PhD Annalisa Orenti Sara Pizzamiglio, MSC ADMINISTRATIVE

Maria Chiara Piano

The Medical Statistics Biometry and Bioinformatics Unit (MSBB) provides quantitative support to research activities of INT. Moreover, MSBB bridges collaborative relationships with other national and international research groups. The INT group activity is governed by a convention with the University of Milan. Areas of method development and application pertinent to MSBB activities include assay development and quality control, predictive models for diagnosis and prognosis, planning and design of observational or randomized studies, data management and study monitoring, and techniques to report and interpret clinical study results. The main topics in epidemiological research are the relationships between dietary habits and risk of cancer, to implement innovative statistical multivariate models in the analysis of dietary data, and to develop predictive models for cancer risk. Biostatistics for Oriented Basic Research and Quality Control (P. Verderio) The team applies statistical methods to different phases of the biomarker development process in oncology. Specifically, it provides statistical analysis of quality control studies for tumor biomarkers and in vitro-diagnostic tools; studies for the evaluation of inherited diseases in oncology; studies for setting up and validation of biological assays; studies of preclinical pharmacology and testing new molecular detection strategies based on innovative technologies Biostatistics for Bioinformatics and Translational Research (E.M. Biganzoli) This team follows the transfer of basic preclinical research to the clinical setting, resorting to quantitative approaches for assessment of the impact of new technologies in oncology, according to cost-benefit principles and sustainability perspectives. Collaborative studies are ongoing related to the comparison of different high-throughput platforms for miRNA, qRT-PCR, and high throughput assays in cancer. Keywords: computational tools and algorithms, randomized trials, methods to handle data features and anomalies

2010 RELEVANT NOTES Collaborations

Contributions

International Agency for Research in Cancer (IARC), Lyon

Paolo Verderio: Editorial Board of Journal of Clinical Oncology

Biostatistics Branch, National Cancer Institute, Bethesda

Elia Biganzoli: co-organiser of the session "Multivariable model-building with continuous variables â&#x20AC;&#x201C; a comparison of flexible regression approaches" International Biometric Society Conference Florianopolis, Brazil, 2010

Molecular and Nutritional Epidemiology Unit , ISPO Florence ISS-ACC Bioinformatics Oncology Network RNBIO INNS Biopattern Special Interest Group Italian Network for Quality Assessment of Tumor Biomarkers (SPIDIA) â&#x20AC;&#x201C; European Project - FP7 Program

Publications A BRCA1 promoter variant (rs11655505) and breast cancer risk. J Med Genet. 2010;47:268-70 Histology-Specific Nomogram for Primary Retroperitoneal Soft Tissue Sarcoma. Cancer. 2010; 116: 2429-36 Alcohol consumption and lung cancer risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) study. Am J Epidemiol. 2010 171:36-44

Editorial Board of Source Code in Biology and Medicine Adriano Decarli: member of the Executive Committee of the International Society of Clinical Biostatistics (ISCB) and President of the Biometric Society (Italian Region)


SHARED RESEARCH RESOURCES

149

CLINICAL EPIDEMIOLOGY AND TRIAL ORGANIZATION

HEAD Luigi Mariani, MD, PhD STAFF MEMBERS

Rosalba Miceli, PhD Salvatore Lo Vullo, BSc Flavia Mattana, BSc ADMINISTRATIVE

Maria Chiara Piano

The Unit provides biostatistical support in a broad array of clinic-based research projects, and is actively involved in methodological research and clinically-oriented teaching activities. The personnel has expertise across a wide range of statistical methods and research designs, and has extensive experience working with biomedical and clinical investigators in diverse disciplines, from design of the investigational plan through analysis and publication of study results. The Unit has participated in a total of 104 projects (mainly in surgical, medical, or hematologic oncology), of which 78 were activated during the last year. The Unit’s research objectives are: a) methodologies for performing nested case-control studies; b) design and sample size calculation for adaptive trials; c) development of nomograms from piecewise survival models. Grant-supported specific research projects included: • Design and analysis of phase I studies: methodological aspects and practical applications in oncology. • Evaluation of biomarker efficacy in postoperative monitoring of early breast cancer. The utility of CEA and CA15.3 in breast cancer follow up is being challenged in an ongoing multicenter randomized trial comparing biomarker based versus standard follow up. • Hepato-Oncology: a multidisciplinary approach for an emerging specialty. An integrated project investigating the validity of innovative approaches in prevention, diagnosis, and therapy of liver cancer. • Translational research on molecular markers in gastric cancer patients treated with adjuvant therapy. Nested case control study focusing on different molecular factors biologically relevant for gastric cancer progression and associated with Helicobacter pylori infection. Keywords: biostatistics, study design, data analysis

2010 RELEVANT NOTES Collaborations ABO Association - Identification of serum tumor markers in breast carcinoma (http://www.fondazioneabo.org/)

Publications Histology specific nomogram for primary retroperitoneal soft tissue sarcoma. Cancer. 2010;116:2429-36. Comparison of the prognostic value of assessing tumor diameter versus tumor volume, at diagnosis or in response to initial chemotherapy, in rhabdomyosarcoma. J Clin Oncol. 2010;28:1322-8.


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TISSUE BANK

DIRECTORS OF THE FACILITY

Giuseppe Pelosi, MD Maria Grazia Daidone, Biol Sci D, PhD STAFF MEMBERS

Silvia Veneroni, Biol Sci D Corrado Avarino, Technician Gloria Morandi, Technician

Since 2002, the Tissue Bank Facility of the INT has been dedicated to the collection and distribution of neoplastic, preneoplastic, and normal tissues from human subjects. This resource is a project of INT Scientific Directorate, with day-to-day staff supervision provided by personnel from the Departments of Pathology and Experimental Oncology & Molecular Medicine. The activities are overseen by an interdepartment advisory committee, which also evaluates and approves research projects depending on the availability of tissue specimens. Adopting TUBAFROST procedures, although slightly modified to comply with local conditions, the INT Tissue Bank stores frozen samples (primary and metastatic lesions, with corresponding normal tissues) and contributes specimens to more than 30 specific research projects dealing with breast, ovarian, lung, head and neck, thyroid, colorectal, endometrial, and renal cancers, in addition to soft tissue sarcomas, melanoma, and pediatric tumors. All patients/subjects sign an informed consent document (approved by the Independent Ethics Committee and filed in the patientsâ&#x20AC;&#x2122; record) to donate the leftover tissue/biological specimens after diagnostic procedures have been completed for future studies at the INT Tissue Bank. It is a one-time general consent using a two step decision procedure. At the time of surgical and/or medical procedures, patients are told how samples and health information will be obtained, what risks future research uses pose to them, and whether the research will have any impact on their clinical care. They can choose whether their samples and associated information may or may not be used for future research, relying on an Independent Ethics Committee for the approval of biologically and/or clinically relevant studies. Otherwise, patients will be contacted repeatedly to provide study specific authorization for the use of biological samples and associated personal information. Guidelines have been proposed to define responsibilities for Tissue Bank management, policies, and procedures to protect patient confidentiality and privacy, and establish priorities for specimen distribution. In particular, in 2010 the personnel of INT Tissue Bank collaborated with INT Independent Ethics Committee to develop a set of recommendations on critical aspects pertaining to the use of biological samples for research purposes. In collaboration with the INT Division of Information Technology and the Politecnico of Milan, approaches for tracking biological specimens through radiofrequency identification technology have been set up, and an integrated data base is now under implementation to link information related to biospecimens to pathologic diagnosis, minimum clinical data set, and follow-up information and to allow a dynamic and user-friendly interface for pre-clinical and clinical studies. In 2010, the INT Tissue Bank stored frozen specimens from 1,520 new cases. Investigations have been carried out to assess the impact of biospecimen handling on biomarker research in colon cancer tissues and corresponding normal mucosa, to analyze the baseline specimens (frozen within 20 minutes after surgical removal) of these series of cases across 5 miRNA microarray platforms and compare their hybridization performance. Time elapsed between surgery and freezing of samples appears to have a strong impact on sample quality and should be considered as a mandatory variable to control for clinical implications of inadequate tissue handling.

Biological specimens collected in the INTM BioBank from 2006 to 2010 (7261 specimens for an overall of 14676 aliquots)

Cumulative accrual of specimens in the BioBank of Istituto Nazionale Tumori from 2006 to 2010


SHARED RESEARCH RESOURCES

151

FUNCTIONAL GENOMICS CORE FACILITY

HEAD

Silvana Canevari, Bio Sci D STAFF MEMBERS

Vera Cappelletti, Biol Sci D Rosaria Orlandi, Biol Sci D Maria Luisa Sensi, Biol Sci D RESEARCH MEMBERS

Marina Bagnoli, Biol Sci D, Loris De Cecco, Biol Sci D POSTDOCTORAL FELLOWS

Maurizio Callari, Biotech D Pinciroli Patrizia, Biol Sci D TECHNICIAN

Edoardo Marchesi

The activities of the Functional Genomics core facility are based on wet analyses performed using the Illumina platform and computational analyses using two dedicated workstations. The research group comprises full time personnel involved in wet analyses and personnel dedicating part of their institutional activity to computational analysis of wet and in silico data. Thanks to external training courses, in-house further specialization and fruitful interaction with the Medical Statistics, Biometry, and Bioinformatics Unit, the core facility performs: study design; RNA and DNA extraction; quality controls; all labeling and hybridization methodologies required for high quality analysis; data processing and normalization; full computational analysis. During 2010, 1,700 samples arising from experimental or clinical studies were analyzed for: whole genome expression; Illumina DASL (cDNA-mediated annealing, selection, extension and ligation) assay; miRNA whole expression. Furthermore, the core facility staff elaborated in silico analyses using publicly available datasets from ovary, breast, thyroid, and prostate cancers, as well as melanoma and B-cell lymphomas. Computational and functional analyses are performed using the open source Bioconductor 2.1 and R Software Packages; candidate protein interactions are evaluated using Ingenuity Pathway Analysis 5.0 (Ingenuity Systems Inc, CA, USA) software. A survey of custom satisfaction related to a total of 70 studies conducted from July 2007 to June 2010 indicated that 89% of the results are satisfactory or above expectancy and at least 50% contributed to the generation of new hypotheses.

2010 RELEVANT NOTES Collaborations ABO Association - Identification of serum tumor markers in breast carcinoma (http://www.fondazioneabo.org/)

Publications Histology specific nomogram for primary retroperitoneal soft tissue sarcoma. Cancer. 2010;116:2429-36. Comparison of the prognostic value of assessing tumor diameter versus tumor volume, at diagnosis or in response to initial chemotherapy, in rhabdomyosarcoma. J Clin Oncol. 2010;28:1322-8.


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CANCER PROTEOMICS - MOLECULAR MECHANISMS

HEAD Italia Bongarzone, Biol Sci D RESEARCH MEMBER

Francesca Miccichè, Biol Sci D POSTDOCTORAL FELLOWS

Mattia Cremona, Biol Sci D, PhD Caccia Dario, Biotech D, PhD Elena Vaghi, Biotech D, PhD TECHNICIANS

Piera Mondellini Maida De Bortoli

The laboratory develops proteomics applications in cancer including the discovery of novel cancer and treatment signatures, the investigation of oncogenesis mechanisms, and the discovery of novel protein targets for therapeutic intervention. Main research projects include: 1) discovery of biomarkers potentially useful for developing a multiparametric analysis to identify individuals at high risk of lung cancer. A potential cluster of cytokines useful for evaluation of lung cancer risk was recently identified. The effective power of this pattern is now the object of further studies in a larger number of subjects. Several methods of breath analysis have been set up, ranging from measurement of exhaled breath biomarkers and volatile organic compound (VOC) assessment using mass spectrometry, to analysis of various proteins and metabolites in exhaled breath condensate (EBC); 2) signaling pathway profiling of renal cell carcinoma for targeted therapy. Laser capture microdissection (LCM) and reverse-phase protein arrays (RPPAs) were used to determine the signaling pathway status in tumor cells of a large panel of primary clear cell renal cancers. The results demonstrate that clear renal cell carcinoma could be stratified on the basis of the activated signaling proteins and this type of analysis could be useful in the rationale selection of the most appropriate therapeutic approach; 3) relationships between FAK signaling, microtubule dynamics and drug response. The results support the concept that FAK activity in various cancer cell line types is associated with constitutive activation of anti-apoptotic signaling pathways and drug resistance. Other projects: • identification of immunodominant non-Hodgkin lymphoma-restricted antigen(s) as novel biotarget(s) for therapy. • signaling pathway profiling of colorectal cancer liver metastases for targeted therapy. • cerebrospinal fluid proteome from central nervous system pediatric tumors: patient-related patterns. Keywords: mass spectrometry, cancer biomarkers, human fluids, signaling pathways, targeted therapy

2010 RELEVANT NOTES Technologies 1-D and 2-D electrophoretic protein separations, DIGE technology, MALDI-TOF mass spectrometry (Voyager DE-STR), and SELDI-TOF technology (PCS 4000)

Collaborations Istituto Superiore di Sanità Istituto Nazionale per la Ricerca sul Cancro (IST), Genoa IRCCS Ospedale Oncologico, Bari IRCCS S. Maria Nuova, Reggio Emilia Applied Biology at the University of Brescia George Mason University, Center for Applied Proteomics and Molecular Medicine, Virginia, USA Laboratori d'Investigació UdL/HUAV Dept. Medicina Experimental Universitat de Lleida, Spain

Publications Elevated levels of the acute-phase serum amyloid are associated with heightened lung cancer risk. Cancer. 2010;116:1326-35 Dasatinib reduces FAK phosphorylation increasing the effects of RPI-1 inhibition in a RET/PTC1-expressing cell line. Mol cancer. 2010;9:278


SHARED RESEARCH RESOURCES

153

ANIMAL HOUSE

HEAD

Giacomo Manenti, Chem D, PhD IN STAFF

Gaetano Melillo, Angelo Farina, Giuseppina Liguori, Cosimo Placido, Cristina Ripoli, Giovanna Ripoli, Nazareno Roberti, Massimiliano Scaranello, Carlo Salandra

Modelling human cancer in mice is an unsurpassed need to validate candidate genes involved in transformation and cancer progression as well as to study new therapeutic options. Microarray technology, gene expression profiles, and genomics provide an multitude of genes that require validation. The search for molecules that interfere with their function requires a complex biological system wherein to test efficacy in clinical applications. Technologies for the manipulation of the mouse embryo including homologous recombination and the similarity of human and mouse genome have allowed the creation of mouse models of human pathologies, which are essential for studying complex cancer traits and testing novel therapeutics. Carcinogenesis is associated with disruption of tissue architecture, with consequent induction of proinflammatory cytokines and chemokines in a milieu in which leukocytes are present and further recruited. Despite such an inflammatory environment, tumors can evade immune surveillance through mechanisms of resistance or induction of tolerance. In this context, mice knockout (KO) for ECM genes and inflammatory molecules, when crossed with transgenic mice carrying oncogenes, permits study of the role of inflammation within variable tumor microenvironments. Cancer immunotherapy has long been studied at INT, and tumor prone transgenic mice complement such studies by testing cancer vaccines in the setting of immunoprevention and therapy of small and large tumors rather than in more artificial transplantable models. At INT, several transgenic mice reproducing the characteristics of human cancers occurring in prostate, mammary gland, thyroid, colon, and melanocytes have been created and collected. Other transgenic mice carry clonotypic T cell receptors (TCR) or correspondent antigens under tissue specific promoters. The collection includes several mice KO for genes encoding certain cytokines and their receptors, chemokines, signal transduction molecules, ECM proteins, and metalloproteases. The mouse facility includes several areas for breeding, and a dedicated laboratory is equipped with an X-ray irradiator, and a non-invasive imaging system using micro-ultrasound and microPET. This large mouse collection has had an impact on studies at INT, allowing the discovery of new processes related to tumor biology, immunotherapy, and chemotherapy, and, more importantly, enabling us to investigate the underlying mechanisms. During 2010, published papers reporting animal studies contributed for about 24% of the total Impact Factor of the Department of Experimental Oncology and Molecular Medicine.

Ethics Committee for Experimentation on Animals (CESA) Marco A. PIEROTTI, President Giacomo MANENTI, Secretary Alessandro ADDIS Carlo BATTISTON Filiberto BELLI Mario P COLOMBO Luca GIANNI Giuseppe PELOSI Francesca VALVO In compliance with the national legislation (D.L.116/92), the Research Projects requiring animal studies are critically evaluated for approval by the CESA before being submitted to the Italian Ministry of Health.


EDUCATION AND TRAINING

155

EDUCATION & TRAINING

INT is strongly committed to educating future research scientists and clinicians and is directly engaged in quality education and training. INT offers a wide range of educational activities for clinical and experimental researchers at different stages of their professional experience. PhD studentships, postdoctoral research fellowships, graduate student training, medical residency training, psychology and social work training, as well as continuing medical education are all included in the portfolio of educational opportunities offered to staff and external participants. Invited lectures, seminars and workshops in a variety of research disciplines related to cancer are regularly arranged. Participants in education and training programs are encouraged to attend also the interdepartmental journal clubs, clinical case discussions and grand rounds as well as other multidisciplinary activities aimed to create interspecialistic knowledge. Academic Programs INT provides education and training at various levels, including undergraduate, graduate as well as postgraduate medical and biotechnology students, physicians, nursing students, and nurses. On the basis of formal agreements with the University of Milan, INT hosts the Chairs of Medical Oncology (Prof Alessandro M. Gianni), Hematology (Prof Paolo Corradini), Medical Statistics and Biometry (Prof

Adriano Decarli), Anesthesiology (Professor Martin Langer) and Pathology (Prof Giuseppe Pelosi). A number of staff members have a joint appointment as professors at the University of Milan and contribute to the regular curriculum at this University. INT hosts the “Postgraduate School in Oncology”, the “Postgraduate Medical School in Pathology”, and the 3-year degree in “Nursing Sciences” of the University of Milan. Additionally, INT participates in the degree in “Biotechnology and Molecular Medicine in Oncology”, as well as in two PhD programs of the University of Milan (“Hematology” and “Medical Biotechnology”). Doctoral (PhD) training program at INT The INT is an Affiliated Research Centre of the Open University, Milton Keynes, UK, providing a PhD Program in Life and Biomolecular Sciences. The program run at INT meets the requirements of the Quality Assurance Agency (QAA) for Higher Education Code of Practice INT provides direct support for these training positions and offers fellowship/grants to European Community postgraduate students holding a degree in Medicine, Biological Sciences or Pharmacy. Students are involved in several activities, including induction courses, generic skills training, journal club meetings, and seminars. At present, 19 students are carrying out their training program as shown below.

PHD STUDENTS AND RESEARCH TOPICS - OPEN UNIVERSITY, LONDON Burocchi Alessia

Bortolomai Ileana

Modulation of regulatory T cell suppression in tumors through OX40

Anania Maria Chiara

Identification and characterization of tumor-initiating cells from gynecological malignancies

Role of genes differentially expressed in thyroid carcinogenesis

Bertolini Giulia

Vizioli Maria Grazia

Isolation in vitro propagation and characterization of lung cancer stem cells

Role of oncogene-induced senescence and DNA damage response in thyroid carcinogenesis

Cossa Giacomo Modulation of sensitivity to platinum compounds in ovarian carcinoma cell systems

Perego Michela Phenotypical and functional studies on putative cancer stem cells of human melanoma

Zappasodi Roberta

Exploring the role of microRNA in early lung cancer

Active and adoptive immunotherapy in indolent lymphoproliferative diseases

Catucci Irene

Colombo Francesca

Boeri Mattia

Identification of low penetrance alleles genetic modifiers and mutation analysis in familial breast cancer cases

In vitro analysis of functional polymorphisms modulating individual risk of lung cancer

Piovan Claudia

Frullanti Elisa

MicroRNAs in breast tissue biology and disease: involvement in development and tumorigenesis processes

Genome-wide identification of functional polymorphisms modulating individual risk of lung cancer

Santangelo Alessandra

Crippa Elisabetta

SPARC, a matricellular protein that protect tumors from therapy

Sasso Marianna Biomarkers of aggressive phenotype in triple negative breast cancer

Bianchi Francesca FHIT oncosuppressor gene in carcinogenesis

Identification of miRNA target gene pairs involved in hereditary breast cancer

Passafaro Alfonso Role of SPARC in inflammation and cancer

Rigoni Alice Mast cells at the interface between external challenges and immune regulation in colitis and colorectal cancer


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In 2010 , two students were awarded a PhD degree: Paolo Gandellini and Marilena Iorio. Masters • Academic Master in Epidemiology. This is a joint appointment with the University of Torino, ISI Foundation and INT Division of Etiologic Epidemiology and Prevention. • Master in Rectal Surgery. INT and ARECO (Association for the European Research in Surgical Oncology) offer a Rectal Surgery Master for medical doctors with Surgery degree. • Academic Course in Oncologic Lymphology. The course is designed for physicians and students graduating in lymphology and oncologic lymphology. The Division of Palliative Care, Pain Therapy and Rehabilitation is the scientific coordinator and is in charge of the educational activities, referred to the Medical Faculty of the University of Milan. • Master of Palliative Medicine for Nurses. Under the direction of the University of Milan and in collaboration with INT, this academic course trains graduated nurses to provide palliative care to patients with cancer diseases. • Master in Medical Statistics and Statistical Methods for Epidemiological Research. MSSME is aimed for graduate with Medicine, Biological Sciences, Physics or Statistics degree. Postgraduate course in biostatistics are also provided. Postgraduate students are often directly involved in research projects coordinated by MSBB members Other Courses The Pathology Department is involved in the training programs of the Postgraduate Medical Schools of Pathology, Endocrinology and Respiratory Medicine (University of Milan) and of the Soft Tissue Pathology, Postgraduate School of Pathology (Insubria University of Varese). The Anesthesia Department is involved in the training program and residency of the Postgraduate School for Anesthesia and Intensive Care, hosts a number of residents/students and organizes part of the formal teaching in the program of the postgraduate course of the Medical School - University of Milan. Residents in Anesthesia and Intensive Care, Cardiology, Nutritional Support (University of Milan and Milano-Bicocca) work within all the Units of the Department. Many Staff Members have teaching positions or are tutors in postgraduate medical schools or in national/international master programs in Supportive Cancer Care, in Organization, Management and Care in Hospice and in INT Nursing School. Within the Surgery Department, the Division of Colorectal Surgery is affiliated with the General Surgery Residency Programs of the Milano-Bicocca and Pavia Universities; the

Division of Gastrointestinal and Hepatopancreatobiliary Surgery and Liver Transplantation is a training center for the University of Milan and the Italian College of Surgeons and is chosen for clinical fellowships by many visiting clinicians and surgeons every year. In the area of clinical and training activities, the Plastic and Reconstructive Surgery Unit holds weekly and 3-monthly surgery courses for Italian and foreign surgeons. The Gynecologic Oncology Division is chosen for clinical fellowships by many visiting surgeons from Italy and other countries every year. It also organizes a biennial international meeting, and a gynecologic oncology course with more than 50 participants three times a year. The Otorhinolaringology Surgery Division has close links with the University, and is involved in postgraduate teaching and supervising of junior medical staff. In collaboration with the Human Morphology Department of the University of Milan, this Division activated two research doctoral degrees to develop a new non-invasive method to evaluate the functionality of the mimetic musculature after iatrogenic damage to the facial nerve. The Division also collaborates with the Otorhinolaryngoiatric School of Specialization of the University of Milan, hosting students for practical training and organizing lessons and courses. The Thoracic Surgery Division collaborates with the General Surgery and Thoracic Surgery School of Specialization of the University of Milan, hosting students for practical training. Many postdoctoral fellows attend the Melanoma and Sarcoma Division that collaborates actively with several medical universities. The Senology Division collaborates with the University of Milan to teaching and research projects. The Medical Staff of the Diagnostic Imaging and Radiotherapy Department is involved in educational activities cooperating with the University of Milan and Milano-Bicocca in the Radiology, Radiotherapy, and Medical Oncology Specialization Schools, in the “Clinical Application of Nuclear Medicine”, Nuclear Medicine School of Specialization. The Radiotherapy Unit also provides tutoring of radiography and radiation technician students. Continuing Medical Education Program The educational and training program promotes professional, cultural and human growth of INT employees. During 2010, the INT ECM Provider has proposed 203 events in the main areas (clinical governance, learning on the job, risks prevention and emergency management, etc.) of ECM-CPD (159 were accredited), attracting the interest and the participation of resident and visiting health professionals. In particular, the educational initiatives included in the Business Formation Plan (BFP) have achieved a total amount of 26,347 formative credits, involving 3,963 people.


EDUCATION AND TRAINING

SEMINARS AND CONFERENCES JANUARY Viktor Umansky Department of Thoracic Surgery, Thoraxklinik, University of Heidelberg, Heidelberg

Melanoma immunosuppressive microenvironment in RET transgenic mouse model MARCH Giuseppe Toffoli Experimental and Clinical Pharmacology Division, The Aviano National Cancer Institute and Center for Molecular Biomedicine, Italy

Pharmacogenetics in cancer: Transferring translational research into clinical practice APRIL Sylvia Janetzki Cancer Vaccine Consortium of the Cancer Research Institute, New York, NY

New Developments and Proven Solutions for ELISpot Assays Anna B. Lach Scientific Consultantul Pawinskiego 5a/D – Warszawa

MSCCP technology – a novel approach towards biomaker discovery and personalized medicine MAY Elizabeth H. Blackburn Morris Herzstein Professor, Department of Biochemistry & Biophysics. University of California. San Francisco

Telomeres and telomerase in human health and disease JUNE W. Nicol Keith Centre for Oncology & Applied Pharmacology, University of Glasgow, Cancer Research UK beatson Laboratories – Glasgow

Why is cellular senescence an attractive target for drug discovery? and Career progression, funding & fellowships & scientific networking in the facebook era Jan van Oostrum Novartis Institutes for BioMedical Research, Basel

Pathway Proteomics using protein Microarrays Curzio Rüegg Department of Medicine, Faculty of Science, University of Fribourg, Fribourg

Tumor-Host interaction in angiogenesis and tumor progression Giorgio Inghirami Department of Biomedical Science and Human Oncology, Department of Pathology, Center of Experimental Medicine and Research. CeRMS. University of Turin

Dissecting the role of ALK in anaplastic large cell lymphoma JULY Peter B. Bach Memorial Sloan-Kettering Cancer Center - Epidemiology and Biostatistics Department - NY

The International meta-analysis on lung cancer screening: recent data

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SCIENTIFIC REPORT 2010

Bice Bruppacher CovalX AG, CH-8952 Schlieren. Switzerland

High-mass MALDI-TOF mass spectromery and chemical cross-linking for interaction analysis Ian G. Mills Uro-Oncology Research Group, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge

Transcriptional regulation of metabolism, stress responses and autophagy in prostate cancer SEPTEMBER Adrian Harris The Weatherall Institute of Molecular Medicine, University of Oxford

Mechanisms of response and resistance to anti-angiogenesis therapy OCTOBER Wilhelm Engstrรถm Division of Pathology, Pharmacology and Toxicology, Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala

Scaffold proteins and the control of cell proliferation in normal and malignant cells Dieter Fuchs VisualSonics Inc.

Presentation on high-resolution in vivo micro-imaging for small animal research John A. Ryals Metabolon, Inc., Durham, North Carolina

Global metabolism: non-targeted metabolomic analysis platform and its application in biological research NOVEMBER Phillip Beckhove Translational Immunology Unit, German Cancer Research Center, Heidelberg

Regulation of T-Cell response in cancer patients Chiara Malinverno Department of Anatomy, Pharmacology and Forensic Medicine, University of Parma, Parma

The role of TRAIL in apoptosis and differentiation Daniel Peeper Molecular Genetics. The Netherland Cancer Institute, Amsterdam

Unraveling cancer cell signaling networks & screening for novel drug targets DECEMBER Irene Chiolo Lawrence Berkeley National Laboratory Life Sciences Division Berkeley, CA

Spatial and temporal regulation of double-strand break repair in heterochromatin and its role in genome stability


PUBLICATIONS

159

PUBLICATIONS Publications (overall 426 - IF 2274.62) INT authors only 92 (IF 388.28)

Collaborations with foreign Institutions 197 (IF 1321.47)

The successful research collaboration is shown by the high number of scientific articles published with other national Institutions (137, 32%) and with foreign Institutions (197, 46%). Collaborations with national Institutions 137 (IF 564.63)

Plesko I., Primic-Zakelj M., Rachtan J., Tagliabue G., Tumino R., Traina A., Tryggvadottir L., Vercelli M., Sant M.: Variation in ‘standard care’ for breast cancer across Europe: a EUROCARE-3 high resolution study. Eur J Cancer 2010; 46: 1528-1536 [IF 4.121]

1 Agnoli C., Berrino F., Abagnato C.A., Muti P., Panico S., Crosignani P., Krogh V.: Metabolic syndrome and postmenopausal breast cancer in the ORDET cohort: A nested case-control study. Nutr Metab Cardiovasc Dis 2010; 20: 41-48 [IF 3.517]

8

2

Allen N.E., Tsilidis K.K., Key T.J., Dossus L., Kaaks R., Lund E., Bakken K., Gavrilyuk O., Tjonneland A., Olsen A., Fournier A., Fabre A., Clavel-Chapelon F., Chabbert-Buffet N., Sacerdote C., Krogh V., Bendinelli B., Tumino R., Panico S., et al.: Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European prospective investigation into cancer and nutrition. Am J Epidemiol 2010; 172: 1394-1403 [IF 5.589]

Alaggio R., Collini P., Randall R.L., Barnette P., Million L., Coffin C.M.: Undifferentiated high-grade pleomorphic sarcomas in children: a clinicopathologic study of 10 cases and review of literature. Pediatr Dev Pathol 2010; 13: 209-217 [IF 1.163]

3 Aldinucci D., Gloghini A., Pinto A., De Filippi R., Carbone A.: The classical Hodgkin’s lymphoma microenvironment and its role in promoting tumour growth and immune escape. J Pathol 2010; 221: 248-263 [IF 6.466]

4 Aldinucci D., Pinto A., Gloghini A., Carbone A.: Chemokine receptors as therapeutic tools in Hodgkin lymphoma: CCR4 and beyond. (Letter) Blood 2010; 115: 746-747 [IF 10.555]

5 Aldinucci D., Rapana B., Olivo K., Lorenzon D., Gloghini A., Colombatti A., Carbone A.: IRF4 is modulated by CD40L and by apoptotic and anti-proliferative signals in Hodgkin lymphoma. Br J Haematol 2010; 148: 115-118 [IF 4.597]

6 Aleksandrova K., Jenab M., Boeing H., Jansen E., Bueno-deMesquita H.B., Rinaldi S., Riboli E., Overvad K., Dahm C.C., Olsen A., Tjonneland A., Boutron-Ruallt M.C., Clavel-Chapelon F., Morois S., Palli D., Krogh V., Tumino R., Vineis P., Panico S., Kaaks R., Rohrmann S., Trichopoulou A., Lagiou P., Trichopoulos D., van Duijnhoven F.J., Leufkens A.M., Peeters P.H., Rodríguez L., Bonet C., Sanchez M.J., Dorronsoro M., Navarro C., Barricarte A., Palmqvist R., Hallmans G., Khaw K.T., Wareham N., Allen N.E., Spencer E., Romaguerra D., Norat T., Pischon T.: Circulating Creactive protein concentrations and risks of colon and rectal cancer: a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Am J Epidemiol 2010; 172: 407-418 [IF 5.589]

7 Allemani C., Storm H., Voogd A.C., Holli K., Izarzugaza I., Torrella-Ramos A., Bielska-Lasota M., Aareleid T., Ardanaz E., Colonna M., Crocetti E., Danzon A., Federico M., Garau I., Grosclaude P., Hédelin G., Martinez-Garcia C., Peignaux K.,

9 Alvaro D., Cannizzaro R., Labianca R., Valvo F., Farinati F., Avuzzi B., Buscarini E., Fornasarig M., Iacono C., Maiero S., Mosconi S., Muto P., Tasca C., Vanin V.: Cholangiocarcinoma: A position paper by the Italian Society of Gastroenterology (SIGE), the Italian Association of Hospital Gastroenterology (AIGO), the Italian Association of Medical Oncology (AIOM) and the Italian Association of Oncological Radiotherapy (AIRO). Dig Liver Dis 2010; 42: 831-838 [IF 2.972]

10 Amendola E., Sanges R., Galvan A., Dathan N., Manenti G., Ferrandino G., Alvino F.M., Di Palma T., Scarfò M., Zannini M., Dragani T.A., De Felice M., Di Lauro R.: A locus on mouse chromosome 2 is involved in susceptibility to congenital hypothyroidism and contains an essential gene expressed in thyroid. Endocrinology 2010; 151: 1948-1958 [IF 4.752]

11 Amtul Z., Uhrig M., Supino R., Beyreuther K.: Phospholipids and a phospholipid-rich diet alter the in vitro amyloid-beta peptide levels and amyloid-beta 42/40 ratios. Neurosci Lett 2010; 481: 73- 77 [IF 1.925]

12 Anichini A., Molla A., Vegetti C., Bersani I., Zappasodi R., Arienti F., Ravagnani F., Maurichi A., Patuzzo R., Santinami M., Pircher H., Di Nicola M., Mortarini R.: Tumor-Reactive CD8+ Early Effector T Cells Identified at Tumor Site in Primar y and Metastatic Melanoma. Cancer Res 2010; 70: 8378-8387 [IF 7.543]


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13 Antinori S., Corbellino M., Necchi A., Corradini P., Vismara C., Montefusco V., Gianni A.M.: Immune reconstitution inflammatory syndrome associated with Aspergillus terreus pulmonary infection in an autologous stem cell transplant recipient. Case report Transpl Infect Dis 2010; 12: 64-68 [IF 2.063]

14 Antoniou A.C., Beesley J., McGuffog L., Sinilnikova O.M., Healey S., Neuhausen S.L., Ding Y.C., Rebbeck T.R., Weitzel J.N., Lynch H.T., Isaacs C., Ganz P.A., Tomlinson G., Olopade O.I., Couch F.J., Wang X., Lindor N.M., Pankratz V.S., Radice P., Manoukian S., Peissel B.G., Zaffaroni D., Barile D., Viel A., Allavena A., Dall’Olio V., Peterlongo P., et al.: Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction. Cancer Res 2010; 70: 9742-9754 [IF 7.543]

15 Antoniou A.C., Wang X., Fredericksen Z.S., McGuffog L., Tarrell R., Sinilnikova O.M., Healey S., Morrison J., Kartsonaki C., Lesnick T., Ghoussaini M., Barrowdale D., EMBRACE, Peock S., Cook M., Oliver C., Frost D., Eccles D., Manoukian S., Radice P., Peterlongo P., et al.: A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptornegative breast cancer in the general population. (Letter) Nat Genet 2010; 42: 885- 892 [IF 34.284]

16 Anttila A., Arbyn M., Veerus P., Viberga I., Kurtinaitiene R., Valerianova Z., Apostol I., Baili P., Micheli A.: Barriers in cervical cancer screening programs in new European Union member states. Tumori 2010; 96: 515-516 [IF 0.863]

17 Apostol I., Baban A., Nicula F., Suteu O., Coza D., Amati C., Baili P., Micheli A., Amati C., Casella I., Cifalà A., Esposito M., Saltarelli S., Di Salvo F., Berrino F., Gatta G., Sant M., Ciccolallo L., Allemani C., on behalf of the EUROCHIP Working Group: Cer vical cancer screening in Bulgaria - past and present experience. Tumori 2010; 96: 545-552 [IF 0.863]

18 Arbyn M., Antoine J., Valerianova Z., Magi M., Stengrevics A., Smailyte G., Suteu O., Micheli A.: Trends in cervical cancer incidence and mortality in Bulgaria, Estonia, Latvia, Lithuania and Romania. Tumori 2010; 96: 517-523 [IF 0.863]

19 Ardoino I., Miceli R., Berselli M, Mariani L., Biganzoli E., Fiore M., Collini P., Stacchiotti S., Casali P.G., Gronchi A.: Histology-specific nomogram for primary retroperitoneal soft tissue sarcoma. Cancer 2010; 116: 2429-2436 [IF 5.418]

20 Bagnardi V., Randi G., Lubin J., Consonni D., Lam T.K., Subar A.F., Goldstein A.M., Wacholder S., Bergen A.W., Tucker M.A., Decarli A., Caporaso N.E., Bertazzi P.A., Landi M.T.: Alcohol consumption and lung cancer risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) study. Am J Epidemiol 2010; 171: 36-44 [IF 5.589]

21 Bagnoli M., Canevari S., Mezzanzanica D.: Cellular FLICEinhibitor y protein (c-FLIP) signalling: A key regulator of receptor-mediated apoptosis in physiologic context and in cancer. Int J Biochem Cell Biol 2010; 42: 210-213 [IF 4.887]

22 Balestra M.R., Baratti D., Crippa F., Laterza B., Kusamura S., Langer M., Deraco M.: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in a patient with peritoneal mesothelioma and HIV infection. Tumori 2010; 96: 340-344 [IF 0.863]

23 Bamia C., Halkjær J., Lagiou P., Trichopoulos D., Tjønneland A., Berentzen T.L., Overvad K., Clavel-Chapelon F., Boutron-Ruault M.C., Rohrmann S., Linseisen J., Steffen A., Boeing H., May A.M., Peeters P.H., Bueno-de-Mesquita B.H., van den Berg S.W., Dorronsoro M., Barricarte A., Rodriguez Suarez L., Navarro C., González C.A., Boffetta P., Pala M. V., Hallmans G., Trichopoulou A.: Weight change in later life and risk of death amongst the elderly: the European Prospective Investigation into Cancer and Nutrition-Elderly Network on Ageing and Health study. J Intern Med 2010; 268: 133-144 [IF 5.942]

24 Bandieri E., Sichetti D., Luppi M., Di Biagio K., Ripamonti C., Tognoni G., Belfiglio M., Romero M.: Is pain in patients with haematological malignancies under-recognised? The results from Italian ECAD-O survey. (Letter) Leuk Res 2010; 34e: 334-335 [IF 2.358]

25 Baratti D., Kusamura S., Cabras A., Laterza B., Balestra M.R., Deraco M.: Lymph node metastases in diffuse malignant peritoneal mesothelioma. Ann Surg Oncol 2010; 17: 45-53 [IF 4.13]

26 Baratti D., Kusamura S., Laterza B., Balestra M.R., Deraco M.: Early and long-ter m postoperative management following cytoreductive surger y and hyperthermic intraperitoneal chemotherapy. World J Gastrointest Oncol 2010; 2: 36-43

27 Baratti D., Pennacchioli E., Kusamura S., Fiore M., Balestra M.R., Colombo C., Mingrone E., Gronchi A., Deraco M.: Peritoneal sarcomatosis: is there a subset of patients who may benefit from cytoreductive surger y and hyperthermic intraperitoneal chemotherapy? Ann Surg Oncol 2010; 17: 3220-3228 [IF 4.13]

28 Baratti D., Scivales A., Balestra M.R., Ponzi P., Di Stasi F., Kusamura S., Laterza B., Deraco M.: Cost analysis of the combined procedure of cytoreductive surger y and hyperthermic intraperitoneal chemotherapy (HIPEC). Eur J Surg Oncol 2010; 36: 463-469 [IF 2.564]

29 Baratti D., Vaira M., Kusamura S., D’Amico S., Balestra M.R., Cioppa T., Mingrone E., De Simone M., Deraco M.: Multicystic peritoneal mesothelioma: outcomes and patho-biological features in a multi-institutional series treated by cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). Eur J Surg Oncol 2010; 36: 1047-1053 [IF 2.564]

30 Barazzetti G., Borreani C., Miccinesi G., Toscani F.: What “best practice” could be in Palliative Care: an analysis of statements on practice and ethics expressed by the main Health Organizations. BMC Palliat Care 2010; 9: 1-9

31 Barisella M., Collini P., Orsenigo M., Aiello A., Paties C.T., Dileo P., Pilotti S.: Unusual myogenic and melanocytic differentiation of soft tissue pPNETs: an immunohistochemical and molecular study of 3 cases. Am J Surg Pathol 2010; 34: 1002-1006 [IF 4.062]

32 Baselga J., Gelmon K.A., Verma S., Wardley A., Conte P.F., Miles D., Bianchi G.V., Cortes J., McNally V.A., Ross G.A., Fumoleau P., Gianni L.: Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010; 28: 1138-1144 [IF 17.793]

33 Basilico N., Parapini S., Sisto F., Omodeo-Salè F., Coghi P., Ravagnani F., Olliaro P., Taramelli D.: The lipid moiety of haemozoin (Malaria Pigment) and P. falciparum parasitised red


PUBLICATIONS

blood cells bind synthetic and native endothelin-1. J Biomed Biotechnol 2010; 2010: 854927 [IF 1.75]

34 Baujat B., Bourhis J., Blanchard P., Overgaard J., Ang K.K., Saunders M., Le Maitre A., Bernier J., Horiot J.C., Maillard E., Pajack T.F., Poulsen M.G., Bourredjem A., O’Sullivan B., Dobrowsky W., Andrwej H., Skòadowski K., Hay J.H., Pinto L.H.J., Fu K.K., Fallai C., Sylvester R., Pignon J.P., MARCH Collaborative Group: Hyperfractionated or accelerated radiotherapy for head and neck cancer. Cochrane Database Syst Rev 2010; 12:CD: 2026 [IF 5.653]

35 Beccaro M., Caraceni A., Costantini M., on behalf of the ISDOC Study Group: End-of-life care in Italian hospitals: quality of and satisfaction with care from the caregivers’ point of view—results from the Italian Survey of the Dying of Cancer. J Pain Symptom Manage 2010; 39: 1003-1015 [IF 2.423]

36 Beggs A.D., Latchford A.R., Vasen H.F.A., Moslein G., Alonso A., Aretz S., Bertario L., Blanco I., Bulow S., Burn J., Capella G., Colas C., Friedl W., Moller P., Hes F.J., Jarvinen H., Mecklin J.P., Nagengast F.M., Parc Y., Phillips R.K.S., Hyer W., Ponz de Leon M., Renkonen-Sinisalo L., Sampson J.R., Stormorken A., Tejpar S., Thomas H.J.W., Wijnen J.T., Clark S.K., Hodgson S.V.: PeutzJeghers syndrome: a systematic review and recommendations for management. Gut 2010; 59: 975-986 [IF 9.357]

37 Belluti F., Fontana G., Dal Bo L., Carenini N., Giommarelli C., Zunino F.: Design, synthesis and anticancer activities of stilbenecoumarin hybrid compounds: Identification of novel proapoptotic agents. Bioorg Med Chem 2010; 18: 3543-3550 [IF 2.822]

38 Beretta G.L., Benedetti V., Cossa G., Asaraf Y.G.A., Bram E., Gatti L., Corna E., Carenini N., Colangelo D., Howell S.B., Zunino F., Perego P.: Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin. Biochem Pharmacol 2010; 79: 1108- 1117 [IF 4.254]

39 Beretta G.L., Cossa G., Gatti L., Zunino F., Perego P.: Tyrosyl-DNA phosphodiesterase 1 targeting for modulation of camptothecinbased treatment. Curr Med Chem 2010; 17: 1500-1508 [IF 4.708]

40 Beretta S., Polastri D., Clerici C.A., Casanova M., Cefalo G., Ferrari A., Luksch R., Massimino M., Meazza C., Podda M., Spreafico F., Terenziani M., Fossati Bellani F.: End of life in children with cancer: experience at the pediatric oncology department of the Istituto Nazionale Tumori in Milan. Pediatr Blood Cancer 2010; 54: 88-91 [IF 2.134]

41 Bernier J., Licitra L.: Chemotherapy: Chemoradiation in head-andneck cancer-are we any closer? (News - Letter) Nat Rev Clin Oncol 2010; 7: 247-249 [IF 8.075]

42 Berrino F.: Trends of Nutritional Epidemiology in Europe. Epidemiol Prev 2010; 34: 15-18 [IF 0.705]

43 Bertolini G., Gatti L., Roz L.: The “stem” of chemoresistance. Cell Cycle 2010; 9: 628-629 [IF 4.087]

44 Bhoori S., Sposito C., Germini A., Coppa J., Mazzaferro V.: The challenges of liver transplantation for hepatocellular carcinoma on cirrhosis. Transpl Int 2010; 23: 712-722 [IF 3.254]

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45 Bhoori S., Toffanin S., Sposito C., Germini A., Pellegrinelli A., Lampis A., Mazzaferro V.: Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: a proof of principle. Case Report J Hepatol 2010; 52: 771-775 [IF 7.818]

46 Bianchini G., Iwamoto T., Qi Y., Coutant C., Shiang C.Y., Wang B., Santarpia L., Valero V., Hortobagyi G.N., Symmans W.F., Gianni L., Pusztai L.: Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer. Cancer Res 2010; 70: 8852-8868 [IF 7.543]

47 Bianchini G., Qi Y., Alvarez R.H., Iwamoto T., Coutant C., Ibrahim N.K., Valero V., Cristofanilli M., Green M.C., Radvanyi L., Hatzis C., Hortobagyi G. N., Andre F., Gianni L., Symmans F., Pusztai L.: Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J Clin Oncol 2010; 28: 4316-4323 [IF 17.793]

48 Bisogno G., Ferrari A., Rosolen A., Alaggio R., Scarzello G., Garaventa A., Arcamone G., Carli M.: Sequential intensified chemotherapy with stem cell rescue for children and adolescents with desmoplastic small round-cell tumor. Bone Marrow Transplant 2010; 45: 907-911 [IF 2.998]

49 Boffetta P., Couto E., Wichmann J., Ferrari P., Trichopoulos D., Bueno-de-Mesquita H.B., van Duijnhoven F.J., Büchner F.L., Key T., Boeing H., Nothlings U., Linseisen J., Gonzales C.A., Overvad K., Nielsen M.R.S., Tjønneland A., Olsen A., Clavel-Chapelon F., Boutron-Ruault M.C., Morois S., Lagiou P., Naska A., Benetou V., Kaaks R., Rohrmann S., Sieri S., Vineis P., Palli D., van Gils C.H., Peeters P.H., Lund E., Brustad M., Engeset D., Huerta J.M., Rodriguez L., Sanchez M.J., Dorronsoro M., Barricarte A., Hallmans G., Johansson I., Manjer J., Sonestedt E., Allen N.E., Bingam S., Khaw K.T., Slimani N., Jenab M., Mouw T., Norat T., Riboli E., Trichopoulou A.: Fruit and vegetable intake and overall cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 2010; 102: 529-537 [IF 14.069]

50 Bolis G., Scarfone G., Raspagliesi F., Mangili G., Danese S., Scollo P., Lo Russo D., Villa A., Aimone P.D., Scambia G.: Paclitaxel/carboplatin versus topotecan/paclitaxel/carboplatin in patients with FIGO suboptimally resected stage III-IV epithelial ovarian cancer a multicenter, randomized study. Eur J Cancer 2010; 46: 2905-2912 [IF 4.121]

51 Bombardieri E., Ambrosini V., Aktolun C., Baum R.P., BishofDelaloye A., Del Vecchio S., Maffioli L., Mortelmans L., Oyen W., Pepe G., Chiti A.: 111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging. Eur J Nucl Med Mol Imaging 2010; 37: 1441-1448 [IF 4.531]

52 Bombardieri E., Coliva A., Maccauro M., Seregni E., Orunesu E., Chiti A., Lucignani G.: Imaging of neuroendocrine tumours with gamma-emitting radiopharmaceuticals. Q J Nucl Med Mol Imaging 2010; 54: 3-15 [IF 2.877]

53 Bombardieri E., Giammarile F., Aktolun C., Baum R.P., Bishof Delaloye A., Maffioli L., Moncayo R., Mortelmans L., Pepe G., Reske S.N., Castellani M.R., Chiti A.: (131)I/ (123)IMetaiodobenzylguanidine (mIBG) scintigraphy: procedure guidelines for tumour imaging. Eur J Nucl Med Mol Imaging 2010; 37: 2436-2446 [IF 4.531]


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54 Bonvalot S., Miceli R., Berselli M., Causeret S., Colombo C., Mariani L., Bouzaiene H., Le Pèchoux C., Casali P.G., Le Cesne A., Fiore M., Gronchi A.: Aggressive surgery in retroperitoneal soft tissue sarcoma carried out at high-volume centers is safe and is associated with improved local control. Ann Surg Oncol 2010; 17: 1507-1514 [IF 4.13]

55 Bortolomai I., Canevari S., Facetti I., De Cecco L., Castellano G., Zacchetti A., Alison M.R., Miotti S.: Tumor initiating cells: Development and critical characterization of a model derived from the A431 carcinoma cell line forming spheres in suspension. Cell Cycle 2010; 9: 1194-1206 [IF 4.087]

56 Bossi P., Granata R., Bergamini C., Mirabile A., Locati L., Licitra L.: Comment on “Acute toxicity of three versus two courses of cisplatin for radiochemotherapy of locally advanced squamous cell carcinoma of the head and neck (SCCHN): a matched pair analysis”, by Rades et coll. (Letter) Oral Oncol 2010; 46: 888-889 [IF 3.123]

57 Bouvier A.M., Sant M., Verdecchia A., Forman D., Damhuis R., Coebergh J.W., Crocetti E., Crosignani P., Gafa L., Launoy G., Martinez-Garcia C., Plesko I., Pompe-Kirn V., Rachtan J., Velten M., Vercelli M., Zwierko M., Esteve J., Faivre J.: What reasons lie behind long-term survival differences for gastric cancer within Europe? Eur J Cancer 2010; 46: 1086-1092 [IF 4.121]

58 Bouwhuis M.G., Suciu S., Testori A., Kruit W.H., Sales F., Patel P., Punt C.J., Santinami M., Spatz A., Ten Hagen T.L., Eggermont A.M.M.: Phase III trial comparing adjuvant treatment with pegylated interferon Alfa-2b versus obser vation: prognostic significance of autoantibodies— EORTC 18991. J Clin Oncol 2010; 28: 2460-2466 [IF 17.793]

59 Bravi F., Edefonti V., Bosetti C., Talamini R., Montella M., Giacosa A., Franceschi S., Negri E., Ferraroni M., La Vecchia C., Decarli A.: Nutrient dietary patterns and the risk of colorectal cancer: A case-control study from Italy. Cancer Causes Control 2010; 21: 1911-1918 [IF 3.199]

60 Brunelli C., Zecca E., Martini C., Campa T., Fagnoni E., Bagnasco M., Lanata L., Caraceni A.: Comparison of numerical and verbal rating scales to measure pain exacerbations in patients with chronic cancer pain. Health Qual Life Outcomes 2010; 8: 42 [IF 2.456]

61 Buchner F.L., Bueno de Mesquita H.B., Linseisen J., Boshuizen H.C., Kiemeney L.A., Ros M.M., Over vad K., Hansen L., Tjonneland A., Raaschou-Nielsen O., Clavel-Chapelon F., BoutronRuault M.C., Touillaud M., Kaaks R., Rohrmann S., Boeing H., Nothlings U., Trichopoulou A., Zylis D., Dilis V., Palli D., Sieri S., Vineis P., Tumino R., Panico S., Peeters P.H.M., van Gils C.H., Lund E., Gram I.T., Braaten T., Martinez C., Agudo A., Arriola L., Ardanaz E., Navarro C., Rodriguez L., Manjer J., Wirfalt E., Roddam A.W., Bingham S., Khaw K.T., Slimani N., Bofetta P., Byrnes G., Norat T., Michaud D. Riboli E.: Fruits and vegetables consumption and the risk of histological subtypes of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control 2010; 21: 357-371 [IF 3.199]

62 Buchner F.L., Bueno-de-Mesquita H.B., Ros M.M., Overvad K., Dahm C.C., Hansen L., Tjonneland A., Clavel-Chapelon F., Boutron-Ruault M.C., Touillaud M., Kaaks R., Rohrmann S., Boeing H., Nothlings U., Trichopoulou A., Zylis D., Dilis V., Palli D., Sieri S., Vineis P., Tumino R., Panico S., Peeters P.H.M., van Gils C.H., Lund E., Gram I.T., Braaten T., Sanchez M.J., Agudo A., Larranaga N., Ardanaz E., Navarro C., Arguelles M.V., Manjer J., Wirfalt E.,

Hallmans G., Rasmuson T., Key T.J., Khaw K.T., Wareham N., Slimani N., Vergnaud A.C., Xun W.W., Kiemeney A.L.M., Riboli E.: Variety in fruit and vegetable consumption and the risk of lung cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 2010; 19: 22782286 [IF 4.31]

63 Buckland G., Agudo A., Lujan L., Jakszyn P., Bueno-de-Mesquita H.B., Palli D., Boeing H., Carneiro F., Krogh V., Sacerdote C., Tumino R., Panico S., Nesi G., Manjer J., Regnér S, Johansson I., Stenling R., Sanchez M.J., Dorronsoro M., Barricarte A., Navarro C., Quirós J.R., Allen N.E., Key T.J., Bingham S., Kaaks R., Overvad K., Jensen M., Olsen A., Tjønneland A., Peeters P.H., Numans M.E., Ocké M.C., Clavel-Chapelon F., Morois S., BoutronRuault M.C., Trichopoulou A., Lagiou P., Trichopoulos D., Lund E., Couto E., Boffeta P., Jenab M., Riboli E., Romaguera D., Mouw T., González C.A.: Adherence to a Mediterranean diet and risk of gastric adenocarcinoma within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study. Am J Clin Nutr 2010; 91: 381-390 [IF 6.307]

64 Busacca S., Germano S., De Cecco L., Rinaldi M., Comoglio F., Favero F., Murer B., Mutti L., Pierotti M.A., Gaudino G.: MicroRNA signature of malignant mesothelioma with potential diagnostic and prognostic implications. Am J Respir Cell Mol Biol 2010; 42: 2008-2011 [IF 4.319]

65 Busia A., Laffranchi A., Viviani S., Bonfante V., Villani F.: Cardiopulmonary toxicity of different chemoradiotherapy combined regimens for Hodgkin’s disease. Anticancer Res 2010; 30: 43814388 [IF 1.428]

66 Buttarelli F., Massimino M., Antonelli M., Lauriola L., Nozza P., Donofrio V., Arcella A., Oliva M.A., Di Rocco C., Giangaspero F.: Evaluation status and prognostic significance of O6methylguanine-DNA methyltransferase (MGMT) promoter methylation in pediatric high grade gliomas. Childs Nerv System 2010; 26: 1051-1056 [IF 1.214]

67 Caccia D., Miccichè F., Cassinelli G., Mondellini P., Casalini P., Bongarzone I.: Dasatinib reduces FAK phosphorylation increasing the effects of RPI-1 inhibition in a RET/PTC1-expressing cell line. Mol Cancer 2010; 9: 278 [IF 4.16]

68 Calabrò E., Randi G., La Vecchia C., Sverzellati N., Marchianò A., Villani F., Zompatori M., Cassandro R., Harari S., Pastorino U.: Lung function predicts lung cancer risk in smokers: a tool for targeting screening programmes. Eur Respir J 2010; 35: 146-151 [IF 5.527]

69 Camisaschi C., Casati C., Rini F., Perego M., De Filippo A., Triebel F., Parmiani G., Belli F., Rivoltini L., Castelli C.: LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol 2010; 184: 65456551 [IF 5.646]

70 Campa D., Husing A., McKay J.D., Sinilnikova O., Vogel U., Tjonneland A., Over vad K., Stegger J., Clavel-Chapelon F., Chabbert-Buffet N., Fagherazzi G., Trichopoulou A., Zylis D., Oustoglou E., Rohrmann S., Teucher B., Fisher E., Boeing H., Masala G., Krogh V., Sacerdote C., et al.: The INSIG2 rs7566605 polymorphism is not associated with body mass index and breast cancer risk. BMC Cancer 2010; 10: 563 [IF 2.736]

71 Cantù G., Riccio S., Colombo S., Pompilio M., Formillo P.: Recent advances in managing human papillomavirus-positive oropharyngeal tumors. F1000 Med Rep 2010; 2:pii: 17


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72 Cantù G., Solero C.L., Riccio S., Colombo S., Pompilio M., Aboh I.V., Formillo P., Arana G.H.: Surgery for malignant maxillary tumors involving the middle cranial fossa. Skull Base 2010; 20: 5560 [IF 0.663]

73 Capello D., Scandurra M., Poretti G., Rancoita P.M.V., Mian M., Gloghini A., Deambrogi C., Martini M., Rossi D., Greiner T.C., Chan W.C., Ponzoni M., Moreno S.M., Piris M.A., Canzonieri V., Spina M., Tirelli U., Inghirami G., Rinaldi A., Zucca E., Favera R.D., Cavalli F., Larocca L.M., Kwee I., Carbone A., Gaidano G., Bertoni F.: Genome wide DNA-profiling of HIV-related B-cell lymphomas. Br J Haematol 2010; 148: 245-255 [IF 4.597]

74 Capri G., Chang J., Chen S.C., Conte P., Cwiertka K., Jerusalem G., Jiang Z., Johnson S., Kaufman B., Link J., Schutte J., Oliva C., Parikh R., Preston A., Rosenlund J., Selzer M., Zembryki D., De Placido S.: An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Ann Oncol 2010; 21: 474480 [IF 5.647]

75 Caraceni A., Cavaliere F., Galante D., Landoni G.: A year in Review in Minerva Anestesiologica, 2009. Minerva Anestesiol 2010; 76: 158-168 [IF 1.614]

76 Caraceni A., Zecca E., Martini C., Brunelli C., Pigni A., Gorni G., Galbiati A., Ibazeta M., Hjermstad M., Kaasa S.: The validity of average 8-h pain intensity assessment in cancer patients. Eur J Pain 2010; 14: 441-445 [IF 3.612]

77 Caramuta S., Egyházi S., Rodolfo M., Witten D., Witten D., Hansson J., Larsson C., Lui W.O.: MicroRNA Expression Profiles Associated with Mutational Status and Survival in Malignant Melanoma. J Invest Dermatol 2010; 130: 2062-2070 [IF 5.543]

78 Carbone A., Ceserman E., Gloghini A., Drexler H.G.: Understanding pathogenetic aspects and clinical presentation of primary effusion lymphoma through its derived cell lines. AIDS 2010; 24: 479-490 [IF 4.909]

79 Carbone A., Gloghini A., Aiello A., Testi M.A., Cabras A.: B-cell lymphomas with features intermediate between distinct pathologic entities. From pathogenesis to pathology. Hum Pathol 2010; 41: 621-631 [IF 2.961]

80 Carcangiu M.L., Radice P., Casalini P., Bertario L., Merola M., Sala P.: Lynch syndrome—related endometrial carcinomas show a high frequency of nonendometrioid types and of high FIGO grade endometrioid types. Int J Surg Pathol 2010; 18: 21-26 [IF 0.912]

81 Carella M., Spreafico F., Palumbo O., Storlazzi C.T., Tabano S., Miozzo M., Miglionico L., Calvano S., Sindici G., Gamba B., Impera L., Collini P., Zelante L., Radice P., Perotti D.: Constitutional ring chromosome 11 mosaicism in a Wilms tumor patient: Cytogenetic, molecular and clinico- pathological studies. Am J Med Genet A 2010; 152: 1756-1763 [IF 2.404]

82 Carey L., Winer E., Viale G., Cameron D., Gianni L.: Triplenegative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol 2010; 7: 683-692 [IF 8.075]

83 Carlessi L., Buscemi G., Fontanella E., Delia D.: A protein phosphatase feedback mechanism regulates the basal phosphorylation of Chk2 kinase in the absence of DNA damage.

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Biochim Biophys Acta - Molecular Cell Research 2010; 1803: 1213-1223 [IF 4.374]

84 Carrara M., Fallai C., Gambarini G., Negri A.: Fricke gel-layer dosimetry in high dose-rate brachytherapy. Appl Radiat Isot 2010; 68: 722-725 [IF 1.094]

85 Carrara M., Gambarini G., Borroni M., Tomatis S., Cerrotta A., Fallai C., Olmi P., Zonca G.: Feasibility study of a dosimeter for in vivo measurements of the absolute dose delivered in high dose rate brachytherapy. Nuovo Cimento Soc. Ital. Fis. B-Basic Top. Phys. 2010; 125: 667-673 [IF 0.265]

86 Casali P.G.: Do rare cancers deserve specific strategies for cancer research? (Reflection and Reaction) Lancet Oncol 2010; 11: 506507 [IF 14.47]

87 C a s a l i P. G . , B l a y J . Y. , D i l e o P. , F e r r a r i A . , G r o n c h i A . : Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl.5): 98-102 [IF 5.647]

88 Casali P.G., Blay J.Y., Dileo P., Gronchi A., Ferrari A.: Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl. 5): 198203 [IF 5.647]

89 Casali P.G., Sanfilippo G.R., D’Incalci M.: Trabectedin therapy for sarcomas. Curr Opin Oncol 2010; 22: 342-346 [IF 4.088]

90 Caselli D., Carraro F., Castagnola E., Ziino O., Frenos S., Milano G.M., Livadiotti S., Cesaro S., Marra N., Zanazzo C., Meazza C., Cellini M., Aricò M.: Morbidity of pandemic H1N1 influenza in children with cancer. Pediatr Blood Cancer 2010; 55: 226-228 [IF 2.134]

91 Castellani M.R., Seghezzi S., Chiesa C., Aliberti G., Maccauro M., Seregni E., Orunesu E., Luksch R., Bombardieri E.: 131I-MIBG treatment of pheochromocytoma: low versus intermediate activity regimens of therapy. Q J Nucl Med Mol Imaging 2010; 54: 100113 [IF 2.877]

92 Castellano G., Torrisi E., Ligresti G., Nicoletti F., Malaponte G., Travali S., McCubrey A., Canevari S., Libra M.: Yin Yang 1 overexpression in diffuse large B-cell lymphoma is associated with B- cell transformation and tumor progression. Cell Cycle 2010; 9: 557-563 [IF 4.087]

93 Catucci I., Yang R., Verderio P., Pizzamiglio S., Heesen L., Hemminki K., Sutter C., Wappenschmidt B., Dick M., Arnold N., Bugert P., Niederacher D., Meindi A., Schmutzler R.K., Bartram C.C., Ficarazzi F., Tizzoni L., Zaffaroni D., Manoukian S., Barile M., Pierotti M.A., Radice P., Burwinkel B., Peterlongo P.: Evaluation of SNPs in miR-146a, miR196a2 and miR-499 as low- penetrance alleles in German and Italian familial breast cancer cases. Hum Mutat 2010; 31 E: 1052-1057 [IF 6.887]

94 Cavo M., Tacchetti P., Patriarca F., Petrucci M.T., Pantani L., Galli M., Di Raimondo F., Crippa C., Zamagni E., Palumbo A., Offidani M., Corradini P., Narni F., Spadano A., Pescosta N., Lambertenghi Deliliers G., Ledda A., Cellini C., Caravita T., Tosi P., Baccarani M., Montefusco V., Gianni A.M., Magni M., for the GIMEMA Italian Myeloma Network: Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed


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multiple myeloma: a randomised phase 3 study Lancet 2010; 376: 2075-2085 [IF 30.758]

95 Cecchetto G., Alaggio R., Bisogno G., Virgone C., Dall’Igna P., Terenziani M., Boldrini R., D’Onofrio V., Ferrari A., Bernini G.: Sex cord-stromal tumors of the testis in children. A clinicopathologic report from the Italian TREP project. J Pediatr Surg 2010; 45: 1868-1873 [IF 1.43]

96 Cellai I., Petrangolini G., Tortoreto M., Pratesi G., Luciani P., Deledda C., Benvenuti S., Ricordati C., Gelmini S., Ceni E., Galli A., Balzi M., Faraoni P., Serio M., Peri A.: In vivo effects of rosiglitazone in a human neuroblastoma xenograft. Br J Cancer 2010; 102: 685-692 [IF 4.346]

97 Chan A.T.C., Gregoire V., Lefebvre J.L., Licitra L., Felip E.: Nasopharyngeal cancer: EHNS- ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl. 5): 187-189 [IF 5.647]

98 Chiappetta G., Ottaiano A., Vuttariello E., Monaco M., Galdiero F., Gallipoli A., Pilotti S., Jodice G., Manoukian S., Colombo M., Ripamonti C.B., Pallante P.L., Radice P., Fusco A.: HMGA1 protein expression in familial breast carcinoma patients. Eur J Cancer 2010; 46: 332-339 [IF 4.121]

99 Chiodoni C., Colombo M.P., Sangaletti S.: Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis. Cancer Metastatis Rev 2010; 29: 295-307 [IF 9.345]

100 Cogo P.E., Poole D., Codazzi D., Boniotti C., Capretta A., Langer M., Luciani D., Rossi C., Bertolini G.: Outcome of children admitted to adult intensive care units in Italy between 2003 and 2007. Intensive Care Med 2010; 36: 1403-1409 [IF 5.168]

101 Colombo N., Peiretti M., Parma G., Lapresa M., Mancari R., Carinelli S., Sessa C., Castiglione M., on behalf of the ESMO Guidelines Working Group: Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl. 5):v: 23-30 [IF 5.647]

102 Concolino D., Roversi G., Muzzi G.L., Sestito S., Colombo E.A., Volpi L., Larizza L., Strisciuglio P.: Clericuzio-type poikiloderma with neutropenia syndrome in three sibs with mutations in the C16orf57 gene: delineation of the phenotype. Am J Med Genet A 2010; 152A: 2588-2594 [IF 2.404]

103 Corradini P., Farina L.: Allogeneic transplantation for lymphoma: long-term outcome. Curr Opin Hematol 2010; 17: 522-530 [IF 5.193]

104 Cossu F., Malvezzi F., Canevari G., Mastrangelo E., Lecis D., Delia D., Seneci P., Scolastico C., Bolognesi M., Milani M.: Recognition of Smac-mimetic compounds by the BIR domain of cIAP1. Protein Sci 2010; 19: 2418-2429 [IF 3.256]

105 Cozzaglio L., Coladonato M., Biffi R., Coniglio A., Corso V., Dionigi P., Gianotti L., Mazzaferro V., Morgagni P., Rosa F., Rosati R., Roviello F., Doci R.: Duodenal fistula after elective gastrectomy for malignant disease : an italian retrospective multicenter study. J Gastrointest Surg 2010; 14: 805-811 [IF 2.402]

106 Cremona M., Calabrò E., Randi G., De Bortoli M., Mondellini P., Verri C., Sozzi G., Pierotti M.A., La Vecchia C., Pastorino U., Bongarzone I.: Elevated levels of the acute-phase serum amyloid

are associated with heightened lung cancer risk. Cancer 2010; 116: 1326-1335 [IF 5.418]

107 Crocetti E., Buzzoni C., Crosignani P., AIRTUM Working Group: [Numbers: Childhood cancer: after the peak reached around 2000 the incidence seems to stabilize.]. Epidemiol Prev 2010; 36: 4 [IF 0.705]

108 Crocetti E., Buzzoni C., Crosignani P., AIRTUM Working Group.: [Numbers: Colorectal cancer: if the actual trend persists, the gap between North and South will disappear in 2019 Acute effects of air pollution in Brindisi (Italy):]. Epidemiol Prev 2010; 34: 69 [IF 0.705]

109 Crosignani P.: [An estimate of health impacts of air pollution reduction.]. Epidemiol Prev 2010; 36: 69 [IF 0.705]

110 C r o s i g n a n i P. , A m e n d o l a P. , S c a b u r r i A . , C h i a p p i n o G . , Marinaccio A.: Confounders and confusion: Dealing with cancer cases of occupational origin. Am J Ind Med 2010; 53: 1002-1005 [IF 1.721]

111 Dall’Igna P., Cecchetto G., Bisogno G., Conte M., Lelli Chiesa P., D’Angelo P., De Leonardis F., De Salvo G., Favini F., Ferrari A.: on behalf of the TREP Group: Pancreatic tumors in children and adolescents: the Italian TREP project experience. Pediatr Blood Cancer 2010; 54: 675-680 [IF 2.134]

112 D’Angelo P., Carli M., Ferrari A., Manzitti C., Mura R., Miglionico L., Di Cataldo A., Grigoli A., Cecchetto G., Bisogno G., for the AIEOP Soft Tissue Sarcoma Committee: Breast metastases in children and adolescents with rhabdomyosarcoma: Experience of the Italian Soft Tissue Sarcoma Committee. Pediatr Blood Cancer 2010; 55: 1306-1309 [IF 2.134]

113 D’Angelo P., Catania S., Zirilli G., Collini P., Tropia S., Perotti D., Terenziani M., Spreafico F.: Severe polyuria and polydipsia in hyponatremic-hypertensive syndrome associated with Wilms tumor. Pediatr Blood Cancer 2010; 55: 566-569 [IF 2.134]

114 De Angelis C.G., Crippa F.: Imaging techniques in diagnostic approaches. Tumori 2010; 96: 817- 822 [IF 0.863]

115 De Cesare M., Sfondrini L., Campiglio M., Sommariva M., Bianchi F., Perego P., van Rooijen N., Supino R., Rumio C., Zunino F., Pratesi G., Tagliabue E., Balsari A.: Ascites regression and survival increase in mice bearing advanced-stage human ovarian carcinomas and repeatedly treated intraperitoneally with CpGODN. J Immunother 2010; 33: 8-15 [IF 3.203]

116 De Franco M., Colombo F., Galvan A., De Cecco L., Spada E., Milani S., Ibanez O.M., Dragani T.A.: Transcriptome of normal lung distinguishes mouse lines with different susceptibility to inflammation and to lung tumorigenesis. Cancer Lett 2010; 294: 187-194 [IF 3.741]

117 de Girolamo L., Bertolini G., Cervellin M., Sozzi G., Volpi P.: Treatment of chondral defects of the knee with one step matrixassisted technique enhanced by autologous concentrated bone marrow: in vitro characterisation of mesenchymal stem cells from iliac crest and subchondral bone. Injury 2010; 41: 1172-1177 [IF 2.383]

118 De Grassi A., Segala C., Iannelli F., Volorio S., Bertario L., Radice P., Bernard L., Ciccarelli F.D.: Ultradeep sequencing of a human


PUBLICATIONS

ultraconserved region reveals somatic and constitutional genomic instability. PloS Biol 2010; 8: e: 1000275 [IF 12.916]

119 de Herder W.W., Mazzaferro V., Tavecchio L., Wiedenmann B.: Multidisciplinary approach for the treatment of neuroendocrine tumors. Tumori 2010; 96: 833-846 [IF 0.863]

120 De Milito A., Canese R., Marino M.L., Borghi M., Iero M., Villa A., Venturi G., Lozupone F., Iessi E., Logozzi M., Della Mina P., Santinami M., Rodolfo M., Podo F., Rivoltini L., Fais S.: pHdependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer 2010; 127: 207-219 [IF 4.722]

121 Degl’Innocenti D., Alberti C., Castellano G., Greco A., Miranda C., Pierotti M.A., Seregni E., Borrello M.G., Canevari S., Tomassetti A.: Integrated Ligand-Receptor Bioinformatic and In Vitro Functional Analysis Identifies Active TGFA/EGFR Signaling Loop in Papillary Thyroid Carcinomas. PLoS ONE 2010; 5: e: 12701 [IF 4.351]

122 Del Vecchio M., Mortarini R., Canova S., Di Guardo L., Pimpinelli N., Sertoli M.R., Bedognetti D., Queirolo P., Morosini P., Perrone T., Bajetta E., Anichini A.: Bevacizumab plus Fotemustine as Firstline Treatment in Metastatic Melanoma Patients: Clinical Activity and Modulation of Angiogenesis and Lymphangiogenesis Factors. Clin Cancer Res 2010; 16: 5862-5872 [IF 6.747]

123 Demicheli R., Ardoino I., Boracchi P., Coradini D., Agresti R., Ferraris C., Gennaro M., Hrushesky W.J.M., Biganzoli E.: Recurrence and mortality according to Estrogen Receptor status for breast cancer patients undergoing conservative surgery. Ipsilateral breast tumour recurrence dynamics provides clues for tumour biology within the residual breast. BMC Cancer 2010; 10: 656 [IF 2.736]

124 Demicheli R., Ardoino I., Boracchi P., Lozza L., Biganzoli E.: Ipsilateral breast tumour recurrence (IBTR) dynamics in breast conserving treatments with or without radiotherapy. Int J Radiat Biol 2010; 86: 542-547 [IF 1.842]

125 Demicheli R., Biganzoli E., Ardoino I., Boracchi P., Coradini D., Greco M., Moliterni A., Zambetti M., Valagussa P., Gukas I.D., Bonadonna G.: Recurrence and mortality dynamics for breast cancer patients undergoing mastectomy according to estrogen receptor status: Different mortality but similar recurrence. Cancer Sci 2010; 101: 826-830 [IF 3.771]

126 Deraco M., Baratti D., Cabras A., Zaffaroni N., Perrone F., Villa R., Jocollè J., Balestra M.R., Kusamura S., Laterza B., Pilotti S.: Experience with peritoneal mesothelioma at the Milan National Cancer Institute. World J Gastrointest Oncol 2010; 2: 76-84

127 Di Leva G., Gasparini P., Piovan C., Ngankeu A., Garofalo M., Taccioli M., Iorio M., Li M., Volinia S., Alder H., Nakamura T., Nuovo G., Liu Y., Nephew K.P., Croce C.M.: MicroRNA cluster 221- 222 and estrogen receptor alpha interactions in breast cancer. J Natl Cancer Inst 2010; 102: 706-721 [IF 14.069]

128 Di Sabatino A., Biancheri P., Piconese S., Rosado M., Ardizzone S., Rovedatti L., Ubezio C., Massari A., Sampietro G.M., Foschi D., Bianchi Porro G., Colombo M.P., Carsetti R., MacDonald T.T., Corazza G.: Peripheral regulatory T cells and serum transforming growth factor-ß: relationship with clinical response to infliximab in Crohn’s disease. Inflamm Bowel Dis 2010; 16: 1891-1897 [IF 4.643]

165

129 Ditto A., Martinelli F., Hanozet F., Reato C., Solima E., Zanaboni F., Grijuela B., Carcangiu M.L., Haeusler E.A., Raspagliesi F.: Class III NSRH: oncological outcome in 170 cervical cancer patients. Gynecol Oncol 2010; 119: 192-197 [IF 3.733]

130 Dodero A., Crocchi R., Patriarca F., Miceli R., Castagna L., Ciceri F., Bramanti S., Frungillo N., Milano R., Crippa F., Fallanca F., E n g l a r o E . , C o r r a d i n i P. : P r e t r a n s p l a n t a t i o n [ 1 8 F]fluorodeoxyglucose positron emission tomography scan predicts outcome in patients with recurrent Hodgkin lymphoma or aggressive non-Hodgkin lymphoma undergoing reduced- intensity conditioning followed by allogeneic stem cell transplantation. Cancer 2010; 116: 5001- 5011 [IF 5.418]

131 Dossus L., Allen N., Kaaks R., Bakken K., Lund E., Tjonneland A., Olsen A., Overvad K., Clavel- Chapelon F., Fournier A., BhabbertBuffet N., Boeing H., Schutze M., Tricholoulou A., Trichopoulos D., Lagiou P., Palli D., Krogh V., Tumino R., Vineis P., Mattiello A., Bueno-de- Mesquita H.B., Onland-Moret N.C., Peeters P.H.M., Dumeaux V., Redondo M.L., Duell E., Sanchez-Cantalejo E., Arriola L., Chirlaque M.D., Ardanaz E., Manjer E., Borgquist S., Lukanova A., Lundin E., Khaw K.T., Wareham N., Key T., Chajes V., Rinaldi S., Slimani N., Mouw T., Gallo V., Riboli E.: Reproductive risk factors and endometrial cancer: the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2010; 127: 442-451 [IF 4.722]

132 Dossus L., Rinaldi S., Becker S., Lukanova A., Tjonneland A., Olsen A., Stegger J., Overvad K., Chabbert-Buffet N., Jimenez-Corona A., Clavel-Chapelon F., Rohemann S., Tuecher B., Boeing H., Schutze M., Trichopoulou A., Benetou V., Lagiou P., Palli D., B e r r i n o F. , P a n i c o S . , Tu m i n o R . , S a c e r d o t e C.: Obesity, inflammatory markers, and endometrial cancer risk: a prospective case- control study. Endocr-Relat Cancer 2010; 17: 1007-1019 [IF 4.282]

133 Dragani T.A.: Risk of HCC: genetic heterogeneity and complex genetics. J Hepatol 2010; 52: 252-257 [IF 7.818]

134 Ducceschi M., Pusceddu S., Platania M.: False positives and false negatives in neuroendocrine tumors diagnosis: clinical reports. Tumori 2010; 96: 827-832 [IF 0.863]

135 Duell E.J., Travier N., Lujan-Barroso L., Boutron-Ruault M.C., ClavelChapelon F., Palli D., Krogh V., Mattiello A., Tumino R., Sacerdote C., Rodriguez L., Sanchez-Cantalejo E., Navarro C., et al.: Menstrual and reproductive factors, exogenous hormone use, and gastric cancer risk in a cohort of women from the European prospective investigation into cancer and nutrition. Am J Epidemiol 2010; 172: 1384-1393 [IF 5.589]

136 Early Breast Cancer Trialists’ Collaborative Group, (EBCTCG), Bonadonna G., Camerini T., De Palo M., Di Mauro M.G., Formelli F., Valagussa P.: (EBCTCG), Correa C, McGale P, Taylor C, Wang Y, Clarke M, Davies C, Peto R, Bijker N, Solin L, Darby S.Overview of the Randomized Trials of Radiotherapy in Ductal Carcinoma In Situ of the Breast. J Natl Cancer Inst Monogr 2010; 41: 162-177 [IF 14.069]

137 Edefonti V., Bravi F., Garavello W., La Vecchia C., Parpinel M., Franceschi S., Dal Maso L., Bosetti C., Boffetta P., Ferraroni M., Decarli A.: Nutrient-based dietary patterns and laryngeal cancer: evidence from an exploratory factor analysis. Cancer Epidemiol Biomarkers Prev 2010; 19: 18-27 [IF 4.31]


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138 Edefonti V., Bravi F., La Vecchia C., Randi G., Ferraroni M., Garavello W., Franceschi S., Talamini R., Boffetta P., Decarli A.: Nutrient-based dietary patterns and the risk of oral and pharyngeal cancer. Oral Oncol 2010; 46: 343-348 [IF 3.123]

139 Elliott K.S., Zeggini E., McCarthy M.I., Gudmundsson J., Sulem P., Stacey S.N., Thorlacius S., Amundadottir L., Grönberg H., Xu J., Gaborieau V., Eeles R.A., Neal D.E., Donovan J.L., Hamdy F.C., Muir K., Hwang S.J., Spitz M.R., Zanke B., Carvajal-Carmona L., Brown K.M., Australian Melanoma Family Study Investigators,, Hayward N.K., Macgregor S., Tomlinson I.P., Lemire M., Amos C.I., Murabito J.M., Isaacs W.B., Easton D.F., Brennan P., PanScan Consortium,, Barkardottir R.B., Gudbjartsson D.F., Rafnar T., Hunter D.J., Chanock S.J., Stefansson K., Ioannidis J.P., Krogh V.: Evaluation of association of HNF1B variants with diverse cancers: collaborative analysis of data from 19 genome-wide association studies. PLoS ONE 2010; 5: e: 10858 [IF 4.351]

140 Endogenous Hormones and Breast Cancer, Collaborative Group,, Key T.J., Appleby P.N., Reeves G.K., Roddam A.W., Krogh V., Micheli A., Berrino F.: Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol 2010; 11: 530-542 [IF 14.47]

141 Escudier B., Bellmunt J., Négrier S., Bajetta E., Melichar B., Bracarda S., Ravaud A., Golding S., Jethwa S., Sneller V.: Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010; 28: 2144-2150 [IF 17.793]

142 Eussen J.P.M., Vollset S.E., Hustad S., Midttun O., Meier K., Fredriksen A., Ueland P.M., Jenab M., Slimani N., Boffetta P., Overvad K., Thorlacius-Ussing O., Tjonneland A., Olsen A., ClavelChapelon F., Boutron-Ruault M.C., Morois S., Weikert C., Pishon T., Linseisen J., Kaaks R., Trichopoulou A., Zilis D., Katsoulis M., Palli D., Pala M. V., Vineis P., et al.: Plasma vitamins B2, B6, and B12, and related genetic variants as predictors of colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2010; 19: 2549-2561 [IF 4.31]

143 Eussen S.J., Vollset S.E., Hustad S., Midttun O., Meyer K., Fredriksen A., Ueland P.M., Jenab M., Slimani N., Ferrari P., Agudo A., Sala N., Capella G., Del Giudice G., Palli D., Boeing H., Weikert C., Bueno-de-Mesquita H.B., Buchner F.L., Carneiro F., Berrino F., Vineis P., Tumino R., Panico S., Berglund G., Manjer J., Stenling R., Hallmans G., Martinez C., Arrizola L., Barricarte A., Navarro C., Rodriguez L., Bingham S., Linseisen J., Kaaks R., Overvad K., Tjonneland A., Peeters P.H.M., Numans M.E., ClavelChapelon F., Boutron-Ruault M.C., Morois S., Trichopoulou A., Lund E., Plebani M., Riboli E., Gonzales C.A.: Vitamins B2 and B6 and genetic polymorphisms related to one-carbon metabolism as risk factors for gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.1 Cancer Epidemiol Biomarkers Prev 2010; 19: 28-38 [IF 4.31]

144 Eussen S.J., Vollset S.E., Igland J., Meyer K., Fredriksen A., Ueland P.M., Jenab M., Slimani N., Boffetta P., Overvad K., Tjønneland A., Olsen A., Clavel-Chapelon F., Boutron-Ruault M.C., Morois S., Weikert C., Pischon T., Linseisen J., Kaaks R., Trichopoulou A., Zilis D., Katsoulis M., Palli D., Berrino F., Vineis P., Tumino R., Panico S., Peeters P.H.M., Bueno-de-Mesquita H.B., Mar tinez C., Dorronsoro M., Ardanaz E., Navarro C., Rodriguez L., Van Guelpen B., Palmqvist R., Manjer J., Ericson U., Bingham S., Khaw K.T., Norat T., Riboli E.: Plasma folate, related genetic variants, and colorectal cancer risk in EPIC. Cancer Epidemiol Biomarkers Prev 2010; 19: 1328- 1340 [IF 4.31]

145 Falvella F.S., Galvan A., Colombo F., Frullanti E., Pastorino U., Dragani T.A.: Promoter Polymorphisms and Transcript Levels of Nicotinic Receptor CHRNA5. J Natl Cancer Inst 2010; 102: 13661370 [IF 14.069]

146 Fangusaro J., Massimino M., Rotkowski S., Gururangan S.: Noncerebellar primitive neuroectodermal tumors (PNET): Summary of the Milan consensus and state of the art workshop on marrow ablative chemotherapy with hematopoietic cell rescue for malignant brain tumors of childhood and adolescents. Pediatr Blood Cancer 2010; 54: 628-640 [IF 2.134]

147 Fauquembergue E., Toutirais O., Tougeron D., Drouet A., Le Gallo M., Desille M., Cabillic F., de La Pintière C.T., Iero M., Rivoltini L., Baert-Desurmont S., Leprince J., Vaudry H., Sesboué R., Frébourg T., Latouche J.B., Catros V.: HLA-A*0201-restricted CEA-derived p e p t i d e C A P 1 i s n o t a s u i t a b l e t a r g e t f o r T- c e l l - b a s e d immunotherapy. J Immunother 2010; 33: 402-413 [IF 3.203]

148 Favini F., Resti A.G., Collini P., Casanova M., Meazza C., Trecate G., Ferrari A.: Inflammator y myofibroblastic tumor of the conjunctiva: response to chemotherapy with low-dose methotrexate and vinorelbine. (Brief Report) Pediatr Blood Cancer 2010; 54: 483-485 [IF 2.134]

149 Feng W., Orlandi R., Zhao N., Carcangiu M.L., Tagliabue E., Xu J., Bast R.C., Yu Y.: Tumor suppressor genes are frequently methylated in lymph node metastases of breast cancers. BMC Cancer 2010; 10: 378 [IF 2.736]

150 Ferrari A., Casanova M., Massimino M., Sultan I.: Peculiar features and tailored management of adult cancers occurring in pediatric age. Expert Rev Anticancer Ther 2010; 10: 1837-1851 [IF 2.493]

151 Ferrari A., Miceli R., Casanova M., Meazza C., Favini F., Luksch R., Catania S., Fiore M., Morosi C., Mariani L.: The symptom interval in children and adolescents with soft tissue sarcomas. Cancer 2010; 116: 177-183 [IF 5.418]

152 Ferrari A., Miceli R., Meazza C., Casanova M., Favini F., Morosi C., Trecate G., Marchianò A., Luksch R., Cefalo G., Terenziani M., Spreafico F., Polastri D., Podda M., Catania S., Schiavello E., Giannatempo P., Gandola L., Massimino M., Mariani L.: Comparison of the prognostic value of assessing tumor diameter versus tumor volume at diagnosis or in response to initial chemotherapy in rhabdomyosarcoma. J Clin Oncol 2010; 28: 1322-1328 [IF 17.793]

153 Ferrari A., Sultan I.: When adult cancers occur in children. (Editorial) Expert Rev Anticancer Ther 2010; 10: 1683-1685 [IF 2.493]

154 Ferrari A., Thomas D., Franklin A.R.K., Hayes-Lattin B.M., Mascarin M., van der Graaf W., Albritton K.H.: Starting an adolescent and young adult program: some success stories and some obstacles to overcome. J Clin Oncol 2010; 28: 4850-4857 [IF 17.793]

155 Finlay J.L., Massimino M.: A consensus and state-of-the-art workshop: marrow ablative chemotherapy with hematopoietic cell rescue for malignant brain tumors of childhood and adolescence. (Commentary) Pediatr Blood Cancer 2010; 54: 634 [IF 2.134]

156 Folini M., Gandellini P., Longoni N., Profumo V., Callari M., Pennati M., Colecchia M., Supino R., Veneroni S., Salvioni R.,


PUBLICATIONS

Valdagni R., Daidone M.G., Zaffaroni N.: miR-21: an oncomir on strike in prostate cancer. Mol Cancer 2010; 9: 12 [IF 4.16]

157 Folini M., Pivetta C., Zagotto G., De Marco C., Palumbo M., Zaffaroni N., Sissi C.: Remarkable interference with telomeric function by a G-quadruplex selective bisantrene regioisomer. Biochem Pharmacol 2010; 79: 1781-1790 [IF 4.254]

158 Formelli F., Cavadini E., Luksch R., Garaventa A., Appierto V., Persiani S.: Relationship among pharmacokinetics and pharmacodynamics of fenretinide and plasma retinol reduction in neuroblastoma patients. Cancer Chemother Pharmacol 2010; 66: 993-998 [IF 2.654]

159 Franzetti F., Antonelli M., Bassetti M., Blasi F., Langer M., Scaglione F., Nicastri E., Lauria F.N., Carosi G., Moroni M., Ippolito G., and the GISIG: (Gruppo Italiano di Studio sulle I n f e z i o n i G r a v i ) Wo r k i n g G r o u p o n H o s p i t a l - A s s o c i a t e d Pneumonia.: Consensus document on controversial issues for the treatment of hospital-associated pneumonia. Int J Infect Dis 2010; 14 Suppl. 4: 55-65 [IF 2.167]

160 Frapolli R., Tamborini E., Virdis E., Bello E., Tarantino E., Marchini S., Grosso F., Sanfilippo G.R., Gronchi A., Tercero J.C., Peloso G., Casali P.G., Pilotti S., D’Incalci M.: Novel models of myxoid liposarcoma xenografts mimicking the biological and pharmacologic features of human tumors. Clin Cancer Res 2010; 16: 4958-4967 [IF 6.747]

161 Frapolli R., Zucchetti M., Sessa C., Marsoni S., Viganò L., Locatelli A., Rulli E., Compagnoni A., Bello E., Pisano C., Carminati P., D’Incalci M.: Clinical pharmacokinetics of the new oral camptothecin gimatecan: the inter-patient variability is related to alpha1-acid glycoprotein plasma levels. Eur J Cancer 2010; 46: 505-516 [IF 4.121]

162 Freisling H., Fahey M.T., Moskal A., Ocké M.C., Ferrari P., Jenab M., Norat T., Naska A., Welch A.A., Navarro C., Schulz M., Wirfält E., Casagrande C., Amiano P., Ardanaz E., Parr C., Engeset D., Grioni S., Sera F., Bueno-de-Mesquita B., van der Schouw Y.T., Touvier M., Boutron-Ruault M.C., Halkjaer J., Dahm C.C., Khaw K.T., Crowe F., Linseisen J., Kröger J., Huybrechts I., Deharveng G., Manjer J., Agren A., Trichopoulou A., Tsiotas K., Riboli E., Bingham S., Slimani N.: Region-specific nutrient intake patterns exhibit a geographical gradient within and between European countries. J Nutr 2010; 140: 1280-1286 [IF 4.091]

163 Gallo V., Neasham D., Airoldi L., Ferrari P., Jenab M., Boffetta P., Overvad K., Tjonneland A., Clavel-Chapelon F., Boeing H., Pala M. V., Palli D., Panico S., Tumino R., Arriola L., Lund E., Bueno-DeMesquita B., Peeters P.H., Melander O., Hallmans G., Riboli E., Saracci R., Vineis P.: Second-hand smoke, cotinine levels, and risk of circulatory mortality in a large cohort study of never-smokers. Epidemiology 2010; 21: 207-214 [IF 5.511]

164 Galvan A., Dragani T.A.: Nicotine dependence may link the 15q25 locus to lung cancer risk. Carcinogenesis 2010; 31: 331333 [IF 4.795]

165 Galvan A., Falvella F.S., Frullanti E., Spinola M., Incarbone M., Nosotti M., Santambrogio L., Conti B., Pastorino U., GonzalesNeira A., Dragani T.A.: Genome-wide association study in discordant sibships identifies multiple inherited susceptibility alleles linked to lung cancer. Carcinogenesis 2010; 31: 462-465 [IF 4.795]

167

166 Galvan A., Ioannidis J.P.A., Dragani T.A.: Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer. Trends Genet 2010; 26: 132-141 [IF 8.689]

167 Galvan A., Vorraro F., Cabrera W.H., Ribeiro O.G., Pazzaglia S., Mancuso M., Zolin A., Milani S., Ibanez O.M., Dragani T.A.: Genetic heterogeneity of inflammator y response and skin tumorigenesis in phenotypically selected mouse lines. Cancer Lett 2010; 295: 54-58 [IF 3.741]

168 Gambarini G., Bartesaghi G., Agosteo S., Vanossi E., Carrara M., Borroni M.: Determination of gamma dose and thermal neutron fluence in BNCT beams from the TLD-700 glow curve shape. Radiat Meas 2010; 45: 640-642 [IF 0.973]

169 Gambarini G., Bartesaghi G., Burian J., Carrara M., Merek M., Negri A., Pirola L., Viererbl L.: Fast-neutron dose evaluation in BNCT with Fricke gel layer detectors. Radiat Meas 2010; 45: 1398-1401 [IF 0.973]

170 Gandellini P., Folini M., Zaffaroni N.: Emerging role of microRNAs in prostate cancer: implications for personalized medicine. Discov Med 2010; 9: 212-218

171 Gasparini P., Bertolini G., Binda M., Magnifico A., Albano L., Tortoreto M., Pratesi G., Facchinetti F., Abolafio G., Roz L., Tagliabue E., Daidone M.G., Sozzi G.: Molecular cytogenetic characterization of stem-like cancer cells isolated from established cell lines. Cancer Lett 2010; 296: 206-215 [IF 3.741]

172 Gatta G., Capocaccia R., Trama A., Martinez-Garcia C., Berrino F., Casali P.G., Gronchi A., Licitra L., Olmi P., Ruzza M., Sowe S., Tagliabue G., Contiero P., the RARECARE Working Group: The Burden of Rare Cancers in Europe. Adv Exp Med Biol 2010; 686: 285-303 [IF 2.02]

173 Gatta G., Zigon G., Aareleid T., Ardanaz E., Bielska-Lasota M., Galceran J., Gozdz S., Hakulinen T., Martinez-Garcia C., Plesko I., Zakelj M.P., Rachtan J., Tagliabue G., Vercelli M., Faivre J.: Patterns of care for European colorectal cancer patients diagnosed 1996-1998: A EUROCARE High Resolution Study. Acta Oncol 2010; 49: 776-783 [IF 2.265]

174 Gatti L., Perego P., Leone R., Apostoli P., Carenini N., Corna E., Allievi C., Bastrup U., De Munari S., Di Giovine S., Nicoli P., Grugni M., Natangelo M., Pardi G., Pezzoni G., Singer J.W., Zunino F.: Novel bis-platinum complexes endowed with an improved pharmacological profile. Mol Pharm 2010; 7: 207-216 [IF 5.408]

175 Gaudet M.M., Kirchhoff T., Green T., Vijai J., Korn J.M., Guiducci C., Segre A.V., McGee K., McGuffog L., Kartsonaki C., Morrison J., Healey S., Sinilnikova O.M., Stoppa-Lyonnet D., Peterlongo P., Manoukian S., Barile M, Viel A., Radice P.: Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer. Plos Genet 2010; 6:e: 1001183 [IF 9.532]

176 Gennaro M., Valeri B., Casalini P., Carcangiu M.L., Gronchi A., Conti A.R., Agresti R., Greco M.: Angiosarcoma of the breast and vascular endothelial growth factor receptor. Tumori 2010; 96: 930935 [IF 0.863]


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177 Germano G., Frapolli R., Simone M., Tavecchio M., Erba E., Pesce S., Pasqualini F., Grosso F., Sanfilippo G.R., Casali P.G., Gronchi A., Virdis E., Tarantino E., Pilotti S., Greco A., Nebuloni M., Galmarini C.M., Tercero J.C., Mantovani A., D’Incalci M., Allavena P.: Antitumor and anti- inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 2010; 70: 22352244 [IF 7.543]

178 Ghedini G.C., Ciravolo V., Tortoreto M., Giuffrè S., Bianchi F., Campiglio M., Mortarino M., Figini M., Coliva A., Carcangiu M.L., Zambetti M., Piazza T., Ferrini S., Ménard S., Tagliabue E., Pupa S.: Shed HER2 extracellular domain in HER2-mediated tumor growth and in trastuzumab susceptibility. J Cell Physiol 2010; 225: 256-265 [IF 4.586]

179 Gianni L., Eiermann W., Semiglazov V., Manikhas A., Lluch A., Tjulandin S., Zambetti M., Vazquez F., Byakhow M., Lichinitser M., Climent M.A., Ciruelos E., Ojeda B., Mansutti M., Bozhok A., Baronio R., Feyereislova A., Barton C., Valagussa P., Baselga J.: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010; 375: 377-384 [IF 30.758]

180 Gianni L., Lladò A., Bianchi G.V., Cortes J., Kellokumpu P.L., Cameron D.A., Miles D., Salvagni S., Wardley A., Goeminne J.C., Hersberger V., Baselga J.: Open-Label, Phase II, Multicenter, Randomized Study of the Efficacy and Safety of Two Dose Levels of Pertuzumab, a Human Epidermal Growth Factor Receptor 2 Dimerization Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol 2010; 28: 1131-1137 [IF 17.793]

181 Gianotti L., Braga M., Biffi R., Bozzetti F., Mariani L., on behalf the GlutamItaly Research Group of SINPE: Metabolic and clinical effects of parenteral L-alanine-L-glutamine in surgical oncology. Nutritional Therapy & Metabolism 2010; 28: 77-85

182 Ginsburg O.M., Kim-Sing C., Foulkes W.D., Ghadirian P., Lynch H.T., Sun P., Narod S.A., Manoukian S., Hereditary Breast Cancer Clinical Study Group: BRCA1 and BRCA2 families and the risk of skin cancer. Fam Cancer 2010; 9: 789-493 [IF 2.189]

183 Giommarelli C., Zuco V., Favini E., Pisano C., Dal Piaz F., De Tommasi N., Zunino F.: The enhancement of antiproliferative and proapoptotic activity of HDAC inhibitors by curcumin is mediated by Hsp90 inhibition. Cell Mol Life Sci 2010; 67: 995-1004 [IF 6.09]

184 Giordano A., Uccelli M.M., Pucci E., Martinelli V., Borreani C., Lugaresi A., Trojano M., Granella F., Confalonieri P., Radice D., Solari A., on behalf of the SIMS-Trial group: The Multiple Sclerosis Knowledge Questionnaire: a self-administered instrument for recently diagnosed patients. Mult Scler 2010; 16: 100-111 [IF 3.279]

185 Giuliani N., Lisignoli G., Novara F., Storti P., Zaffaroni N., Villa R., Sammarelli G., Agnelli L., Todoerti K., Bernardo M.E., Manferdini C., Colla S., Abeltino M., Bolzoni M., Rocci A., Gabusi E., Palumbo A., Zuffardi O., Neri A., Rizzoli V.: Bone osteoblastic and mesenchymal stromal cells lack primarily tumoral features in multiple myeloma patients. Leukemia 2010; 24: 1368-1370 [IF 8.296]

186 Gonzalez C.A., Riboli E., Krogh V., on behalf of EPIC: Diet and cancer prevention: Contributions from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Eur J Cancer 2010; 46: 2555-2562 [IF 4.121]

187 Greco A., Miranda C., Pierotti M.A.: Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Mol Cell Endocrinol 2010; 321: 44-49 [IF 3.503]

188 Gregoire V., Lefebvre J.L., Licitra L., Felip E.: Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl. 5): 184-186 [IF 5.647]

189 Grindeal E.M., Renkonen-Sinisalo L., Vasen H., Evans G., Sala P., Blanco I., Gronwald J., Apold J., Eccles D.M., Sanchez A.A., Sampson J., Jarvinen H.J., Bertario L., Crawford G.C., Stormorken A.T., Maehle L., Moller P.: Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds. J Med Genet 2010; 47: 99-102 [IF 5.751]

190 Gregorc V., Zucali P.A., Santoro A., Ceresoli G.L., Citterio G., De Pas T.M., Zilembo N., De Vincenzo F., Simonelli M., Rossoni G., Spreafico A., Viganò M.G., Fontana F., De Braud F.G., Bajetta E., Caligaris-Cappio F., Bruzzi P., Lambiase A., Bordignon C.: Phase II study of asparagine-glycine-arginine-human tumor necrosis factor alpha, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma. J Clin Oncol 2010; 28: 2604-2611 [IF 17.793]

191 Gronchi A., Blay J.I., Trent J.C.: The role of high-dose imatinib in the management of patients with gastrointestinal stromal tumor. Review Cancer 2010; 116: 1847-1858 [IF 5.418]

192 Gronchi A., Lo Vullo S., Colombo C., Collini P., Stacchiotti S., Mariani L., Fiore M., Casali P.G.: Extremity soft tissue sarcoma in a series of patients treated at a single institution: local control directly impacts survival. Ann Surg 2010; 251: 506-511 [IF 7.9]

193 Guiducci C., Tripodo C., Sangaletti S., Colombo M.P., Coffman R.L., Barrat F.J.: Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J Exp Med 2010; 207: 2931-2942 [IF 14.505]

194 Guzzo M., Locati L., Prott F.J., Gatta G., McGurk M., Licitra L.: Major and minor salivary gland tumors. Crit Rev Oncol Hematol 2010; 74: 134-148 [IF 5.269]

195 HAEMACARE, Sant M., Karjalainen-Lindsberg M.L., Maynadiè M., Raphael M., Ferretti S., Giacomin A., Tereanu C., GiraldoCastellano P., Gragera R.M., Martos-Jimènez C., Lutz J.M., Visser O., Allemani C., De Angelis R., Berrino F., Sowe S., Margutti C., Crosignani P., Ward D.: Manual for coding and reporting haematological malignancies. Tumori 2010; 96: iA: 1-32 [IF 0.863]

196 Haugen D., Hjermstad M.J., Hagen N., Caraceni A., Kaasa S., European Palliative Care: Research Collaborative (EPCRC). Assessment and classification of cancer breakthrough pain: a systematic literature review. Pain 2010; 149: 476-482 [IF 5.371]

197 Haupt R., Garaventa A., Gambini C., Parodi S., Cangemi S., Casale F., Viscardi E., Bianchi M., Prete A., Jenkner A., Luksch R., Di Cataldo A., Favre C., D’Angelo P., Zanazzo G.A., Arcamone G., Izzi G.C., Gigliotti A.R., Pastore G., De Bernardi B.: Improved


PUBLICATIONS

survival of children with neuroblastoma between 1979 and 2005: a report of the Italian Neuroblastoma Registry. J Clin Oncol 2010; 28: 2331-2338 [IF 17.793]

198 Hermann S., Rohrmann S., Linseisen J., Nieters A., Khan A., Gallo V., Overvad K., Tjonneland A., Raaschou-Nielsen O., Bergmann M.M., Boeing H., Becker N., Kaaks R., Bueno-de-Mesquita H., May A.M., Vermeulen R.C.H., Bingham S., Khaw K.T., Key T.J., Travis R.C., Trichopoulou A., Georgila C., Triantafylou D., Celentano E., Krogh V., Masala G., Tumino R., Agudo A., Altzibar J.M., Ardanaz E., Martinez-Garcia C., Arguelles Suarez M.V., Tormo M.J., Braaten T., Lund E., Manjer J., Zackrisson S., Hallmans G., Malmer B., Boffetta P., Brennan P., Slimani N., Vineis P., Riboli E.: Level of education and the risk of lymphoma in the European prospective investigation into cancer and nutrition. J Cancer Res Clin Oncol 2010; 136: 71-77 [IF 2.261]

199 Hindorf C., Glatting G., Chiesa C., Lindèn O., Flux G.: EANM Dosimetry Committee guidelines for bone marrow and whole-body dosimetry. Eur J Nucl Med Mol Imaging 2010; 37: 1238-1250 [IF 4.531]

200 Hoeft B., Linseisen J., Beckmann L., Müller-Decker K., Canzian F., Husing A., Kaaks R., Vogel U., Jakobsen M.U., Overvad K., Hansen R.D., Knuppel S., Boeing H., Trichopoulou A., Koumantaki Y., Trichopoulos D., Berrino F., Palli D., Panico S., Tumino R., Bueno-de-Mesquita H.B., van Duijnhoven F.J., van Gils C.H., Peeters P.H., Dumeaux V., Lund E., Castano J.M.H., Munox X., Rodriguez L., Barricarte A., Manjer J., Jirstrom K., Van Guelpen B., Hallmans G., Spencer E.A., Crowe F.L., Khaw K.T., Wareham N., Morois S., Boutron-Ruault M.C., Clavel- Chapelon F., Chajes V., Jenab M., Boffetta P., Vineis P., Mouw T., Norat T., Riboli E., Nieters A.: Polymorphisms in fatty acid metabolism-related genes are associated with colorectal cancer risk. Carcinogenesis 2010; 31: 466-472 [IF 4.795]

201 Hogendoorn P.C.W., on behalf of the ESMO/EUROBONET Working Group, Athanasou N., Bielack S., De Alava E., Dei Tos A.P., Ferrari S., Gelderblom H., Grimer R., Hall K.S., Hassan B., Hogendoorn P.C.W., Jurgens H, Paulussen M., Rozeman L., Taminiau A.H.M., Whelan J., VanelD., Casali P.G., Dileo P., Ferrari A., Gronchi A.: Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl. 5): 204-213 [IF 5.647]

202 Huber V., De Milito A., Harguindey S., Reshkin S.J., Wahl M.L., Rauch C., Chiesi A., Pouysségur J., Gatenby R.A., Rivoltini L., Fais S.: Proton dynamics in cancer. J Transl Med 2010; 8: 57 [IF 3.407]

203 Huerta J.M., Navarro C., Chirlaque M.D., Tormo M.J., Steindorf K., Buckland G., Carneiro F., Johnsen N.F., Overvad K., Stegger J., Tjonneland A., Boutron-Ruault M.C., Clavel-Chapelon F., Morois S., Boeing H., Kaaks R., Rohrmann S., Vigl M., Lagiou P., Trichopoulos D., Trichopoulou A., Bas Bueno-de-Mesquita H., Monninkhof E.M., Numans M.E., Peeters P.H., Mattiello A., Pala M. V., Palli D., Tumino R., Vineis P., Agudo A., Ardanaz E., Arriola L., MolinaMontes E., Rodriguez L., Lindkvist B., Manjer J., Stenling R., Lund E., Crowe F.L., Key T.J., Khaw K.T., Wareham N.J., Jenab M., Norat T., Romaguerra D., Riboli E., Gonzales C.A.: Prospective study of physical activity and risk of primary adenocarcinomas of the oesophagus and stomach in the EPIC (European Prospective Investigation into Cancer and nutrition) cohort. Cancer Causes Control 2010; 21: 657-669 [IF 3.199]

204 Iacovelli R., Raimondi C., Palazzo A., Cortesi E., Procopio G.: Neoadjuvant targeted therapy in renal cell carcinoma. (Letter) Nat Rev Urol 2010; 7: 2c: 1 [IF 2.615]

169

205 Iapichino G., Marzorati S., Umbrello M., Baccalini R., Barassi A., Cainarca M., Colombo Pavini F., Mantovani E., Mauri A., Moroni B., Noto A., Melzi D’Eril G.V., Langer M.: Daily monitoring of biomarkers of sepsis in complicated long-term ICU-patients: can it support treatment decisions? Minerva Anestesiol 2010; 76: 814823 [IF 1.614]

206 Imberti R., Cusato M., Villani P., Carnevale L., Iotti G.A., Langer M . , R e g a z z i M . : S t e a d y - S t a t e P h a r m a c o k i n e t ics and BAL Concentration of Colistin in Critically III Patients After IV Colistin Methanesulfonate Administration. Chest 2010; 138: 1333-1339 [IF 6.36]

207 Invernizzi G., Ruprecht A.A., Mazza R., De Marco C., Tagliapietra L., Michieletto F., Allegri F., Sbrogiò L., Boffi R.: Fumare in macchina: l’inquinamento da polveri, da composti organici volatili e da monossido di carbonio. L’effetto dell’apertura del finestrino. Epidemiol Prev 2010; 34: 35-42 [IF 0.705]

208 Iodice S., Barile M., Totmensz N., Feroce I., Bonanni B., Radice P., Bernard L., Maisonneuve P., Gandini S.: Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a metaanalysis. Eur J Cancer 2010; 46: 2275-2284 [IF 4.121]

209 Iorio M., Piovan C., Croce C.: Interplay between microRNAs and the epigenetic machinery: An intricate network. Biochim Biophys Acta - Gene Regulatory Mechanisms 2010; 1799: 694-701 [IF 3.475]

210 Iorio E., Ricci A., Bagnoli M., Pisanu M.E., Castellano G., Di Vito M., Venturini E., Glunde K., Bhujwalla Z.M., Mezzanzanica D., Canevari S., Podo F.: Activation of phosphatidylcholine cycle enzymes in human epithelial ovarian cancer cells. Cancer Res 2010; 70: 2126-2135 [IF 7.543]

211 Jenab M., Bueno de Mesquita H.B., Ferrari P., van Duijnhoven F.J., Norat T., Pischon T., Jansen E.H., Slimani N., Byrnes G., Rinaldi S., Tjønneland A., Olsen A., Overvad K., Boutron-Ruault M.C., ClavelChapelon F., Morois S., Kaaks R., Linseisen J., Boeing H., Bergmann M.M., Trichopoulou A., Misirli G., Trichopoulos D., Berrino F., Vineis P., Panico S., Palli D., Tumino R., Ros M.M., van Gils C.H., Peeters P.H., Brustad M., Lund E., Tormo M.J., Ardanaz E., Rodriguez L., Sanchez M.J., Dorronsoro M., Gonzales C.A., Hallmans G., Palmqvist R., Roddam A., Key T.J., Khaw K.T., Autier P., Hainaut P., Riboli E.: Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study. BMJ 2010; 340: b: 5500 [IF 13.66]

212 Johansson M., Relton C., Ueland P.M., Vollset S.E., Midttun O., Nygard O., Slimani N., Boffetta P., Jenab M., Clavel-Chapelon F., Boutron-Ruault M.C., Fagherazzi G., Kaaks R., Rohrmann S., Weikert C., Beueno-de-Mesquita H.B., Ros M.M., van-Gils C.H., Peeters P.H.M., Agudo A., Barriacarte A., Navarro C., Rodriguez L., Sanchez M.J., Larranaga N., Khaw K.T., Wareham N., Allen N.E., Crowe F., Gallo V., Norat T., Krogh V., Masala G., Panico S., Sacerdote C., Tumino R., Trichopoulou A., Lagiou P., Trichopoulos D., Rasmuson T., Hallmans G., Riboli E., Vineis P., Brennan P.: Serum B vitamin levels and risk of lung cancer. JAMA 2010; 303: 2377-2385 [IF 28.899]

213 Kaasa S., Caraceni A.: Palliative cancer care research. (Editorial) Palliat Med 2010; 24: 259-260 [IF 2.031]

214 Kelly C.M., Krishnamurthy S., Bianchini G., Litton J.K., GonzalesAngulo A.M., Hortobagyi G.N., Pusztai L.: Utility of oncotype DX


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risk estimates in clinically intermediate risk hormone receptorpositive, HER2-normal, grade II, lymph node-negative breast cancers. Cancer 2010; 116: 5161- 5167 [IF 5.418]

215 Kusamura S., Baratti D., Zaffaroni N., Villa R., Laterza B., Balestra M.R., Deraco M.: Pathophysiology and biology of peritoneal carcinomatosis. World J Gastrointest Oncol 2010; 2: 12-18

216 Labianca R., Beretta G.D., Kildani B., Milesi L., Merlin F., Mosconi S., Pessi M.A., Prochilo T., Quadri A., Gatta G., de Braud F., Wils J.: Colon cancer. Crit Rev Oncol Hematol 2010; 74: 106- 133 [IF 5.269]

217 Lafferty-Whyte K., Bilsland A., Cairney C.J., Hanley L., Jamieson N.B., Zaffaroni N., Oien K.A., Burns S., Roffey J., Boyd S.M., Keith W.N.: Scoring of senescence signalling in multiple human tumour gene expression datasets, identification of a correlation between senescence score and drug toxicity in the NCI60 panel and a pro-inflammator y signature correlating with sur vival advantage in peritoneal mesothelioma. BMC Genomics 2010; 11: 532 [IF 3.759]

218 Lafferty-Whyte K., Bilsland A., Hoare S.F., Burns S., Zaffaroni N., Cairney C.J., Keith W.N.: TCEAL7 inhibition of c-Myc activity in alternative lengthening of telomeres regulates hTERT expression. Neoplasia 2010; 12: 405-414 [IF 5.025]

219 Lahmann P.H., Cust A.E., Friedenreich C.M., Schulz M., Lukanova A., Kaaks R., Lundin E., Tjonneland A., Halkjaer J., Severinsen M.T., Over vad K., Fournier A., Chabbert-Buffet N., ClavelChapelon F., Dossus L., Pischon T., Boeing H., Trichopoulou A., Lagiou P., Naska A., Palli D., Grioni S., Mattiello A., Tumino R., Sacerdote C., Redondo M.L., Jakszyn P., Sánchez M.J., Tormo M.J., Ardanaz E., Arriola L., Manjer J., Jirström K., Bueno-deMesquita H.B., May A.M., Peeters P.H., Onland-Moret N.C., Bingham S., Khaw K.T., Allen N.E., Spencer E., Rinaldi S., Slimani N., Chajes V., Michaud D., Norat T., Riboli E.: Anthropometric measures and epithelial ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2010; 126: 2404-2415 [IF 4.722]

220 Lampati L., Maggioni E., Langer M., Malacarne P.: Value of tracheal aspirate surveillance cultures. (Letter) Minerva Anestesiol 2010; 76: 470-471 [IF 1.614]

221 Langevin S.M., Ioannidis J.P.A., Vineis P., Taioli E., Dragani T.A., Genetic Susceptibility to: Environmental Carcinogens group (GSEC).: Assessment of cumulative evidence for the association between glutathione S-transferase polymorphisms and lung cancer: application of the Venice interim guidelines. Pharmacogenet Genomics 2010; 20: 586-597 [IF 3.991]

222 Larizza L., Roversi G., Volpi L.: Rothmund-Thomson syndrome. Orphanet J Rare Dis 2010; 5: 2 [IF 5.825]

223 Lavazza C., Carlo Stella C., Giacomini A., Cleris L., Righi M., Sia D., Di Nicola M., Magni M., Longoni P., Milanesi M., Francolini M., Gloghini A., Carbone A., Formelli F., Gianni A.M.: Human CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis- inducing ligand target both tumor cells and tumor vasculature. Blood 2010; 115: 2231-2240 [IF 10.555]

224 Lecis D., Drago C., Manzoni L., Seneci P., Scolastico C., Mastrangelo E., Bolognesi M., Anichini A., Kashkar H., Walczar H., Delia D.: Novel SMAC-mimetics synergistically stimulate

melanoma cell death in combination with TRAIL and Bortezomib. Br J Cancer 2010; 102: 1707-1716 [IF 4.346]

225 Leo F., Bellini R., Conti B., Delledonne V., Tavecchio L., Pastorino U.: Superior vena cava resection in thoracic malignancies: does prosthetic replacement pose a higher risk? Eur J Cardiothoracic Surg 2010; 37: 764-769 [IF 2.397]

226 Leo F., Furia S., Duranti L., Pastorino U.: Extraluminal cardiac paraganglioma: unexpected diagnosis of a large mediastinal mass. Images in cardio-thoracic surgery. Eur J Cardiothoracic Surg 2010; 137: 1470 [IF 2.397]

227 Leo F., Girotti P., Tavecchio L., Conti B., Delledonne V., Pastorino U.: Anterior diaphragmatic plication in mediastinal surgery: the “reefing the mainsail” technique. Ann Thorac Surg 2010; 90: 2065-2067 [IF 3.644]

228 Leoncini E., Botto L.D., Cocchi G., Anneren G., Bower C., Halliday J., Amar E., Bakker M.K., Bianca S., Canessa Tapia M.A., Castilla E.E., Csaky-szunyogh M., Sastgiri S., Feldkamp M.L., Gatt M., Hirahara F., Landau D., Lowry R.B., Marengo L., McDonnell R., Mathew T.M., Morgan M., Mutchinick O.M., Pierini A., Poetzsch S., Ritvanen A., Scarano G., Siffel C., Sípek A., Szabova E., Tagliabue G., Vollset S.E., Wer telecki W., Zhuchenko L., Mastroiacovo P.: How valid are the rates of Down syndrome internationally? Findings from the International Clearinghouse for Birth Defects Surveillance and Research. Am J Med Genet A 2010; 152: 1670-1680 [IF 2.404]

229 Lepage C., Ciccolallo L., De Angelis R., Bouvier A.M., Faivre J., Gatta G., Berrino F., Allemani C., Baili P., Lucca F., Micheli A., Sant M., Sowe S., Zigon G., Crosignani P., and the EUROCARE working group: European disparities in malignant digestive endocrine tumours survival. Int J Cancer 2010; 126: 2928-2934 [IF 4.722]

230 Lepage C., Sant M., Verdecchia A., Forman D., Esteve J., Faivre J., and the EUROCARE working group: Operative mortality after gastric cancer resection and long-term survival differences across Europe. Br J Surg 2010; 97: 235-239 [IF 4.077]

231 Licitra L., Locati L., Greco A., Granata R., Bossi P.: Multikinase inhibitors in thyroid cancer. Eur J Cancer 2010; 46: 1012-1018 [IF 4.121]

232 Lualdi M., Leo E., Battaglia L., Colombo A., Marchesini R., Poiasina E., Vannelli A., Morelli D.: Colorectal cancer detection by means of optical fluoroscopy. A study on 494 subjects. Front Biosci (Elite Ed) 2010; 694-700

233 Lucci M.A., Orlandi R., Triulzi T., Tagliabue E., Balsari A., Villa Moruzzi E.: Expression profile of tyrosine phosphatases in HER2 breast cancer cells and tumors. Cell Oncol 2010; 32: 361-372 [IF 4.169]

234 Magni M., Di Nicola M., Carlo Stella C., Devizzi L., Guidetti A., Matteucci P., Gianni A.M.: Efficacy and safety of high-dose chemotherapy with in vivo purged auto-SCT in relapsed follicular lymphoma: long-term follow-up. (Letter) Bone Marrow Transplant 2010; 45: 1119-1120 [IF 2.998]

235 Magni M., Di Nicola M., Testi M.A., Cabras A., Devizzi L., Guidetti A., Matteucci P., Viviani S., Bonfante V., Carniti C., Ricca I., Carbone A., Carlo Stella C., Gianni A.M.: Radioimmunotherapy


PUBLICATIONS

and secondary leukemia: a case report. Leuk Res 2010; 34: e: 1-4 [IF 2.358]

236 Maio M., Nicolay H.J.M., Ascierto P.A., Belardelli F., Camerini R., Colombo M.P., Queirolo P., Ridolfi R., Russo V., Fonsatti E., Parmiani G., Anichini A., Camisaschi C., Castelli C., NIBIT: Seventh annual meeting of the Italian Network for Tumor Biotherapy (NIBIT), Siena, 1-3 October 2009. Cancer Immunol Immunother 2010; 59: 1895-1901 [IF 3.791]

237 Maio M., Nicolay H.J.M., Ascierto P.A., Belardelli F., Camerini R., Colombo M.P., Queirolo P., Ridolfi R., Russo V., Fonsatti E., Parmiani G., Castelli C., Del Vecchio M., Di Nicola M., Maccalli C., Rivoltini L., for the NIBIT: Sixth annual meeting of the Italian network for tumor biotherapy (NIBIT), Siena, 16-18 October 2008. Cancer Immunol Immunother 2010; 59: 963-969 [IF 3.791]

238 Majno P.E., Mentha G., Mazzaferro V.: Partial hepatectomy versus radiofrequency ablation for hepatocellular carcinoma: confirming the trial that will never be, and some comments on the indications for liver resection. (Editorial) Hepatology 2010; 51: 1116-1118 [IF 10.84]

239 Malacarne P., Boccalatte D., Acquarolo A., Agostini F., Anghileri A., Giardino M., Giudici D., Langer M., Livigni S., Nascimben E., Rossi C., Bertolini G.: Epidemiology of nosocomial infection in 125 italian intensive care units. Minerva Anestesiol 2010; 76: 13-23 [IF 1.614]

240 Marcos-Gragera R., Cervantes-Amat M., Vicente M.L., de Sanjose S., Guallar E., Godoy C., Calvo C., Giraldo P., Sant M., PerisBonet R., Martos M.C.: Population-based incidence of childhood leukaemias and lymphomas in Spain (1993-2002). Eur J Cancer Prev 2010; 19: 247- 255 [IF 2.205]

241 Martello G., Rosato A., Ferrari F., Manfrin A., Cordenonsi M., Dupont S., Enzo E., Dupont S., Enzo E., Guzzardo V., Rondina M., Spurce T., Parenti A.R., Daidone M.G., Bicciato S., Piccolo S.: A MicroRNA targeting dicer for metastasis control. Cell 2010; 141: 1195-1207 [IF 31.152]

242 Martinez-Ramos D., Escrig-Sos J., Torrella-Ramos A., AlcadeSanchez M., Salvador-Sanchis J.L., Ferraris C., Greco M.: Prognostic Significance of the Number of Negative Axillary Lymph Nodes in Patients with pT1-2 N0 M0 Breast Cancer: A PopulationBased Study. (Letter) Breast J 2010; 16: 437-439 [IF 1.61]

243 Massi D., Franchi A., Alos L., Cook M., Di Palma S., Enguita A.B., Ferrara G., Kazakov D.V., Mentzel T., Michal M., Panelos J., Rodriguez-Peralto J.L., Santucci M., Tragni G., Zioga A., Dei Tos A.P.: Primary cutaneous leiomyosarcoma: clinicopathological analysis of 36 cases. Histopathology 2010; 56: 251-262 [IF 3.855]

244 Massimino M., Cohen K.J., Finlay L.: Is there a role for myeloablative chemotherapy with autologous hematopoietic cell rescue in the management of childhood high-grade astrocytomas? Pediatr Blood Cancer 2010; 54: 641-643 [IF 2.134]

245 Massimino M., Spreafico F., Riva D., Biassoni V., Poggi G., Solero C., Gandola L., Genitori L., Modena P., Simonetti F., Potepan P., Casanova M., Meazza C., Clerici C.A., Catania S., Sardi I., Giangaspero F.: A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma. J Neurooncol 2010; 100: 65-71 [IF 2.752]

171

246 Maurichi A., Miceli R., Camerini T., Contiero P., Patuzzo R., Tragni G., Crippa F., Romanidis K., Ruggeri R., Carbone A., Santinami M.: Pure desmoplastic melanoma: a melanoma with distinctive clinical behavior. Ann Surg 2010; 252: 1052-1057 [IF 7.9]

247 Mazza R., Invernizzi G.: Fumare in auto ser ve una legge? Epidemiol Prev 2010; 34: 7-8 [IF 0.705]

248 Mazza R., Lina M.B., Boffi R., Invernizzi G., De Marco C., Pierotti M.A.: Taking care of smoker cancer patients: a review and some recommendations. Ann Oncol 2010; 21: 1404-1409 [IF 5.647]

249 Meazza C., Bisogno G., Gronchi A., Fiore M., Cecchetto G., Alaggio R., Milano G.M., Casanova M., Carli M., Ferrari A.: Aggressive fibromatosis in children and adolescents: the Italian experience. Cancer 2010; 116: 233-240 [IF 5.418]

250 Meazza C., Casanova M., Ferrari A., Trecate G.: Objective response to hydroxyurea in a patient with heavily pre-treated aggressive fibromatosis. (Letter) Pediatr Blood Cancer 2010; 55: 587- 588 [IF 2.134]

251 Meazza C., Casanova M., Luksch R., Podda M., Favini F., Cefalo G., Massimino M., Ferrari A.: Prolonged 14-day continuous infusion of high-dose ifosfamide with an external portable pump: feasibility and efficacy in refractory pediatric sarcoma. Pediatr Blood Cancer 2010; 55: 617-620 [IF 2.134]

252 Menvielle G., Boshuizen H., Kunst A.E., Vineis P., Dalton S.O., Bergmann M.M., Hermann S., Veglia F., Ferrari P., Overvad K., Raaschou-Nielsen O., Tjonneland A., Kaaks R., Linseisen J., Palli D., Krogh V., Tumino R., Rodriguez L., Agudo A., Sanchez M.J., Arozena J.M., Cirera L., Ardanaz E., Bingham S., Khaw K.T., Boffetta P., Duell E., Slimani N., Gallo V., Riboli E., Bueno- deMesquita H.B.: Occupational exposures contribute to educational inequalities in lung cancer incidence among men: Evidence from the EPIC prospective cohort study. Int J Cancer 2010; 126: 19281935 [IF 4.722]

253 Metcalfe K., Lubinski J., Lynch H.T., Ghadirian P., Foulkes W.D., Kim-Sing C., Neuhausen S., Tung N., Rosen B., Gronwald J., Ainsworth P., Swets K., Eisen A., Sun P., Narod S.A., Manoukian S., for the Hereditary Breast Cancer Clinical Study: Group: Family history of cancer and cancer risks in women with BRCA1 or BRCA2 mutations. J Natl Cancer Inst 2010; 102: 1874-1878 [IF 14.069]

254 Meynet O., Scotlandi K., Pradelli E., Manara M.C., Colombo M.P., Schmid-Antomarchi H., Picci P., Bernard A., Bernard G.: Xg expression in Ewingâ&#x20AC;&#x2122;s sarcoma is of prognostic value and contributes to tumor invasiveness. Cancer Res 2010; 70: 37303738 [IF 7.543]

255 Mezzanzanica D., Bagnoli M., De Cecco L., Valeri B., Canevari S.: Role of microRNAs in ovarian cancer pathogenesis and potential clinical implications. Int J Biochem Cell Biol 2010; 42: 1262- 1272 [IF 4.887]

256 Michaud D.S., Gallo V., Schlehofer B., Tjonneland A., Olsen A., Overvad K., Dahm C.C., Kaaks R., Lukanova A., Boeing H., Schutze M., Trichopoulou A., Bamia C., Kyrozis A., Sacerdote C., Agnoli C., Palli D., Tumino R., et al.: Reproductive factors and exogenous hor mone use in relation to risk of glioma and meningioma in a large European cohort study. Cancer Epidemiol Biomarkers Prev 2010; 19: 2562-2569 [IF 4.31]


172

SCIENTIFIC REPORT 2010

257 Michaud D.S., Gallo V., Schlehofer B., Tjønneland A, Olsen A., Overvad K., Dahm C.C., Teucher B., Lukanova A., Boeing H., Schutze M., Trichopoulou A., Lagiou P., Kyrozis A., Sacerdote C., Krogh V., Masala G., Tumino R., Mattiello A., Bueno de Mesquita H.B., Ros M.M., Peeters P.H.M., van Gils C.H., et al: Coffee and tea intake and risk of brain tumors in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study. Am J Clin Nutr 2010; 92: 1145-1150 [IF 6.307]

258 Mickisch G., Gore M., Escudier B., Procopio G., Walzer S., Nuijten M.: Costs of managing adverse events in the treatment of first-line metastatic renal cell carcinoma: bevacizumab in combination with interferon-alpha2a compared with sunitinib. Br J Cancer 2010; 102: 80-86 [IF 4.346]

259 Milione M., Seregni E.: Pathological diagnosis and tumor markers. Tumori 2010; 96: 810-816 [IF 0.863]

260 Mirabile A., Devizzi L., Gianni L., Cabras A., Carbone A.: MALT lymphoma and Kaposi sarcoma in an HIV-negative patient. (Letter) Am J Hematol 2010; 85: 815-817 [IF 2.61]

261 Miranda C., Fumagalli T., Anania M.C., Vizioli M.G., Pagliardi S., Pierotti M.A., Greco A.: Role of STAT3 in in vitro transformation triggered by TRK oncogenes. PLoS ONE 2010; 5:e: 9446 [IF 4.351]

262 Mologni L., Dekhil H., Ceccon M., Purgante S., Lan C., Cleris l., Magistroni V., Formelli F., Gambacorti-Passerini C.B.: Colorectal tumors are effectively eradicated by combined inhibition of {beta}catenin, KRAS, and the oncogenic transcription factor ITF2. Cancer Res 2010; 70: 7253-7263 [IF 7.543]

263 Moreno L., Pollack I.F., Duffner P.K., Geyer J.R., Grill J., Massimino M., Finlay J.L., Zacheroulis S.: Utility of cerebrospinal fluid cytology in newly diagnosed childhood ependymoma. J Pediatr Hematol Oncol 2010; 32: 515-518 [IF 1.022]

264 Morselli M., Bandieri E., Zanin R., Buonaccorso L., D’Amico R., Forghieri F., Pietramaggiori A., Potenza L., Berti A., Cacciapaglia G., Molitierno A., Galli L., Artioli F., Ripamonti C., Bruera E., Torelli G., Luppi M.: Pain and emotional distress in leukemia patients at diagnosis. (Letter) Leuk Res 2010; 34 e: 67-68 [IF 2.358]

265 Motzer R.J., Escudier B., Oudard S., Huston T.E., Porta C., Bracarda S., Grunwald V., Thompson J.A., Figlin R.A., Hollaender N., Kay A., Ravaud A., Bajetta E., for the Record-1 Study Group: Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer 2010; 116: 4256-4265 [IF 5.418]

266 Mussi C., Ronollenfitsch U., Jakob J., Tamborini E., Reichardt P., Casali P.G., Fiore M., Hohenberger P., Gronchi A.: Post-imatinib surger y in advanced/metastatic GIST: is it worthwhile in all patients? Ann Oncol 2010; 21: 403-408 [IF 5.647]

267 Musso L., Dallavalle S., Merlini L., Bava A., Nasini G., Penco S., Giannini G., Giommarelli C., De Cesare M., Zuco V., Vesci L., Pisano C., Dal Piaz F., De Tommasi N., Zunino F.: Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors. Bioorg Med Chem 2010; 18: 6031-6043 [IF 2.822]

268 Muzza M., Degl’Innocenti D., Colombo C., Perrino M., Ravasi E., Rossi S., Cirello V., Beck-Peccoz P., Borrello M.G., Fugazzola L.:

T h e t i g h t r e l a t i o n s h i p b e t w e e n p a p i l l a r y t h y r o i d c a n c e r, autoimmunity and inflammation: clinical and molecular studies. Clin Endocrinol 2010; 72: 702-708 [IF 3.201]

269 Nagel G., Linseisen J., van Gils C.H., Peeters P.H., Boutron-Ruault M.C., Clavel-Chapelon F., Romieu I., Tjonneland A., Olsen A., Roswall N., Witt P.M., Overvad K., Rohrmann S., Kaaks R., Drogan D., Boeing H., Trichopoulou A., Stratigakou V., Zylis D., Engeset D., Lund E., Skeie G., Berrino F., Grioni S., Mattiello A., Masala G., Tumino R., Zanetti R., Ros M.M., Bueno-de-Mesquita H.B., Ardanaz E., Sanchez M.J., Huer ta J.M., Amiano P., Rodrìguez L., Manjer J., Wirfalt E., Lenner P., Hallmans G., Spencer E.A., Key T.J., Bingham S., Khaw K.T., Rinaldi S., Slimani N., Boffetta P., Gallo V., Norat T., Riboli E.: Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Breast Cancer Res Treat 2010; 119: 753-765 [IF 4.697]

270 Necchi A., Nicolai N., Salvioni R.: Re: Roisin M. Connolly, John A. McCaffrey. High-dose chemotherapy plus stem cell transplantation in advanced germ cell cancer: a review. Eur Urol 2009;56:57-64. (Letter) Eur Urol 2010; 57: e: 5-6 [IF 7.667]

271 Negri T., Tarantino E., Orsenigo M., Reid J.F., Gariboldi M., Zambetti M., Pierotti M.A., Pilotti S.: Chromosome band 17q21 in breast cancer: Significant association between beclin 1 loss and HER2/NEU amplification. Genes Chromosom Cancer 2010; 49: 901-909 [IF 3.858]

272 Negri T., Virdis E., Brich S., Bozzi F., Tamborini E., Tarantino E., Jocollè J., Cassinelli G., Grosso F., Sanfilippo G.R., Casalini P., Greco A., Pierotti M.A., Pilotti S.: Functional mapping of receptor tyrosine kinases in myxoid liposarcoma. Clin Cancer Res 2010; 16: 3581-3593 [IF 6.747]

273 Nicolai N., Miceli R., Necchi A., Biasoni D., Catanzaro M.A., Milani A., Piva L., Pizzocaro G., Stagni S., Torelli T., Salvioni R.: Retroperitoneal Lymph Node Dissection with No Adjuvant Chemotherapy in Clinical Stage I Nonseminomatous Germ Cell Tumours: Long-Term Outcome and Analysis of Risk Factors of Recurrence. Eur Urol 2010; 58: 912-918 [IF 7.667]

274 Nicolai N., Necchi A., Piva L., Stagni S., Catanzaro M.A., Biasoni D., Milani A., Torelli T., Salvioni R.: [Retroperitoneal surgery in the treatment of germ-cell tumors of the testis: retroperitoneal lymph node dissection (RPLND). Urologia 2010; 77: 84-87

275 Nicoloso M.S., Sun H., Spizzo R., Kim H., Wickramasinghe P., Shimizu M., Wojcik S.E., Ferdin J., Kunej T., Xiao L., Manoukian S., Secreto G., Ravagnani F., Wang X., Radice P., Croce C.M., Davuluri R.V., Calin G.A.: Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility. Cancer Res 2010; 70: 2789-2798 [IF 7.543]

276 Orbach D., Rey A., Cecchetto G., Oberlin O., Casanova M., Thebaud E., Scopinaro M., Bisogno G., Carli M., Ferrari A.: Infantile fibrosarcoma: management based on the European experience. J Clin Oncol 2010; 28: 318-323 [IF 17.793]

277 Orlandi E., Palazzi M., Pignoli E., Fallai C., Giostra A., Olmi P.: Radiobiological basis and clinical results of the simultaneous integrated boost (SIB) in intensity modulated radiotherapy (IMRT) for head and neck cancer: A review. Crit Rev Oncol Hematol 2010; 73: 111-125 [IF 5.269]

278 Palumbo A., Bringhen S., Rossi D., Cavalli M., Larocca A., Ria R., Offidani M., Patriarca F., Nozzoli C., Guglielmelli T., Benevolo G.,


PUBLICATIONS

Callea V., Baldini L., Morabito F., Grasso M., Leonardi G., Rizzo M., Falcone A.P., Gottardi D., Montefusco V., Musto P., Petrucci M.T., Ciccone G., Boccadoro M.: Bor tezomib-melphalanprednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalanprednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 2010; 28: 5101-5109 [IF 17.793]

279 Palumbo A., Gay F., Falco P., Crippa C., Montefusco V., Patriarca F., Rossini F., Caltagirone S., Benevolo G., Pescosta N., Guglielmelli T., Bringhen S., Offidani M., Giuliani N., Petrucci M.T., Musto P., Liberati A.M., Rossi G., Corradini P., Boccadoro M.: Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol 2010; 28: 800807 [IF 17.793]

280 Park Y., Spiegelman D., Hunter D.J., Albanes D., Bergkvist L., Buring J.E., Freudenheim J.L., Giovannucci E., Goldbohm R.A., Harnack L., Kato I., Krogh V., Leitzmann M.F., Limburg P.J., Marshall J.R., McCullogh M.L., Miller A.B., Rohan T.E., Schatzkin A., Shore R., Sieri S., Stampfer M.J., Virtamo J., Weijenberg M., Willet W.C., Wolk A., Zhang S.M., Smith-Warner S.A.: Intakes of vitamins A, C, and E and use of multiple vitamin supplements and risk of colon cancer: a pooled analysis of prospective cohort studies. Cancer Causes Control 2010; 21: 1745-1757 [IF 3.199]

281 Pasanisi P., Villarini A., Bruno E., Raimondi M., Gargano G., Berrino F.: Nutritional advice to breast cancer survivors Support Care Cancer 2010; 18 (Suppl. 2): 29-33 [IF 2.089]

282 Pastorino U.: The development of an international registry. J Thorac Oncol 2010; 5 (Suppl.2): 196-197 [IF 4.547]

283 Pastorino U.: Lung cancer screening. Br J Cancer 2010; 102: 1681-1686 [IF 4.346]

284 Pastorino U., Treasure T.: A historical note on pulmonar y metastasectomy. J Thorac Oncol 2010; 5 (Suppl.2): 132-133 [IF 4.547]

285 Pedranzini L., Mottadelli F., Ronzoni S., Rossella F., Ferracin M., Magnani I., Roversi G., Colapietro P., Negrini M., Pelicci P.G., Larizza L.: Differential cytogenomics and miRNA signature of the Acute Myeloid Leukaemia Kasumi-1 cell line CD34+38compartment. Leuk Res 2010; 34: 1287-1295 [IF 2.358]

286 Pennacchioli E., Fiore M., Collini P., Radaelli S., Dileo P., Stacchiotti S., Casali P.G., Gronchi A.: Alveolar soft part sarcoma: clinical presentation, treatment, and outcome in a series of 33 patients at a single institution. Ann Surg Oncol 2010; 17: 32293233 [IF 4.13]

287 Perego P., Cossa G., Zuco V., Zunino F.: Modulation of cell sensitivity to antitumor agents by targeting survival pathways. Biochem Pharmacol 2010; 80: 1459-1465 [IF 4.254]

288 Perego P., Gatti L., Beretta G.L.: The ABC of glycosylation. (Letter) Nat Rev Cancer 2010; 10: 523 [IF 29.538]

289 Perego M., Tortoreto M., Tragni G., Mariani L., Deho P., Carbone A., Santinami M., Patuzzo R., Della Mina P., Villa A., Pratesi G., Cossa G., Perego P., Daidone M.G., Alison M.R., Parmiani G., Rivoltini L., Castelli C.: Heterogeneous phenotype of human melanoma cells with in vitro and in vivo features of tumor-initiating cells. J Invest Dermatol 2010; 130: 1877-1886 [IF 5.543]

173

290 Perotti A., Locatelli A., Sessa C., Hess D., Viganò L., Capri G., Maur M., Cerny T., Cresta S., Rojo F., Albanell J., Marsoni S., Corradino I., Berk L., Rivera V.M., Haluska F., Gianni L.: Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine. J Clin Oncol 2010; 28: 4554-4561 [IF 17.793]

291 Perrone F., Bossi P., Cortellazzi B., Locati L., Quattrone P., Pierotti M.A., Pilotti S., Licitra L.: TP53 Mutations and Pathologic Complete Response to Neoadjuvant Cisplatin and Fluorouracil Chemotherapy in Resected Oral Cavity Squamous Cell Carcinoma. J Clin Oncol 2010; 28: 761- 766 [IF 17.793]

292 Perrone A., Jocollè J., Pennati A., Deraco M., Baratti D., Brich S., Orsenigo M., Tarantino E., De Marco C., Bertan C., Cabras A., Bertulli R., Pierotti M.A., Zaffaroni N., Pilotti S.: Receptor tyrosine kinase and downstream signalling analysis in diffuse malignant peritoneal mesothelioma. Eur J Cancer 2010; 46: 2837-2848 [IF 4.121]

293 Pessina A., Bonomi A., Cavicchini L., Albella B., Cerrato L., ParentMassin D., Sibiril Y., Parchment R., Behrsing H., Verderio P., Pizzamiglio S., Giangreco M., Baglio C., Coccè V., Sisto F., Gribaldo L.: Prevalidation of the rat CFU-GM assay for in vitro toxicology applications. Altern Lab Animal - ATLA 2010; 38: 105117 [IF 1.58]

294 Petersen G.M., Amundadottir L., Fuchs C., Kraft P., StolzenbergSolomon R.Z., Jacobs K.B., Arslan A.A., Bueno-de-Mesquita H.B., Gallinger S., Gross M., Helzlsouer K., Holly E.A., Jacobs E.J., Klein A.P., LaCroix A., Li D., Mandelson M.T., Olson S.H., Risch H.A., Zheng W., Albanes D., Bamlet W.R., Berg C.D., BoutronRuault M.C., Buring J.E., Bracci P.M., Canzian F., Clipp S., Cotterchio M., de Andrade M., Duell E.J., Gaziano J.M., Giovannucci E.L., Goggins M., Hallmans G., Hankinson S.E., Hassan M., Howard B., Hunter D.J., Hutchinson A., Jenab M., Kaaks R., Kooperberg C., Krogh V., Kurtz R.C., Lynch S.M., McWilliams R.R., Mendelsohn J.B., Michaud D.S., Parikh H., Patel A.V., Peeters P.H., Rajkovic A., Riboli E., Rodriguez L., Seminara D., Shu X.O., Thomas G., Tjønneland A., Tobias G.S., Trichopoulos D., Van Den Eeden S.K., Virtamo J., Wactawski-Wende J., Wang Z., Wolpin B.M., Yu H., Yu K., Zeleniuch-Jacquotte A., Fraumeni J.F. Jr., Hoover R.N., Hartge P., Chanock S.J.: A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. (Letter) Nat Genet 2010; 42: 224-228 [IF 34.284]

295 Piccioni F., Langer M., Fumagalli L., Haeusler E.A., Conti B., Previtali P.: Thoracic paravertebral anaesthesia for awake videoassisted thoracoscopic surgery daily. Anaesthesia 2010; 65: 1221-1224 [IF 2.855]

296 Piconese S., Pittoni P., Burocchi A., Gorzanelli A., Carè A., Tripodo C., Colombo M.P.: A non- redundant role for OX40 in the competitive fitness of Treg in response to IL-2. Eur J Immunol 2010; 40: 2902-2913 [IF 5.179]

297 Pierigè F., De Marco C., Orlotti N.I., Dominici S., Biagiotti S., Serafini S., Zaffaroni N., Magnani M., Ross L.: Cytotoxic activity of 2-Fluoro-ara-AMP and 2-Fluoro-ara-AMP-loaded er ythrocytes against human breast carcinoma cell lines. Int J Oncol 2010; 37: 133-142 [IF 2.447]

298 Pierotti M.A., Negri T., Tamborini E., Perrone F., Pricl S., Pilotti S.: Targeted Therapies: The Rare Cancer Paradigm. Mol Oncol 2010; 4: 19-37 [IF 2.661]


174

SCIENTIFIC REPORT 2010

299 Pietrantonio F., Di Bartolomeo M., Buzzoni R., Bajetta E.: Acute immune-mediated thrombocytopenia due to oxaliplatin administration: a case report Tumori 2010; 96: 154-156 [IF 0.863]

300 Pigni A., Brunelli C., Gibbins J., Hanks G., Deconno F., Kaasa S., Klepstad P., Radbruch L., Caraceni A.: Content development for EUROPEAN GUIDELINES on the use of opioids for cancer pain: a systematic review and Expert Consensus Study. Minerva Anestesiol 2010; 76: 833-843 [IF 1.614]

301 Pineau P., Volinia S., McJunkin K., Marchio A., Battiston C., Terris B., Mazzaferro V., Lowe S.W., Croce C.M., Dejean A.: miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci - USA 2010; 107: 264-269 [IF 9.432]

302 Pisano C., Vesci L., MilazzoF.M., Guglielmi M.B., Foderà R., Barbarino M., D’Incalci M., Zucchetti M., Petrangolini G., Tortoreto M., Perego P., Zuco V., Orlandi A., Passeri D., Carminati P., Cavazza C., Zunino F.: Metabolic approach to the enhancement of antitumor effect of chemotherapy: a key role of acetyl-L-carnitine. Clin Cancer Res 2010; 16: 3944-3953 [IF 6.747]

303 Pizzamiglio S., Cossa G., Gatti L., Beretta G.L., Corna E., Tinelli S., Verderio P., Perego P.: Simultaneous confidence intervals to compare gene expression profiles using ABC transporter TaqMan microfluidic cards. Oncol Reports 2010; 23: 853-860 [IF 1.588]

304 Pizzocaro G., Algaba F., Horenblas S., Solsona E., Tana S., Van Der Poel H., Watkin N.A.: EAU penile cancer guidelines 2009. Eur Urol 2010; 57: 1002-1012 [IF 7.667]

305 Podda M., Luksch R., Polastri D., Gandola L., Piva L., Collini P., Cefalo G., Terenziani M., Ferrari A., Casanova M., Spreafico C., Meazza C., Castellani M.R., Catania S., Schiavello E., Marchianò A., Massimino M.: Neuroblastoma in patients over 12 years old: a 20-year experience at the Istituto Nazionale Tumori of Milan. Tumori 2010; 96: 684-689 [IF 0.863]

306 Podo F., Buydens L.M., Degani H., Hilhorst R., Klipp E., Gribbestad I.S., Van Huffel S., van Laarhoven H.W.M., Luts J., Monleon D., Postma G.J., Schneiderhan-Marra N., Santoro F., Wouters H., Russnes H.G., Sorlie T., Tagliabue E., Børresen-Dale A.L., for the FEMME Consortium.: Triple-negative breast cancer: Present challenges and new perspectives. Mol Oncol 2010; 4: 209-229 [IF 2.661]

307 Polesel J., Franceschi S., Suligoi B., Crocetti E., Falcini F., Guzzinati M., Zanetti R., Tagliabue G., Russo A., Luminari S., Stracci F., De Lisi V., Ferretti S., Mangone L., Budroni M., Limina R.M., Piffer S., Serraino D., Bellù F., Giacomin A., Donato A., Madeddu A., Vitarelli S., Fusco M., Tessandori R., Tumino R., Piselli P., Dal Maso L., for the Cancer and AIDS Registries Linkage (CARL), Study: Cancer incidence in people with AIDS in Italy. Int J Cancer 2010; 127: 1437-1445 [IF 4.722]

308 Porretti L., Cattaneo A., Colombo F., Lopa R., Rossi G., Mazzaferro V., Battiston C., Svegliati- Baroni G., Bertolini F., Rebulla P., Prati D.: Simultaneous characterization of progenitor cell compartments in adult human liver. Cytometry A 2010; 77A:: 31-40 [IF 3.032]

309 Price A.J., Allen N.E., Appleby P.N., Crowe F.L., Jenab M., Rinaldi S., Slimani N., Kaaks R., Rohrmann S., Boeing H., Pischon T., Benetou V., Naska A., Trichopoulou A., Palli D., Sieri S., Tumino R., Vineis P., Bueno-de-Mesquita H.B., Donate I., González C.A., Sánchez M.J., Chirlaque M.D., Ardanaz E., Larrañaga N.,

Larrañaga N., Khaw K.T., Rodwell S., Gallo V., Michaud D.S., Riboli E., Key T.J.: Plasma phytanic acid concentration and risk of prostate cancer: results from the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr 2010; 91: 1769-1776 [IF 6.307]

310 Procopio G., Verzoni E., Guadalupi V., Iacovelli R., Bajetta E.: Is it possible to optimize the use of targeted therapies in the treatment of renal cell carcinoma? (Letter) Tumori 2010; 96: 794-795 [IF 0.863]

311 Procopio G., Verzoni E., Bajetta E.: Feasibility and activity for sequencing targeted therapies for the treatment of advanced renal cell carcinoma. (Letter) Med Oncol 2010; 27: 1267-1268 [IF 1.227]

312 Psyrri A., Licitra L., Lacombe D., Schuuring E., Budach W., Ozsahin M., Knecht R., Vermorken J.B., Langendijk J.A.: Strategies to promote translational research within the European Organisation for Research and Treatment of Cancer (EORTC) Head and Neck C a n c e r G r o u p : a r e p o r t f r o m t h e Tr a n s l a t i o n a l R e s e a r c h Subcommittee. Ann Oncol 2010; 21: 1952-1960 [IF 5.647]

313 Puppo P., Conti G., Francesca F., Mandressi A., Naselli A., Nicolai N., Colecchia M., and the AURO.it guideline committe: New Italian guidelines on bladder cancer, based on the World Health Organization 2004 classification. BJU Int 2010; 106: 168-179 [IF 2.865]

314 Querzoli P., Coradini D., Pedriali M., Boracchi P., Ambrogi F., Raimondi E., La Sorda R., Lattanzio Rinaldi R., Lunardi M., Frasson C., Modesti F., Ferretti S., Piantelli M., Iacobelli S., Biganzoli E., Nenci I., Alberti S.: An immunohistochemically positive E-cadherin status is not always predictive for a good prognosis in human breast cancer. Br J Cancer 2010; 103: 1835-1839 [IF 4.346]

315 Rancati A., Nava M., Tessari L.: Simultaneous augmentation and periareolar mastopexy: selecting the correct implant. Aesthetic Plast Surg 2010; 34: 33-39 [IF 1.179]

316 Rancati T., Schwarz M., Allen A.M., Feng F., Popovtzer A., Mittal B., Eisbruch A.: Radiation dose-volume effects in the larynx and pharynx. Int J Radiat Oncol Biol Phys 2010; 76 (Suppl.3): S: 6469 [IF 4.592]

317 Randi G., Edefonti V., Ferraroni M., La Vecchia C., Decarli A.: Dietary patterns and the risk of colorectal cancer and adenomas. Nutr Rev 2010; 68: 389-408 [IF 3.443]

318 Raspagliesi F., Ditto A., Selvaggi L., Frigerio L., Melpignano M., Scambia G., Apolloni C., Scollo P., Pignata S., Benedetti Panici P.: A Phase 2 Multicenter Study of Irinotecan and Cisplatinum as Neoadjuvant Treatment in Patients With Locally Advanced Cervical Cancer. Int J Gynecol Cancer 2010; 20: 1569-1575 [IF 2.179]

319 Richiardi L., De Marco L., Gillio-Tos A., Merletti F., Fiano V., Palli D., Masala G., Agnoli C., Tagliabue G., Panico S., Mattiello A., Tumino R., Frasca G., Vineis P., Sacerdote C.: Persistent infection by HCV and EBV in peripheral blood mononuclear cells and risk of non-Hodgkin’s lymphoma. Cancer Epidemiol 2010; 34: 709-712 [IF 2.056]

320 Rinaldi S., Claveland R., Norat T., Biessy C., Rohrmann S., Linseisen J., Boeing H., Pishon T., Panico S., Agnoli C., Palli D., Tumino R., Vineis P., Peeters P.H.M., van Gils C.H., Bueno-deMesquita B.H., Vrieling A., Allen N.E., Roddam A., Bingham S.,


PUBLICATIONS

Khaw K.T., Manjer J., Borgquist S., Dumeaux V., Gram I.T., Lund E., Trichopoulou A., Makygiannis G., Benetou V., Molina E., Suarez I.D., Gurrea A.B., Gaonzales C.A., Tormo M.J., Altzibar J.M., Olsen A., Tjonneland A., Gronbaek H., Overvad K., ClavelChapelon F., Boutron-Rualt M.C., Morois S., Slimani N., Boffetta P., Jenab M., Riboli E., Kaaks R.: Serum levels of IGF-I, IGFBP-3 and colorectal cancer risk: results from the EPIC cohort, plus a metaanalysis of prospective studies. Int J Cancer 2010; 126: 1702-1715 [IF 4.722]

321 Rinke A., Ricci S., Bajetta E., Jelic S.: Pharmacological therapy of neuroendocrine tumors: Tumori 2010; 96: 847-857 [IF 0.863]

322 Ripamonti C., Borreani C., Maruelli A., Proserpio T., Pessi M., Miccinesi G.: System of belief inventory (SBI-15R): a validation study in Italian cancer patients on oncological, rehabilitation, psychological and supportive care settings. Tumori 2010; 96: 1016-1021 [IF 0.863]

323 Ripamonti C., Piccinelli C., Pessi M., Clerici C.A.: Modern computer technologies facilitate communication with a young cancer patient. Tumori 2010; 96: 609-612 [IF 0.863]

324 Rivoltini L., Mazzaferro V.: Exploiting liver immunity for the prevention of hepatic metastases. (Editorial) J Hepatol 2010; 53: 596-598 [IF 7.818]

325 Rocchi A., Manara M.C., Sciandra M., Zambelli D., Nardi F., Nicoletti G., Garofalo C., Meschini S., Astolfi A., Colombo M.P., Lessnick S.L., Picci P., Scotlandi K.: CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis. J Clin Invest 2010; 120: 668-680 [IF 15.387]

326 Romanaguera D., Norat T., Vergnaud A.C., Mouw T., May A.M., Agudo A., Buckland G., Slimani N., Rinaldi S., Couto E., ClavelChapelon F., Boutron-Ruault M.C., Cottet V., Teucher B., Bergmann M., Boeing H., Tjonneland A., Halkjaer J., Jakobsen M.U., Dahm C.C., Travier N., Rodriguez L., Sanchez M.J., Agnoli C., et al.: Mediterranean dietary patterns and prospective weight change in participants of the EPIC-PANACEA project. Am J Clin Nutr 2010; 92: 912-921 [IF 6.307]

327 Romei C., Mariotti S., Fugazzola L., Taccaliti A., Pacini F., Opocher G., Mian C., Castellano M., degli Uberti E., Ceccherini I., Cremonini N., Seregni E., Orlandi F., Ferolla P., Puxeddu E., Giorgino F., Colao A., Loli P., Bondi F., Cosci B., Botticini V., Cappai A., Zatelli M.C., Faggiano A., Grancia G., Brandi M.L., Falchetti A., Pinchera A., Elisei R., and the ItaMen network: Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol 2010; 163: 301-308 [IF 3.539]

328 Rossi S., Gasparotti D., Toffolatti L., Pastrello C., Gallina G., Marzotto A., Sartor C., Barbareschi M., Cantaloni C., Messerini L., Bearzi I., Arrigoni G., Mazzoleni G., Fletcher J.A., Casali P.G., Ta l a m i n i R . , M a e s t r a R . , D e i To s A . P. : M o l e c u l a r a n d clinicopathologic characterization of gastrointestinal stromal tumors (GISTs) of small size. Am J Surg Pathol 2010; 34: 1480-1491 [IF 4.062]

329 Rossini A., Zanobbio L., Palazzo M., Sfondrini L., Morelli D., Tagliabue E., Balsari A., Rumio C.: Influence of lignans depletion on murine mammary gland morphology. Nutr Cancer 2010; 62: 237-242 [IF 1.974]

175

330 Rota Nodari L., Ferrari D., Giani F., Rodriguez-Menendez V., Tredici G., Delia D., Vescovi A.L., De Filippis L.: Long-term survival of human neural stem cells in the ischemic rat brain upon transient immunosuppression. PLoS ONE 2010; 5:e: 14035 [IF 4.351]

331 Ruella M., Rocci I., Ricca I., Carniti C., Lobetti Bodoni C., Caracciolo D., Boccadoro M., Carlo Stella C., Corradini P., Tarella C.: Comparative assessment of telomere length before and after hematopoietic SCT: role of grafted cells in determining posttransplant telomere status. Bone Marrow Transplant 2010; 45: 505-512 [IF 2.998]

332 Rundle A., Richie J., Steindorf K., Peluso M., Over vad K., Raaschou-Nielsen O., Clavel-Chapelon F., Linseisen J.P., Boeing H., Trichopoulou A., Palli D., Krogh V., Tumino R., Panico S., Buenode-Mesquita H.B., Peerers P.H., Lund E., Gonzales C.A., Martinez C., Dorronsoro M., Barricarte A., Tormo M.J., Quiros J., Agudo A., Berglund G., Jarvholm B., Bingham S., Key T.J., Gormally E., Saracci R., Kaaks R., Riboli E., Vineis P.: Physical activity and lung cancer among non-smokers: a pilot molecular epidemiological study within EPIC. Biomarkers 2010; 15: 20-30 [IF 1.608]

333 Rusconi F., Mancinelli E., Colombo G., Cardani R., Da Riva L.C., Bongarzone I., Meola G., Zippel R.: Proteome profile in Myotonic Dystrophy type 2 myotubes reveals dysfunction in protein processing and mitochondrial pathways. Neurobiol Dis 2010; 38: 273-280 [IF 4.518]

334 Rutkowski S., Cohen B., Finlay J., Luksch R., Ridola V., ValteauCouanet D., Hara J., Garre M.L., Grill J.: Medulloblastoma in young children. Review Pediatr Blood Cancer 2010; 54: 635-637 [IF 2.134]

335 Rutkowski S., von Hoff K., Emser A., Zwiener I., Pietsch T., Figarella-Branger D., Giangaspero F., Ellison D.W., Garre M.L., Biassoni V., Grundy R.G., Finlay J.L., Dhall G., Raquin M.A., Grill J.: Sur vival and prognostic factors of early childhood medulloblastoma: an international meta- analysis. J Clin Oncol 2010; 28: 4961-4968 [IF 17.793]

336 Saberi Hosnijeh F., Krop E.J.M., Scoccianti C., Krogh V., Palli D., Panico S., Tumino R., Sacredote C., Nawroly N., Portengen L., Linseisen J., Vineis P., Vermeulen R.: Plasma cytokines and future risk of non-Hodgkin lymphoma (NHL): a case-control study nested in the Italian European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev 2010; 19: 15771584 [IF 4.31]

337 Salerno D., Brogioli D., Cassina V., Turchi D., Beretta G.L., Seruggia D., Ziano R., Zunino F., Mantegazza F.: Magnetic tweezers measurements of the nanomechanical properties of DNA in the presence of drugs. Nucleic Acids Res 2010; 38: 7089-7099 [IF 7.479]

338 Samori C., Beretta G.L., Varchi G., Guerrini A., Di Micco S., Basili S., Bifulco G., Riccio R., Moro S., Bombardelli E., Zunino F., Fontana G.: Structure-activity relationship study of 16?athiocamptothecins: an integrated in vitro and in silico approach. ChemMedChem 2010; 5: 2006- 2015 [IF 3.232]

339 Sangaletti S., Tripodo C., Ratti C., Piconese S., Porcasi R., Salcedo R., Trichieri G., Colombo M.P., Chiodoni C.: Oncogene-driven intrinsic inflammation induces leukocyte production of tumor necrosis factor that critically contributes to mammar y carcinogenesis. Cancer Res 2010; 70: 7764-7775 [IF 7.543]


176

SCIENTIFIC REPORT 2010

340 Sant M., Allemani C., Tereanu C., De Angelis R., Capocaccia R., Visser O., Marcos-Gragera R., Maynadiè M., Simonetti A., Lutz J.M., Berrino F., and the HAEMACARE Working Group: Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010; 116: 3724-3734 [IF 10.555]

341 Santilli G., Lamorte G., Carlessi L., Ferrari D., Rota Nodari L., Binda E., Delia D., Vescovi A.L., De Filippis L.: Mild hypoxia enhances proliferation and multipotency of human neural stem cells. PLoS ONE 2010; 5: e: 8575 [IF 4.351]

342 Sarina B., Castagna L., Farina L., Patriarca F., Benedetti F., Carella A.M., Falda M., Guidi S., Ciceri F., Bonini A., Ferrari S., Malagola M., Morello E., Milone G., Bruno B., Mordini N., Viviani S., Levis A., Giordano L., Santoro A., Corradini P., for Gruppo Italiano Trapianto di Midollo Osseo: Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood 2010; 115: 3671-3677 [IF 10.555]

343 Sbrogiò L., Frison G., Tagliapietra L., Michieletto F., Allegri F., De Marco C., Mazza R., Boffi R., Ruprecht A.A., Invernizzi G.: La prevalenza dell’abitudine a fumare in automobile i risultati dello studio osservazionale in Veneto. Epidemiol Prev 2010; 34: 43-47 [IF 0.705]

344 Schernhammer E.S., Berrino F., Krogh V., Secreto G., Micheli A., Venturelli E., Grioni S., Sempos C.T., Cavalleri A., Schunemann H.J., Strano S., Muti P.: Urinary 6-Sulphatoxymelatonin levels and risk of breast cancer in premenopausal women: the ORDET cohort. Cancer Epidemiol Biomarkers Prev 2010; 19: 729-737 [IF 4.31]

345 Schmoll H.J., Jordan K., Huddart R., Laguna Pes M.P., Horwich A., Fizazi K., Kataja V., Necchi A., Nicolai N., Salvioni R., on behalf of the ESMO Guidelines Working Group: Testicular seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl. 5): 147-154 [IF 5.647]

346 Schmoll H.J., Jordan K., Huddart R., Laguna Pes M.P., Horwich A., Fizazi K., Kataja V., Salvioni R., Nicolai N., Necchi A., on behalf of the ESMO Guidelines Working Group: Testicular non- seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl. 5): 140-146 [IF 5.647]

347 Schnitzbauer A.A., Zuelke C., Graeb C., Rochon J., Bilbao I., Burra P., de Jong K.P., Duvoux C., Kneteman N.M., Adam R., Bechstein W.O., Becker T., Beckebaum S., Chazouillères O., Cillo U., Colledan M., Fandrich F., Gugenheim J., Hauss J.P., Heise M., Hidalgo E., Jamieson N., Königsrainer A., Lamby P.E., Lerut J.P., Mäkisalo H., Margreiter R., Mazzaferro V., Mutzbauer I., Otto G., Pageaux G.P., Pinna A.D., Pirenne J., Rizell M., Rossi G., Rostaing L, Roy A., Turrion V.S., Schmidt J., Troisi R.I., van Hoek B., Valente U., Wolf P., Wolters H., Mirza D.F., Scholz T., Steininger R., Soderdahl G., Strasser S.I., Jauch K.W., Neuhaus P., Schlitt H.J., Geissler E.K.: A prospective randomised, open-labeled, trial comparing sirolimus- containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 2010; 10: 190 [IF 2.736]

348 Scioletti A.P., Brancati F., Gatta V., Antonucci I., Peissel B.G., Pizzuti A., Mortellaro C., Tetè S., Gherlone E., Palka G., Stuppia L.: Two novel mutations affecting splicing in the IRF6 gene associated with van der Woude syndrome. J Craniomaxillofac Surg 2010; 21: 1654-1656 [IF 1.252]

349 Seregni E., Maccauro M., Coliva A., Castellani M.R., Bajetta E., Aliberti G., Vellani C., Chiesa C., Martinetti A., Bogni A., Bombardieri E.: Treatment with tandem [90Y]DOTA-TATE an [177Lu] DOTA-TATE of neuroendocrine tumors refractor y to conventional therapy: preliminary results. Q J Nucl Med Mol Imaging 2010; 54: 84-91 [IF 2.877]

350 Sessa C., Tosi D., Viganò L., Albanell J., Hess D., Maur M., Cresta S., Locatelli A., Angst R., Rojo F., Coceani N., Rivera V.M., Berk L., Haluska F., Gianni L.: Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel. Ann Oncol 2010; 21: 1315-1322 [IF 5.647]

351 Sichetti D., Bandieri E., Romero M., Di Biagio K., Luppi M., Belfiglio M., Tognoni G., Ripamonti C., for ECAD Working Group: Impact of setting of care on pain management in patients with cancer: a multicentre cross-sectional study. Ann Oncol 2010; 21: 2088-2093 [IF 5.647]

352 Siena S., Crinò L., Danova M., Del Prete S., Cascinu S., Salvagni S., Schiavetto I., Vitali M., Bajetta E.: Dose-dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surger y or radiosurgery: a multicenter phase II study. Ann Oncol 2010; 21: 655-661 [IF 5.647]

353 Sieri S., Krogh V., Berrino F., Evangelista A., Agnoli C., Brighenti F., Pellegrini N., Palli D., Masala G., Sacerdote C., Veglia F., Tumino R., Frasca G., Grioni S., Pala M. V., Mattiello A., Chiodini P., Panico S.: Dietar y glycemic load and index and risk of coronary heart disease in a large italian cohort: the EPICOR study. Arch Int Med 2010; 170: 640-647 [IF 9.813]

354 Signoroni S., Vitellaro M., Sala P., Bertario L.: Biomarkers in familial adenomatous polyposis: role and significance. Front Biosci (Schol Ed) 2010; 2: 413-421

355 Solari A., Martinelli V., Trojano M., Lugaresi A., Granella F., Giordano A., Messmer Uccelli M., D’Alessandro R., Pucci E., Confalonieri P., Borreani C., on behalf of the SIMS-Trial group: An information aid for newly diagnosed multiple sclerosis patients improves disease knowledge and satisfaction with care. Mult Scler 2010; 16: 1393-1405 [IF 3.279]

356 Solari A., Mattarozzi K., Addis A., Giordano A., Russo P.M., Messmer Uccelli M., D’Alessandro R., Borreani C., on behalf of the SIMS-Trial group and of the: GERONIMUS group: Development and validation of a patient self-assessed questionnaire on satisfaction with communication of the multiple sclerosis diagnosis. Mult Scler 2010; 16: 1237-1247 [IF 3.279]

357 Spina M., Gloghini A., Tirelli U., Carbone A.: Therapeutic options for HIV-associated lymphomas. Expert Opin Pharmacother 2010; 11: 2471-2481 [IF 2.018]

358 Spinola M., Falvella F.S., Colombo F., Sullivan J.P., Shames D.S., Girard L., Spessotto P., Minna J.D., Dragani T.A.: MFSD2A is a novel lung tumor suppressor gene modulating cell cycle and matrix attachment. Mol Cancer 2010; 9: 62 [IF 4.16]

359 Spreafico F., Collini P., Terenziani M., Marchianò A., Piva L.: Renal cell carcinoma in children and adolescents. Expert Rev Anticancer Ther 2010; 10: 1967-1978 [IF 2.493]


PUBLICATIONS

360 Squadrelli-Saraceno M., Compan A., Bimbi G., Gatto L., Riccio S., Colombo S.: Autonomous reparative unit (ARU): a new concept of repairing free flap donor site with local full-thickness skin graft. Acta Otorhinolaryngol Ital 2010; 30: 40-46

361 Stacchiotti S., Casali P.G., Lo Vullo S., Mariani L., Palassini E., Mercuri M., Alberghini M., Pilotti S., Zanella L., Gronchi A., Picci P.: Chordoma of the mobile spine and sacrum: a retrospective analysis of a series of patients surgically treated at two referral centers. Ann Surg Oncol 2010; 17: 211-219 [IF 4.13]

362 Stacchiotti S., Grosso F., Negri T., Palassini E., Morosi C., Pilotti S., Gronchi A., Casali P.G.: Tumor response to sunitinib malate observed in clear-cell sarcoma. (Letter) Ann Oncol 2010; 21: 1130-1131 [IF 5.647]

363 Stacchiotti S., Negri T., Palassini E., Conca E., Gronchi A., Morosi C., Messina A., Pastorino U., Pierotti M.A., Casali P.G., Pilotti S.: Sunitinib malate and figitumumab in solitary fibrous tumor: patterns and molecular bases of tumor response. Mol Cancer Ther 2010; 9: 1286-1297 [IF 4.953]

364 Stranges S., Sieri S., Vinceti M., Grioni S., Guallar E., Laclaustra M., Muti P., Berrino F., Krogh V.: A prospective study of dietary selenium intake and risk of type 2 diabetes. BMC Public Health 2010; 10: 564 [IF 2.223]

365 Sultan I., Casanova M., Al-Jumaily U., Meazza C., RodriguezGalindo C., Ferrari A.: Soft tissue sarcomas in the first year of life. Eur J Cancer 2010; 46: 2449-2456 [IF 4.121]

366 Sultan I., Casanova M., Ferrari A., Rihani R., Rodriguez-Galindo C.: Differential features of nasopharyngeal carcinoma in children and adults: a SEER study. Pediatr Blood Cancer 2010; 55: 279284 [IF 2.134]

367 Sultan I., Ferrari A.: Selecting multimodal therapy for rhabdomyosarcoma. Expert Rev Anticancer Ther 2010; 10: 12851301 [IF 2.493]

368 Sultan I., Rodriguez-Galindo C., El-Taani H., Pastore G., Casanova M., Gallino G., Ferrari A.: Distinct features of colorectal cancer in children and adolescents: a population-based study of 159 cases. Cancer 2010; 116: 758-765 [IF 5.418]

369 Sverzellati N., Ingegnoli A., Calabrò E., Randi G., La Vecchia C., Marchianò A., Kughigk J.M., Hansell D.M., Zompatori M., Pastorino U.: Bronchial diverticula in smokers on thin-section CT. Eur Radiol 2010; 20: 88-94 [IF 3.589]

370 Sverzellati N., Calabrò E., Kunighk J.M., Randi G., Pastorino U.: Letter to the editor re: Evolution of emphysema in relation to smoking. Eur Radiol 2010; 20: 1621-1622 [IF 3.589]

371 Tagliabue E., Balsari A., Campiglio M., Pupa S.: HER2 as a target for breast cancer therapy. Expert Opin Biol Ther 2010; 10: 711724 [IF 3.215]

372 Tamborini E., Virdis E., Negri T., Orsenigo M., Brich S., Conca E., Gronchi A., Stacchiotti S., Manenti G., Casali P.G., Pierotti M.A., Pilotti S.: Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas.1 Neuro-Oncology 2010; 12: 776-789 [IF 4.984]

177

373 Terenziani M., D’Angelo P., Bisogno G., Boldrini R., Cecchetto G., Collini P., Conte M., De Laurentis T., Ilari I., Indolfi P., Inserra A., Piva L., Siracusa F., Spreafico F., Tamaro P., Lo Curto M.: Teratoma with a malignant somatic component in pediatric patients: the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience. Pediatr Blood Cancer 2010; 54: 532-537 [IF 2.134]

374 The GASTRIC (Global Advanced/ Adjuvant Stomach, Tumor Research International Collaboration) Group*, Bajetta E., Di Bartolomeo M.: Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA 2010; 303: 1729-1737 [IF 28.899]

375 The InFact Global H1N1 Collaboration, Langer M.: InFACT: a global critical care research response to H1N1. Lancet 2010; 375: 11-13 [IF 30.758]

376 The International Prognostic Factors Study Group, Necchi A., Salvioni R., Nicolai N.: Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol 2010; 28: 4906-4911 [IF 17.793]

377 Theodoratou E., Campbell H., Tenesa A., Houlston R., Webb E., Lubbe S., Broderick P., Gallinger S., Croitoru E.M., Jenkins M.A., Win A.K., Cleary S.P., Koessler T., Pharoah P.D., Kury S., Bezieau S., Buecher B., Ellis N.A., Peterlongo P., Offit K., Aaltonen L.A., Enholm S., Lindblom A., Szhou X.L., Tomlinson I.P., Moreno V., Blanco I., Capella G., Barnetson R., Porteous M.E., Dunlop M.G., Farrington S.M.: A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer 2010; 103: 1875-1884 [IF 4.346]

378 Thomas D.M., Albritton K.H., Ferrari A.: Adolescent and young adult oncology: an emerging field. J Clin Oncol 2010; 28: 47814782 [IF 17.793]

379 Tiberio P., Cavadini E., Abolafio G., Formelli F., Appierto V.: 4-oxoN-(4- hydroxyphenyl)retinamide: two independent ways to kill cancer cells. PLoS ONE 2010; 5:e: 13362 [IF 4.351]

380 Toffanin S., Friedman S.L., Llovet J.M.: Obesity, Inflammatory Signaling, and Hepatocellular Carcinoma-An Enlarging Link. Cancer Cell 2010; 17: 115-117 [IF 25.288]

381 Tomlinson I.P.M., Dunlop M., Campbell H., Zanke B., Gallinger S., Hudson T., Koessler T., Pharoah P.D., Niittymakix I., Tuupanenx S., Aaltonen L.A., Hemminki K., Lindblom A., Forsti A., Sieber O., Lipton L., van Wezel T., Morreau H., Wijnen J.T., Devillee P., Matsuda K., Nakamura Y., Castellvì- Bel S., Ruiz-Ponte C., Castells A., Carracedo A., Ho J.W.C., Sham P., Hofstra R.M.W., Vodicka P., Brenner H., Hampe J., Schafmayer C., Tepel J., Schreiber S., Volzke H., Lerch M.M., Schmidt C.A., Buch S., Moreno V., Villanueva C.M., Peterlongo P., Radice P., Echeverry M.M., Velez A., Carvajal-Carmona L., Scott R., Penegar S., Broderick P., Tenesa A., Houlston R.S.: COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer. Br J Cancer 2010; 102: 447-454 [IF 4.346]

382 Tovar V., Alsinet C., Villanueva A., Hoshida Y., Chiang D.Y., Solè M., Thung S., Moyano S., Toffanin S., Minguez B., Cabellos L., Peix J., Schwartz M., Mazzaferro V., Bruix J., Llovet J.M.: IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol 2010; 52: 550559 [IF 7.818]


178

SCIENTIFIC REPORT 2010

383 Trecate G., Manoukian S., Suman L., Vergnaghi D., Marchesini M., Agresti R., Ferraris C., Peissel B.G., Scaramuzza D., Bergonzi S.: Is there a specific magnetic resonance phenotype characteristic of hereditary breast cancer? Tumori 2010; 96: 363-384 [IF 0.863]

384 Tripodo C., Gri G., Piccaluga P.P., Frossi B., Guarnotta C., Piconese S., Franco G., Vetri V., Pucillo C.E., Florena A.M., Colombo M.P., Pileri S.A.: Mast cells and Th17 cells contribute to the lymphoma-associated pro-inflammatory microenvironment of angioimmunoblastic T-cell lymphoma. Am J Pathol 2010; 177: 792-802 [IF 5.673]

385 Truong T., Sauter W., McKay J.D., Hosgood H.D. 3rd., Gallagher C., Amos C.I., Spitz M., Muscat J., Lazarus P., Illig T., Wichmann H.E., Bickeböller H., Risch A., Dienemann H., Zhang Z.F., Naeim B.P., Yang P., Zienolddiny S., Haugen A., Le Marchand L., Hong Y.C., Kim J.H., Duell E.J., Andrew A.S., Kiyohara C., Shen H., Matsuo K., Suzuki T., Seow A., Ng D.P., Lan Q., Zaridze D., Szeszenia-Dabrowska N., Lissowska J., Rudnai P., Fabianova E., Constantinescu V., Bencko V., Foretova L., Janout V., Caporaso N.E., Albanes D., Thun M., Landi M.T., Trubicka J., Lener M., Lubinski J., EPIC-lung, Wang Y., Chabrier A., Boffetta P., Brennan P., Hung R.J., Krogh V.: International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants. Carcinogenesis 2010; 31: 625-633 [IF 4.795]

386 Tsilidis K.K., Allen N.E., Key T.J., Bakken K., Lund E., Berrino F., Fournier A., Olsen A., Tjonneland A., Overvad K., Boutroun-Rualt M.C., Clavel-Chapelon F., Byrnes G., Chajes V., Rinaldi S., ChangClaude J., Kaaks R., Bergmann M., Tagliabue G., et al.: Oral contraceptives, reproductive history and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer 2010; 103: 1755-1759 [IF 4.346]

387 Turinetto V., Porcedda P., Minieri V., Orlando L., Lantelme E., Accomasso L., Amoroso A., De Marchi M., Zannini L., Delia D., Giachino C.: A novel defect in mitochondrial p53 accumulation following DNA damage confers apoptosis resistance in Ataxia Telangiectasia and Nijmegen Breakage Syndrome T-cells. DNA Repair (Amst) 2010; 9: 1200-1208 [IF 4.199]

388 Valente M., Catena L., Milione M., Pusceddu S., Formisano B., Bajetta E.: Common Diagnostic Challenges in the Histopathologic Diagnosis of Neuroendocrine Lung Tumors: A Case Report. Case Rep Oncol 2010; 2: 202-207

389 Valerianova Z., Panayotova Y., Amati C., Baili P., Micheli A., Amati C., Casella I., Cifalà A., Esposito M., Saltarelli S., Di Salvo F., Ciampichini R., Berrino F., Gatta G., Sant M., Ciccolallo L., Allemani C., on behalf of the EUROCHIP Working Group: Cervical cancer screening in Bulgaria - past and present experience. Tumori 2010; 96: 538-544 [IF 0.863]

390 Valvo F., Avuzzi B., Bozzerri F.: The Association of Chemotherapy and Radiotherapy in Squamous Cell Carcinoma of Anal Canal. Curr Drug Ther 2010; 5: 220-228

391 Valvo F., Mantello G., Coco C., Corvò R., Gambacorta M.A., G e n o v e s i D . , L u p a t t e l l i M . , Va l e n t i n i V. : R e c t a l c a n c e r multidisciplinary treatment: evidences, consensus and perspectives. Tumori 2010; 96: 185-190 [IF 0.863]

392 van Boeckel P.G.A., Boshuizen H.C., Seiersema P.D., Vrieling A., Kunst A.E., Ye W., Sund M., Michaud D.S., Gallo V., Spencer E.A., Trichopoulou A., Benetou V., Orfanos P., Cirera L., Duell E.J.,

Rohrmann S., Hemann S., Masala G., Manjer J., Mattiello A., Lindkvist B., Sanchez M.J., Pala M. V., Peeters P.H.M., et al.: No association between educational level and pancreatic cancer incidence in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol 2010; 34: 696-701 [IF 2.056]

393 van den Bergh R.C., Vasarainen H., van der Poel H.G., Vis-Maters J.J., Rietbergen J.B., Pickles T., Cornel E.B., Valdagni R., Jaspars J.J., van der Hoeven J., Staerman F., Oomens E.H., Rannikko A., Roemeling S., Steyerberg E.W., Roobol M.J., Schröder F.H., Bangma C.H.: Short- term outcomes of the prospective multicentre ‘Prostate Cancer Research International: Active Surveillance’ study. BJU Int 2010; 105: 956-962 [IF 2.865]

394 Vannelli A., Battaglia L., Poiasina E., Leo E.: Diagnosis of rectal c a n c e r b y Ti s s u e R e s o n a n c e I n t e r a c t i o n M e t h o d . B M C Gastroenterol 2010; 10: 45 [IF 1.886]

395 Vanossi E., Gambarini G., Carrara M., Mariani M.: Polymer gels for in-phantom dose imaging in radiotherapy. Appl Radiat Isot 2010; 68: 772-775 [IF 1.094]

396 Vartanian J.P., Henry M., Marchio A., Suspene R., Aynaud M.M., Guetard D., Cervantes- Gonzales M., Battiston C., Mazzaferro V., Pineau P., Dejean A., Wain-Hobson S.: Massive APOBEC3 editing of hepatitis B viral DNA in cirrhosis. PLoS Pathog 2010; 6(5) e: 1000928 [IF 8.978]

397 Vasen H.F., Möslein G., Alonso A., Aretz S., Bernstein I., Bertario L., Blanco I., Bulow S., Burn J., Capella G,, Colas C., Engel C., Frayling I., Rahner N., Hes F.J., Hodgson S., Mecklin J.P., Moller P., Myrhoj T., Nagengast F.M., Parc Y., Ponz de Leon M., RenkonenSinisalo L., Sampson J.R., Stormorken A., Tejpar S., Thomas H.J.W., Wijnen J., Lubinski J., Jarvinen H., Claes E., Heinimann K., Karagiannis J.A., Lindblom A., Dove-Edwin I., Muller H.: Recommendations to improve identification of hereditary and familial colorectal cancer in Europe. Fam Cancer 2010; 9: 109115 [IF 2.189]

398 Veerus P., Arbyn M., Amati C., Baili P., Micheli A., Casella I., Cifalà A., Esposito M., Saltarelli S., Di Salvo F., Ciampichini R., Berrino F., Gatta G., Sant M., Ciccolallo L., Allemani C., on behalf of the EUROCHIP Working Group: Impact of implementing a nationwide cer vical cancer screening program on female population coverage by Pap-tests in Estonia. Tumori 2010; 96: 524-528 [IF 0.863]

399 Venturini L., Motta R., Gronchi A., Daidone M.G., Zaffaroni N.: Prognostic relevance of ALT- associated markers in liposarcoma: a comparative analysis. BMC Cancer 2010; 10: 254 [IF 2.736]

400 Verderio P., Mangia A., Ciniselli C.M., Tagliabue P., Paradiso A.: Biomarkers for Early Cancer Detection - Methodological Aspects Breast Care 2010; 5: 62-65 [IF 0.5]

401 Verderio P., Mangia A., Orlando C., Belfiglio M., Marchetti A., Bertario L., Chiappetta G., Gion M., Tonini G.P., Podo F., Vocaturo A., Silvestrini R., Lombardo C., Paradiso A.: Research trends for early cancer biomarker detection in Italy: an Integrated Program in Oncology (PIO) survey. Tumori 2010; 96: 721-725 [IF 0.863]

402 Verderio P., Pizzamiglio S., Southey A.B., Spurdle A.B., Hopper J.L., Chen X., Beesley J., Australian Ovarian Cancer Study Group kConFab, Schmutzler R.K., Engel C., Burwinkel B., Bugert P., Ficarazzi F., Manoukian S., Barile M., Wappenschmidt B., Chenevix-Trench G., Radice P., Peterlongo P.: A BRCA1 promoter


PUBLICATIONS

variant (rs11655505) and breast cancer risk. J Med Genet 2010; 47: 268-270 [IF 5.751]

403 Vergnaud A.C., Norat T., Romaguera D., Mouw T., May A.M., Travier N., Luan J., Wareham N., Slimani N., Rinaldi S., Couto E., Clavel-Chapelon F., Boutron-Ruault M.C., Cottet V., Palli D., Agnoli C., Panico S., Tumino R., Vineis P., Agudo A., Rodriguez L., Sanchez M.J., Amiano P., Barricarte A., Huerta J.M., Key T.J., Spencer E.A., Bueno-de-Mesquita B., Buchner F.L., Orfanos P., Naska A., Trichopoulou A., Rohrmann S., Hermann S., Boeing H., Buijsse B., Johansson I., Hellstrom V., Manjer J., Wirfalt E., Jakobsen U., Overvad K., Tjonneland J., Halkjaer J., Lund E., Braaten T., Engeset D., Odysseos A., Riboli E., Peeters P.H.M.: Meat consumption and prospective weight change in participants of the EPIC-PANACEA study. Am J Clin Nutr 2010; 92: 398-407 [IF 6.307]

404 Viberga I., Engele L., Baili P., Micheli A., Amati C., Casella I., CifalĂ A., Esposito M., Saltarelli S., Di Salvo F., Ciampichini R., Berrino F., Gatta G., Sant M., Ciccolallo L., Allemani C., on behalf of the EUROCHIP Working Group: Past, present and future of the cervical cancer screening in Latvia Tumori 2010; 96: 529-537 [IF 0.863]

405 Vicus D., Finch A., Rosen B., Fan I., Bradley L., Cass I., Sun P., Karlan B., McLaughlin J., Narod S.A., Manoukian S., and the Hereditary Ovarian Cancer Clinical Study: Group: Risk factors for carcinoma of the fallopian tube in women with and without a germline BRCA mutation. Gynecol Oncol 2010; 118: 155-159 [IF 3.733]

406 Villanueva A., Hoshida Y., Toffanin S., Lachenmayer A., Alsinet C., Savic R., Cornella H., Llovet J.M.: New Strategies in Hepatocellular Carcinoma: Genomic Prognostic Markers. Clin Cancer Res 2010; 16: 4688-4694 [IF 6.747]

407 Vincenzi B., Perrone G., Santini D., Grosso F., Silletta M., Frezza A., Rossi S., Russo A., Rabitti C., Gebbia N., Badalamenti G., Casali P.G., Onetti Muda A., Dei Tos A.P., Tonini G.: PML downregulation in soft tissue sarcomas. J Cell Physiol 2010; 224: 644648 [IF 4.586]

408 Vitolo U., Barosi G., Fanti S., Gianni A.M., Martelli M., Petrini M., Zinzani P.G., Tura S.: Consensus conference on the use of 90yttrium-ibritumomab tiuxetan therapy in clinical practice. A project of the Italian society of hematology. Am J Hematol 2010; 85: 147155 [IF 2.61]

409 Viviani S., Di Nicola M., Bonfante V., Di Stasi A., Carlo Stella C., Matteucci P., Magni M., Devizzi L., Valagussa P., Gianni A.M.: Long-term results of high-dose chemotherapy with autologous bone marrow or peripheral stem cell transplant as first salvage treatment for relapsed or refractory Hodgkin lymphoma: a single institution experience. Leuk Lymphoma 2010; 51: 1251- 1259 [IF 2.397]

410 Vizioli M.G., Sensi M.L., Miranda C., Cleris L., Formelli F., Anania M.C., Pierotti M.A., Greco A.: IGFBP7: an oncosuppressor gene in thyroid carcinogenesis. Oncogene 2010; 29: 3835-3844 [IF 7.135]

411 Volinia S., Galasso M., Costinean S., Tagliavini L., Gamberoni G., Drusco A., Marchesini J., Mascellani N., Sana M.E., Jarour R.A., Desponts C., Teitell M., Baffa R., Aqueilan R., Iorio M., Taccioli C., Garzon R., Di Leva G., Fabbri M., Catozzi M., Previati M., Ambs S., Palumbo T., Garofalo M., Veronese A., Bottoni A., Gasparini P., Harris C.C., Visone R., Pekarsky Y., de la Chapelle A., Bloomston M., Dillhoff M., Rassenti L.Z., Kipps T.J., Huebner K., Pichiorri F.,

179

Lenze D., Cairo S., Buendia M.A., Pineau P., Dejean A., Zanesi N., Rossi S., Calin G.A., Liu C.G., Palatini J., Negrini M., Vecchione A., Rosengerg A., Croce C.M.: Reprogramming of miRNA networks in cancer and leukemia. Genome Res 2010; 20: 589-599 [IF 11.342]

412 Volpi L., Roversi G., Colombo E.A., Leijsten N., Concolino D., Calabria A., Mencarelli M.A., Fimiani M., Macciardi F., Pfundt R., Schoenmakers E.F., Larizza L.: Targeted next-generation sequencing appoints c16orf57 as clericuzio-type poikiloderma with neutropenia gene. Am J Hum Genet 2010; 86: 72-76 [IF 12.303]

413 Vorrano F., Galvan A., Cabrera W.H.K., Carneiro P.S., Ribeiro O.G., De Franco M., Starobinas N., Jensen J.R., Seman M., Dragani T.A., Ibanez O.C.M.: Genetic Control of IL-1{beta} Production and Inflammatory Response by the Mouse Irm1 Locus. J Immunol 2010; 185: 1616-1621 [IF 5.646]

414 Vrieling A., Bueno de Mesquita H.B., Boshuizen H.C., Michaud D.S., Severinsen M.T., Overvad K., Olsen A., Tjonneland A., Clavel-Chapelon F., Boutron-Ruault M.C., Kaaks R., Rohrmann S., Boeing H., NĂśthlings U., Trichopoulou A., Moutsiou E., Dilis V., Palli D., Krogh V., Panico S., Tumino R., Vineis P., van Gils C.H., Peeters P.H.M., Lund E., Gram I.T., Rodriguez L., Agudo A., Larranaga N., Sanchez M.J., Navarro C., Barricarte A., Manjer J., Lindkvist B., Sund M., Ye W., Bingham S., Khaw K.T., Roddam A., Key T., Boffetta P., Duell E.J., Jenab M., Gallo V., Riboli E.: Cigarette smoking, environmental tobacco smoke exposure and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2010; 126: 2394-2403 [IF 4.722]

415 Yao J.C., Catena L., Colao A., Paganelli G.: Perspectives in the development of novel treatment approaches Tumori 2010; 96: 858-873 [IF 0.863]

416 Zacharoulis S., Ashley S., Moreno L., Gentet J.C., Massimino M., Frappaz D.: Treatment and outcome of children with relapsed ependymoma: a multi-institutional retrospective analysis. Childs Nerv System 2010; 26: 905-911 [IF 1.214]

417 Zappasodi R., Pupa S., Ghedini G.C., Bongarzone I., Magni M., Cabras A., Colombo M.P., Carlo Stella C., Gianni A.M., Di Nicola M.: Improved clinical outcome in indolent B-cell lymphoma patients vaccinated with autologous tumor cells experiencing immunogenic death. Cancer Res 2010; 70: 9062-9072 [IF 7.543]

418 Zerbi A., Falconi M., Rindi G., Delle Fave G., Tomassetti P., Pasquali C., Capitanio V., Boninsegna L., Di Carlo V., Bajetta E., and the members of the AISP-Network Study Group: Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. Am J Gastroenterol 2010; 105: 1421-1429 [IF 6.012]

419 Zhang X., Albenes D., Beeson W.L., van den Brandt P.A., Buring J.E., Flood A., Freudenheim J.L., Giovannucci E.L., Goldbohm R.A., Jaceldo-Siegl K., Jacobs E.J., Krogh V., Larsson S.C., Marshall J.R., McCullough M.L., Miller A.B., Robien K., Rohan T.E., Schatzkin A., Sieri S., Spiegelman D., Virtamo J., Wolk A., Willett W.C., Zhang S.M., Smith-Warner S.A.: Risk of colon cancer and coffee, tea, and sugar-sweetened soft drink intake: pooled analysis of prospective cohort studies. J Natl Cancer Inst 2010; 102: 771-783 [IF 14.069]

420 Zilembo N., Vitali M., Pietrantonio F., Platania M., Del Vecchio M., Bajetta E.: An unusual large pleural mesothelioma with an outstanding clinical response and long lasting survival: a case


180

SCIENTIFIC REPORT 2010

report and literature review. Tumori 2010; 96: 1031-1034 [IF 0.863]

421 Zito F.A., Verderio P., Simone G., Angione V., Apicella P., Bianchi S., Conde A.F., Hameed O., Ibarra J., Leong A., Pennelli N., Pezzica E., Vezzosi V., Ventrella V., Pizzamiglio S., Paradiso A., Ellis I.: Reproducibility in the diagnosis of needle core biopsies of non-palpable breast lesions: an international study using virtual slides published on the world-wide web. Histopathology 2010; 56: 720-726 [IF 3.855]

422 Zonios G., Dimou A., Carrara M., Marchesini R.: In Vivo Optical Properties of Melanocytic Skin Lesions: Common Nevi, Dysplastic Nevi and Malignant Melanoma. Photochem Photobiol 2010; 86: 236-240 [IF 2.253]

423 Zuco V., Benedetti V., De Cesare M., Zunino F.: Sensitization of ovarian carcinoma cells to the atypical retinoid ST1926 by the histone deacetylase inhibitor, RC307: enhanced DNA damage response. Int J Cancer 2010; 126: 1246-1255 [IF 4.722]

424 Zuco V., Supino R., Favini E., Tortoreto M., Cincinelli R., Croce A.C., Bucci F., Pisano C., Zunino F.: Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma. Biochem Pharmacol 2010; 79: 535-541 [IF 4.254]

425 Zuco V., Benedetti V., Zunino F.: ATM- and ATR-mediated response to DNA damage induced by a novel camptothecin, ST1968. Cancer Lett 2010; 292: 186-196 [IF 3.741]

426 Zurardelli M., Peissel B.G., Manoukian S., Zaffaroni D., Barile M., Pensotti V., Cavallari U., Masci G., Mariette F., Benski A.C., Santoro A., Radice P.: Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics. Breast Cancer Res Treat 2010; 124: 251258 [IF 4.697]


182

SCIENTIFIC REPORT 2010

INDEPENDENT ETHICS COMMITTEE

Established in 1973, the institutional Independent Ethics Committee reviews all new clinical studies submitted by investigators and approved by the Scientific Review Board. In May 2010, the Committee was renewed. In 2010, 76 new clinical studies received their ethical approval. The median time from submission to discussion was 25 days, a result obtained thanks to monthly meetings of the Committee and an optimized pathway for study clearance, which is carried out in close cooperation with all other relevant institutional bodies (General and Legal Affairs Unit, Economic and Financial Resource Management Unit, and the Pharmacy). This tight interinstitutional collaboration results in an efficient streamlining of the various scientific and administrative components of the ethical review process. In 2010, the Independent Ethics Committee maintained its focus on tissue "donation" for biobanking. The concept of a donation was initially formalized by the Ethics Committee in a general statement and then submitted for discussion to experts from different disciplines, including law, ethics and privacy, as well as patient representatives. A consensus document was published, and was presented with an ad-hoc public event organized in parallel with the 2010 Congress of the European Society for Medical Oncology. At present, a new draft informed consent for all institutional patients is under construction, with a view to sharing it with the national authority on privacy protection.

Chairman Roberto Satolli Members Maria Angela Armiraglio Marco Braga (until April 2010) Renato Bricchetti (until november 2010) Luigi Cajazzo (from May 2010) Gianfranco Canti Francesca Crippa Floriani (from May 2010) Alessandrea Currò (until April 2010) Paolo Fontana Marina Garassino (from May 2010) Momcilo Jankovic (from May 2010) Annamaria Mancuso (until April 2010) Giuseppe Masera (until April 2010) Antonio Miadonna (from May 2010) Silvano Milani (until April 2010) Paolo Spriano (from May 2010) Valter Torri (from May 2010) Giorgio Tresoldi (until April 2010) Rita Vetere (from May 2010)

Members ex-officio Lucio Ascani Marco A. Pierotti Francesco Reitano Scientific Secretariat Paolo G. Casali Administratives Raffaella DidonĂŠ Patrizia Polo


ONGOING CLINICAL STUDIES

183

ONGOING CLINICAL STUDIES Breast Carcinoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

98/01

Celio L.

1998

III

24

Closed accrual

Randomized double-blind trial in postmenopausal women with primary breast cancer who have received adjuvant tamoxifen for 2-3 years, comparing subsequent adjuvant exemestane treatment with further tamoxifen Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

99/02

Bajetta E.

1999

III

72

Closed accrual

A phase III study to evaluate letrozole as adjuvant endocrine therapy for postmenopausal women with receptor-(ER and/or PgR) positive tumor Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

02/03

Gianni L.

2002

III

35

Closed accrual

A multicenter, randomized, controlled open-labeled trial of paclitaxel-containing chemotherapy (AT&T) followed by CMF versus the same chemotherapy plus Herceptin in women with locally advanced breast cancer and HER2/C-ERBB2 overexpression and amplification, with a parallel observational study of the same chemotherapy regimen alone, in patients with HER2 negative tumors (or 1+ by immunohistochemistry) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

03/32

Berrino F.

2003

Observational

2290

256

Prognostic significance of blood concentrations of testosterone and insulin in women with early breast cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

04/06

Gianni A.M.

2004

Pilot

4

2

Immunization of patients with locally advanced/metastatic breast and ovary cancer with autologous monocyte-derived dendritic cells loaded with apoptotic/necrotic autologous tumor cells exposed to heat shock Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/39

Nava M.

2005

III

377

35

Prevention of capsule formation around prosthesis under the pectoralis major muscle, in breast reconstruction, by one local application of mitomycin-C Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/68

Gianni L.

2006

II

7

Closed accrual

A phase II, single arm, multicenter study to evaluate the efficacy and safety of the combination of Omnitarg and Herceptin in patients with HER2-positive metastatic breast cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/39

Gianni L.

2006

III

14

Closed accrual

A randomized, open-label, 2-arm, multicentre, phase III study to evaluate the efficacy and safety of bevacizumab in combination with Trastuzumab/Docetaxel compared with Trastuzumab/Docetaxel alone as first line treatment for patients with HER-2 positive locally recurrent or metastatic breast cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/04

Gianni L.

2007

II

8

Closed accrual

A randomized, double-blind, phase II trial of Fulvestran plus Enzastaurin versus Fulvestran plus Placebo in aromatase inhibitor resistant metastatic breast cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

07/24

Nava M.

2008

II

36

Patients enrolled in 2010

Prevention of postoperative pain by using botulinic toxin in patients candidates to mastectomy and immediate reconstruction with expander and in patients candidates to additive contralateral mastoplastic in the second reconstructive phase Study code

Coordinator

Activated (closed)

Phase

Total patients

07/37

Berrino F.

2007

-

250

Patients enrolled in 2010

Randomized trial of diet, physical activity and breast cancer recurrences: the DIANA-5 study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/43

Gianni L.

2007

IIb

26

2

A multinational double-blind, randomized phase IIb cooperative group study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with chemotherapy and/or endocrine therapy in patients with locally recurrent or metastatic breast cancer


184

SCIENTIFIC REPORT 2010

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/47

Gianni L.

2007

II

28

Closed accrual

A randomized multicentric international phase II study of Herceptin速 and docetaxel versus docetaxel in association with OmnitargTM and Herceptin速 versus OmnitargTM and Herceptin速 in the treatment of locally advanced HER-2 positive breast cancer, inflammatory or early breast cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/65

Manoukian S., Vergnaghi D., Bergonzi S.

2008

Observational

106

6

Italian ISS network for the surveillance of women at high breast cancer risk (ISSIN-HIBCR) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/18

Gianni L.

2008

II

319

117

Phase II study. Safety of the scheme of adjuvant or primary sequential chemotherapy in operable breast cancer at high risk (AT x 3 - CMF x 3) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/65

Gianni L.

2009

II

5

Closed accrual

A randomized, multicenter, phase II study of the efficacy and safety of trastuzumab-MCC-DM1 vs trastuzumab (Herceptin) and Docetaxel (Taxotere) in patients with metastatic HER2-positive breast cancer who have not received prior chemotherapy for metastatic disease Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/76

Berrino F.

2010

III

80

80

Tevere project: primary prevention of breast cancer by diet, physical activity or Metformin assumption Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/07

Gianni A.M.

2009

II

29

15

Phase II study to evaluate the efficacy and tolerability of sorafenib in treatment of post-surgical and post-radiotherapy edema of the upper limb in subjects affected with breast neoplasms Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/16

Gianni L.

2009

III

5

3

A randomized, multicenter, phase III open-label study of the efficacy and safety of trastuzumab-MCC-DM1 vs capecitabine+lapatinib in patients with HER2positive locally advanced or metastatic breast cancer who have received prior trastuzumab-based therapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/18

Gianni L.

2009

II

2

Closed accrual

A phase Ib/II, open-label study of the safety, tolerability and efficacy of trastuzumab-MCC-DM1 in combination with pertuzuamb administered intravenously to patients with HER2 positive locally advanced or metastatic breast cancer who have previously received trastuzumab Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/33

Gianni L.

2010

Ib

2

2

A phase Ib, open label, dose escalation study of the safety and pharmacology of P13-kinase inhibitor GDC-0941 in combination with paclitaxel and bevacizumab in patients with locally recurrent or metastatic breast cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/63

Gianni L.

2010

III

4

4

A randomized phase III, double-blind, placebo-controlled multicenter trial of daily everolimus in combination with trastuzumab and vinorelbine, in pretreated women with HER2/neu over-expressing locally advanced or metastatic breast cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/67

Gianni L.

2010

II

8

8

Multicenter, randomized, open label study evaluating a poly(AFP-ribosio) polymerase-1(PARP-1) inibitor, SAR240550 (BSI-201), administered twice weekly or weekly, in combination with gemcitabine/carboplatin, in patients with Triple Negative breast Cancer (mTNBC) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/68

Raspagliesi F.

2010

III

1

1

A multi-centre, open-label, randomized, two arm phase III trial of bevecizumab plus chemotherapy versus chemotherapy alone in patients with platinumresistant, epithelial ovarian, fallopian tube or primary peritoneal cancer

Gastrointestinal Cancers Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

04/17

Casali P.

2005

II

22

Closed accrual

A phase II, open-label study of PTK787/ZK222584 in the treatment of metastatic gastrointestinal stromal tumors (GISTs) resistant to imatinib mesylate


ONGOING CLINICAL STUDIES

Study code

Coordinator

Activated (closed)

Phase

Total patients

04/28

Bajetta E.

2005

III

71

185

Patients enrolled in 2010

Open-label randomized, multicenter phase III study of adjuvant chemotherapy in radically resected adenocarcinoma of the stomach or gastroesophageal junction: comparison of sequential treatment (CPT11 + 5-FU/LV TXT + CDDP versus a 5-FU/LV regimen) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/11

Casali P.

2005

III

36

Closed accrual

Localized, completely resected, gastointestinal stromal tumors (GIST) expressing KIT receptor: a controlled randomized trial on adjuvant imatinib mesylate (Glivec) versus no further therapy after complete surgery Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/19

Casali P.

2005

II

25

Closed accrual

A treatment protocol for patients with gastrointestinal stromal tumor who are ineligibile for partecipation in other SU011248 protocols and are refractory to or intolerant of imatinab mesylate Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/27

Bajetta E.

2005

II

55

Closed accrual

Randomized phase II trial testing the efficacy of three bevacizumab -containing first-line regimen from metastatic colorectal cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/33

Buzzoni R.

2005

III

38

Closed accrual

A randomized, three arm multinational phase III study to investigate bevacizumab (q3w r q2w) in combination with either intermittent capecitabine plus oxaliplatin (Xelox) (q3w) or fluorouracil/leucovorin with oxaliplatin (Folfox-4) versus Folfox-4 regimen alone as adjuvant chemotherapy in colon carcinoma: the AVANT study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/37

Casali P.

2005

I

11

Closed accrual

A phase I multicenter, dose escalation study of AMN107 in combination with imatinib on a continuous daily dosing schedule in adult patients with imatinib-resistant gastrointestinal stromal tumors (GIST) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/49

Bajetta E.

2005

II

39

Closed accrual

Capecitabine time table and radiotherapy in the adjuvant treatment of cancer of the rectum Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/24

Gavazzi C.

2006

III

83

18

Home enteral nutrition in malnourished patients after major surgery for gastrointestinal malignancy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/27

Buzzoni R.

2006

II

3

Closed accrual

An open-label, stratified, single-arm phase II study of RAD001 in patients with advanced pancreatic neuroendocrine tumor (NET) after failure of cytotoxic chemotherapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/54

Bajetta E.

2006

III

1

Closed accrual

Phase III, randomized, double-blind, stratified, comparative, placebo controlled, parallel group, multicentre study to assess the effect of deep subcutaneous injections of lanreotide autogel 120 mg administered every 28 days on tumour progression free surivival in patients with non functioning entero-pancreatic endocrine tumour Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/56

Casali P.

2006

-

13

Closed accrual

A treatment protocol for patients continuing from a prior SU011248 protocol Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/75

Mazzaferro V.

2006

II

39

Closed accrual

A prospective randomized, open-label trial comparing Sirolimus-containing versus mTOR -inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/09

Regalia E.

2007

-

54

Closed accrual

LIVER MATCH. An Italian multicentric study to evaluate the impact of donor-recipient matching in the outcome of liver transplantation at short, medium and long term


186

SCIENTIFIC REPORT 2010

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/25

Casali P.

2007

Observational

36

Closed accrual

A study of the genetic polymorphisms of patients with gastrointestinal stromal tumors (GIST) and of their predictive value of clinical activity of tyrosin kinase inhibitors Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/32

Casali P.

2007

Observational

54

4

The global observational registry colllecting longitudinal data on advanced GIST patients (GOLD reGISTry) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/52

Bajetta E.

2007

III

88

26

A randomized trial investigating the role of FOLFOX-4 regimen duration (3 versus 6 months) and bevacizumab as adjuvant therapy for patients with stage II/III colon cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

07/60

Di Bartolomeo M.

2008(31/03/10)

II

18

Patients enrolled in 2010

A double-blind, randomized, placebo-controlled, phase II study of enzastaurin with 5-FULV plus bevacizumab as maintenance regimen following fist-line therapy for metastatic colorectal cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/61

Di Bartolomeo M.

2008

III

13

Closed accrual

A multinational, randomized, double-blind study, comparing the efficacy of aflibercept once every 2 weeks versus placebo in patients with metastatic colorectal cancer (MCRC) treated with irinotecan/5-FU combination (FOLFIRI) after failure of an oxaliplatin based regimen Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/69

Di Bartolomeo M.

2007

III

9

Closed accrual

A double-blind, randomized, multicenter, phase III study of bevacizumab in combination with capecitabine and cisplatin versus placebo in combination with capecitabine and cisplatin, as first-line therapy in patients with advanced gastric cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/08

Dragani T. Leo E.

2008

-

725

378

Patients enrolled in 2010

Accrual of patients with colorectal cancer and of healthy sisters/brothers for studies on genetic risk factors Study code

Coordinator

Activated (closed)

Phase

Total patients

08/16

Leo E. Gallino G.

2008

-

98

Epidemiological study of the risk of colorectal cancer in association to long-term exposure to water disinfection products Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/27

Buzzoni R.

2008

II

18

8

Perioperative treatment with COI-E (capecetabine, oxaliplatin, irinotecan and cetuximab) of liver metastasis of colorectal carcinoma potentially resectable although at high risk of recurrences Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/29

Bajetta E.

2008

II

17

3

First line UFT,Oxaliplatin and Erbitux combination (TEFAFOX-E) in elderly (â&#x2030;Ľ 70 years) metastatic colorectal patients: a phase II I.T.M.O. study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/38

Mazzaferro V.

2008

III

46

12

A phase III randomized, double-blind, placebo-controlled study of sorafenib as adjuvant treatment for hepatocellular carcinoma after surgical resection or local ablation (STORM) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/56

Casali P.

2008

II

10

3

An open-label, multicenter, single-arm study to evaluate the efficacy of nilotinib in adult patients with metastatic or unresectable gastrointestinal stromal tumors in first line treatment Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/61

Casali P.

2008

III

11

Closed accrual

An open label, multicenter, expanded access study of imatinib mesylate in adult patients with GIST in adjuvant setting after R0-resection Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/71

Bajetta E.

2008

II

22

3

Efficacy and safety of RAD001 (Everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase II I.T.M.O. study


ONGOING CLINICAL STUDIES

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/01

Bajetta E.

2009

III

1

0

187

Open label extension study of lanreotide autogel 120 mg in patients with non functioning entero-pancreatic endocrine tumour Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/12

Bajetta E.

2009

II

30

15

Capecetabine in combination with oxaliplatin, irinotecan and bevacizumab (COI-B regime) as first.line therapy for metastatic colorectal cancer: a phase II ITMO study Study code

Coordinator

Activated (closed)

Phase

Total patients

09/15

Mazzaferro V.

2009

II

3

Patients enrolled in 2010

A phase II randomized, double-blind, placebo-controlled study of sorafenib or placebo in combination with transarterial chemoembolization (TACE) performed with DC bead and doxorubicin for intermediate stage hepatocellular carcinoma (HCC) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/24

Mazzaferro V.

2009

III

6

2

A randomized, double-blind, multicenter phase III study of brivanib plus best supportive care (BSC) versus placebo plus BSC in subjects with advanced hepatocellular carcinoma (HCC) who have failed or are intolerant to sorafenib Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/30

Mazzaferro V.

2007(31/12/10)

II

52

Closed accrual

Radioembolization with Yttrium-90 glass microspheres for intermediate or advanced hepatocellular carcinoma not eligible to curative approach: a phase II study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/31

Casali P.

2009

III

9

7

An open-label, multicenter study to evaluate the efficacy of nilotinib in adult patients with gastrointestinal stromal tumors resistant to imatinib and sunitinib Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/37

Mazzaferro V.

2009

Observational

28

14

Development of programs for weak subjects within the transplant system: optimal use of organs Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/61

Mazzaferro V.

2010

II

2

2

An uncontrolled open label multicenter phase II safety study of BAY73-4506 in patients with hepatocellular carcinoma (HCC) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/79

Casali P.

2010

Observational

51

51

Observational study of plasma levels of Imatinib in patients with gastrointestinal stromal tumor Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/80

Mazzaferro V.

2009

III

3

2

Controlled extension of conventional criteria for liver tranplantation in hepatocellular carcinoma (HCC): a prospective validation study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/47

Mazzaferro V.

2010 (31/12/10)

Observational

320

320

Genomic predictors and oncogenic drivers in hepatocellular carcinoma

Genital apparatus Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/05

Raspagliesi F.

2005

II

79

3

Sentinel node detection in endometrial cancer: a multicenter study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/29

Villa S.

2005

I-II

31

Closed accrual

Irradiation of the prostate sheath and pelvic lymph nodes with intensity modulated photon beams in patients with clinically localized cancer of the prostate: phase I-II study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/34

Bajetta E.

2006

II

5

Closed accrual

A randomized multicenter phase II trial of Patupilone (EPO906) plus Prednisone versus Docetaxel (Taxotere) plus Prednisone in patients with metastatic hormone refractory prostate cancer


188

Study code

SCIENTIFIC REPORT 2010

Coordinator

06/78 Daidone M.G., Salvioni R.

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

2006

Observational

150

3

Analysis of serum protein profiles for the early diagnosis of prostate cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/46

Valdagni R.

2007

-

142

49

Prostate cancer research international: active surveillance (PRIAS) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/54

Nicolai N.

2008

-

7

2

Identification of men with a genetic predisposition to prostate cancer: target screening in BRCA1/2 mutation carriers and controls - the IMPACTstudy Study code

Coordinator

Activated (closed)

Phase

Total patients

07/67

Raspagliesi F.

2008

III

18

Patients enrolled in 2010

A randomized, double-blind, placebo controlled, multicentre trial of abagovomab maintenance therapy in patients with epithelial ovarian cancer after complete response to first line chemotherapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/72

Procopio G.

2008

III

4

Closed accrual

A phase III, randomized, double-blind study to assess the efficacy and safety of 10 mg ZD4054 versus placebo in patients with hormone-resistant prostate cancer and bone metastasis who are pain freee or middly symptomatic Study code

Coordinator

Activated (closed)

Phase

Total patients

08/10

Bajetta E.

2008

Pilot

37

Patients enrolled in 2010

Medical treatment with Ketoconazole of the advanced adenocarcinoma of the prostate. A pilot study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/30

Buzzoni R.

2008

III

2

2

A phase III, randomized, placebo-controlled, double-blind study to assess the efficacy and safety of once-daily orally administered ZD4054 10 mg in non-metastatic hormone-resistant prostate cancer patients Study code

Coordinator

08/43 Raspagliesi F. Cerrotta A.

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

2008

III

1

1

Randomized phase III trial comparing concurrent chemoradiation and adjuvant chemotherapy with pelvic radiation alone in high risk and advanced stage endometrial carcinoma Study code

08/54

Coordinator

Zanaboni F. Raspagliesi F.

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

2008

II

35

12

A prospective phase II multicentric study of weekly topotecan and cisplatin (topocis) as neoadjuvant treatment in patients with locally advanced squamous cervical cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/10

Raspagliesi F.

2009

III

14

12

Carboplatin and Paclitaxel administered every three weeks vs Carboplatin and Paclitaxel administered weekly to patients with ovary carcinoma: multicentric randomized study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/11

Raspagliesi F.

2009

-

13

0

TOTEM: controlled, randomized, multicenter clinical study investigating 2 follow-up regimens with different intensity in patients treated for endometrial carcinoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/17

Raspagliesi F.

2009

I

1

1

Phase I study on the intraperitoneal administration of ONCO-FID-P in patients with peritoneal carcinosis from an ovarian, gastric, breast, bladder or colon tumor Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/38

Raspagliesi F.

2009

II

5

5

A phase II, double-blind, placebo-controlled, multi-centre, randomized study of ZD4054 plus carboplatin and paclitaxel or placebo plus carboplatin and paclitaxel in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/65

Raspagliesi F.

2010

-

11

11

LION - Lymphadenectomy in ovarian neoplasm. An open-randomized, prospective, multicenter trial. A project of the AGO Stydy Group


ONGOING CLINICAL STUDIES

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/71

Raspagliesi F.

2010

III

2

2

189

A phase III study to evaluate the efficacy and safety of pazopanib monotherapy versus placebo in women who have not progressed after first line chemotherapy for epithelial ovarian, fallopian tube, or primary peritoneal cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/38

Salvioni R.

2010

II

9

9

Tandem transplantation of autologous hematopoietic progenitors in relapsed/refractory patients with metastatic germinal tumors

Head & Neck and Thyroid Cancers Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/42

Licitra L.

2007

II

30

Closed accrual

SAMITAL in the prevention and care of mucositis induced by chemoradiation therapy in the treatment of cervico-facial neoplasias Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/05

Licitra L.

2008

II

5

Closed accrual

A phase II, randomized trial of chemoradiation with or without Panitumumab in subjects with unresected, locally advanced squamous cell carcinoma of the head and neck Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/46

Licitra L.

2008

II

9

1

An open label single arm trial investigating zalutumumab, a human monoclonal anti-EGD receptor antoboby, in combination with best supportive care, in patients with non-curable squamous cell carcinoma of the head and neck who have failed standard platinum-based chemotherapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/04

Licitra L.

2009

II

13

2

Phase II, multicenter, open-label, single arm trial to evaluate the safety and efficacy of oral E7080 in medullary and iodine-131 refractory, unresectable differentiated thyroid cancers, stratified by histology Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/05

Licitra L.

2009

III

8

5

An internationall, randomized, double-blinded, phase III efficacy study of XL184 versus placebo in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/52

Licitra L.

2009

I-II

6

2

Open-label, randomized, controlled phase I/II study of cilengitide to evaluate the safety and efficacy of the combination of different regimens of cilengitide added to cisplatin, 5-FU, and cetuximab in subjects with recurrent/metastatic squamous cell cancer of the head and neck (ADVANTAGE) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/02

Licitra L.

2010

II

7

7

Phase II study of Pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/29

Locati L.

2010

II

12

12

Sorafenib in recurrent and/or metastatic salivary gland carcinomas

Hematologic Malignancies Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

04/14

Corradini P.

2004

I-II

6

Closed accrual

Rituximab maintenance treatment versus no further after a brief induction therapy with FDN + rituximab in elderly patients with advanced stage previously untreated follicular lymphoma Study code

Coordinator

04/32 Gianni A.M., Di Nicola M.

Activated (closed)

Phase

Total patients

2004

Observational

20

Patients enrolled in 2010

Prospective observational study in the adult with Burkittâ&#x20AC;&#x2122;s lymphoma of a polychemotherapy scheme in use in pediatrics Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/02

Corradini P.

2005

I-II

4

Closed accrual

A multicenter, open-label study of oral melphalan, and CC-5013 (Revlimid) (MPR) as induction therapy in elderly newly diagnosed multiple myeloma patients


190

Study code

SCIENTIFIC REPORT 2010

Coordinator

05/34 Gianni A.M., Corradini P.

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

2005

III

36

6

Multicentric randomized phase III study that compares high-dose chemotherapy with rituximab and autotransplantation of circulating hemopoietic precursors with CHOP with rituximab administered every 14 days as first-line therapy for patients at high risk with large B-cell non-Hodgkin’s lymphoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/64

Corradini P.

2006

III

10

Closed accrual

Randomized comparison of conditioning regimens of reduced intensity containing respectively anti-lymphocyte globulin versus alemtuzumab in allogeneic transplantation from non-family donors: global study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/12

Corradini P.

2006

II

12

Closed accrual

A phase II, multicenter study of bortezomib, pegylated liposomal doxorubicin, dexamethasone (PAD) as induction and melphalan (MEL 100) as transplant, in elderly newly diagnosed multiple myeloma patients Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/13

Corradini P.

2006

III

9

Closed accrual

A phase III, multicenter, randomized open-label study of velcade, melphalan, prednisone and thalidomide (V-MPT) versus velcade, melphalan, prednisone (V-MP) in elderly untreated multiple myeloma patients Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/14

Corradini P.

2006

III

13

Closed accrual

A phase III, prospective, randomized clinical study with velcade-thalidomide-dexamethasone versus thalidomide-dexamethasone for previously untreated patients with symptomatic multiple myeloma who are candidates to receive double autologous transplantation Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/28

Corradini P.

2006

III

4

Closed accrual

Zevalin at myeloablative doses in aggressive lymphomas of elderly patients Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/44

Corradini P.

2006

II

15

3

Intensive chemo-immunotherapy as first-line in adult patients with peripheral T-cell lymphoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/45

Corradini P.

2007

III

5

Closed accrual

A phase IIIb study of MabThera (rituximab) maintenance therapy in patients with follicular Non-Hodgkin’s Lymphoma who have responded to induction therapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/50

Corradini P.

2006

II

12

Closed accrual

A phase II, multicenter study of Melphalan 100 mg/m2 (MEL 100) as transplant, Revlimid and Prednisone (RP) as consolidation and Revlimid alone as maintenance in elderly newly diagnosed multiple myeloma patients Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/55

Corradini P.

2007

II

12

4

Bortezomib and dexamethasone treatment before donor lymphocyte infusions for myeloma patients progressing or relapsing after allogenetic transplantation of hematophoietic cells (FM-MYEL-06-01) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/67

Corradini P.

2007

II

3

Closed accrual

A phase II, multi-center, ranodmized, open label study of Velcade, Doxorubicin and Dexamethasone (PAD) vs Thalidomide and Dexamethasone (TD) in advanced and refractory multiple myeloma patients Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/38

Corradini P.

2007

III

6

1

A multicentric randomized trial in adult patients with acute myelogenous leukemia (AML) to compare: 1) a standard-dose versus high-dose remission induction regimen, and 2) an autologous blood stem cell transplantation versus an autologous blood cell-supported multicycle high-dose chemotherapy program,, within a risk-oriented postremission strategy reserving allogeneic stem cell transplantation for high-risk cases Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/48

Corradini P.

2007

II

10

7

Reduced intensity conditioning with high-dose rituximab followed by allogeneic transplantation of hematopoietic cells for the treatment of relapsed/refractory B-cell non Hodgkin’s lymphomas


ONGOING CLINICAL STUDIES

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/55

Corradini P.

2008

II

8

Closed accrual

191

Treatment with imatinib mesylate (Glivec) of severe chronic scleroderma-like GVHD, refractory to conventional immunosuppressive therapy Study code

Coordinator

Activated (closed)

07/63

Corradini P.

2008

Phase

Observational

Total patients

Patients enrolled in 2010

7

0

Lombardy registry of HCV positive lymphomas Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/76

Gianni A.M.

2008

II

30

4

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

2008

III

7

Closed accrual

Phase II study of Sorafenib for refractory/relapsed malignant lymphomas Study code

Coordinator

08/02 Gianni A.M. Corradini P.

A phase III, multicentre, randomized, controlled study to determine the efficacy and safety of lenalidomide, melphalan and prednisone (MPR) versus melphalan (200 mg/m2) followed by stem cell transplant in newly diagnosed multiple myeloma subjects Study code

Coordinator

Activated (closed)

08/14

Corradini P.

2008

Phase

Total patients

Patients enrolled in 2010

-

48

A study of the protein profile expression with mass spectrometry (SELDI-TOF) for the identification of prognostic markers in the plasma of patients with chronic lymphatic leukemia Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/24

Corradini P.

2008

I-II

6

1

A phase Ia/II, multi-center, open-label study of HCD122 admnistered intravenously once weekly for four weeks in adult patients with advanced nonhodgkin’s or Hodgkin’s lymphoma who have progressed after least two prior therapies Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/33

Gianni A.M.

2008

II

33

12

Phase II study of perifosine in combination with sorafenib for refractory/relapsed malignant lymphomas Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/34

Corradini P.

2008

III

2

1

A randomized comparison between conditioning regimens to allogeneic transplant of hemopoietic stem cells containing I.V. Busulfan (I.V. Bu; Busilvex) with Fludarabin (BUFLU) versus I.V. Busulfan with Cyclophosphamide (BUCY2) in 40-55 years patients with acute myeloid leukemia (AML) in complete remission Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/44

Corradini P.

2008

-

50

1

Comparision of whole body diffusion weighted magnetic resonance imaging (DW-MRI) with skeletal X-ray and MRI of the spine for the assessment of bone disease in multiple myeloma Study code

Coordinator

08/49 Gianni A.M. Corradini P.

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

2008

II

15

4

Multicentre clinical study with early treatment intensification in patients with high-risk Hodgkin lymphoma, identified as FDG-PET scan positive after two conventional BVD courses Study code

Coordinator

09/09 Gianni A.M. Corradini P.

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

2009

III

7

3

Phase III study comparing rituximab-supplemented ABVD (R-ABVD) with ABVD followed by involved-field radiotherapy (ABVD-RT) in limited-stage (stage I-IIA with no areas of bulk) Hodgkin’s lymphoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/13

Corradini P.

2009

II

1

0

Safety and efficacy of lenalidomide as main therapy in patients with newly diagnosed multiple myeloma following a tandem autologous-allogeneic transplant Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/23

Corradini P.

2009

Observational

15

7

A non-interventional observational post authorization safety study of subjects treated with lenalidomide Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/39

Corradini P.

2009

III

13

10

Phase III intergroup multicentre, randomized, controlled 3 arm parallel group study to determine the efficacy and safety of lenalidomide in combination with dexamethasone (Rd9 versus melphalan, prednisone and lenalidomide (MPR) versus cyclophosphamide, prednisone and lenalidomide (CPR) in newly diagnosed multiple myeloma subjects


192

SCIENTIFIC REPORT 2010

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/46

Corradini P.

2009

III

15

10

A phase III, multicentre, randomized, controlled study to determine the efficacy amd safety of ciclophosphamide, lenalidomide and dexamethasone (CRD) versus melphalan (200 mg/m2) followed by stem cell transplant in newly diagnosed multiple myeloma subjects Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/59

Gianni A.M.

2009

I-II

9

9

Phase I/II of dexamethasone, ofatumumab and bendamustine (TREANDA) (DOT) as first-line treatment of mantle cell lymphoma (MCL) in the elderly Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/69

Corradini P.

2010

III

9

9

A multicenter, randomized, double-blind, placebo controlled phase III study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed multiple myeloma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/76

Corradini P.

2010

II

2

2

Brief induction chemoimmunotherapy with rituximab + bendamustine + mitoxantrone followed by rituximab in elderly patients with advanced stage previously unrtreated follicular lymphoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/07

Corradini P.

2010

-

2

2

Monitoring of human polyomavirus reactivation in patients with lymphoproliferative disease treated with chemotherapy, chemotherapy and rituximab, and rituximab Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/12

Corradini P.

2010

I-II

2

2

A phase I/II, multicenter, open label study of pomalidomide cyclophosphamide and prednisone (PCP) in patients with multiple myeloma relapsed and/or refractory to lenalidomide Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/13

Corradini P.

2010

Observational

8

8

Prospective audit on stem cell mobilization in malignant lymphoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/31

Gianni A.M.

2010

III

1

1

A randomized, double-blind, placebo-controlled phase III study of SGN-35 (brentuximab vedotin) and best supportive care (BSC) versus placebo and BSC in the treatment of patients at high risk of residual Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/49

Magni M.

2010

Observational

70

70

Outcome of second-line treatment in patients with relapsed follicular lymphoma according to the type of first-line treatment received

Lung Cancers Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/53

Pastorino U.

2006

-

4097

210

Spiral CAT, biomarkers and proteomic analysis, associated to a program of primary prevention for the early diagnosis of lung cancer: randomized study in subjects at high risk: project MILD Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/18

Platania M.

2007

III

5

1

START - Stimulating Targeted Antigenic Responses To NSCLC Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/22

Bajetta E.

2007

II

8

Closed accrual

Randomized phase II study of pemetrexed versus pemetrexed and carboplatin as second line chemotherapy in advanced non-small cell lung cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/35

Bajetta E.

2007

II

4

Closed accrual

A phase II study of NGR-hTNF administered as single agent every 3 weeks in patients affected by advanced or metastatic malignant pleural mesothelioma previously treated with no more than one systemic therapeutic regimen


ONGOING CLINICAL STUDIES

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/28

Bajetta E.

2008

II

5

Closed accrual

193

Phase II study of the combination of bevacizumab plus pemetrexed and carboplatin as first line therapy in patients with malignant pleural mesothelioma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/40

Bajetta E.

2008

II

17

5

A phase II, randomized, doble blind, two arm, parallel study of vandetanib (ZACTIMA, ZA6474) plus gemcitabine (Gemzar) versus gemcitabine plus placebo as first line treatment of advanced 8stage IIIB or IV) non small cell lung cancer (NSCLC) elderly patients Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/63

Zilembo N.

2008

II

2

Closed accrual

A randomized phase II study of ixabepilone plus carboplatin and paclitaxel plus carboplatin in subjects with advanced non small cell lung cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/64

Bajetta E.

2008

III

9

4

A phase III, randomized, double.blind, placebo-controlled multi-center study of ASA404 in combination with docetaxel in second-line treatment of patients with advanced or metastatic (stage IIIb/IV) non-small cell lung cancer (NSCLC) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/27

Zilembo N.

2009

II

25

13

A randomized phase II study with NGR-hTNF in combination with standard chemotherapy regimen vs standard chemotherapy regimen in non-pretreated patients with advanced non-small cell lung cancer (NSCLC) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/74

Buzzoni R.

2010

III

8

8

A randomized, multicenter, open-label phase III study of gemcitabine-cisplatin chemotherapy plus IMC-11F8 versus gemcitabine-cisplatin chemotherapy alone in the first-line treatment of patients with squamous stage IIIb or IV non-small cell lung cancer (NSCLC) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/75

Buzzoni R.

2010

III

1

1

A randomized, multicenter, open-label phase III study of pemetrexed-cisplatin chemotherapy plus IMC-11F8 versus pemetrexed-cisplatin chemotherapy alone in the first-line treatment of patients with nonsquamous stage IIIb or IV non-small cell lung cancer (NSCLC) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/03

Platania M.

2010

III

4

4

A phase III, randomized, double-blind, placebo controlled study of oral talactoferrin in addition to best supportive care in patients with non-small cell lung cancer who have failed two or more prior treatment regimens Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/09

Pastorino U.

2010

Observational

20

20

Observational feasibility study of autologous adipose tissue derived mesenchymal stem cell transplantation, after laser resection of lung, in 20 metastasectomies Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/10

Bajetta E.

2010

III

1

1

Randomized proteomic stratified phase III study of second line erlotinib versus chemotherapy in patients with inoperable non-small cell lung cancer- PROSE Study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/41

Pastorino U.

2010

I-II

22

22

A prospective randomized phase I/II study on anatomic lung resections using laser, without mechanical suturing devices for parenchyma and synthetic materials for aerostasis versus standard treatment

Melanoma Study code

01/36

Coordinator

Activated (closed)

Santinami M., Cascinelli N.

2002

Phase

Total patients

Patients enrolled in 2010

III

112

Closed accrual

Peg intron versus observation after regional node dissection in AJCC stage III (TxN1/2M0) melanoma patients: a randomized trial Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

03/25

Rivoltini L.

2003

I-II

21

Closed accrual

A phase I-II study of active vaccination with autologous T-lymphocytes trasduced with HSV-TK and MAGE-A3 in patients with metastatic melanoma and expression of MAGE-A3


194

SCIENTIFIC REPORT 2010

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/06

Bajetta E.

2006(29/04/10)

II

10

Closed accrual

A phase II, open-label, single arm study to evaluate the efficacy, safety, tolerability and pharmacokinetics of ticilimumab in patients with advanced refractory and/or relapsed melanoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/43

Bajetta E.

2007 (16/03/10)

II

16

Closed accrual

Italian Multicenter Phase II Trial using Fotemustine plus Bevacizumab As First-Line Therapy in Metastatic Melanoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/11

Bajetta E.

2008

I

9

2

A dose-finding study with fotemustine fixed dose in combination with docetaxel in pretreated with metastatic melanoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/52

Santinami M.

2009

III

21

11

A double-blind, randomized, placebo-controlled phase III study to assess the efficacy of recMAGE-A3 + AS15 ASCI as adjuvant therapy in patients with MAGE-A3 positive resected stage III melanoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/55

Bajetta E.

2008

III

8

Closed accrual

A multicenter, randomized, double-blind study of dacarbazine with or without Genasense in chemotheapy naive subjects with advanced melanoma and low LDH (the AGENDA trial) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/73

Santinami M.

2009

I

8

1

Phase I dose-finding study of tumor-targeting human monoclonal antibody-cytokine fusion protein L19TNFalfa plus melphalan using isolated inferior limb perfusion in patients with in-transit stage III/IV melanoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/42

Del Vecchio M.

2009

III

1

1

An open label, multicenter, phase III trial of ABI-007 vs dacarbazine in previously untreated patients with metastatic malignant melanoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/06

Del Vecchio M.

2010

III

10

10

BRIM 3: a randonized, open-label, controlled, multicenter, phase III study in previuosly untreated patients with unresectable stage IIIC or stagerIV melanoma with V600E BRAF mutation receiving RO5185426 or dacarbazine

Sarcomas Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

01/46

Gronchi A.

2001

III

96

Closed accrual

Localized high-risk soft-tissue sarcomas of the extremities and superficial trunk in adults: an integrated approach comprising 3 or 5 cycles of adjuvant chemotherapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

03/31

Casali P.

2003

II-III

10

0

EUROpean Bone Over 40 Sarcoma Study. An european treatment protocol for bone-sarcoma in patients older than 40 years Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

03/45

Gronchi A.

2003

Pilot

39

4

Pre-operative chemo-radiation therapy in retroperitoneal soft tissue sarcomas (Âą RT boost) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

03/46

Bertulli R.

2004

II

21

Closed accrual

Ifosfamide at high doses in prolonged continuous infusion by a portable infusion system in soft-tissue sarcomas typical of the adult in an advanced phase in second/further line chemotherapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

04/01

Bertulli R.

2004

II

15

Closed accrual

Patients enrolled in 2010

Gemcitabine in leiomyosarcoma in an advanced phase in second or further line of chemotherapy Study code

Coordinator

Activated (closed)

Phase

Total patients

04/20

Corradini P.

2004

II

2

Transplant of hemopoietic stem cells from family HLA-identical donor after conditioning at reduced intensity in soft tissue sarcoma in a metastatic phase


ONGOING CLINICAL STUDIES

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

04/33

Casali P.

2004

II

16

Closed accrual

195

Phase II study of imatinib mesylate in chordoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/31

Ferrari A.

2005

III

62

20

A protocol for localized non-rhabdomyosarcoma soft tissue sarcoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/32

Ferrari A.

2005

III

93

30

EpSSG NRSTS 2005. A protocol for localized non-rhabdomyosarcoma soft tissue sarcoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/53

Casali P.

2006

II

23

1

Trabectedin (ET743) in metastatic or locally advanced cell liposarcoma pretreated with chemotherapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/11

Stacchiotti S.

2007

II

10

Closed accrual

Patients enrolled in 2010

Open-label trial of imatinib in patients with desmoid tumor and chondrosarcoma Study code

Coordinator

Activated (closed)

Phase

Total patients

07/39

Casali P.

2007

II

11

Phase II, non randomized, open-label, single arm trial of patients with advanced or metastatic osteosarcomas, administered with pemetrexed (Alimta, 500 mg/m2 by intravenous infusion of 10 minutes) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/01

Casali P.

2008

Pilot

1

Closed accrual

A pivotal trial to determine the efficacy and safety of AP23573 when administered as maintenance therapy to patients with metastatic soft-tissue or bone sarcoma Study code

Coordinator

Activated (closed)

Phase

Total patients

08/04

Casali P., Casanova M.

2008

I-II

11

A phase I/phase II study of CP-751,871 in patients with relapsed and/or refractory Ewingâ&#x20AC;&#x2122;s sarcoma family of tumors

Patients enrolled in 2010 Casali P.

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/22

Casali P.

2008

II

3

Closed accrual

Phase II, non-randomized study of second line tretment with sarafenib (BAY 43-9006) in patients affected by relapsed high-grede osteosarcoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/25

Casali P.

2008

III

2

1

A multinational, randomized, double-blind placebo controlled study of AVE8062 (25 mg/m2) administered every 3 weeks, in patients with advanced stage soft tissue sarcoma treated with cisplatin (75 mg/m2) after failure of antracycline and ifosfamide chemotherapies Study code

Coordinator

Activated (closed)

Phase

Total patients

08/26

Casali P.

2008

II

11

Patients enrolled in 2010

Multicenter, single-arm, single-stage, phase II trial to determine the preliminary efficaccy and safety of RAD001 in patients with histological evidence of progressive or metastatic bone or soft tissue sarcomas Study code

Coordinator

Activated (closed)

Phase

Total patients

08/45

Casali P.

2008

III

1

Patients enrolled in 2010

A randomized, multicenter, phase III trial of Trabectedin (yondelis) versus doxorubicin-based chemotherapy as first-line therapy in patients with traslocation related sarcomas (TRS) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/57

Casali P.

2008

III

11

Closed accrual

A randomized double-blind phase III trial of pazopanib versus placebo in patients with soft tissue sarcoma whose disease has progressed during or following prior therapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/62

Casali P.

2008

II

14

4

Open label, multi-center, phase II study denosumab in subject with giant cell tumor of bone Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/58

Casali P.

2009

II

9

6

Phase II study of lapatinib in EGRF/HER2NEU positive advanced chordoma


196

SCIENTIFIC REPORT 2010

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/78

Casali P. Raspagliesi F.

2010

II

2

2

A phase II randomized - non comparative - study on the activity of trabectedin or gemcitabine + docetaxel in metastatic or locally relapsed uterine leiomyosarcoma pretreated with conventional chemotherapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/30

Casali P.

2010

II

4

4

Randomized phase II study evaluating two doses of NGR-hTNF administered either as single agent or in combination with doxoribicin in patients with advanced soft tissue sarcoma (STS)

Urinary apparatus Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/38

Bajetta E.

2006

II

56

Closed accrual

A randomized open-label multicenter phase II study of first line therapy with Sorafenib in association with IL-2 versus Sorafenib alone in patients with unresectable and/or metastatic renal cell cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/62

Buzzoni R.

2007

III

8

Closed accrual

A randomized, double-blind, placebo-controlled, multicenter phase III study to compare the safety and efficacy of RAD001 plus best supportive care (BSC) versus BSC plus placebo in patients with metastatic carcinoma of the kidney which has progressed on VEGF receptor tyrosine kinase inhibitor therapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/53

Procopio G.

2007

III

5

3

Sunitinib treatment of renal adjuvant cancer (S-TRAC): a randomized double-blind phase III study of adjuvant sunitinib vs placebo in subjetcs with high risk RCC Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/41

Procopio G.

2008

II

7

1

A randomized, open label, multi-center phase II study to compare bevacizumab plus RAD001 versus interferon alfa-A plus bevacizumab for the first-line treatment of patients with metastatic clear cell carcinoma of the kidney Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/51

Procopio G.

2008

III

5

Closed accrual

Axitinib (AG 013736) as second line therapy for metastatic renal cell cancer: AXIS trial Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/70

Salvioni R.

2009

II

31

30

Phase II study with the multi-target tyrosine-kinase inhibitor Pazopanib (GW786034) for patients with relapsed or refractory urothelial cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/11

Procopio G.

2010

II

2

2

Phase II study of sunitinib in metastatic renal cancer with non-clear cell histology

Pediatric tumors Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

95/26

Cefalo G. Luksch R.

1995

II

83

5

Immunotherapy (IL-2 and activated circulating mononucleate cells) and pre- and post-surgical antineoplastic chemotherapy in the primary treatment of osteosarcoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

01/33

Luksch R.

2001

II

31

Closed accrual

Prospective randomized study for the treatment of nonmetastatic osteosarcoma of the extremities Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

01/40

Luksch R.

2002

III

44

5

Protocol NB-AR-01: First European Cooperative Study for high-risk neuroblastoma Study code

Coordinator

01/41 Seregni E.,Bombardieri E.

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

2001

Observational

277

17

Protocol for evaluation and therapy of the diencephalohypophysial alterations in pediatric patients with cerebral neoplasms


ONGOING CLINICAL STUDIES

Study code

Coordinator

Activated (closed)

Phase

Total patients

03/12

Massimino M.

2003

Observational

36

197

Patients enrolled in 2010

Second protocol for diagnosis and treatment of ependymoma in a pediatric age Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

03/13

Luksch R.

2003

II

17

2

Non-controlled clinical study for the treatment of Ewing’s sarcoma in relapse Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

03/14

Spreafico F.

2003

Observational

81

9

Wilms’ tumor: diagnostic-therapeutic protocol AIEOP 2003 Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

03/16

Terenziani M.

2003

III

276

40

Germ cell tumors: diagnostic-therapeutic protocol AIEOP 2003 Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

04/21

Gandola L.

2004

III

14

Closed accrual

(HIT-SIOP PNET 4. A SIOP and GPOH TRIAL). A prospective randomized controlled trial of hyperfractionated versus conventionally fractionated radiotherapy in standard-risk medulloblastoma Study code

05/17

Coordinator

Luksch R. Castellani M.R.

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

2005

II

1

0

Phase II protocol with combined chemotherapy and 131I-MIBG in the treatment of patients with neuroblastoma resistant or in relapse (I-METCH) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/26

Luksch R.

2006

Pilot

5

1

Ewing’s family tumors at high risk: pilot study comprising a window-therapy with cisplatin, intensive chemotherapy, RT, consolidation with non-myeloablative immunosuppressive chemotherapy and allotransplant of hemopoietic cells Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

05/60

Ferrari A.

2005

II

2

Closed accrual

Open study with Glivec (imatinib mesylate) in the treatment of patients affected by refractory desmoplastic small round cell tumor, that expresses a molecular target of Glivec (PDGF-R e/o c-KIT) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/23

Luksch R.

2006

II

7

1

Phase II study of Glivec (Imatinib Mesylate) in patients with advanced neuroblastoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/30

Luksch R., Anichini A.

2006

Observational

148

4

Study of the immune response to tumor-associated antigen in pediatric patients with solid tumors for the development of innovative immunological therapies Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/05

Cefalo G.

2007(31/07/10)

II

16

3

A phase II study on the chemosensitizer efficacy and of proton pump inhibitors (PPI) in the primary chemotherapy of osteosarcoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/08

Cefalo G.

2007

III

13

2

LCH-III. Treatment protocol of the third international study for Langerhan’s cell histiocytosis Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/17

Luksch R.

2008(06/06/10)

II

2

Closed accrual

A phase II study of safety and efficacy of a single dose of pegfilgrastim, 100 mcg/kg (max 6 mg) after mobilizing chemotherapy in the collection of peripheral autologous stem cells in oncologic pediatric patients Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/31

Luksch R.

2007

-

14

4

Guidelines for the treatment of patients with localized resectable neuroblastoma and analysis of prognostic factors Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/36

Casanova M.

2007

II

5

Closed accrual

International randomized study to evaluate the addition of docetaxel to the combination of cisplatin-5-fluorouracil (TCF) vs. cisplatin-5-fluorouracil (CF) in the induction treatment of nasopharyngeal carcinoma (NPC) in children adolescent


198

SCIENTIFIC REPORT 2010

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/13

Casanova M.

2008

II

4

0

Open-label, multi-center, randomized, two stage adaptive design study of the combination of bevacizumab with standard chemotherapy in minor patients with metastatic rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma or Ewing sarcoma/soft tissue primitive neuroectdermal tumour Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/17

Cefalo G.

2008

II

10

4

HL PED 2008 Hodgkin’s lymphoma. A therapeutic protocol for sequels reduction Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/22

Casali P. Luksch R.

2009

III

4

3

A phase II study on the efficacy of dose intensification in patients with non-metastatic Ewing’s sarcoma Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/25

Casali P. Luksch R.

2009

II

2

2

Therapeutic protocol with high-dose chemotherapy, radiotherapy, maintenance therapy with low-dose Cyclophosphamide and anti-COX2 in metastatic Ewing’s sarcoma: ISG/AIEOP study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/57

Casanova M.

2009

II

7

7

Phase II single-arm studies of temozolomide in combination with topotecan in refractory or relapsing neuroblastoma and opther paediatric solid tumor Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/63

Massimino M.

2010

Observational

10

10

Brain tumor in children: an aid to parent child communication about the disease

Palliative care Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/01

Ripamonti C.

2007

I-II

34

Closed accrual

Treatment of the osteonecrosis of the mandible by medical gaseous ozone and in oily suspension. A phase I-II study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/69

Caraceni A.

2010

Observational

17

17

A multicentric data collection on terminal/palliative sedation therapy and its monitoring for refractory symptoms

Miscellanea Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

02/27

Terenziani M.

2002

Pilot

153

60

Program of control in patients subjected to radiotherapy comprising the breast region during infancy and adolescence Study code

05/66

Coordinator

Tagliabue G. Contiero P.

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

2006

Observational

10738

536

Registry of congenital malformations in Lombardy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

06/77

Celio L.

2007

II

10

Closed accrual

Phase II study oh PHA-739358 administered by a 24-Hour IV infusion every 14 days in advanced/metastatic breast, ovary, colorectal, pancreatic, small cell lung and non-small-cell lung cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/03

Buzzoni R.

2007

III

8

Closed accrual

A randomized, double-blind, placebo controlled, multicenter phase III study in patients with advanced carcinoid tumor receiving Sandostatin LAR and RAD001 or Sandostatin LAR and placebo Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/40

Gianni L.

2007

I

23

3

Dose-finding study of Caelix and RAD001 in patients with advanced solid tumors


ONGOING CLINICAL STUDIES

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

07/73

Bombardieri E.

2007

II

32

16

199

Evaluation of the efficacy of the associated treatment [90 Y-DOTA, Tyr(3)] Octreotate and [177Lu-DOTA, Tyr(3)] Octreotate in patients with neuroendocrine neoplasias expressing receptors for somatostatin, refractory to conventional biotherapy and/or chemotherapy treatments Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/12

Gianni L.

2008

Ib

57

31

An open-label, safety, pharmacockinetics and pharmacodynamic dose escalation phase Ib study of pazopanib in combination with epirubicin or doxorubicin in subjects with advanced solid tumors Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/15

Bajetta E.

2008

III

13

0

Patients enrolled in 2010

Sorafenib long term extension program (STEP) Study code

Coordinator

Activated (closed)

Phase

Total patients

08/19

Gianni L.

2008

I

9

An open-label, non-randomized, dose esclation, safety and pharmacokinetics phase I study of AVE8062 in combination with cisplatin administered on day 1 followed by docetaxel on day 2, every 3 weeks, in patients with advanced solid tumors Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/21

Buzzoni R.

2008

III

6

Closed accrual

MAGELLAN - Multicenter, randomized, parallel group efficacy superiority study in hospitalized medically iLL patients comparing rivaroxaban with anoxaparin Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/32

Licitra L.

2008

II

6

Closed accrual

Randomized phase II feasibility study of Cetuximab combined with 4 cycles of TPF followed by platinum based chemo-radiation strategies Study code

Coordinator

Activated (closed)

Phase

Total patients

08/48

Borreani C.

2008

-

61

Patients enrolled in 2010

Study of the psychological impact of prevention programmes in women who underwent BRCA1/BRCA2 genetic test Study code

Coordinator

Activated (closed)

Phase

08/50

Favaro M.

III

2

Total patients

Patients enrolled in 2010

ALBumin Italian Outcome Sepsis study- ALBIOS STUDY â&#x20AC;&#x153;Efficacy of albumin administration for volume replacement in patients with severe sepsis or septic shockâ&#x20AC;? Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/69

Caraceni A.

2008

IV

2

2

A randomized, double-blind, placebo-controlled study of a fixed dose of subcutaneous methylnaltrexone in adults with advanced illness and opioid-induced constipation:efficacy, safety, and additional health outcomes Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

08/70

Caraceni A.

2008

IV

1

1

Open extension study to evaluate the safety of a fixed subcutaneous dose of methylnaltrexone in patients with advanced diseases and constipation from opioids Caraceni A. Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/06

Bajetta E.

2009

II

35

13

An open label, single arm, phase II study of combination RAD001 and octreotide LAR in patients with advanced neuroendocrine tumors as fist line treatment Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/08

Tognoli E.

2009

II

60

60

Methadone for postoperative analgesia after balanced anaesthesia integrated with low dose ketamine S(+) Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/32

Decarli A.

2009

Observational

445

445

Epidemiologic studies on environmental risk factors and their interactions with genetic factors of bladder cancer and sarcomas Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/35

Pastorino U.

2009

-

374

371

Efficay of thermal treatment for respiratory airways in heavy smokers


200

SCIENTIFIC REPORT 2010

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/36

Gianni L.

2009

I-II

4

2

Dose-finding study of combination of trabectedin and cisplatin in patients with advanced solid tumors Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/41

Licitra L.

2009

III

18

17

Role of aprepitant in prevention of late vomiting due to cisplatin: a controlled, double-blind study Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/47

Gianni L.

2009

I

8

5

A phase I. open label, multicenter, study to assess the safety. Tolerability and pharmacology of AZ D2281 in combination with liposomal doxorubicin (Caelyx) in patients with advanced solid tumors Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/53

Gianni L.

2009

I

12

8

Phase I dose escalation study evaluating the safety and tolerability of PankomabGEX tm in patients with advanced, TA-MUC1 positive solid malignancies who are not longer eligible for standard therapy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/54

Gianni L.

2009

I

10

10

Phase Ib study of CC-5013 and paclitaxel in patients with advanced solid tumors Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/55

Gianni L.

2009

I

15

15

Phase I dose finding and pharmacokinetic study of daily administrations of the intravenous camptothecin Namitecan (ST1968) in patients with refractory or recurrent solid tumors Study code

Coordinator

Activated (closed)

Phase

Total patients

09/72

Corradini P.

2009

Observational

52

Patients enrolled in 2010

Evaluation of the immune response after anti-flu vaccination against H1N1 pandemic virus in oncologic and hematologic patients Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

09/73

Ravagnani F.

2010(30/06/10)

-

12

12

Spectra Optia- 2 generation MNC protocol: faeasibility study for the collection of autologous stem cells nd

Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/04

Nicolai N.

2010

-

31

31

A prospective evaluation of morbidity parameters and postoperative and medium-term quality of life of patients submitted to videolaparoscopic vs open retroperitoneal lymphadenectomy Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/20

Meroni E.

2010

Observational

1

1

Walflex Italian National Esophageal Registry Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/32

Gianni L.

2010

I

1

1

Dose-escalation, PK and safety study with single agent CetuGEX in patients with locally advanced and/or metastatic cancer Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/42

Gianni A.M.

2010

I

2

2

An open-label, non-randomized dose escalation, safety and pharmacokinetics phase I study of ombrabulin (AVE8062) in combination with bevacizumab administered by intravenous infusion every 3 weeks in patients with advanced solid tumors Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/55

Morosi C.

2010

-

1

1

Evaluation of the response according to dimensional and tissue criteria using contrast-enhanced amplifier ultrasonography in patients with soft tissue sarcomas or gastrointestinal stromal tumors (GIST) after molecular target therapies - CONTICANET Study code

Coordinator

Activated (closed)

Phase

Total patients

Patients enrolled in 2010

10/68

Ripamonti C.

2010

Observational

55

55

Validation in Italian language of the questionnaire â&#x20AC;&#x153;patient dignity inventoryâ&#x20AC;? and evaluation of the relationship between perceived dignity and parameters of physical, emotional, spiritual and religious well-being in patients with solid and hematologic tumors in active oncological therapy


ONGOING PROJECTS SUPPORTED BY DIFFERENT ORGANIZATIONS

201

ONGOING PROJECTS SUPPORTED BY DIFFERENT ORGANIZATIONS ALLEANZA CONTRO IL CANCRO – ISTITUTO SUPERIORE DI SANITA’

• • • • • • • • • • • • • • • •

Assistance needs in senior adults. Confounding variables in the patient-caregiver relationship National Telepathology Network (Teseo) National network for clinical trials and GMP structures for tumor biotherapy National network “START project” (State of the Art in Oncology) National Italian Network of hereditary/familial tumors: establishment of shared operative tools for assistance and research Development of idiotypic vaccines for phase I/II trials of subset-specific immunotherapy of B lymphomas Biological combined and target therapies in solid tumors: phase I-II studies National network of biobanks in oncology New molecules of inflammation: transfer from laboratory to patient bedside Development of new therapies in skeletal muscle sarcomas: comparison between immunotherapy and target therapy National network of tumor registries: indicators and cancer control in Italy National bioinformatics network in oncology National service of information in oncology Tumor microenvironment as therapeutic target Identification of markers for the prevision of the response to new antitumor drugs (HDAC inhibitors, tyrosine kinase and ionic pumps) Application of chemotherapy to the remodulation of the antitumoral immune response: a study of the “proof of concept” mechanisms in humans

ASSOCIAZIONE BIANCA GARAVAGLIA

Research activity in pediatric tumors

ASSOCIAZIONE ITALIANA PER LA LOTTA AL NEUROBLASTOMA

Different pathways involved in pediatric CNS tumors: molecular basis and applicative studies

ASSOCIAZIONE ITALIANA PER LA RICERCA SUL CANCRO

• • • • • • • • • • • • • • • • • • • • • • • • •

Comprehensive diagnosis and treatment for intracranial pediatric ependymoma Early innovative diagnostic procedures of lung cancer progression Identification of genes expressed in human melanoma and regulating antitumor immunity Breast carcinoma extracellular matrix and response to therapy Molecular markers in lung carcinogenesis for early diagnosis, response to therapy and target identification Morphologic criteria and molecular targets in hepatocellular carcinoma: pre-clinical and clinical implications Tumor-host interaction affecting immunological and clinical responses in vaccinated colorectal cancer patients Anti-CD20 antibody before allogeneic transplantation: clinical and biological implications in B-cell lymphomas Molecular signatures from paraffin-embedded tissue predicting clinical outcome of breast cancer patients Wilms’ tumor: molecular prognostic markers and candidate gene analyses Treatment with tandem 90Y-DOTA-TATE and 177Lu-DOTA-TATE of GEP tumors refractory to conventional therapy Identification of potential biopredictors of targeted treatments and monitoring of response/resistance balance Agonists and antagonists of Toll-like Receptor 9 in oncological experimental models Fhit degradation in breast cancer proliferation: a potential target of novel therapeutic strategies Identification of therapeutic targets for ovarian cancer by functional genomics and biomolecular analysis Extracellular matrix at the intersection between tumor and immune system Stemness signature and breast cancer progression: relationship and strategies of interference DNA damage responses and Chk2 regulation and interaction with novel targets Molecular mechanisms of epithelial thyroid carcinogenesis: role of selected molecules and pathways Expression profiling and functional analysis of microRNAs in prostate cancer Contribution of drug transporters to resistence to platinum compounds in ovarian cancer patients Anti-cancer vaccines in early disease for achieving effective immunological control of tumor progression Overcoming drug resistence by modulation of cytotoxic response and protective pathways Targeted therapy: disclosing the response limit in imatinib-treated tumors Relationships between FAK signaling, microtubule dynamics and drug response


202

• • • • • • • • • • • • • • • • • • •

SCIENTIFIC REPORT 2010

Involvement of microRNAs in HER2-and estrogen-mediated pathways in human breast cancer Targeting autophagy in cancer therapy Melanoma interaction with the microenvironment: role of transcription factors and pro-inflammatory cytokines Classification of BRCA1 and BRCA2 alleles: integrating in vitro analyses and multifactorial likelihood models Randomized trial of diet, physical activity and breast cancer recurrences: the Diana-5 study Molecular and cellular imaging in cancer Efficacy of thermal treatment for respiratory airways in heavy smokers EPIC-ITALY: a molecular epidemiology prospective project on diet, genetic susceptibility and cancer risk Identification of immunodominant non-Hodgkin lymphoma-restricted antigen(s) as novel biotarget(s) for therapy Identification of telomere maintenance mechanism-relatedgenes and miRNAs as prognostic and terapeutic tools Translational research on molecular markers in gastric cancer patients treated with adjuvant therapy Influence of lung tissue microenviroment on tumorigenesis Identification of progression markers for a clinical impact in metastatic melanoma Interactions between regulatory T cells and mast cells in cancer Altered choline metabolism in ovary cancer: prognostic relevance of choline kinase activity and expression Role of the heparanase/heparan sulfate system as a therapeutic target in sarcoma therapy Cell therapy with TRAIL-armed, genetically engineered or phenotypically redirected, effectors Personalized pain control in cancer care: the contribution of opioid pharmacogenomics Prostate cancer survival patients in Italy

COMPAGNIA DI SAN PAOLO

• • •

EUROCARE 5 – EUROpean CAncer REgistry-based study on survival and CARE of European cancer patients. Differences between Italian areas and comparison with european countries Development of an in vitro and in vivo model for the study of lung cancer stem cells to develop selectively target innovative therapeutic approaches EPICOR 2 – Study on the risk of coronary heart disease related to behaviour, biological and genetic susceptibility markers in the EPICOR collaboration in Italy and Europe

EUROPEAN COMMISSION

• • • • • • • • • • • • • • • •

CONTICANET - CONnective TIssue CAncer NETwork to integrate european experience in adult and children Cancerimmunotherapy - Cancer immunology and immunotherapy IDEFICS - Identification and prevention of Dietary- and lifestyle-induced health EFfects in Children and infantS SIGHT - Systems for in-situ theranostics using micro-particles triggered by ultrasound InterAct - Examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes EPCRC - Improved treatment of pain, depression, and fatigue through translation research (life sciences, genomics and biotechnology for health) CHEMORES - Molecular mechanisms underlying CHEMOtherapy RESistance, therapeutic escape, efficacy, and toxicity RARECARE - Surveillance of rare cancers in Europe DYNAMO-HIA - Development of a DYNAmic MOdelling tool to assess health impact of policies OPCARE9 – Optimizing Cancer Patient Care through the Advancement of Research and Education EUROCHIP-III Common Actions IMPASHS - Evaluation of the IMPAct of Smoke-free policies in Member States on exposure to second-hand smoke and tobacco consumption MAGNIFYCO - MAGnetic Nanocontainers For combined hyperthermia and COntrolled drug release SPIDIA - Standardisation and improvement of generic pre-analytical tools and procedures for in vitro diagnostics Three modality contrast imaging using multi-functionalized microballons (3MICRON) ENVIROGENOMARKERS. Genomic Biomarkers of Environmental Health

FONDAZIONE BANCA DEL MONTE DI LOMBARDIA

Development of an innovative method based on mass spectrometry for early diagnosis and monitoring of cancer progression

FONDAZIONE CARIPLO

• • •

SPARC, a matrix protein that supports tumor growth and protects tumor from therapies Identification and biomolecular characterization of cancer stem cells of ovarian cancer for the development of new diagnostic and therapeutic approaches Expression profiles and functional analysis of microRNA in prostate cancer


ONGOING PROJECTS SUPPORTED BY DIFFERENT ORGANIZATIONS

• • •

203

Phosphoproteomics of cutaneous melanoma: from biology of cancer stem cells to the identification of new therapeutic targets Inhibitors of apoptosis proteins (IAPs) as anticancer therapeutics The role of religious beliefs/practices and spirituality on life quality and adaptation to disease of oncological patients in advanced phase of disease

FONDAZIONE GUIDO BERLUCCHI

The cerebral tumor in children: a help to parent children communication about the disease

FONDAZIONE ITALO MONZINO

• •

Characterization and use of molecular targets for immunobiological therapies in prostate cancer Prostate cancer research international active surveillance (PRIAS).

ISTITUTO SUPERIORE DI SANITÀ

• • • • • •

Surveillance of rare cancers in Italy Innovative management of patients with diffuse malignant peritoneal mesothelioma: clinical-diagnostic pathway and new therapeutic targets Genotype/phenotype analysis of neurodegenerative and again-prone syndromes caused by mutations in the DNA damage response/repair pathway Micro-RNA genes and antisense sequence Management of MILD project database, randomization, accrual of 200 smokers and proteomic analysis of at least 200 samples Identification of individual lung cancer risk in heavy smokers by proteomic profile analysis in subjects randomized in two groups (spiral CT vs observation) (Help-MILD Project)

LEGA ITALIANA PER LA LOTTA CONTRO I TUMORI

• • • •

Psychological evaluation in women with hereditary susceptibility to breast cancer submitted to screening test for BRCA1 and BRCA2 genes Lynch syndrome: predictive models of cancer risk and biomarkers for the identification of subjects with germinal mutations in MMR genes Anti-smoking counseling A study of the native fluorescence of plasma in the diagnosis of colorectal neoplasias

MINISTERO DELLA SALUTE

• • • • • • • • • • • • • • • • • • • •

Identification of new therapeutic targets and optimization of resistant tumors The effectiveness of the LCP in improving end-of-life care in hospital. A cluster randomized trial Regional cancer networks’ models comparative assessment and study of their integration CAREMORE: joint Community and CAncer REgistry MOdel on REhabilitation Optimization of target therapies Cancer stem cells, drug resistance and niche in minimal residual disease New protocols and targets for the treatment of brain and other solid tumors Controlled extension of conventional criteria for liver transplantation in hepatocarcinoma (HCC): a prospective validation study Development of programs for weak subjects such as patients waiting kidney transplant for more than 10 years or seropositive subjects (optimal use of organs) New immunotherapeutic approaches to neuroblastoma Analytical and clinical validation of biomarkers for non-invasive early diagnosis of digestive tract carcinoma PET molecular imaging as prognostic and predictor indicator of response to therapy Diagnosis and molecular pathogenesis of virus-associated tumors Multidimensional characterization of solid tumors Detection of the oncologic disease at early stage Research of new prognostic and therapy oriented-biomarkers Tumor radioresistance and predictive markers of the response to radiotherapy Targeting of tumor-associated myeloid cells Validation of new biomarkers: their role in the prognosis and therapy guidance Identification of new vaccination strategies for the treatment of limited disease or the prevention of recurrences in patients


204

• • • • • • • • • • • • • • • • • • • • • • • •

• • • • • • • • •

SCIENTIFIC REPORT 2010

with solid tumors Targeting tumor-related immunosuppression for new combined approaches for immunotherapy Integrated genomic analyses for the identification of genetic markers of breast cancer metastasis Surrogate markers of antiangiogenic therapy in triple receptor negative breast cancer Cancer prevention: development of evidence-based intervention models Multidimensional characterization of human tumors: organizational structure for managing the integrated program and pathologists network for clinical validation of new tumor markers HUCARE - HUmanization of CAncer care in Italy: implementation of evidence-based REccomendations Analytical and clinical validation of new biomarkers for early diagnosis: the network, the resources, the methodology, the QC, the analysis of data Post-genomic approaches for the identification of high-risk cancers: evaluation and optimization of cost/benefits for the National Health System Experimental evaluation of the effectiveness of quality programs to improve pain management both in hospital and at home Innate immunity and gastrointestinal cancer as paradigm: from new molecules to bedside Centrosomes and centrosome-associated regulatory proteins in menome maintenance and in the DNA damage response New therapeutic strategies based on modulation of immune response in prostate cancer patients Melanoma and integrated chip technologies:identification of novel prognosticators and (immuno)therapeutic protocols Regulatory T cell immunotherapy after haploidentical stem cell transplantation Oncology project of molecular medicine: female tumors Use of integrated PET/CT as a first line re-staging technique in oncological patients Comprehensive host-and-tumor characterization for individualizing breast cancer treatment strategies Identification and isolation of normal and tumoral lung stem cells as a tool for the definition of new therapeutic strategies in lung cancer Integrated unit for the concerted translational early development of new drugs and/or therapeutic approaches in solid tumors Personalized treatment of sarcoma Hepato-Oncology: a multidisciplinary approach for an emerging specialty Efficacy of pharmacological prevention with Varenicline and subsequent screening with yearly CT in heavy smokers Development of radiolabelled radiopharmaceuticals for tumor charcterization, molecular imaging and therapy Improvement of acute and chronic pain management at the “Fondazione IRCCS Istituto Nazionale dei Tumori”; research on the organization and implementation: - institution of an “acute, postoperative and procedure related pain team” implementation of invasive procedures such as neural blockade or implantation of specialized devices for drug delivery in patients with severe pain difficult to control with systemic drug administration - implementation of chronic pain symptom control: multidisciplinary hospital team Research on health determinants and risk reduction interventions National epidemiological surveillance system for the prevention of occupational cancer cases A system of integrated skills to improve security in chemotherapy Rational combinations of molecularly targeted agents in lymphoproliferative disorders A regional network of oncologic biobanks for scientific research and care of cancer Women with BRCA1 and BRCA2 gene mutations: clinical and psychological care Information as first medicine: the National Assistance and Information service in Oncology Tumors in Italy: the portal of oncologic epidemiology for professionals and people Survival and care for tumors in Italy and Europe

MINISTERO DELL’UNIVERSITÀ E DELLA RICERCA

• • •

Identification of disease genes by genotyping at high population density Identification of innovative antitumoral agents: from genomics to therapy New drugs for anticancer target therapy

REGIONE BASILICATA

Controlled extension of conventional criteria for liver transplantation in hepatocarcinoma (HCC): a prospective randomised study using down-staging response and the metroticket model as predictors of survival (extension trial)

REGIONE LOMBARDIA

• •

Lombardy Network in Oncology Definition of the individual risk of cancer in smokers by functional and radiological analysis of the lung damage, genetic and proteomic profile


ONGOING PROJECTS SUPPORTED BY DIFFERENT ORGANIZATIONS

• • • • • • • •

205

Prevention of postoperative pain by using botulinic toxin in patients candidates to mastectomy and immediate reconstruction with expander and in patients candidates to additive contralateral mastoplastic in the second reconstructive phase Allogeneic transplantation of hematopoietic stem cells for the salvage therapy of non-Hodgkin’s lymphomas Biobanks project for colorectal carcinoma Extracorporeal photochemotherapy for GVHD prophylaxis in patients submitted to allogeneic stem cell transplantation with reduced-intensity conditioning Patient transfusion safety: from safe and integrated transfusions in hospital to total blood traceability and management of clinical risk with Radio Frequency Identification (RFID) technology Adverse drug reaction signals in oncology Development of an experimental model within Lombardy Network in Oncology for identification and follow-up of women with and at risk for hereditary breast cancer An experimental model of a pediatric hemato-oncological network between Varese hospital and referring centers for the treatment of pediatric oncological pathology


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Cover image

Scientific Report 2010

Predictive, Personalized, Preventive, Participatory Cancer Medicine. P4 Medicine is a systems approach fueled by information science, a holistic concept of wellness and disease, emerging technologies to explore new dimensions of patient data space, and new analytical technologies that will decipher the billions of data points associated with each individual. (Leroy Hood, 2004)

Editor Marco A. Pierotti

The Istituto Nazionale dei Tumori adopts this holistic approach to cancer, in particular by placing the ill person at the heart of its philosophy of care and research.

Editorial Committee Silvana Canevari, Aurora Costa, Alessandro M. Gianni, Vincenzo Mazzaferro, Giuseppe Pelosi, Mario Santinami Editorial management and Graphic Design Rosaria Parentela Collaborators Tiziana Camerini, Daniela Majerna Copy editing and Translation Patrick Moore Photographer Massimo Brega (except photographs on pages 89 and 135)

Fondazione IRCCS Istituto Nazionale dei Tumori Via G. Venezian, 1 - 20133 Milan - Italy Scientific Directorate Tel. +39 02 2390 2300 Fax +39 02 2390 3141 direzionescientifica@istitutotumori.mi.it http://www.istitutotumori.mi.it

Printed in June 2011 by Bozzi Multimedia s.r.l. 20026 Novate Milanese (MI)

Copyright Š 2011 Fondazione IRCCS Istituto Nazionale dei Tumori. No part of this communication may be cited, reproduced, stored in a retrieval system, or transmitted by electronic or other means without prior written permission of the Scientific Director and the appropriate investigator.


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Fondazione IRCCS Istituto Nazionale dei Tumori

SCIENTIFIC REPORT 2010

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FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI

Via G. Venezian 1 20133 Milano, Italy

www.istitutotumori.mi.it

FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI

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Scientific Report 2010  
Scientific Report 2010  

Research and clinical activity at INT

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