IRFMN
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ANNUAL REPORT 2009
DEPARTMENT OF ONCOLOGY
STAFF
Chief Maurizio D’INCALCI, M.D.
Oncological Studies Office and Docu...
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ANNUAL REPORT 2009
Laboratory for the development of new pharmacological strategies
Head Valter TORRI, M.D.
Labora...
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ANNUAL REPORT 2009
CURRICULA
Maurizio D'Incalci obtained his Medical Degree cum Laude from the University of Milan...
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ANNUAL REPORT 2009
Selected publications
• Corli O, Apolone G, Pizzuto M, Cesaris L et al. Illness awareness in te...
IRFMN
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ANNUAL REPORT 2009
codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon ...
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ANNUAL REPORT 2009
• Bonezzi K., Taraboletti G., Borsotti P., Bellina F., Rossi R., Giavazzi R. Vascular disruptin...
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ANNUAL REPORT 2009
Selected publications
• Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allave...
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ANNUAL REPORT 2009
3: 111-121, 2004.
• Vikhanskaya F.*, Bani M.R.*., Borsotti P., Ghilardi C., Ceruti R., Ghisleni...
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ANNUAL REPORT 2009
• Paulis M., Bensi M., Orioli D., Mondello C., Mazzini G., D’Incalci M., Falcioni C., Radaelli ...
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ANNUAL REPORT 2009
• Margosio B, Rusnati M, Bonezzi K, Cordes B-lA, Annis DS, Urbinati C, Giavazzi R, Presta M, R...
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ANNUAL REPORT 2009
• Marangon E, Sala F, Caffo O, Galligioni E, D'Incalci M, Zucchetti M. Simultaneous determinat...
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ANNUAL REPORT 2009
The selective activity of Trabectedin against human myxoid liposarcoma appears related to the
...
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ANNUAL REPORT 2009
Soluble human VEGFC levels in serum and ascites correlate with tumor progression and
metastati...
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ANNUAL REPORT 2009
A randomized trial of patients with high risk (stage IcG3, IIG3 with myometrial invasion >50%,...
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ANNUAL REPORT 2009
Istituto Regina Elena, Roma
Istituto Superiore di Sanità
Laboratorio Cell factory, Policlinico...
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ANNUAL REPORT 2009
MD Anderson Cancer Center, Houston, Texas, USA
MRC, London, U.K.
National Cancer Institute (NC...
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ANNUAL REPORT 2009
Detection and Prevention, Cancer Letters, Cancer Research, Carcinogenesis, Chemico-
Biological...
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ANNUAL REPORT 2009
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, January 13, 2009.
Investigators’ Meetin...
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ANNUAL REPORT 2009
Conference: XVII Conferenza Nazionale AIOM: Clinical pathways nel carcinoma del colon
retto: d...
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ANNUAL REPORT 2009
Conference: XXVII Conferenza Nazionale di Citometria, Centro Congressi Ferrara (Italy),
Octobe...
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ANNUAL REPORT 2009
Conference: Nuovi orizzonti nella gestione del paziente oncologico con BTcP: Valutazione
della...
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ANNUAL REPORT 2009
GlaxoSmithKline, Verona
Grunenthal Italia, Milano
Indena SpA
Institut de Recherche Pierre Fabr...
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ANNUAL REPORT 2009
J Cell Mol Med 2009 13 : 1565-1576
Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecc...
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ANNUAL REPORT 2009
Graziano F, Ruzzo A, Canestrari E, Loupakis F, Santini D, Rulli E, Humar B, Galluccio N, Bison...
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ANNUAL REPORT 2009
Exenatide for type 2 diabetes
Lancet 2009 373 : 122
Bardella M T, Elli L, De Matteis S, Floria...
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ANNUAL REPORT 2009
Taraboletti G, Bonezzi K
Inhibitors of angiogenesis based on thrombospondin-1
In :Recent advan...
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ANNUAL REPORT 2009
Cervellini I, Bello E, Frapolli R, Porretta-Serapiglia C, Oggioni N, Canta A, Lombardi R, Camo...
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ANNUAL REPORT 2009
RESEARCH ACTIVITIES
Laboratory of Cancer Pharmacology
Mode of action of Ecteinascidins
A proje...
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ANNUAL REPORT 2009
The Biophysics Unit is engaged in theoretical and methodological studies aimed at a critical
e...
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ANNUAL REPORT 2009
We aim to use flow cytometric (cell-population based analysis) and time-lapse
imaging (single ...
marionegri.it/mn/en/docs/sezioni/ricerca/estrattiRapporto/...
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  1. 1. IRFMN 1 ANNUAL REPORT 2009 DEPARTMENT OF ONCOLOGY STAFF Chief Maurizio D’INCALCI, M.D. Oncological Studies Office and Documentation Scientific Documentalist Stefania FILIPPESCHI, Chemist Laboratory of Cancer Pharmacology Head Maurizio D’INCALCI, M.D. Biophysics Unit Head Paolo UBEZIO, Phys.D. Flow Citometry Unit Head Eugenio ERBA, Biochem.D Cancer Clinical Pharmacology Unit Head Massimo ZUCCHETTI, Chem.Pharm.D. Laboratory of Molecular Pharmacology Head Massimo BROGGINI, Ph.D. DNA Repair Unit Head Giovanna DAMIA, M.D. Laboratory of Biology and Therapy of Metastasis Head Raffaella GIAVAZZI, Biol.Sci.D., Ph.D. Tumor Angiogenesis Unit Head Giulia TARABOLETTI, Biol.Sci.D. Unit located in Bergamo Molecular Cancer Therapeutics Unit Head Maria Rosa BANI, Biol.Sci.D., Ph.D.
  2. 2. IRFMN 2 ANNUAL REPORT 2009 Laboratory for the development of new pharmacological strategies Head Valter TORRI, M.D. Laboratory of Clinical Trials Head Irene FLORIANI, Dr.Sci.Biol., Dr.Stat., Ph.D. Laboratory of Translational and Outcome Research in Oncology Head Giovanni APOLONE, M.D. Gynecology Oncology Unit Head Roldano FOSSATI, M.D. CERP: Center for the Evaluation and Research on Pain Head Giovanni APOLONE, M.D. Oscar CORLI, M.D. Laboratory of Medical Research and Consumer Involvement Head Paola MOSCONI, Biol.Sci.D.
  3. 3. IRFMN 3 ANNUAL REPORT 2009 CURRICULA Maurizio D'Incalci obtained his Medical Degree cum Laude from the University of Milan in 1977. After specializing in Pharmacology at the Mario Negri Institute of Milan and in Oncology at the University of Genoa, he worked in the Laboratory of Molecular Pharmacology of the National Cancer Institute in Bethesda, MD, USA. Since 1986 he has been chief of the Laboratory of Cancer Chemotherapy at the Mario Negri Institute and since 1996 he has become chief of the Department of Oncology at the Mario Negri Institute. He has been President of the Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer (EORTC). From 1994 to 1997 he was Chairman of the New Drug Development Coordinating Committee and from 1997 to 2000 he was chairman of the Research Division of the EORTC. He has been member of the Board of the EORTC from April 2000 to 2003. From 1997 he is the Preclinical Coordinator of the Southern Europe New Drug Organization (SENDO) and since 2006 the Chairman of the New Agents Committee (NAC). From 2006 he is president of the Scientific Committee of the Mario Negri Gynecologic Oncology group (MaNGO). From 2007 he is member of the Scientific Committee of the Italian Association for Cancer Research (AIRC). He is on the editorial board of many international cancer-related scientific journals and since September 2000 he is Editor for Experimental Oncology of the European Journal of Cancer. Dr D'Incalci is author of more than 440 papers on cancer chemotherapy published in peer reviewed international journals, and of several chapters in books on cancer chemotherapy. Selected publications • Frapolli R, Zucchetti M, Sessa C, Marsoni S, Vigano' 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 α(1)-acid glycoprotein plasma levels. Eur J Cancer 2009 E-pub. • Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecchio M, Erba E, Grosso F, Gronchi A, Aman P, Casali P, D'Incalci M, Pilotti S, Mantovani R. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol Cancer Ther, 8 : 449-457 (2009). • Marchini S, Mariani P, Chiorino G, Marrazzo E, Bonomi R, Fruscio R, Clivio L, Garbi A, Torri V, Cinquini M, Dell'Anna T, Apolone G, Broggini M, D'Incalci M. Analysis of gene expression in early-stage ovarian cancer Clin Cancer Res, 14 : 7850-7860 (2008). • Grosso F., Jones R.L. Demetri G.D., Judson I.R., Blay J.Y., Le Cesne A., Sanfilippo R., Casieri P., Collini P., Dileo P., Spreafico C., Stacchiotti S., Tamborini E., Tercero J.C., Jimeno J., D’Incalci M., Gronchi A., Fletcher J.A., Pilotti S., Casali P.G. Efficacy of Trabectedin (ET-743) in advanced pre-treated myxoid liposarcomas. Lancet Oncology, 2007; 8:595-602. • Salvati E., Leonetti C., Rizzo A., Scarsella M., Mottolese M., Galati R., Sperduti I., Stevens M., D’Incalci M., Blasco M., Chiorino G., Horard B., Gilson E., Zupi G., Biroccio A. Telomere damage promotes antitumoral activity of the G- quadruplex ligand RHPS4. J. Clin. Invest., 2007; 117:3236-3247. • Tavecchio M., Natoli C., Ubezio P., Erba E., D’Incalci M. Dynamics of cell cycle phase perturbations by Trabectedin (ET-743) in nucleotide excision repair (NER)-deficient and NER-proficient cells, unravelled by a novel mathematical simulation approach. Cell proliferation, 2007; 40: 885-904. Giovanni Apolone, got his Medical degree in 1982 (Pavia, Italy) and his post-doctoral specializations in Internal Medicine in 1987 (Pavia, Italy) and Pharmacological Research (1992). He is Head of the Laboratory of Translational and Outcome Research. He is also Vice-President of the Ethics Committee of the European Institute of Oncology in Milan (Italy) and listed as National Expert at the European Agency for the Evaluation of Medicinal products (EMEA) in London (UK). His main fields of interest are: • Methodological, ethical and regulatory aspects of clinical research, with special emphasis on oncology and the cancer pain. • Health care evaluation with special emphasis on oncology; • Development and validation of case-mix and patient-reported outcome measures; • Education and health promotion research and programs. He is author or co-author of more than 270 publications, mostòy in International peer-reviewed Journals. Mean Impact Factor, computed on peer-reviewed papers: 3.2. H-index (from ISI-Web of knowledge, March 2010): 30. Number of citations: 4111. Average citation per item: 32.37. Number of papers with >50 citations: 19.
  4. 4. IRFMN 4 ANNUAL REPORT 2009 Selected publications • Corli O, Apolone G, Pizzuto M, Cesaris L et al. Illness awareness in terminal cancer patients: an Italian study. Palliative Medicine, 23: 354-9, 2009 • Riva E, Tettamanti M, Mosconi M, Apolone, G et al. Association of Mild Anemia with Hospitalization and Mortality in the Elderly The “Health and Anemia” Population-Based Study. Haematologica, 94 (1): 22-28, 2009 • Apolone G, Corli O, Negri E, Mangano S, Montanari M, Greco MT. Effects of transdermal buprenorphine on patients- reported outcomes in cancer patients. Results from the Cancer Pain Outcome Research (CPOR) Study Group. Clinical J Of Pain, 25:671-682, 2009 • Apolone G, Corli O, et al. Pattern and quality of care of cancer pain management. Results from the Cancer Pain Outcome Research Study Group (CPOR SG). Br J Cancer, 100:1566-74, 2009. • Apolone G, on behalf of the 2008 Erice Group. The 2008 Erice Statement toward a more humanistic oncology. J Amb care Manage 32:252-258,2009. • De Andrea S, Corli O, Moschetti I, Apolone G. Managing severe cancer pain. The role of TDS buprenorphine: a systematic review. Therapeutics and Clinical Risk management, 5:1-12, 2009. • Gallus S, Tramacere I, La Vecchia C, Colombo P, Zuccaro P, Paleari L, Cesario A, Russo P, Apolone G. Use of pharmacotherapy for smoking cessation in Italy. Arch Intern Med 169: 1927-1928, 2009. Massimo Broggini followed the faculty of Science of the University of Milan, got the specialization in Biochemistry at Mario Negri Institute, and the PhD degree at the Open University, London,UK. He worked in the laboratory of Molecular Pharmacology of the National Cancer Institute of Bethesda, Md, in 1986. From 1991 he is the head of the Molecular Pharmacology Unit of the Mario Negri Institute and from 1999 he his the head of the Laboratory of Molecular Pharmacology of the same Institute. His main fields of interest are the study of the mechanism of action of new anticancer agents, the search of altered proteins and genes in human cancer and the study of oncosuppressor genes. He is member of the "Pharmacology and Molecular Mechanisms Group" of the European Organisation for the Research and Treatment of Cancer (EORTC) and of the American Association for Cancer Research. He is in the Editorial board of the European Journal of Cancer. He is author of more than 100 articles published in international journals. Principali pubblicazioni • Zangrossi S, Marabese M, Broggini M, Giordano R, D'Erasmo M, Montelatici E, Intini D, Neri A, Pesce M, Rebulla P, Lazzari L. Oct-4 expression in adult human differentiated cells challenges its role as a pure stem cell marker. Stem Cells. 2007;25(7):1675-80. • Marrazzo E, Marchini S, Previdi S, Broggini M. Questioning the oncogenic role of DeltaNp73alpha in different cell lines expressing p53 or not. Cancer Biol Ther. 2006;5(7):794-803. • Polato F, Codegoni A, Fruscio R, Perego P, Mangioni C, Saha S, Bardelli A, Broggini M. PRL-3 phosphatase is implicated in ovarian cancer growth. Clin Cancer Res. 2005 11:6835-9. • Maffucci T, Piccolo E, Cumashi A, Iezzi M, Riley AM, Saiardi A, Godage HY,Rossi C, Broggini M, Iacobelli S, Potter BV, Innocenti P, Falasca M. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects. Cancer Res. 2005;65:8339-49. • Marabese M, Marchini S, Sabatino MA, Polato F, Vikhanskaya F, Marrazzo E, Riccardi E, Scanziani E, Broggini M. Effects of inducible overexpression of DNp73alpha on cancer cell growth and response to treatment in vitro and in vivo. Cell Death Differ. 2005;12:805-14. • Sabatino MA, Colombo T, Geroni C, Marchini S, Broggini M. Enhancement of in vivo antitumor activity of classical anticancer agents by combination with the new, glutathione-interacting DNA minor groove-binder, brostallicin. Clin Cancer Res. 2003;9:5402-8. Irene Floriani got her degree in Biological Sciences at the University of Milan in 1988, her degree in Biostatistics and Experimental Statistics at the University of Milan in 2003 and her phD in Life Sciences at Open University of London (UK) in 2005. After ten-year experience in pharmaceutical industry, in 2002 she became Head of the Biometry and Data Management Unit of the Laboratory of Clinical Research in Oncology and since 2006 she is Head of Laboratory of Clinical Trials. She is also member as bio-statistician of three Italian Ethics Committees. Her main fields of interest are: statistical aspects of methodology of clinical research with focus on Controlled Clinical Trials in Oncology; Systematic Overview of the medical literature and Methodological aspects of diagnostic test evaluation. Selected publications • Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I, Bencardino K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F. KRAS
  5. 5. IRFMN 5 ANNUAL REPORT 2009 codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 2009 101 : 715-721 • Signorelli M, Lissoni AA, Cormio G, Katsaros D, Pellegrino A, Selvaggi L, Ghezzi F, Scambia G, Zola P, Grassi R, Milani R, Giannice R, Caspani G, Mangioni C, Floriani I, Rulli E, and Fossati R. Modified radical hysterectomy versus extrafascial hysterectomy in the treatment of stage I endometrial cancer: results from the ILIADE randomized study. Ann Surg Oncol 2009 16 : 3431-3441 • Floriani I, Santini D, Torri V, Cremolini C, Falcone A, Loupakis F. Do we need biopsies of metastases for colorectal cancer patients? Br J Cancer 2009 101 : 374-375 • Garattini S, Torri V, Floriani I. Cetuximab for metastatic colorectal cancer. N Engl J Med 2009 361 : 96 • Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi G, Graziano F, Cremolini C, Rulli E, Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I, Cascinu S, Falcone A. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol 2009 27 : 2622-2629 • Ferrari D, Fiore J, Codecà C, Di Maria G, Bozzoni S, Bordin V, Caldiera S, Luciani A, Zonato S, Floriani I, Foa P. A phase II study of carboplatin and paclitaxel for recurrent or metastatic head and neck cancer. Anticancer Drugs 2009 20 : 185-190 • Lissoni AA, Colombo N, Pellegrino A, Parma G, Zola P, Katsaros D, Chiari S, Buda A, Landoni F, Peiretti M, Dell'anna T, Fruscio R, Signorelli M, Grassi R, Floriani I, Fossati R, Torri V, Rulli E. A phase II, randomized trial of neo-adjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap- 02 Italian Collaborative Study. Ann Oncol 2009 20 : 660-665 • Graziano F, Ruzzo A, Canestrari E, Loupakis F, Santini D, Rulli E, Humar B, Galluccio N, Bisonni R, Floriani I, Maltese P, Falcone A, Tonini G, Catalano V, Fontana A, Giustini L, Masi G, Vincenzi B, Alessandroni P, Magnani M.Variations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectal cancer. Pharmacogenomics J 2009 9 : 78-84 • Mandalà M, Barni S, Floriani I, Isa L, Fornarini G, Marangolo M, Mosconi S, Corsi D, Rulli E, Frontini L, Cortesi E, Zaniboni A, Aglietta M, Labianca R. Incidence and clinical implications of venous thromboembolism in advanced colorectal cancer patients: The 'GISCAD-alternating schedule' study findings. Eur J Cancer 2009 45 : 65-73 Raffaella Giavazzi got her Biological Sciences degree (1979) at the University of Milan, and her Ph.D. in Pharmacology at the Mario Negri Institute of Milan (1984), followed by a specialization in pharmacology (1994) at the University of Milan. From 1981 to 1983 she was a Fellow in the Cancer Metastasis and Treatment Laboratory, NCI-FCRDC, Frederick, MD., and from 1983 to 1985 Assistant Professor at the Department of Cell Biology of M.D. Anderson Hospital and Tumour Institute, University of Texas System Cancer Centre in Houston (TX). Raffaella Giavazzi’s research interests are in the field of tumour biology and pharmacology. Specifically, she is studying aspects related to the metastatic process and angiogenesis. She is involved in the pre- clinical evaluation of new therapeutic strategies against cancer focusing on the angiogenesis inhibitors and combination therapies. From 1986 to 1993 she was Head of the Cancer Metastasis Treatment Unit and since 1993 she has been the Head of the Laboratory of Biology and Treatment of Metastasis at Mario Negri Institute for Pharmacological Research. She is also adjutant Professor in Oncology, Medical School-University of Brescia, member of the Teaching Committee for the PhD course in Physiology-Pharmacology-Molecular and Cellular Tossicology-University of Siena, member of the Executive Committee at SENDO (South Europe New Drug Development Organization) and member of the Executive Committee of the European Association for Cancer Research (EACR). She was consulting scientist for the NCI-Drug Therapeutics Program, USA (1996-2006); She is a member of the American Association for Cancer Research (AACR), International Metastases Research Society, EORTC-Screening and Pharmacology Group, European Association for Cancer Research (EACR), Italian Cancer Society (SIC) of which she was President (2006-2007). She is on the Editorial Board of international scientific journals such as the European Journal of Cancer, Journal of Clinical & Experimental Metastasis, and The International Journal of Biological Markers. She has published approximately 200 articles on “peer reviewed” scientific journals. Selected publications • Rösli C., Borgia B., Schliemann C., Gunther M., Wunderli-Allenspach H., Giavazzi R., Neri D. Comparative analysis of the membrane protome of closely related metastatic and non-metastatic tumor cells. Cancer Research, 69(13):5406-14, 2009. • Cesca M., Frapolli R., Berndt A., Scarlato V., Richter P., Kosmehl H., D’Inclaci M., Ryan A.J., Giavazzi R. The effects of vandetanib on paclitaxel tumor distribution and antitumor activity in a xenograft model of human ovarian carcinoma. Neoplasia, 11(11):1155-64, 2009.
  6. 6. IRFMN 6 ANNUAL REPORT 2009 • Bonezzi K., Taraboletti G., Borsotti P., Bellina F., Rossi R., Giavazzi R. Vascular disrupting activity of tubulin-binding 1,5-Diaryl-1H-imidazoles. Journal of Medical Chemistry, 52:7906-10, 2009. • Borgia B., Rösli C., Fugmann T., Schliemann C., Cesca M., Neri D., Giavazzi R. A proteomic approach for the identification of vascular markers of liver metastasis. Cancer Research, 70(1):309-18, 2010. • Ghilardi C., Chiorino G., Dossi R., Nagy Z., Giavazzi R., Bani M.R. Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium. BMC Genomics, 30(9), 201, 2008. • Giavazzi R., Bani M.R.,Taraboletti G.: Tumor–host interaction in the optimization of paclitaxel-based combination therapies with vascular targeting compounds. Cancer Metastasis Rev. 26:481–88, 2007 Paola Mosconi got her Biological Science degree (Milan 1982) and the specialisation in Pharmacological Research (Milan 1984). Her main areas of interest are: • development of strategies to involve patients-consumer associations in the health debate, and research projects; • assessment of the quality of life, translation and cultural adaptation of questionnaires for quality of life; • studies to evaluate the type of information on diseases and treatments received by patients, mainly cancer patients; set-up of websites targeted on consumers/patients www.partecipasalute.it, www.paincare.it, www.fondazioneMattioli.it ; • studies to evaluate the consumers’ level of satisfaction with the health services and care. Paola Mosconi has participated as a teacher, or coordinator, to the realization of training course on “Methodological aspects of clinical research” or “Evaluation of quality of life” for health care professionals and representatives of voluntary associations. Selected publications • Mosconi P, Donati S, Colombo C, Mele A, Liberati A, Satolli R. The Consensus Conference WorkingGroup. Informing women about hormone replacement therapy: the Consensus conference statement. BMC Woman Health Journal 2009; 9:14 doi:10.11886/1472-6874-9-14 • Donati S, Cotichini R, Mosconi P, Satolli R, Colombo C, Liberati A, Mele A Menopause: knowledge, attitude and practice among Italian women.Maturitas 2009; 20; 63(3):246-52. • Mosconi P, Colombo C, Satolli R, Liberati A. PartecipaSalute, an Italian project to involve lay people, patients’ associations and scientific-medical representatives on the health debate. Health Expectations 10: 194-204, 2007. O’Connel D, Mosconi P. An active role for patients in clinical research? Drug Development Research 67 (3): 188-192, 2006. • Mosconi P, Colombo Cinzia, La Bianca R, Apolone G. Oncologists' opinions about research ethics committees in Italy: an update, 2004. Eur J Cancer Prev 2006; 15: 91-94 • Mosconi P, Poli P, Giolo A, Apolone G. How health consumers feel about clinical research: a questionnaire survey. European Journal of Public Health 15: 372-379, 2005. • Mosconi P, Buchanan M, Kyriakides S, Fernandez-Marcos A, Horvatin J, O'Connell D, Zernik N, on behalf of EUROPA DONNA. EUROPA DONNA: has strength in its heterogeneity. European J Cancer 40: 1145-1149, 2004. Valter Torri got his Medical degree in 1985 and the specialization in medical Oncology in 1989 at the University of Milano. Education: 1985: MD Degree with full honors cum Laude, University of Milano; 1988 Post-Doctoral Degree in Pharmacological Research, Mario Negri Institute, Milano; 1989 Post-Doctoral Degree in Medical Oncology, University of Milano; 1989-1991 Research Fellow at the Biometric Research Branch of Cancer Treatment Evaluation Program, NCI, Bethesda, MD (USA) Areas of Interest: Statistical aspects of clinical research methodology with focus on Controlled Clinical Trials in Oncology; Systematic Overview of the medical literature; Methodological aspects of diagnostic test evaluation. Present Position: Head of Laboratory of Clinical Research In Oncology, Oncology Department, Mario Negri Institute, Milano. Chronology of Professional Appointments: 1983-1985: Clinical research Fellow in Internal Medicine at the University Hospital, University of Milan; 1985-1989: Research assistant at the Clinical Trial Unit of the Laboratory of Clinical Epidemiology, Mario Negri Institute for Pharmacological Research, Milano; 1989-1991: Research fellow at the Biometric Research Branch of Cancer Treatment Evaluation Program, NCI, Bethesda, MD (USA); 1994: Head of Biometric Unit of the Laboratory of Cancer Clinical Epidemiology, Oncology Department, Mario Negri Institute for Pharmacological Research, Milano, Italy; 1995 Vice Director of the Italian “Cochrane” Center; 2001: Head of Laboratory of Clinical Research In Oncology, Oncology Department, Mario Negri Institute, Milano. 2006: Head of Laboratory for the development of new pharmacological strategies , Oncology Department, Mario Negri Institute, Milano. Member of Consiglio Direttivo Nazionale dell’Associazione Italiana di Oncologia Medica
  7. 7. IRFMN 7 ANNUAL REPORT 2009 Selected publications • Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, Mantovani A, Roncalli M, Malesci A. CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncol. 2009; 10 (9): 877-84. • Garassino MC, Borgonovo K, Rossi A, Mancuso A, Martelli O, Tinazzi A, Di Cosimo S, La Verde N, Sburlati P, Bianchi C, Farina G, Torri V. Biological and clinical features in predicting efficacy of epidermal growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis. Anticancer Res. 2009; 29 (7): 2691-701. • Marchini S, Mariani P, Chiorino G, Marrazzo E, Bonomi R, Fruscio R, Clivio L, Garbi A, Torri V, Cinquini M, Dell'Anna T, Apolone G, Broggini M, D'Incalci M. Analysis of gene expression in early-stage ovarian cancer. Clin Cancer Res. 2008 Dec 1;14(23):7850-60. • Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M,Scambia G, Angioli R, Tateo S, Mangili G, Katsaros D, Garozzo G, Campagnutta E,Donadello N, Greggi S, Melpignano M, Raspagliesi F, Ragni N, Cormio G, Grassi R, Franchi M, Giannarelli D, Fossati R, Torri V, Amoroso M, Crocè C, Mangioni C. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008 Dec 3;100(23):1707-16. • Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V,Elias D, O'Callaghan C, Langer B, Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008 Oct 20;26(30):4906-11. • Cascinu S, Labianca R, Barone C, Santoro A, Carnaghi C, Cassano A, Beretta GD, Catalano V, Bertetto O, Barni S, Frontini L, Aitini E, Rota S, Torri V, FlorianiI; Italian Group for the Study of Digestive Tract Cancer, Adjuvant treatment of high-risk, radically resected gastric cancer patients with 5-fluorouracil, leucovorin, cisplatin, and epidoxorubicin in a randomised controlled trial. J Natl Cancer Inst. 2007;99(8):601-7. • Graziano F, Kawakami K, Ruzzo A, Watanabe G, Santini D, Pizzagalli F, Bisonni R, Mari D, Floriani I, Catalano V, Silva R, Tonini G, Torri V, Giustini L, Magnani M Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at-risk Italian population. Int J Cancer 2006 118 : 628-632 • Torri V: Clinical trials and data management In: Oxford textbook of oncology, 2nd. ed. Vol. 1. Oxford Univ. Press, Oxford; 2002 : 1123-1134 Maria Rosa Bani got her Biological Sciences degree at the University of Milan in 1998 attaining the Italian Government Qualification to practice as Biologist in 1990. She obtained the specialization in Pharmacological Research from the Department of Education of the Regional Government of Lombardia in 1991 and the specialization in Biomedical Research from the Department of Education of the Regional Government of Abruzzo in 1993. In 2005 she was awarded the degree of Doctor of Philosophy (PhD), Discipline of Life Sciences of the Open University Research School (UK). From 1991 to 1995 she was a Post Doctoral Fellow in the Cancer Research Division, Sunnybrook Health Science Centre, University of Toronto (Canada); from 2000 to 2001 she was Guest Scientist at the Advance Technology Centre, National Cancer Institute, National Institute of Health (USA). At the MarioNegri Institute for Pharmacological Research she was a Fellow Research Scientist in the Laboratory of Biology and Treatment of Metastasis, Bergamo from 1996 to 2002 and she became a Staff Research Scientist in 2003. In April 2004 she became Head of the Molecular Cancer Therapeutics Unit. She is the Scientific Manager of STROMA(since 2004) and ADAMANT(since2008), two Integrated Projects within the 6th and 7th Framework Programs of the European Commission. She is a member of the American Association for Cancer Research (AACR), the European Association for Cancer Research (EACR) and the Italian Cancer Society (SIC). Maria Rosa Bani research interests are in the field of cancer biology and molecular therapeutics. She is co-author of 34 peer reviewed publications, 2 book chapters and 65 proceedings of which 15 selected for oral presentation at international meetings. Selected publications • Ghilardi C., Chiorino G., Dossi R., Nagy Z., Giavazzi R., Bani M.R. Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium. BMC Genomics, 30(9), 201, 2008. • Giavazzi R., Bani M.R.,Taraboletti G.: Tumor–host interaction in the optimization of paclitaxel-based combination therapies with vascular targeting compounds. Cancer Metastasis Rev. 26:481–88, 2007. • Naumova E., Ubezio P., Garofalo A., Borsotti P., Cassis L., Riccardi E., Scanziani E., Eccles S.A., Bani M.R. & Giavazzi R. The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor, causing apoptosis of endothelial cells and inhibition of angiogenesis. Clinical Cancer Research 12: 1839-1849, 2006. • Bani M.R., Nicoletti M.I., Alkharouf N.W., Ghilardi C., Petersen D., Erba E., Sausville E.A., Liu E.T. and Giavazzi R. Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts. Molecular Cancer Therapeutics
  8. 8. IRFMN 8 ANNUAL REPORT 2009 3: 111-121, 2004. • Vikhanskaya F.*, Bani M.R.*., Borsotti P., Ghilardi C., Ceruti R., Ghisleni G., Marabese M., Giavazzi R., Broggini M. & Taraboletti G. p73 overexpression increases VEGF and reduces thrombospondin-1 production: implication for tumor angiogenesis. Oncogene 20 : 7293-7300, 2001. • Taraboletti G., Sonzogni L., Vergani V., Hosseini G., Ceruti R., Ghilardi C., Bastone A., Toschi E., Borsotti P., Scanziani E., Giavazzi R., Pepper M.S., Stetler-Stevenson W.G. & Bani M.R. Post-transcriptional stimulation of endothelial cell matrix metalloproteinases 2 and 1 by endothelioma cells. Experimental Cell Research 258 : 384-394, 2000. Giovanna Damia obtained her Medical Degree cum Laude from the University of Milan in 1985. After specializing in Pharmacology at the Mario Negri Institute of Milan and in Oncology at the University of Milan, she worked as a post-doctoral fellow in the Laboratory of Experimental Immunology of the National Cancer Institute, Frederick, USA. She worked as a research fellow in the Laboratory of Cancer Chemotherapy at the Mario Negri Institute and since April 2003 she has become chief of the DNA Repair Unit at the Mario Negri Institute. From 1992 to1995 she has been consultant of the General Secretariat of the Progetto Finalizzato CNR "Applicazioni Cliniche della Ricerca Oncologica". Since September 2005 she is Deputy Editor for Experimental Oncology of the European Journal of Cancer. Her main fields of interest are: mechanism of action of anticancer drugs, cell cycle checkpoints and natural compounds. Selected publications • Simone M, Erba E, Damia G, Vikhanskaya F, Di Francesco A M, Riccardi R, Baldeyrou B, Bailly C, Cuevas C, Sousa-Faro J M F, D'Incalci M. Variolin B and its derivate deoxy-variolin B: New marine natural compounds with cyclin-dependent kinase inhibitor activity. Eur J Cancer 2005; 41: 2366-2377 • Carrassa L, Broggini M, Erba E, Damia G. Chk1, but not Chk2, is involved in the cellular response to DNA damaging agents. Differential activity in cells expressing or not p53. Cell Cycle 2004; 3: 1177-1181 • Damia G, Broggini M. Improving the selectivity of cancer treatment by interfering with cell response pathways. Eur J Cancer 2004; 40: 2550-2559 • Damia G, Broggini M. Cell cycle checkpoint proteins and cellular response to treatment by anticancer agents. Cell Cycle 2004; 3: 46-50 • Carrassa L, Broggini M, Vikhanskaya F, Damia G. Characterization of the 5' flanking region of the human chk1 gene. Identification of E2F1 functional sites. Cell Cycle 2003; 2: 604-609 • Damia G, Sanchez Y, Erba E, Broggini M. DNA damage induces p53-dependent down-regulation of hCHK1. J Biol Chem 2001; 276: 10641-10645 Eugenio Erba has obtained his Biological and Biochemmistry Analysis Degree at the University of Urbino. He worked as a research fellow in the Laboratory of Cancer Chemotherapy at the Mario Negri Institute and since 1984 he is head of the Flow Cytometry Unit in the Department of Oncology at the Mario Negri Institute of Milan. He has worked as a visiting fellow in the Department of Istochemistry and Cytochemistry of the University of Leiden, The Netherlands in 1983. Since 1997 he is Teacher of Post-Graduate Studies in Cytometry at the University of Milan and Co-ordinator and Teacher of Post- Graduate Studies in Cytometry for the Italian Cytometry Group. He has been President of the Italian Cytometry Group from 1999 to 2001. Since 2001 he is member of the Executive Board of the Italian Cytometry Group. Scientific areas of interest: studies on the mechanism of action of different compounds with provided antitumoral activity evaluating the mechanism of cell death and cell cycle phase perturbations induced on different human cancer cell lines by using flow cytometry. Co-ordinator of working-group in a quality control study on flow cytometric DNA content analysis in human tumors. Selected publications • C. Forni, M Minuzzo, E. Virdis, E. Tamburini, M. Simone, M. Tavecchio, E. Erba, F. Grosso, A. Gronchi, P.Aman, P. Casali, M. D’Incalci, S. Pilotti , R. Mantovani. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol. Ca. Ther. 8(2), 449-57, 2009 • E. Marrazzo, S. Marchini, M. Tavecchio, T. Alberio, S. Previdi, E. Erba, V. Rotter, M. Broggini The expression of the ΔNp73β isoform of p73 leads to tetraploidy. Eur J Ca 45, 443-53, 2009 • C. Valli, G. Paroni, A. Di Francesco, R. Riccardi, M. Tavecchio, E. Erba, A. Boldetti, M. Giannì, M. Fratelli, C. Pisano, L. Merlini, A. Antoccia, C. Cenciarelli, M. Terao, E. Garattini. Atypical retinoids ST1926 and CD437 are S-phase specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity. Mol. Ca. Ther. 7(9),2941-54, 2008 • L. Roncoroni, L. Elli, E. Delfini, E. Erba, E. Dogliotti, C. Terrai, L. Doneda, MG. Grimoldi, MT. Bardella. Resveratrol inhibits cell growth in a human cholangiocarcinoma cell line. Liver Int. 28(10),1426-36, 2008 • M.Tavecchio, M. Simone, E.Erba, I. Chiolo, G. Liberi, M. Foiani, M. D’Incalci, G. Damia. Role of homologous recombination in trabectedin-induced DNA damage. Eur. J. Ca 44:609-618 (2008)
  9. 9. IRFMN 9 ANNUAL REPORT 2009 • Paulis M., Bensi M., Orioli D., Mondello C., Mazzini G., D’Incalci M., Falcioni C., Radaelli E., Erba E., Raimondi E., De Carli L. Transfer of a Human Chromosomal Vector from a Hamster Cell Line to a Mouse Embryonic Stem Cell Line. Stem Cell , 25:2543-2550 (2007) • Tavecchio M., Natoli C., Ubezio P., Erba E., D’Incalci M. Dynamics of cell cycle perturbations by trabectedin (ET-743) in nucleotide excision repair (NER) –deficient and NER-proficient cells, unravelled by a novel mathematical simulation approach. Cell Prolif., 40:885-904 (2007) • Tognon G., Bernasconi S., Celli N., Faircloth G.T. Cuevas C., Jimeno J., Erba E., D’Incalci M. Induction of resistance to Aplidin® in a human ovarian cancer cell line related to MDR expression. Cancer Biology and Therapy, 4(12): 1325-1330 (2005). Roldano Fossati got his Medical Degree cum Laude from the University of Milan in 1980, his Post- Doctoral Degree in Endocrinolgy cum Laude from the University of Verona in 1983 and his Post- Doctoral Degree in Medical Statistics from the University of Milan in 1992. He has been consultant at the Mario Negri Institute since 1983 and, at present, he is head of the Gynecology and Oncology Unit of the Laboratory of Translational and Outcome Research. Areas of Interest: Statistical and methodologic aspects of clinical research with focus on Controlled Clinical Trials in Oncology; Systematic Overview of the medical literature. Selected publications • P. Benedetti Panici, A. Maggioni, N. Hacker, F. Landoni, S. Ackermann, E. Campagnutta, K. Tamussino, R. Winter, A. Pellegrino, S. Greggi, R. Angioli, N. Manci, G. Scambia, T. Dell'Anna, R. Fossati, I. Floriani, R.S. Rossi, R. Grassi, G. Favalli, F. Raspagliesi, D. Giannarelli, L. Martella, C. Mangioni. Systematic Aortic and Pelvic Lymphadenectomy versus Resection of Bulky Nodes Only in Optimally Debulked Advanced Ovarian Cancer: A Randomized Clinical Trial J Natl Cancer Inst 97:1-6;2005 • Buda A, Fossati R, Colombo N, Fei F, Floriani I, Gueli Alletti D, Katsaros D, Landoni F, Lissoni A, Calzoni C, Sartori E, Scollo P, Torri V, Zola P, Mangioni C. Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: The SNAP01 (Studio Neo-Adjuvante Por. J Clin Oncol 2005; 23: 4137-4145. • Maggioni A, Benedetti Panici P, Dell'anna T, Landoni F, Lissoni A, Pellegrino A, Rossi RS, Chiari S, Campagnutta E, Greggi S, Angioli R, Manci N, Calcagno M, Scambia G, Fossati R, Floriani I, Torri V, Grassi R, Mangioni C.Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br J Cancer. 2006 Sep 18;95(6):699-704. • Maggi R, Lissoni A, Spina F, Melpignano M, Zola P, Favalli G, Colombo A, Fossati R. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006 Aug 7;95(3):266-71 • Fruscio R, Colombo N, Lissoni AA, Garbi A, Fossati R, Ieda' N, Torri V, Mangioni C.A phase II randomised clinical trial comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced epithelial ovarian cancer: long-term survival analysis. Br J Cancer. 2008 Feb 5. • Andrea Alberto Lissoni, Nicoletta Colombo, Antonio Pellegrino, Gabriella Parma, Paolo Zola, Dionyssios Katsaros, Stefania Chiari, Alessandro Buda, Fabio Landoni, Michele Peiretti, Tiziana Dell’Anna, Robert Fruscio, Mauro Signorelli, Roberto Grassi, Irene Floriani, Roldano Fossati , Valter Torri, Eliana Rulli. A phase II, randomized trial of neoadjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap- 02 Italian Collaborative Study. Annals of Oncology, 20:660-665;2009 • Signorelli M, Lissoni AA, Cormio G, Katsaros D, Pellegrino A, Selvaggi L, Ghezzi F, Scambia G, Zola P, Grassi R, Milani R, Giannice R, Caspani G, Mangioni C, Floriani I, Rulli E, Fossati R. Modified Radical Hysterectomy Versus Extrafascial Hysterectomy in the Treatment of Stage I Endometrial Cancer: Results From the ILIADE Randomized Study. Ann Surg Oncol. 2009 Oct 16 Giulia Taraboletti got her degree cum laude in Biological Sciences at the University of Pavia (Pavia, Italy) in 1983, and the specialization in Pharmacological Research at the Mario Negri Institute, Milano, Italy in 1986. From 1986 to 1988 she was a post-doctoral fellow at the Laboratory of Pathology, NCI, NIH, Bethesda, MD, and from 1988-1995 research scientist at Mario Negri Institute in Bergamo, Italy. Since 1995 she is Head of the Unit of Tumor Angiogenesis, at Mario Negri Institute, in Bergamo. Research interests include tumor angiogenesis, endogenous inhibitors of angiogenesis (thrombospondin-1) and preclinical studies of antiangiogenic and vascular disrupting compounds, including tubulin-targeting agents. She is member of Metatasis Research Society (MRS), American Association for Cancer Research (AACR), European Association for Cancer Research (EACR), and the Italian Society of Oncology (SIC). She is on the editorial board of European Journal of Cancer. Selected publications • Bonezzi K., Taraboletti G., Borsotti P., Bellina F., Rossi R., Giavazzi R. Vascular disrupting activity of tubulin-binding 1,5-diaryl-1H-imidazoles. J Med Chem 52, 7906–7910, 2009.
  10. 10. IRFMN 10 ANNUAL REPORT 2009 • Margosio B, Rusnati M, Bonezzi K, Cordes B-lA, Annis DS, Urbinati C, Giavazzi R, Presta M, Ribatti D, Mosher DF, and Taraboletti G. Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic domain. Int J Biochem Cell Biol 40: 700-709, 2008. • Giavazzi R., Bani M.R.,Taraboletti G. Tumor–host interaction in the optimization of paclitaxel-based combination therapies with vascular targeting compounds. Cancer Metastasis Rev, 26:481–88, 2007. • Martinelli M., Bonezzi K., Riccardi E., Kuhn E., Frapolli R., Zucchetti M., Ryan A.J., Taraboletti G., Giavazzi R. Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel. Br J Cancer 97:888-94, 2007. • Margosio B., Marchetti D., Vergani V., Giavazzi R., Rusnati M., Presta M., and Taraboletti G. Thrombospondin-1 as a scavenger for matrix-associated fibroblast growth factor-2. Blood 102: 4399-4406, 2003. • Taraboletti G. Micheletti G, Rieppi M, Poli M, Turatto M, Rossi C, Borsotti P, Roccabianca P, Scanziani E, Nicoletti MI, Bombardelli E, Morazzoni P, Riva A, and Giavazzi R. Antiangiogenic and antitumor activity of IDN 5390, a new taxane derivative. Clin Cancer Res. 8: 1182-1188, 2002 Paolo Ubezio got his B.Sc. degree in Physics at the University of Milan, in 1982, and the specialisation in Pharmacological Research Specialist" at the Mario Negri Institute for Pharmacological Research in 1986. Main activities are: i) Computer simulation of tumor proliferation during/after treatments using models based on the cell cycle; ii) Development of new methods and data analysis tools in flow cytometry and in time-lapse imaging of living cells; iii) Optimization of anticancer drug scheduling. Since 1991 is Head of the Unit of Biophysics at the Mario Negri Institute Selected publications • Ubezio, P.; Lupi, M., Branduardi, D.; Cappella, P., Cavallini, E., Colombo, V., Matera, G., Natoli, C., Tomasoni, D., D’Incalci, M. (2009) Quantitative assessment of the complex dynamics of G1, S and G2M checkpoint activities. Cancer Res. 69: 5234-5240 • Valentini, G., D’Andrea, C., Ferrari, R., Pifferi, A., Cubeddu, R., Martinelli, M., Natoli, C., Ubezio, P. and Giavazzi R. (2008) In-vivo measurement of vascular modulation in experimental tumors using a fluorescent contrast agent. Photochem. Photobiol. 84:1249-1256. • Ubezio, P. and Cameron, D. (2008) Cell killing and resistance in pre-operative breast cancer chemotherapy. BMC Cancer 8:201. • Basse, B., Ubezio, P. (2007) A generalised age and phase structured model of human tumour cell populations both umperturbed and exposed to a range of cancer therapies. Bull. Math. Biol. 69:1673-90. • Lupi, M., Matera, G., Natoli, C., Colombo, V., Ubezio, P. (2007) The Contribution of p53 in the Dynamics of Cell Cycle Response to DNA Damage Interpreted by a Mathematical Model. Cell Cycle 6:943-950. • Lupi, M., Matera, G., Branduardi, D., D'Incalci M. and Ubezio, P. (2004) Cytostatic and cytotoxic effects of topotecan decoded by a novel mathematical simulation approach. Cancer Res. 64: 2825-2832. Massimo Zucchetti obtained his Chem. Pharm. Degree from the University of Milan in 1982. After specializing in Pharmacology at the Mario Negri Institute of Milan (1988), he worked in the Laboratory of Clinical Pharmacology of Department of Oncology at San Giovanni Hospital, Bellinzona, Switzerland (1988-1990). Since 1996 he has been chief of the Cancer Clinical Pharmacology Unit at the Mario Negri Institute. He is member of the Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer (EORTC) from 1988 up to date. His main field of interest are: - Clinical pharmacology, phase I and Phase II studies - Analysis of drugs, development of new analytical method, pharmacokinetic and pharmacodynamic studies in humans in GCP and GLP conditions - Pharmacokinetic, toxicokinetic and metabolic studies in animals - Pharmacokinetic drug interaction Dr Zucchetti is author of more than 90 papers on pre-clinical and clinical cancer chemotherapy published in peer reviewed international journals. Selected publications • Frapolli R., Zucchetti M., Sessa C., Marsoni SA., 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 intra-patients variability is related to α1-acid glycoprotein plasma levels. Eur J Cancer 2010; 46: 505-516. • Sala F., Zucchetti M., Bagnati R., D’Incalci M., Pace S., Capocasa F., Marangon E. Development and validation of a HPLC-MS/MS m,ethod for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative, in human plasma of patients partecipatig in a phase I study. J Chromatogr B: Anal. Tecnol. Biomed. Life Sci. 2009; 31: 18- 26. • Gambacorti-Passerini CB, Tornaghi L, Marangon E, Franceschino A, Pogliani EM, D'Incalci M, Zucchetti M.. Imatinib concentrations in human milk Blood. 2007 Feb 15;109(4):1790.
  11. 11. IRFMN 11 ANNUAL REPORT 2009 • Marangon E, Sala F, Caffo O, Galligioni E, D'Incalci M, Zucchetti M. Simultaneous determination of gemcitabine and its main metabolite, dFdU, in plasma of patients with advanced non-small-cell lung cancer by high-performance liquid chromatography-tandem mass spectrometry. J Mass Spectrom. 2008 Feb;43(2):216-23. • Frapolli R., Marangon E., Zaffaroni M., Colombo T., Falcioni C., Bagnati R., Simone M., D’Incalci M., Manzotti C., Fontana G., Morazzoni P., Zucchetti M. Pharmacokinetics and metabolism in mice of IDN 5390 (13-(N-Boc-3-i- butylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III), a new oral C-seco-taxane derivative with antiangiogenic property effective on paclitaxel-resistant tumors. Drug Metabolism and Disposition, 34(12):2028-2035 (2006). • Rizzari C., Citterio M., Zucchetti M., Conter V., Chiesa R., Colombini A., Malguzzi S., D’Incalci M. Pharmacological study on pegylated asparaginase used in front-line treatment of children with acute lymphoblastic leukemia. Hematologica, 91: 24-31 (2006). ACTIVITIES The Oncology Department comprises three preclinical experimental laboratories (Laboratory of Cancer Pharmacology, Laboratory of Molecular Pharmacology and Laboratory of Biology and Therapy of Metastasis) and four laboratories dealing with clinical research and clinical trials (Laboratory for the Development of New Pharmacological Strategies, Laboratory of Clinical Trials, Laboratory of Translational and Outcome Research in Oncology and Laboratory for Medical Research and Consumer Involvement). The Oncology department hosts the coordination center of two networks of hospitals that carry on clinical research in gynecologic cancer (MaNGO: Mario Negri Gynecologic Oncology) and in cancer pain (CPOR-SG: Cancer Pain Outcome Research Study Group) and a center for cancer pain assessment and research (CERP:Center for the Evaluation and Research on Pain). In some cases research projects are carried out by single laboratories or research units, in other cases by collaborations between different laboratories of the Oncology Department or other departments, or other groups outside the Institute (see National and International Collaborations). Preclinical laboratories focus on the discovery and development of new antitumor and antimetastatic drugs and their new combinations; on tumor biology, not only to acquire new scientific knowledge, but particularly as a base for more selective therapeutic approaches and to identify and evaluate experimental models for discovering and studying new drugs or treatments. Clinical new drug development involves close participation in the activity of SENDO (South Europe New Drug Development Organization) and studies driven by the Laboratory of Cancer Pharmacology, the Laboratory of Molecular Pharmacology and the Laboratory of Biology and Therapy of Metastasis. The Laboratory for the Development of New Pharmacological Strategies, the Laboratory of Clinical Trials, the Laboratory of Translational and Outcome Research in Oncology and the Laboratory for Medical Research and Consumer Involvement are involved in the evaluation of the effects of new therapeutic modalities in phase I/II and in phase III comparative and effectiveness outcome studies. Outcome Research implies organizing trials to clarify the results of certain health care practices and interventions in clinical practice. Observational (surveys) and outcome research (effectiveness) studies are carried out, in collaboration with regional and national health authorities and other scientific associations. At the preclinical and clinical level there are studies of various human tumors, with particular emphasis on ovarian tumors and more recently on soft tissue sarcomas. MAIN FINDINGS At nanomolar concentrations, Trabectedin affects the regulatory mechanisms of the transcription. Nucleotide excision repair deficient cells that are hypersensitive to UV rays and to other DNA damaging drugs are resistant to Trabectedin.
  12. 12. IRFMN 12 ANNUAL REPORT 2009 The selective activity of Trabectedin against human myxoid liposarcoma appears related to the drug ability to modulate the transcription of genes involved in adipocytic differentiation. Trabectedin modulates the transcription of genes involved in pro-inflammatory mechanisms that are potentially relevant for tumor growth and progression. New sarcoma experimental models have been obtained. They will be useful to investigate new drugs for these diseases. Use of mathematical models of tumor growth and anticancer treatment to interpret experimental data and to manage the complexity of underlying biological phenomena. A new method enabling to perform dynamical measures of cell cycle checkpoint activities in response to anticancer treatments. Gene profiling analysis shows specific molecular signatures according to the histotype and prognosis of stage I ovarian carcinoma. The expression of a truncated form of p63 (DNp63) increases with the increased malignancy of ovarian cancer. Patients expressing high levels of DNp63 have a worst prognosis. DNp63 represents therefore a new potential target for selective therapies in this malignancy. CHK1 downregulation by specific inhibitors or siRNA, increases the antitumor activity of 5- fluorouracil in vivo. This effect is particularly evident in p53 deficient tumors indicating that this combination increases the selectivity of this anticancer agent. An anthracycline derivative, Nemorubicin, has a peculiar mechanism of action and is active against tumors resistant to drugs such as cisplatin. A mechanism of resistance against this drug has been identified, which involves the abrogation of the expression of a nucleotide excision repair gene. Overexpression of a truncated form of p73 (DNp73beta) in human cancer cells leads to growth arrest and formation of tetraploid cells, suggesting a role of this isoform in mitosis. A new mechanism of p73 activation mediated by the protease HtrA2 has been identified. After apoptotic stimuli this protease cleaves p73 in the C-terminal region increasing its apoptotic potential. Inositol pentaphosphate analogues interfere with the PI3-kinase-induced phosphorylation of akt and possess antitumor activity in vitro and in vivo, particularly when combined with other anticancer agents. Human umbilical cord-derived stem cells express checkpoints proteins only in specific differentiation stages. It is likely that this is related to the different susceptibility of the cells. Inhibition of PLC gamma, through siRNA technology, reduces the in vivo growth of tumors and reduces the formation of metastasis. Identification of gene transcripts preferentially expressed by tumor associated endothelial cells. Demonstration that the corresponding proteins localize within the tumor stroma. VEGF released by cancer cells modulates the gene expression of the tumor microenvironment (stroma). Identification of transcripts.
  13. 13. IRFMN 13 ANNUAL REPORT 2009 Soluble human VEGFC levels in serum and ascites correlate with tumor progression and metastatic capability in human ovarian carcinoma models. A new antiangiogenic domain of thrombospondin-1 (an endogenous inhibitor of angiogenesis) that binds the angiogenic factor FGF-2 has been identified and characterized. Non peptidic small molecules, mimetic of this domain have been designed as potential inhibitors of angiogenesis. New antineoplastic compounds directed against the tumor vasculature (vascular disrupting agents) have been identified. Proteins for which expression is selectively associated with liver metastasis have been identified in preclinical models of advanced cancer. The expression of protease-activated receptor-1 (PAR-1) correlates with the malignant phenotype of human melanomas and is accountable for their motility and invasive features The response to chemotherapy was a good surrogate endpoint of survival in patients with locally advanced cervix carcinoma. Adjuvant chemotherapy with the regimen vindesin, mitomycin C and cisplatin (MVP) did not improve survival of non small cell lung cancer (NSCLC) patients compared with surgery alone. The website of the project PartecipaSalute (www.partecipasalute.it) has a very innovative character in comparison with the other health Italian sites because it introduces and develops information in a very active way with specific instruments. A randomized phase III trial has shown that pelvic systematic lymphadenectomy in early endometrial cancer does not improve overall survival. As pelvic systematic lymphadenectomy is not devoid of side effects, this trial will spare patients with early endometrial cancer important early and late surgical morbidities. A twin trial in ovarian carcinoma, published in 2005, came to similar conclusions. Results from a systematic review of literature and from a prospective epidemiologic study suggest that an important proportion of patients with cancer pain (up to 43%) receive an analgesic treatments that is not appropriate with the intensity of pain Results from a survey carried out on a national level on a sample of 1801 patients with cancer pain confirm that in Italy a relevant part of cancer patients does not receive an appropriate information about their prognosis: physicians reported that according to their knowledge only 31% received information about their prognosis. An independent survey carried out in a Northern Italian Region confirmed this finding: among 550 patienst treated at home for cancer pain with palliative care , only 58% were classified to be fully aware of ther prognosis. An observational longitudinal study carried out in 110 Italian centers and involving about 1800 patients with metastatic cancer and pain have documented that that in terms of analgesics effectiveness, that each drugs prescribed by investigators (morphine, fentanyl, buprenorphine and oxycodone) were able to reduce the intensity of pain of about 2 points on a 11-eleven point numerical rating scale (p<0.001). The application of specific pe-planned algorithm identified about 30% cases who were classified as non-responders. Preliminary analyses documented some differences between drugs in terms of size of the analgesic effect, dosages required and side effects reported.
  14. 14. IRFMN 14 ANNUAL REPORT 2009 A randomized trial of patients with high risk (stage IcG3, IIG3 with myometrial invasion >50%, and III) endometrial carcinoma showed the substantial equivalence between radiotherapy or chemotherapy as an adjuvant therapy after surgery. Although both radiotherapic and chemotherapic approaches are still unsatisfactory, since the risk of progression or death remains high, this encouraging evidence of clinical activity suggest a possible use of their concurrent or sequential use in an adjuvant setting. A randomized phase III trial has shown that a modified radical (Piver-Rutledge class II) hysterectomy does not improve survival and locoregional control compared to the standard extrafascial (Piver-Rutledge class I) hysterectomy in patients with stage I endometrial cancer . This trial has enrolled 520 patients who have been followed-up for over 5 years The training and information activity organized with the associations of citizens & patients in the framework of the PartecipaSalute project has been finalized to the organization of the Parita task “Participate to the research project with the associations”. Parita is organised to discuss with the scientific community the grey areas of the medical assistance and clinical research identified from the patients and their associations, and to develop specific protocols for future research programs. NATIONAL COLLABORATIONS ASR, Agenzia Sanitaria Regionale, Bologna AIFA, Agenzia Italiana del Farmaco (Roma) Azienda Sanitaria Locale, Rimini Assessorato Sanità, Regione Emilia Romagna Azienda Sanitaria Unica Regionale, Regione Marche Casa Sollievo della Sofferenza, San Giovanni Rotondo (IRCCS) CNPDS, Centro Nazionale per la prevenzione e Difesa Sociale, Milano CNR IGBE, Pavia CNR, Istituto di Chimica del Riconoscimento Molecolare, Milano Cochrane Collaboration ENEA Centro Ricerche, Unità di Tossicologia e Scienze Biomediche, Roma Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milano Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milano Fondazione LUVI, Milano Fondazione Nerina e Mario Mattioli Onlus, Milano Fondazione Salvatore Maugeri, Pavia Fondazione SmithKline (FSK), Milano Fondo Edo Tempia, Laboratorio di Farmacogenomica, Biella I.A.S.I., Roma Istituto Clinico Humanitas, Rozzano MI Istituto Dermopatico dell'Immacolata, Roma Istituto Ortopedico Galeazzi, Milano Istituti Ortopedici Rizzoli, Bologna Istituto Europeo di Oncologia (IEO), Milano Istituto di Fisica, Politecnico di Milano Istituto di Genetica Molecolare CNR, Sezione di Istochimica e Citometria, Pavia Istituto Nazionale per la Ricerca sul Cancro (IST), Genova Istituto Nazionale Tumori Fondazione G. Pascale, Napoli
  15. 15. IRFMN 15 ANNUAL REPORT 2009 Istituto Regina Elena, Roma Istituto Superiore di Sanità Laboratorio Cell factory, Policlinico di Milano Ospedale San Gerardo, Monza, Milano Ospedale San Matteo, Pavia Ospedale Santa Chiara, Trento Rete Oncologica Lombarda (ROL), Milano Università Cattolica del Sacro Cuore, Roma Università di Bari Università di Brescia Università di Chieti Università di L’Aquila Università di Milano Università di Modena e Reggio Emilia Università di Monza Università di Catania Università di Padova Università di Pisa Università di Siena Università “La Sapienza”, Roma Zadig, Agenzia di Giornalismo scientifico INTERNATIONAL COLLABORATIONS ADAMANT Consortium, IP 7th FP, EC ARCAGY (Association de Recherche sur les Cancers Gynécologiques), France Breakthrough Breast Cancer Center, Instutite of Cancer Reasearch, London, U.K. Cancer Biomarkers and Prevention Group, University of Leicester, U.K. Cancer Research UK, London, U.K. EORTC, Brussels, Belgium EUROPA DONNA European Agency for the Evaluation of Medicinal Products (EMEA), London, U.K. European Association for Palliative Care (EAPC) European Network of Gynaecological Oncology Trials groups (ENGOT)Eusoma – (European Society of Breast Cancer Specialist) Florence, Italy Executive Board of GCIG (Gynecologic Cancer Intergroup) Frontier science & technology Research Foundation Southern Europe (FSE) Genome Institute of Singapore (GIS), Singapore German Cancer Research Center, Division of Toxicology and Cancer Risk Factors, Heidelberg, Germany Goteborg University, Lundberg Laboratory for Cancer Research, Goteborg, Sweden Gynecologic Cancer Intergroup (GCIG) Helios Klinikum Erfurt GmbH, Institute of Pathology, Germany Institute of Pathology, Friedrich Schiller University, Jena, Germany Istituto Oncologico della Svizzera Italiana Johns Hopkins University, USA Ludwig Institute for Cancer Research, London, U.K. National Cancer Center, Singapore Stony Brook University, NY, USA Massachusetts General Hospital and Harvard Medical School, USA
  16. 16. IRFMN 16 ANNUAL REPORT 2009 MD Anderson Cancer Center, Houston, Texas, USA MRC, London, U.K. National Cancer Institute (NCI), Bethesda and Frederick, MD, USA Ospedale San Giovanni, Bellinzona, Switzerland Paterson Institute for Cancer Research, Manchester, U.K. Southern Europe New Drug Organization (SENDO), Milan, Italy Swiss Federal Institute of Technology, Zurich, Switzerland The Sackler Institute, University College London, U.K. Tumor Biology and Metastasis Institute of Cancer Research, Sutton, U.K. University College, London Medical School, London, U.K. University of Birmingham, U.K. University of Cincinnati, USA University of Crete Medical School, Greece University of Newcastle, U.K. University of Pau, France University of Wisconsin, Madison, WI, USA Kyoto University, Japan Weizmann Institute of Science, Israel EDITORIAL BOARD MEMBERSHIP Attualità in Senologia (Paola Mosconi) British Journal of Cancer (Maurizio D’Incalci) Chemotherapy (Maurizio D’Incalci) Clinical Experimental Metastasis (Raffaella Giavazzi) Current Opinion in Oncologic, Endocrine and Metabolic Drugs (Maurizio D’Incalci) Current Cancer Therapy Reviews (Raffaella Giavazzi) European Journal of Cancer (Maurizio D’Incalci, Giovanna Damia, Raffaella Giavazzi, Massimo Broggini e Giulia Taraboletti) Health and Quality of Life Outcomes (Giovanni Apolone, Paola Mosconi) International Journal of Biological Markers (Raffaella Giavazzi) International Journal for Quality in Health Care (Giovanni Apolone) Journal of Ambulatory Care and Management (Giovanni Apolone) Journal of B.U.ON. (Maurizio D’Incalci) Journal of Cancer Microenvironment (Raffaella Giavazzi) Journal of Chemotherapy (Raffaella Giavazzi) Journal of Experimental Therapeutics and Oncology (Raffaella Giavazzi) Journal of Medicine and the Person (Giovanni Apolone) Journal of Preventive Medicine anf Hygiene (Giovanni Apolone) Molecular Cancer Therapeutics (Maurizio D’Incalci) Oncology Research (Maurizio D’Incalci) Tumori (Maurizio D’Incalci, Raffaella Giavazzi) www.PartecipaSalute.it (Paola Mosconi) www.fondazionemattioli.it (Paola Mosconi) PEER REVIEW ACTIVITIES American Journal of Pathology, Annals of Oncology, Anti-cancer Drugs, Biochemical Pharmacology, BioMed Central Editorial, British Journal of Cancer, British Journal of Pharmacology, British Medical Journal, Cancer Chemotherapy and Pharmacology, Cancer
  17. 17. IRFMN 17 ANNUAL REPORT 2009 Detection and Prevention, Cancer Letters, Cancer Research, Carcinogenesis, Chemico- Biological Interactions, Clinical & Experimental Metastasis, Clinical Cancer Research, Cytometry, European Journal of Cancer, European Journal of Immunology, European Journal of Neurology, Faseb Journal, Gynecologic Oncology, Health and Quality of Life Outcomes, Health Expectations, European Journal of Neurology, Intensive Care Medicine, International Journal of Biological Markers, International Journal of Cancer, International Journal for Quality in Health Care, Journal of Ambulatory Care and Management, Journal of Biological Chemistry, Journal of Biological Markers, Journal of Cell Biochemistry, Journal of Clinical Oncology, Journal of Experimental Therapeutics and Oncology, Journal of Medicinal Chemistry, Journal of Medicine and the Person, Journal of the National Cancer Institute, Journal of Neurology, Journal of Preventive Medicine and Hygiene, Journal of the National Cancer Institute, Leukemia, Molecular Cancer Therapeutics, Nature Biotechnology, Nature Reviews, Oncology Research, PharmacoEconomics, Quality of Life Research, Science, The Patient: patient- centered outcomes research, Tumori, ZEG Centre for Epidemiology & Health Research. NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP Ethical Committee, Centro di Riferimento Oncologico, Aviano PN, Italy Ethical Committee, Ente Ospedaliero San Paolo, Milan, Italy Ethical Committee, Istituto Europeo di Oncologia, Milan, Italy Ethical Committee, Istituto Neurologico Carlo Besta, Milan, Italy Ethical Committee, Istituto Scientifico Eugenio Medea, Bosisio Parini, Lecco, Italy Ethical Committee, Ospedale San Gerardo, Monza, Milan, Italy Ethical Committee, Ospedale Sant’Anna, Como, Italy Ethical Committee, Ospedale della Valtellina e Valchiavenna, Sondrio, Italy Ethical Committee, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy Ethical Committee, Azienda USL di Bologna, Italy Executive Board of GCIG (Gynecologic Cancer Intergroup) Scientific Committee, Associazione Italiana Ematologia e Oncologia Pediatrica, Monza, Milan, Italy Scientific Committee, Pezcoller Foundation, Trento, Italy Technical-Scientific Commitee, Associazione Italiana per la Ricerca sul Cancro, Milan, Italy Board of Directors, Fondazione Nerina e Mario Mattioli Onlus, Milan, Italy Board of Directors, Società Italiana di Cancerologia (SIC) Board of Directors, Società Italiana di Citometria (GIC) Directional Council Areas-CCI National Advisory Board 8th World Congress of Psycho-Oncology Developmental Therapeutics Program, National Cancer Institute (NCI) Decision Network and Executive Committee, South Europe New Drug Organization (SENDO) Executive Board, Europa Donna Executive Committee, European Asociation for Cancer Research (EACR) Fondazione Attilia Pofferi, Pistoia, Italy NHS R&D National Coordinating Centre for Health Technology Assessment, UK Pezcoller Foundation-ECCO Award University Medical School of Siena, Italy EVENT ORGANIZATION Il Comitato etico: luogo di partecipazione tra laici e tecnici?
  18. 18. IRFMN 18 ANNUAL REPORT 2009 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, January 13, 2009. Investigators’ Meeting “Cetuximab”, Istituto Ricerche Farmacologiche “Mario Negri ”, Milan March 30, 2009. International Clinical Trials’ Day.2009 Strategie di promozione della salute e delle malattie: quale spazio per le evidenze degli studi clinici. Milan, May 20, 2009. Meeting: Assessment of cancer pain in clinics and in research. Need for a common international methodology? Istituto di Ricerche Faramacologiche Mario Negri, Milan, September 9-10, 2009. Investigators’ Meeting “Head & Neck trial” Congresso AIOM, Milan, October 12, 2009. Investigators’ Meeting “Tailor trial” Congresso AIOM, Milan, October 11, 2009. Investigators’ Meeting “TOSCA” Congresso AIOM, Milan, October 11, 2009. Investigators’ Meeting “COMETS” Congresso AIOM, Milan, October 11, 2009. XXVII Conferenza Nazionale di Citometria, Centro Congressi Ferrara, October 14-17, 2009. IV edizione percorso di formazione PartecipaSalute - “L’Accademia del Cittadino”. Milan, Montecatini Terme, October 2009-March 2010. CONFERENCE AND WORKSHOP CONTRIBUTIONS WWoorrkksshhoopp:: CChheemmoorreessiissttaannccee -- aa mmaajjoorr ttrreeaattmmeenntt ffaaiilluurree iinn oonnccoollooggyy.. ““Experimental bases”. Milan (Italy), January 21, 2009. Update sull’angiogenesi ad un anno dalla scomparsa di Judah Folkman. Rome (Italy), January 24, 2009. “Studi preclinici con inibitori dell’angiogenesi”. Meeting: Trabectedin: Soft Tissue Sarcoma Treatment. New Horizons in Oncology. ”Drugs of Marine Origin”. Antequera, Malaga (Spain), February 12, 2009. Conference: Exploitation of research outcomes towards cancer patients’ expectations: European perspectives. ”The importance of translational research for drug development: the example of the marine natural product ET-743”. Bruxelles (Belgium), March 17, 2009. Conference: IV Assemblea Plenaria, Conferenza Provinciale sulla Salute “La malattia che impoverisce. La povertà che fa ammalare “Per discutere del valore del risultato dell’indagine per l’introduzione di nuovi strumenti di misura nella pratica medica”, Turin (Italy), March 26, 2009. CNIO Scientific Symposium: Molecular markers in cancer therapy: present use and future perspectives. San Lorenzo de El Escorial, Madrid (Spain), March 26-27, 2009. “Gene expression analysis of endothelial cells revealed novel markers of tumor vasculature”. “Human Ovarian carcinoma xenografts equipped with different angiogenic phenotype differ in the transcriptional profile profile of their stroma”.
  19. 19. IRFMN 19 ANNUAL REPORT 2009 Conference: XVII Conferenza Nazionale AIOM: Clinical pathways nel carcinoma del colon retto: dalle linee guida alla pratica clinica. Florence (Italy), April 2-4, 2009. Conference: IV Giornata di Studio Novarese “Il Carcinoma Ovarico: conoscenze attuali e prospettive future” La ricerca collaborativa del tumore ovarico: l’esperienza del MaNGO. Santa Margherita Ligure (Italy), April 18, 2009. Meeting: 100th AACR Annual Meeting. Denver (USA), April 18-22, 2009. “PTX-008, a non-peptidic topomimetic of the antiangiogenic galectin-1-targeting anginex: differential antiproliferative activity on cancer and endothelial cells”. “Identification of novel markers of tumor-associated vasculature”. XIII Riunione scientifica annuale, Italian Sarcoma Group. ”Meccanismo d’azione e selettività per alcuni subset di pazienti”. Turin (Italy), April 20-21, 2009. Meeting AGO-OVAR 12 VARGATEF, Frankfurt (Germany) April 28, 2009. Course: Corso di perfezionamento “Formazione clinica, comunicazione e management in Cardiologia": Novità nella ricerca farmacologica cardiovascolare. Istituto di Ricerche Farmacologiche “Mario Negri”, Milan (Italy), May 27, 2009. Meeting: 45° Meeting ASCO, Orlando (USA) May 29 – June 2, 2009. Conference: ESH Conference on Angiogenesis. Helsinki (Finlandia), June 5-8, 2009. “Ovarian tumor models to study lymphatic spread”. Assembly: VI Assemblea Gruppo Mango, Turin (Italy), June 12, 2009. Symposium: 21th Pezcoller Symposium. Trento (Italy), June 11-13, 2009. Novel “vascular markers” highly expressed by human tumor endothelial cells. Meeting: Young Life Scientist 2009 - Networking Angiogenesis: bridging young researchers in the vascular biology field. University of Chester (UK), July 14, 2009. “The rational for combination treatments with vascular targeting therapy”. Meeting: Assessment of cancer pain in clinics and in research. Need for a common international methodology? Istituto di Ricerche Faramacologiche Mario Negri, Milan (Italy), September 9- 10, 2009. Course: Emerging Issues nei Sarcomi dei Tessuti Molli. “Trabectedina: meccanisco di azione e aspetti farmacologici”. Brescia (Italy), September 28, 2009. Congress: XI Congresso Nazionale SIPO “Professionalità ed Innovazione in Psico-Oncologia” Dolore Oncologico: coinvolgere i pazienti nella valutazione e nel trattamento. Senigallia (AN, Italy) October 1-3, 2009. Congress: XI Congresso Nazionale dell’Associazione Italiana di Oncologia Medica (AIOM), Simposio Satellite: Farmaci dal mare: realtà emergente. “Nuovi prodotti naturali marini: stato dell’arte e prospettive”. Milan (Italy), October 10-13, 2009. Meeting: XVI Meeting Internazionale della Società Europea di Ginecologia Oncologica, Belgrado, October 11-14, 2009.
  20. 20. IRFMN 20 ANNUAL REPORT 2009 Conference: XXVII Conferenza Nazionale di Citometria, Centro Congressi Ferrara (Italy), October 14-17, 2009. Conference: International Conference on Tumor Microenvironment: Progression, Therapy & Prevention.Versailles (France), October 20-24, 2009. “Interactions of Tumor Cells with Microenvironmental Cells & Molecules I”. Congress: XVI Congresso Nazionale della Società Italiana di Cure Palliative. Studio di Outcome Mario Negri: dati di confronto nel dolore da cancro. Lecce (Italy), October 27-30, 2009. Congress: II° Convegno di Oncologia Interventistica: Tecniche innovative nel trattamento dei tumori primitivi epatici. ”Importanza degli studi di farmacocinetica per ottimizzare le terapie oncologiche”. Cervesina (PV, Italy), November 6-7, 2009. Congress: II Congresso del Gruppo Oncologico Chirurgico Cooperativo Italiano: Terapie Mediche Innovative in Oncologia. ”Progressi nella terapia medica dei sarcomi dei tessuti molli”. Florence (Italy), November 6-7,2009. Congress: VIII Convegno ACD SIAARTI 2009. Oppioidi a rapido onset nel breakthrough cancer pain. Rome (Italy), November 11-13, 2009 Conference: AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics. Boston (USA), November 15-19, 2009. “Antiangiogenic proprieties of E-3810, a new dual inhibitor of VEGF and FGF receptors”. 51st Annual Meeting of the Italian Cancer Society (SIC). Sesto S. Giovanni (Milan, Italy) November 23-26, 2009. “Protease-activated receptor-1 (PAR-1) expression contributes to the metastatic capabilities of primary melanoma lesions”. “Renal carcinoma as model for anti-angiogenic therapy”. “Antiangiogenic and antineoplastic activity of PTX-008, a nonpeptidic topomimetic of Anginex”. “Lymphatic spread: models of ovarian carcinoma xenografts”. “The effect of vandetanib on tumor vasculature remodeling and paclitaxel uptake reflects the antitumor activity in a xenograft model of human ovarian carcinoma”. “Human Vascular Endothelial Growth Factor affects response to paclitaxel treatment in a model of ovarian carcinoma”. “Dual targeting of cancer and endothelial cells by gonadotropin-releasing hormone agonist to reduce melanoma angiogenesis”. “The isothiocyanate produced from glucomoringin inhibits NF-KB and reduces myeloma growth in nude mice in vivo”. “Molecular mechanisms of resistance to trabectedin of a myxoid liposarcoma cell line”. “Studies on the ‘tumor initiating cell’ of ovarian cancer”. “Generation-wise cell cycle analysis: a new insight into antiproliferative activity of anticancer treatments”. ”From sea to bedside: trabectedin, a success story of translational research”. Congress: V Congresso Nazionale “Approccio globale la paziente oncologico”, Forlì (Italy), November 25-27, 2009.
  21. 21. IRFMN 21 ANNUAL REPORT 2009 Conference: Nuovi orizzonti nella gestione del paziente oncologico con BTcP: Valutazione della frequenza e dell’impatto del BTcP in uno studio longitudinale. Rome (Italy), December 4, 2009. Congress: VII congresso COMU: Problematiche emergenti sull’uso dei nuovi farmaci in oncologia. ”La Trabectedina”. Florence (Italy), December 17-18, 2009. GRANTS AND CONTRACTS AIFA Agenzia Italiana del Farmaco Arcispedale Santa Maria Nuova di Reggio-Emilia Azienda Sanitaria Locale - Rimini Azienda Sanitaria Unica Regionale - MARCHE AIFA Agenzia Italiana del Farmaco Amgem SpA, Milano AIRC Associazione Italiana per la Ricerca sul Cancro ASL Padova ASL Provincia di Lodi Astra Zeneca SpA Astra Zeneca UK AVAPO (Associazione Volontari Assistenza Pazienti Oncologici) Aventis Pharma Azienda Ospedaliera Fatebenefratelli e Oftalmico- Milano Azienda Sanitaria Locale, Rimini Azienda Sanitaria Unica Regionale, Marche Azienda Ospedaliera “Spedali Civili di Brescia” Bracco Imaging SpA, Milan Centro Cochrane Italiano Chiesi Farmaceutici SpA CIPOMO (Collegio Italiano dei Primari Oncologi Medici Ospedalieri) CNPDS, Centro Nazionale per la prevenzione e Difesa Sociale, Milano CNR Consiglio Nazionale delle Ricerche CNR-MIUR Ministero Istruzione Università e Ricerca Compagnia di San Paolo Dompé Eli Lilly Italia SpA Elsevier Science Ltd. EORTC-European Organization for Research and Treatment of Cancer EOS SpA European Commission - 7th Framework Programme (ADAMANT) FIRB-MIUR Fondo per gli Investimenti della Ricerca di Base-Ministero Istruzione Università e Ricerca FIRC Fondazione Italiana per la Ricerca sul Cancro Fondazione Cassa di Risparmio delle Province Lombarde Fondazione SmithKline, Roma Fondazione Lu.V.I. Fondazione Nerina e Mario Mattioli Onlus FSE Frontier Southern Europe GISCAD(Gruppo Italiano Studi di Carcinomi Apparato Digerente)
  22. 22. IRFMN 22 ANNUAL REPORT 2009 GlaxoSmithKline, Verona Grunenthal Italia, Milano Indena SpA Institut de Recherche Pierre Fabre Istituto Clinico Humanitas – Rozzano Istituto Nazionale dei Tumori, Milano Istituto Superiore di Sanità Komen Italia Onlus Lottomatica Medac Merck Sharp & Dome Ministero della Salute Nerviano Medical Science S.r.l. Novartis Novartis Farma SpA Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Oncoethix Optigenex Inc. Pfizer Global Research and Development Pfizer Italia Pharma Mar, SA Pharminox Ltd, UK Policlinico di Padova / C.O.R. Regione Emilia Romagna Regione Lombardia Regione Toscana Regione Veneto Sanofi-Aventis Pharma Sara Bet, Roma SENDO-Tech Srl Sigma-Tau SpA Università degli Studi di Padova Università Federico II – Napoli (Dipartimento di Endocrinologia ed Oncologia molecolare e clinica) SCIENTIFIC PUBLICATIONS (2009) Frapolli R, Zucchetti M, Sessa C, Marsoni S, Vigano' 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 α(1)-acid glycoprotein plasma levels Eur J Cancer 2009 E-pub : Cesca M, Frapolli R, Berndt A, Scarlato V, Richter P, Kosmehl H, D’Inclaci M, Ryan AJ, Giavazzi R The effects of vandetanib on paclitaxel tumor distribution and antitumor activity in a xenograft model of human ovarian carcinoma Neoplasia 2009 11(11) : 1155-64 Ferketich A K, Gallus S, Colombo P, Apolone G, Rossi S, Zuccaro P, La Vecchia C Use of pharmacotherapy while attempting cessation among Italian smokers Eur J Cancer Prev 2009 18 : 90-92 Carrassa L, Sanchez Y, Erba E, Damia G U2OS cells lacking Chk1 undergo aberrant mitosis and fail to activate the spindle checkpoint
  23. 23. IRFMN 23 ANNUAL REPORT 2009 J Cell Mol Med 2009 13 : 1565-1576 Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecchio M, Erba E, Grosso F, Gronchi A, Aman P, Casali P, D'Incalci M, Pilotti S, Mantovani R Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors Mol Cancer Ther 2009 8 : 449-457 Corli O, Apolone G, Pizzuto M, Cesaris L, Cozzolino A, Orsi L, Enterri L Illness awareness in terminal cancer patients: an Italian study Palliat Med 2009 23 : 354-359 Lissoni A A, Colombo N, Pellegrino A, Parma G, Zola P, Katsaros D, Chiari S, Buda A, Landoni F, Peiretti M, Dell'Anna T, Fruscio R, Signorelli M, Grassi R, Floriani I, Fossati R, Torri V, Rulli E A phase II, randomized trial of neo-adjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell ce Ann Oncol 2009 20 : 660-665 Marangon E, Citterio M, Sala F, Barisone E, Lippi A A, Rizzari C, Biondi A, D'Incalci M, Zucchetti M Pharmacokinetic profile of imatinib mesylate and N-desmethyl-imatinib (CGP 74588) in children with newly diagnosed Ph+ acute leukemias Cancer Chemother Pharmacol 2009 63 : 563-566 Sessa C, Perotti A, Noberasco C, de Braud F, Gallerani E, Cresta S, Zucchetti M, Vigano' L, Locatelli A, Jimeno J, Feilchenfeldt J W, D'Incalci M, Capri G, Ielmini N, Gianni L Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer Eur J Cancer 2009 45 : 1153-1161 Naldini A, Filippi I, Ardinghi C, Silini Antonietta, Giavazzi R, Carraro F Identification of a functional role for the protease-activated receptor-1 in hypoxic breast cancer cells Eur J Cancer 2009 45 : 454-460 Marrazzo E, Marchini S, Tavecchio M, Alberio T, Previdi S, Erba E, Rotter V, Broggini M The expression of the ΔNp73β isoform of p73 leads to tetraploidy Eur J Cancer 2009 45 : 443-453 Apolone G, Corli O, Caraceni A, Negri E, Deandrea S, Montanari M, Greco M T, CPOR SG Investigators Pattern and quality of care of cancer pain management. Results from the Cancer Pain Outcome Research Study Group Br J Cancer 2009 100 : 1566-1574 Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi Gianluca, Graziano F, Cremolini C, Rulli E, Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I, Cascinu S, Falcone A PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer J Clin Oncol 2009 27 : 2622-2629 Mandalà M, Barni S, Floriani I, Isa L, Fornarini L, Marangolo M, Mosconi P, Corsi D, Rulli E, Frontini L, Cortesi E, Zaniboni A, Aglietta M, Labianca R, GISCAD Incidence and clinical implications of venous thromboembolism in advanced colorectal cancer patients: the 'GISCAD-alternating schedule' study findings Eur J Cancer 2009 45 : 65-73 Riva E, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, Tallone M V, Detoma P, Giacomin A, Clerico M, Tempia P, Guala A, Fasolo G, Lucca U Association of mild anemia with hospitalization and mortality in the elderly: the Health and Anemia population-based study Haematologica 2009 94 : 22-28
  24. 24. IRFMN 24 ANNUAL REPORT 2009 Graziano F, Ruzzo A, Canestrari E, Loupakis F, Santini D, Rulli E, Humar B, Galluccio N, Bisonni R, Floriani I, Maltese P, Falcone A, Tonini G, Catalano V, Fontana A, Giustini L, Masi G, Vincenzi B, Alessandroni P, Magnani M Variations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectal cancer Pharmacogenomics J 2009 9 : 78-84 Marano R, De Cobelli F, Floriani I, Becker C, Herzog C, Centonze M, Morana G, Gualdi G F, Ligabue G, Pontone G, Catalano C, Chiappino D, Midiri M, Simonetti G, Marchisio F, Olivetti L, Fattori R, Bonomo L, Del Maschio Alessandro, NIMISCAD Study Group Italian multicenter, prospective study to evaluate the negative predictive value of 16- and 64-slice MDCT imaging in patients scheduled for coronary angiography (NIMISCAD-Non Invasive Multicenter Italian Study for Coronary Artery Disease) Eur Radiol 2009 19 : 1114-1123 D'Incalci M The potential impact of marine compounds in the era of targeting therapies In :International Oncology Updates Permanyer Publications, Mallorca (Spain), 2009; 1-18 Corich L, Aranda A, Carrassa L, Bellarosa C, Ostrow J D, Tiribelli C The cytotoxic effect of unconjugated bilirubin in human neuroblastoma SH-SY5Y cells is modulated by the expression level of MRP1 but not MDR1 Biochem J 2009 417 : 305-312 D'Incalci M Adjuvant 5-FU based chemotherapy for colon cancer: match or miss the mismatch? Eur J Cancer 2009 45 : 316-317 Mosconi P, Donati S, Colombo Cinzia, Mele A, Liberati A, Satolli R, Consensus Conference Working Group Informing women about hormone replacement therapy: the Consensus conference statemen BMC Womens Health 2009 9 : 14 Apolone G, Corli O, Negri Emanuele, Mangano S, Montanari M, Greco M T, CPOR SG Investigators Effect of transdermal buprenorphine on patients-reported outcomes in cancer patients. Results from the Cancer Pain Outcome Research (CPOR) Study Group Clin J Pain 2009 25 : 671-682 De Vargas Macciucca M, Casale A, Manganaro L, Floriani I, Fiore F, Marchetti L, Panzironi G Rectal villous tumours: MR features and correlation with TRUS in the preoperative evaluation Eur J Radiol 2009 E-pub : Sessa C, Cresta S, Noberasco C, Capri G, Gallerani E, de Braud F, Zucchetti M, D'Incalci M, Locatelli A, Marsoni S, Corradino I, Minoia C, Zintl P, Gianni L Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours Eur J Cancer 2009 45 : 2116-2122 Pace S, Capocasa F, Tallarico C, Frapolli R, Zucchetti M, Longo A Determination of total and lactone form of a new camptothecin derivative gimatecan (ST1481) and its metabolite ST1698 in human plasma by high-performance liquid chromatography with fluorimetric detection J Pharm Biomed Anal 2009 50 : 507-514 Ferrari D, Fiore J, Codecà C, Di Maria G, Bozzoni S, Bordin V, Caldiera S, Luciani A, Zonato S, Floriani I, Foa P A phase II study of carboplatin and paclitaxel for recurrent or metastatic head and neck cancer Anticancer Drugs 2009 20 : 185-190 Garattini S, Bertele' V, Floriani I, Torri V
  25. 25. IRFMN 25 ANNUAL REPORT 2009 Exenatide for type 2 diabetes Lancet 2009 373 : 122 Bardella M T, Elli L, De Matteis S, Floriani I, Torri V, Piodi L Autoimmune disorders in patients affected by celiac sprue and inflammatory bowel disease Ann Med 2009 41 : 139-143 Infante M, Lutman R F, Imparato S, Di Rocco M, Ceresoli G L, Torri V, Morenghi E, Minuti F, Cavuto S, Bottoni E, Inzirillo F, Cariboni U, Errico V, Incarbone M, Ferraroli G, Brambilla G, Alloisio M, Ravasi G Differential diagnosis and management of focal ground-glass opacities Eur Respir J 2009 33 : 821-827 Stacchiotti S, Collini P, Messina A, Morosi C, Barisella M, Bertulli R, Piovesan C, Dileo P, Torri V, Gronchi A, Casali P G High-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria Radiology 2009 251 : 447-456 Mazziotti G, Floriani I, Bonadonna S, Torri V, Chanson P, Giustina A Effects of somatostatin analogs on glucose homeostasis: a metaanalysis of acromegaly studies J Clin Endocrinol Metab 2009 94 : 1500-1508 Donati S, Cotichini R, Mosconi P, Satolli R, Colombo Cinzia, Liberati A, Mele A Menopause: knowledge, attitude and practice among Italian women Maturitas 2009 63 : 246-252 Bonezzi K, Taraboletti G, Borsotti P, Bellina F, Rossi R, Giavazzi R Vascular disrupting activity of tubulin-binding 1,5-diaryl-1H-imidazoles J Med Chem 2009 52 : 7906-7910 Roesli C, Borgia B, Schliemann C, Gunthert M, Wunderli-Allenspach H, Giavazzi R, Neri D Comparative analysis of the membrane proteome of closely related metastatic and non-metastatic tumor cells Cancer Res 2009 69 : 5406-5414 Apolone G, Corli O, Mosconi P, et al, The 2008 Erice Group The 2008 Erice statement toward a more humanistic oncology J Ambul Care Manage 2009 32 : 252-258 Deandrea S, Corli O, Moschetti I, Apolone G Managing severe cancer pain: the role of transdermal buprenorphine: a systematic review Ther Clin Risk Manag 2009 5 : 707-718 Mosconi P, Donati S, Colombo C, Mele A, Liberati A, Satolli R, Consensus Conference Working Group Informing women about hormone replacement therapy Cancer Journal 2009 15 : 344 Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, Mantovani A, Roncalli M, Malesci A CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study Lancet Oncol 2009 10 : 877-884 Garattini S, Torri V, Floriani I Cetuximab for metastatic colorectal cancer N Engl J Med 2009 361 : 96 Floriani I, Santini D, Torri V, Cremolini C, Falcone A, Loupakis F Do we need biopsies of metastases for colorectal cancer patients? Br J Cancer 2009 101 : 374-375
  26. 26. IRFMN 26 ANNUAL REPORT 2009 Taraboletti G, Bonezzi K Inhibitors of angiogenesis based on thrombospondin-1 In :Recent advances in angiogenesis and antiangiogenesis Bentham, United Arab Emirates, 2009; 112-126 Coltrini D, Ronca R, Belleri M, Zardi L, Indraccolo S, Scarlato V, Giavazzi R, Presta M Impact of VEGF-dependent tumour micro-environment on EDB fibronectin expression by subcutaneous human tumour xenografts in nude mice J Pathol 2009 219 : 455-462 Marangon E, Falcioni C, Manzotti C, Fontana G, D'Incalci M, Zucchetti M Development and validation of a LC–MS/MS method for the determination of the novel oral 1,14 substituted taxane derivatives, IDN 5738 and IDN 5839, in mouse plasma and its application to the pharmacokinetic study J Chromatogr B Analyt Technol Biomed Life Sci 2009 877 : 4147-4153 Sala F, Zucchetti M, Bagnati R, D'Incalci M, Pace S, Capocasa F, Marangon E Development and validation of a HPLC-MS/MS method for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative, in human plasma of patients participating in a Phase I study J Chromatogr B Biomed Appl 2009 877 : 3118-3126 Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I, Bencardino K B, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer Br J Cancer 2009 101 : 715-721 Garassino M C, Borgonovo K, Rossi A, Mancuso A, Martelli O, Tinazzi A, Di Cosimo S, La Verde N, Sburlati P, Bianchi C, Farina G, Torri V Biological and clinical features in predicting efficacy of epidermal growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis Anticancer Res 2009 29 : 2691-2701 Signorelli M, Lissoni A A, Cormio G, Katsaros D, Pellegrino A, Selvaggi L, Ghezzi F, Scambia G, Zola P, Grassi R, Milani R, Giannice R, Caspani G, Mangioni C, Floriani I, Rulli E, Fossati R Modified radical hysterectomy versus extrafascial hysterectomy in the treatment of stage I endometrial cancer: Results from the ILIADE randomized study Ann Surg Oncol 2009 16 : 3431-3441 De Pangher V, Recchia L, Cafferata M, Porta C, Siena S, Giannetta L, Morelli F, Oniga F, Bearz A, Torri V, Cinquini M Malignant peritoneal mesothelioma: a multicenter study on 81 cases Ann Oncol 2009 E-pub : Liberati A, D'Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care Cochrane Database Systematic Reviews 2009 CD000022 Ubezio P, Lupi M, Branduardi D, Cappella P, Cavallini E, Colombo V, Matera G, Natoli C, Tomasoni D, D'Incalci M Quantitative assessment of the complex dynamics of G1, S, and G2-M checkpoint activities Cancer Res 2009 69 : 5234-5240 Damia G, D'Incalci M Contemporary pre-clinical development of anticancer agents - What are the optimal preclinical models? Eur J Cancer 2009 45 : 2768-2781 Cazzola M, Floriani I, Page C P The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data Pulm Pharmacol Ther 2009
  27. 27. IRFMN 27 ANNUAL REPORT 2009 Cervellini I, Bello E, Frapolli R, Porretta-Serapiglia C, Oggioni N, Canta A, Lombardi R, Camozzi F, Roglio I, Melcangi R C, D'Incalci M, Lauria G, Ghezzi P, Cavaletti G, Bianchi R The neuroprotective effect of erythropoietin in docetaxel-induced peripheral neuropathy causes no reduction of antitumor activity in 13762 adenocarcinoma-bearing rats Neurotox Res 2009 E-pub : LAY PRESS SELECTION (2009) Candiani G, Colombo C, Daghini R, Magrini N, Mosconi P, Nonino F, Satolli R. Manuale metodologico: come organizzare una conferenza di consenso Istituto Superiore di Sanità, Sistema Nazionale Linee Guida SNLG, Roma, Novembre 2009 Mosconi P, Satolli R, Donati S, Colombo C, Liberati A, Mele A. TOS: quale informazione alle donne? La conferenza di consenso di Torino Dialogo sui Farmaci 6/2008 dossier:264-269 http://www.torinomedica.com/allegati/2009/All.%20a%20(23)%20Ferraro_PROCEDURE_Pre venzione_01%20febbraio%202009.pdf Mosconi P Ancora a proposito di mammografia e buona informazione http://www.partecipasalute.it/cms_2/node/1101 ; 23/2/2009 Braun C, Mosconi P Il punto sulla pubblicità diretta ai consumatori Ricerca & Pratica 2009 Numero 145 anno 25: 19-28 Mosconi P, Colombo C I cittadini e l’innovazione. L’innovazione nell’assistenza e nuovi strumenti di valutazione Il Pensiero Scientifico Editore, Suppl. 3 Politiche Sanitarie Vol 10 N°.1, 2009 Mosconi P, Satolli R, Liberati A, Donati S, Mele A et al. Quale informazione per la donna in menopausa sulla terapia ormonale sostitutiva? Consensus Conference Torino, 16-17 maggio 2008 Sistema Nazionale per le Linee Guida SNLG-ISS http://www.pnlg.it/cms/files/CC_TOS.pdf giugno 2009: 1-48 Mosconi P La tutela del cittadino nelle attività del comitato etico Janus Numero 34, estate 2009, Zadig editore: 15-16 Mosconi P Milano, capitale morale dell’impegno volontario In: Milano capitale della salute, a cura di Roberto Satolli. Editrice Abitare Segesta, Milano, 2009 Giavazzi R. ADAMANT. In: The Parliament Magazine, issue 285, pag.50, 30 marzo 2009
  28. 28. IRFMN 28 ANNUAL REPORT 2009 RESEARCH ACTIVITIES Laboratory of Cancer Pharmacology Mode of action of Ecteinascidins A project ongoing since several years is about the characterization of marine natural products possessing antitumor activity. In particular we carried on the studies on the effects of ET-743 in cells defective for some DNA repair mechanisms. Cells deficient for Homologous Recombination (HR) are very sensitive to the drug, while cells deficient for Non Homologous End-Joining (NHEJ) are only slightly more sensitive, but surpraisingly cell lines defective for Nucleotide Excision Repair (NER) are less sensitive to ET-743. Flow cytometric analysis coupled to a software of computer simulation, developed in our laboratory, has demonstrated that NER defective cells showed, after ET-743 treatment, cell cycle perturbations different than those occurring in NER proficient cells, probably for the activation of different and more efficient repair mechanisms. We study also a functional evaluation of the DNA repair mechanisms by the cell capacity to recognize and repair double helix breaks with a recently introduced test that is very sensitive to detect the phosphorylation of histone H2AX. An in vitro study is ongoing with flow cytometry and immunofluorescence techniques to evaluate in different tumor cell lines the phosphorylation level of histone H2AX in relation to the distribution of the cells in the different phases of the cell cycle and the cytotoxic effect induced after treatment with ET-743. Studies are in progress on the mechanism of action of new ET-743 derivates compounds that have shown antitumoral activity on cell lines with different DNA repair mechanisms. A new project is the study of the selective action of ET-743 on mixoid lyposarcoma, a pathology representing 10% of all soft tissue sarcomas, trying to understand if the significative antitumor effect is due to a selective action of the compound on pathogenetic alterations characteristic of this pathology. In particular we are trying to evaluate how ET-743 interact with the transcriptional modifications of specific genes due to the translocation FUS-CHOP that characterizes mixoid sarcomas or those caused by the interaction host-tumor, modifying inflammatory and angiogenetic processes. Studies are in progress to obtain cell lines and xenografts of mixoid lyposarcomas exhibiting the same molecular features of the patients’ tumors. Combinations of natural products of marine origin with other anticancer drugs We have observed additive or synergistic activity of ET-743 combined with other anticancer drugs such as cisplatin, doxorubicin, campthotecin and inhibitors of telomerase. Flow Cytometric analysis of the DNA content in human ovarian cancer: clinical correlations Conflicting results have been published on the prognostic significance of DNA aneuploidy on advanced ovary carcinoma (stage III or IV). The Citometry unit has reported one of the largest studies of the scientific literature indicating that the aneuploidy in the advanced ovary carcinoma is not an independent prognostic factor. In a large number of cases of stage I and II ovary tumors DNA content and the percentage of cells in S phase of the cell cycle, has been measured with flow cytometry, demonstrating that in the early stages of the disease DNA content is a prognostic factor important for ovary tumor. Analysis of cell cycle data and interactions of different drugs
  29. 29. IRFMN 29 ANNUAL REPORT 2009 The Biophysics Unit is engaged in theoretical and methodological studies aimed at a critical evaluation of current techniques of investigation of drug effects on heterogeneous cell populations. Several computing tools have been produced to simulate the cell proliferation at different levels (from molecular interactions to in vivo growth of solid tumours) and the process of measure. Collaborations are ongoing with other research groups for design and data analysis of drug combination studies in vitro. In this field, a number of computer programs have been developed, allowing comparative data analysis with the most common models of drug interaction. Evaluation of the complexity of the response of cell populations to treatment with anticancer drugs This project of the Biophysics Unit addresses the issue of establishing a connection between the intracellular drug interactions and the resulting cell cycle perturbations. It starts from the single- cell level of investigation to reach the cell-population level where the relevant end points of treatment efficacy are evaluated by flow cytometry and growth inhibition/cytotoxicity assays. The model adopted for data analysis and interpretation is the result of the merging of two mathematical models. One model describes the cell cycle, exploiting the results of the theory of age-structured cell population dynamics. The second model describes the response to the drug's challenge, using distinct parameters ("effect descriptors") measuring either the strength of cell cycle arrest, damage repair or cell death in every phase (G1, S and G2M). In this way, it is possible to reach a quantitative interpretation of the experimental results, overcoming the current qualitative and partial approaches to this problem, which are unable to resolve the overlapping of cytostatic and cytotoxic effects, and to establish a connection with phase-related events. Applying this procedure we demonstrated complex but biologically consistent patterns of time and dose-dependence for each cell cycle effect descriptor, on a reference cell line of ovarian carcinoma, following a short treatment with melphalan, doxorubicin, topotecan, cisplatin and taxol. Within this project we produced a database containing the values associated to the new effect descriptors, related to few compounds but rich of information about them, especially in the dose and time dependence of the effects. This database will be used to compare the treatment response of the most common drugs adopted in the ovarian carcinoma. Cell cycle dYsregulation in erlotinib-based treatments decoded by flow cytometry and mathematical modeling Epidermal growth factor receptor (EGFR) inhibitors represent one of the most promising class of anticancer compounds, some of them, like erlotinib, are already used for clinical therapy. Nevertheless, so far, the research has focused on molecular interaction of these compounds, somewhat neglecting the study of the dynamics of cell cycle perturbations and underscoring the importance of this issue for the optimization of both single and multidrug therapies. In order to fill this gap, the Biophysics Unit will apply the multidisciplinary approach, exploiting cell cycle simulation tools, to the study of cell cycle perturbations induced by erlotinib as a representative EGFR inhibitor. Studies of the time- and dose-dependence of perturbations induced by treatments are ongoing for single erlotinib treatment or for erlotinib combined with gemcitabine, irinotecan and oxaliplatin. The appreciation and the quantification of these effects will provide an important contribution to the comprehension of the mode of action of erlotinib alone or in combination. Such perspectives are vital if the events are to be decoded and used in predictive models for the exploration of pharmacodynamic actions and in understanding the origins of treatment failure. Anticancer Drug Effects Decoded by Time-Lapse Imaging, Flow Cytometry and Modeling
  30. 30. IRFMN 30 ANNUAL REPORT 2009 We aim to use flow cytometric (cell-population based analysis) and time-lapse imaging (single cell lineage based analysis) techniques to generate data that will be used to predict drug responses in term of the two major determinant of cytostatic/cytotoxic actions of anticancer drugs: specific cell cycle perturbations (detecting accumulation or depletion of cells in G1, S and G2M phases) and the commitment to cell death (apoptosis). The working hypothesis is that quantitative analysis of time-lapse microscopy data could be integrated with the information provided by flow cytometry - allowing for the first time a joint interpretation of both kind of experiments through a common mathematical model that simulate the underlying phenomena. The final goal is to provide new levels of understanding and simulation tools to the cancer research community. Timing the changes of the cellular content of specific proteins inside G1, in exponentially growing cells We developed a method for measuring the content of immunocytochemically detected proteins in individual cells progressing through G1 phase. The feasibility was demonstrated in the analysis of cyclin E levels. The sequence of G1 events is tracked in unaltered cycling conditions, in a cell line in the phase of balanced growth in vitro, to avoid the pitfalls of synchronization. The method is based on i) a bromodeoxyuridine (BrdUrd) pulse-and-chase experimental plan; ii) triparametric flow cytometric detection of DNA, BrdUrd and cyclin E; iii) data analysis supported by the basic mathematical theory of asynchronous growing populations with variable cell cycle phase durations. Pharmacokinetic of new taxane derivates We have performed a study on a new taxane derivative, chemically and biologically different from the conventional ones. For two of this compound, IDN6140, we evaluated the pharmacokinetic profile applying analytical methods based on HPLC/MS/MS technique developed in the Cancer Clinical Pharmacology Unit. It showed high ability to cross the blood brain barrier, high distribution in brain and biological activity even in tumors with low susceptibility to other taxanes (cerebral tumor), suggesting a potential clinical interest- for the therapy of Central Nervous System tumors and metastasis. Clinical pharmacology of CEP-18770 (a new proteasome inhibitor) The study in collaboration with SENDO, was performed in 40 patients defining the pharmacokinetic and the pharmacodynamic profiles of the new proteasoma inhibitor, CEP- 18770, in patients enrolld in the phase I clinical study. This study evidencied for this compound a very long plasma half-life assuring a prolonged drug espostion. Pharmacokinetic/pharmacodynamic correlations showed in the patients studied a significative inhibition of the proteasome activity. Quality assurance program During this last year we started a project aimed to achieve a quality system to bring the Pharmacokinetic Unit inside the Laboratory of Cancer Pharmacology in compliance with Good Laboratory Practice (GLP). On this purpose, as first step, we organized spaces and tools to develop this process starting from the preparation of the standard operating procedures and with the training of the personnel involved.

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