VUmc Cancer Center Amsterdam / VUmc Institute for Cancer & Immunology CCA/V-ICI

Transcription

1 VUmc Cancer Center Amsterdam / VUmc Institute for Cancer & Immunology CCA/V-ICI Annual Report 2008

2 Address VUmc Cancer Center Amsterdam / VUmc Institute for Cancer & Immunology (CCA/V-ICI) VU University Medical Center CCA 3.36 De Boelelaan HV Amsterdam The Netherlands phone: (31) v-ici@vumc.nl website : 1

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4 Contents 1. Introduction 5 2. Organization of CCA/V-ICI Research programs & running projects 3.1 Program 1: Oncogenesis Program 2: Immunopathogenesis Program 3: Disease profiling Program 4: Therapy Input and output data 4.1 Scientific staff Publications Oncogenesis Immunopathogenesis Disease profiling Therapy Evaluation of input and output data Summary of input data Summary of output data Input/ Output correlation Training and Education 5.1. Training and Education Graduate profile for medical students Masters for biomedical students PhD student program CCA/V-ICI evening lectures Scientific committee (CWO) 6.1 CWO: Clinical protocols CWO: Research projects / grant proposals CWO-DEC: Animal related protocols Indicators of esteem 7.1 (Inter)national collaboration Memberships of editorial boards (Inter)national functions Lectures Awards Grants obtained in

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6 Chapter 1: Introduction 1. Introduction CCA/V-ICI is one of the 5 research institutes of the VU University Medical Center. CCA/V-ICI was created to integrate all research efforts in oncology and immunology in such a way that they strengthen themselves to reach well-defined, interconnected goals. Furthermore, CCA/V-ICI aims to create new facilities for fundamental and clinical research, both in terms of laboratory facilities, and technical equipment, and will stimulate cooperation. CCA/V-ICI CCA/V-ICI is positioned horizontally in the structure of the VUMC, thus interfacing with the different divisions of clinical and pre-clinical departments. The CCA/V-ICI organization is built around the top researchers in oncology and immunology in the VUMC. They are the members of the executive board, advising the management board that heads the institute. A detailed description of the organization of CCA/V-ICI, together with the organization scheme is given in chapter 2. The mission of CCA/V-ICI The mission of CCA/V-ICI is to coordinate, stimulate and facilitate: - top level fundamental, translational and patient related research in immunology and cancer, within the framework of a defined number of research themes - top level multidisciplinary patient care - creation of excellent facilities for research and patient care - training of (young) investigators to ensure excellent fundamental and clinical researchers - optimal training of health care workers. To this end the tasks of CCA/V-ICI are: - development of long-term policy - attuning the institutional policy and the policies of the participating (heads of) departments - facilitation and coordination of oncology and immunology research - quality control and stimulation of research by stimulating cross interfaces between departments, research groups and clusters - organization of courses, national and international seminars, entrance examinations, publications, conferences and all that is necessary in this frame work - facilitation of multidisciplinary patient care and early diagnosis - quality control and stimulation of support systems for clinical research - training of health care workers - coordination of the funding of programs. - training, supervision and assessment of graduate students in research The programs of CCA/V-ICI The research projects in CCA/V-ICI are grouped in programs headed by three to five program leaders who are responsible for the organization, the coordination and the quality of the program. The program leaders constitute the Executive Board (EB) of CCA/V-ICI that reports to the director and vice-director(s) of CCA/V-ICI. A long-term policy is developed for the programs, covering the need for personnel and materials, their budgets and their development. An indication is also given as to the focus on research lines. These long-term plans constitute the basis of the long-term policy of CCA/V-ICI. Research projects are evaluated by the program leaders on their (intrinsic) qualities and also on their potential to strengthen the program as a whole. The Scientific Research Committee (CWO) is responsible for the scientific input on protocols and research projects, which guarantees high quality standard. The programs stimulate their mutual coherence in the joined organization of monthly research evenings for all CCA/V-ICI participants. The programs have been chosen in order to enable optimal interaction between fundamental and clinical research (translation). 5

7 Chapter 1: Introduction The programs are: 1. Oncogenesis - Viral oncogenesis - Cancer genomics - Genetic predisposition 2. Immunopathogenesis - Homeostasis control - Inflammation - Host-pathogen interaction - Tumor immunology and pre-clinical immune therapy 3. Disease profiling - Solid tumors - Hematological malignancies - Immunological diseases 4. Therapy - Chemotherapy - Immune therapy - Radiotherapy and surgery - Gene therapy - Quality of life In the programs the focus is on specified types of oncological and immunological malignancies for which bench to bedside expertise is present in a substantial group of fundamental and clinical researchers. The specific types of oncological and immunological malignancies are: - Head and neck cancer - Lung cancer - Colorectal cancer - Hematological malignancies - Hereditary tumors - Brain tumor - Cervical cancer - Prostate cancer - Oesophagus cancer Immunological diseases: - Rheumatoid arthritis - Inflammatory Bowel Disease - Coeliac Disease The aims and perspectives of the programs as well as the projects they include, are described in chapter 3. In chapter 4 all the input and output data of the programs are summarized. CCA/V-ICI future plans CCA/V-ICI aims to take and hold a leading position in fundamental and patient related research in cancer and immunology and to improve curative and palliative patient care and to be an attractive partner for external partners. In particular CCA/V-ICI will focus on: Virus-induced oncogenesis and the role of cancer genes in frequently occurring sporadic and inherited tumors Development of cell based immunotherapy against cancer and new immunosuppressive methods in immunological diseases Classification of diseases and disease monitoring by molecular imaging, genomics and proteomics Introduction and evaluation of new therapeutic modalities, combining immunotherapeutical approaches, DNA technology and improving existing therapy methods Translational research: what benefit will the aforementioned focus points bring for the patients. Through the concerted efforts of the programs with help by frequent program meetings and the monthly organised evening lectures these aims are well within reach of CCA/V-ICI. 6

8 Chapter 1: Introduction Careful selection of new projects, together with personnel, will be the main instrument to reinforce the research programs in the future. Training and education Performing high quality research and patient care is an important goal of CCA/V-ICI. To this end, it is essential to train and to pass on knowledge to students, (young) researchers, technicians as well as to clinicians and care professionals. This educational path includes lectures, workshops, tutorials, practical training and clinical demonstrations. See chapter 5 for more details. To ensure highly qualified professionals in the future, it is essential to provide a well defined educational program starting already at medical and biomedical undergraduate students. CCA/V-ICI is involved in a high number of theoretical and practical courses during the bachelor as well as master phase. Furthermore, a high number of training positions are available at our laboratories. For medical students CCA/V-ICI organizes both an Oncology and an Immunology graduation profile. Furthermore, for the top medical students CCA/V-ICI is providing a Honours Program in Oncology and Immunology. In the General Master Biomedical Sciences CCA/V-ICI organizes the differentiation Immunology. For biomedical students a specific TOP-Master Oncology is available, which is aimed at the training of students for a research function in an oncological research institute. PhD students follow various theoretical and practical courses, most of them organized by the graduate schools in which CCA/V-ICI participate, such as the Oncology Graduate School Amsterdam (Oncologie onderzoeksschool Amsterdam -OOA) and Amsterdam Leiden Institute for Immunology (ALIFI). Monthly CCA/V-ICI lectures are organized in which the program/project leaders of the 4 research programs of CCA/V-ICI are actively involved. These lectures are aimed at achieving more integration of the research performed in the 4 different research programs and for education purposes for researchers in CCA/V-ICI. Postgraduate Education for (care) professionals is organized by the individual departments involved in CCA/V-ICI. In the future these and new activities will be organized together with CCA/V-ICI. Overview 2008 In 2008 a total of 90 clinical protocols were evaluated, with specific attention to the quality and feasibility of the proposed protocol, and 90 of them were approved. In addition, the Scientific Research Committee (CWO) evaluated a total of 40 research projects/grant proposals in A list of these protocols and projects can be found in chapter 6. This year the Chris Meijer Award, a yearly award given by CCA/V-ICI, for PhD students with a specific scientific achievement. was obtained by Lot de Witte. More information about awards can be found in chapter 7. All publications are listed in chapter 4. Below, the 5 key publications per program are listed (x /y): after publications, x: quartile score (1-5), y: impact factor of journal Program 1 1. Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 2008; 8(5): (5 / 29.19) 2. van Zeeburg HJ, Snijders PJF, Wu T, Gluckman E, Soulier J, Surralles J, Castella M, van der Wal JE, Wennerberg J, Califano J, Velleuer E, Dietrich R, Ebell W, Bloemena E, Joenje H, Leemans CR, Brakenhoff RH. Clinical and Molecular Characteristics of Squamous Cell Carcinomas From Fanconi Anemia Patients. J Natl Cancer Inst 2008; 100(22): IF = Meijer CJLM, Berkhof J, Heideman DAM, Snijders PJF. Cervical cancer prevention: who should receive vaccination?. Nat Clin Pract Oncol 2008; 5(1): (5 / 8.217) 4. Ameziane N, Errami A, Leveille F, Fontaine C, de Vries Y, van Spaendonk RM, de Winter JP, Pals G, Joenje H. Genetic subtyping of Fanconi anemia by comprehensive mutation screening. Hum Mutat 2008; 29(1): (4 / 6.273) 5. Overmeer RM, Henken FE, Snijders PJF, Claassen-Kramer D, Berkhof J, Helmerhorst TJ, Heideman DAM, Wilting SM, Murakami Y, Ito A, Meijer CJLM, Steenbergen RDM. Association between dense CADM1 promoter methylation and reduced protein expression in high-grade CIN and cervical SCC. J Pathol 2008; 215(4): (5 / 5.423) 7

9 Chapter 1: Introduction Program 2 1. de Jong MAWP, de Witte L, Oudhoff MJ, Gringhuis SI, Gallay P, Geijtenbeek TBH. TNF-alpha and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo, J Clin Invest 2008; 118(10): (5 / ) 2. Olivier BJ, Schoenmaker T, Mebius RE, Everts V, Mulder CJJ, van Nieuwkerk KM, de Vries TJ, van der Merwe SW. Increased osteoclast formation and activity by peripheral blood mononuclear cells in chronic liver disease patients with osteopenia, Hepatology 2008; 47(1): (5 / ) 3. Bij GJ van der, Oosterling SJ. Bogels M, Bhoelan F, Fluitsma DM. Beelen RHJ, Meijer S, Egmond M van. Blocking alpha2 integrins on rat CC531a colon carcinoma cells prevent operation-induced augmentation of liver metastasis outgrowth. Hepatology 2008; 47(2): (5 / ) 4. Konstantinov SR, Smidt H, de Vos WM, Bruijns SC, Singh SK, Valence F, Molle D, Lortal S, Altermann E, Klaenhammer TR, van Kooyk Y. S layer protein A of Lactobacillus acidophilus NCFM regulates immature dendritic cell and T cell functions, Proc Natl Acad Sci U S A 2008; 105(49): (5 / 9.598) 5. de Witte L, de Vries RD, van d, V, Yuksel S, Litjens M, de Swart RL, Geijtenbeek TBH. DC-SIGN and CD150 have distinct roles in transmission of measles virus from dendritic cells to T- lymphocytes, PLoS Pathog 2008; 4(4): e (5 / 9.336) Program 3 1. van de Loosdrecht AA, Westers TM, Westra AH, Drager AM, van der Velden V, Ossenkoppele GJ. Identification of distinct prognostic subgroups in low- and intermediate-1-risk myelodysplastic syndromes by flow cytometry. Blood 2008; 111(3): (5 / ) 2. van der Laken CJ, Elzinga EH, Kropholler MA, Molthoff CFM, van der Heijden JW, Maruyama K, Boellaard R, Dijkmans BAC, Lammertsma AA, Voskuyl AE. Noninvasive imaging of macrophages in rheumatoid synovitis using (11)C-(R)-PK11195 and positron emission tomography. Arthritis Rheum 2008; 58(11): (5 / 7.677) 3. Verbeek WHM, von Blomberg BME, Scholten PE, Kuik DJ, Mulder CJJ, Schreurs MW. The presence of small intestinal intraepithelial gamma/delta T-lymphocytes is inversely correlated with lymphoma development in refractory celiac disease. Am J Gastroenterol 2008; 103(12): (5 / 6.101) 4. de Langen AJ, Lubberink M, Boellaard R, Spreeuwenberg MD, Smit EF, Hoekstra OS, Lammertsma AA. Reproducibility of Tumor Perfusion Measurements Using 15O-Labeled Water and PET. J Nucl Med 2008; 49(11): (5 / 5.915) 5. van Galen JC, Hoefnagel JJ, Vermeer MH, Willemze R, Dijkman R, Tensen CP, de Boer WP, Meijer CJLM, Oudejans JJ. Profiling of apoptosis genes identifies distinct types of primary cutaneous large B cell lymphoma. J Pathol 2008; 215(3): (5 / 5.423) Program 4 1. Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S. Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2008; 70: ( 5 / 4.29) 2. Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I, Berkers CR, Scheffer GL, Debipersad K, Vojtekova K, Lemos C, van der Heijden JW, Ylstra B, Peters GJ, Kaspers GJL, Dijkmans BAC, Scheper RJ, Jansen G. Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 2008; 112(6): ( 5 / ) 3. Cillessen SAGM, Reed JC, Welsh K, Pinilla C, Houghten R, Hooijberg E, Deurhof J, Castricum KC, Kortman P, Hess CJ, Ossenkoppele GJ, Meijer CJLM, Oudejans JJ. Small-molecule XIAP antagonist restores caspase-9 mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells. Blood 2008; 111(1): ( 5 / ) 4. de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Verpoort KN, Schreuder GM, Ewals JA, Terwiel JP, Ronday HK, Kerstens PJ, Toes RE, de Vries RR, Breedveld FC, Dijkmans BAC, Huizinga TW, Allaart CF. Progression of joint damage in early rheumatoid arthritis: association with HLA- DRB1, rheumatoid factor, and anti-citrullinated protein antibodies in relation to different treatment strategies. Arthritis Rheum 2008; 58(5): ( 5 / 7.677) 5. Vellenga E, van Putten WL, van 't Veer MB, Zijlstra JM, Fibbe WE, van Oers MH, Verdonck LF, Wijermans PW, van Imhoff GW, Lugtenburg PJ, Huijgens PC. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood 2008; 111(2): ( 5 / ) 8

10 Chapter 1: Introduction In 2008 several grants were obtained from various origin. Among industries several foundations like EU, Nederlandse Brandwonden Stichting, NWO, CCA, CRMM, KIKA, KWF and ZonMw grants were obtained. In chapter 7 all indicators of esteem are given, like national and international collaborations and functions, memberships of editorial boards, grants and awards obtained and lectures that were given. 9

11 Chapter 1: Introduction 10

12 Chapter 2: Organization of CCA/V-ICI 2. Organization of CCA/V-ICI Board VUmc Executive Board 1. Oncogenesis Management Board CCA/V-ICI Plenary Meeting 2. Immunopathogenesis Internal Advisory Board 3. Disease profiling External Advisory Board 4. Therapy Scientific Research Committee Translational Management & Care Workgroup Committee for Education & Training Management Board Management Board (MB) members: - Prof. P.C. Huijgens, MD, PhD, director of V-ICI - Prof. W.R. Gerritsen, MD, PhD, director of CCA - Prof. G. Kraal, PhD, deputy director of V-ICI - Prof. C.R. Leemans, MD, PhD, chairman of the internal advisory Board The two directors mutually replace each other, in chairing the MB. The deputy director of V-ICI replaces the director of V-ICI in and externally. The director of CCA coordinates the efforts for improvement of multidisciplinary cancer patient care and is responsible for the communication with the CCA fundraising institutions. The tasks of the director of V-ICI are described in the Management Regulation of the VUmc. The MB meets every week. Management support: - Y.M. Duiker (junior board assistant) - G.K. Kuipers, PhD (senior board assistant) - E.M. Ruhé-Hoogervorst, PhD (senior board assistant) Executive Board The Executive Board of CCA/V-ICI consists of the program leaders. The EB meet every 2 months together with the MB, chaired by one of the MB directors. The EB advises the MB about: - research projects - long-term policy with respect to personnel and materials - first money stream graduate students - allocation of equipment for research of > patient care projects - clinical and translational research 11

13 Chapter 2: Organization of CCA?V-ICI - education - fundraising for cancer research, care and education - early diagnostics - all matters concerning CCA/V-ICI whether on request or not. The complete EB convenes regularly to discuss the long term policy of CCA/V-ICI. Executive Board (EB) members: Program 1: Oncogenesis: - Prof. R.H. Brakenhoff, PhD - Prof. H. Joenje, PhD - Prof. P.J.F. Snijders, PhD Program 2: Immunopathogenesis: - Prof. R.H.J. Beelen, PhD - E. Hooijberg, PhD - Prof. Y. van Kooyk, PhD - Prof. R. Mebius, PhD Program 3: Disease profiling: - Prof. G.A.M.S. van Dongen, PhD - Prof. O.S. Hoekstra, MD, PhD - C. Jimenez, PhD - Prof. C.L. Verweij, PhD Program 4: Therapy: - Prof. B.A.C. Dijkmans, MD, PhD - Prof. G.J. Ossenkoppele, MD, PhD - Prof. G.J. Peters, PhD - Prof. S. Senan, MD, PhD - Prof. H.M.W. Verheul, MD, PhD Plenary meeting CCA/V-ICI The heads of the departments participating in CCA/V-ICI and other persons involved meet once a year during the Plenary Meeting. This meeting advises the Management Board whether on request or not about all matters concerning CCA/V-ICI. Fixed agenda points are: - long-term policy of CCA/V-ICI - annual report - Management Board policy and Executive Board policy. Heads of departments involved in CCA/V-ICI: - Prof. M.A. Blankenstein, PhD - Clinical chemistry - Prof. P.T. Cohen-Kettenis, PhD - Medical Psychology - Prof. S.A. Danner, MD, PhD Internal medicine - Prof. B.A.C. Dijkmans, MD, PhD - Rheumatology - Prof. C.D. Dijkstra, MD, PhD - Molecular Celbiology and Immunology - Prof. H.P. van Geijn, MD, PhD - Obstetrics and Gynaecology - Prof. J.J. Heimans, MD, PhD - Neurology - Prof. P.C. Huijgens, MD, PhD Hematology - Prof. A.A. Lammertsma, MD, PhD - Nuclear Medicine - Prof. C.R. Leemans, MD, PhD Otolaryngology/Head and Neck Surgery - Prof. C. van Kuijk, MD, PhD - Radiology - Prof. S. Loer, MD, PhD - Anesthesiology - Prof. C.J.L.M. Meijer, MD, PhD Pathology - Prof. C.J.L.M. Meijer, a.i., MD, PhD - Surgery - Prof. E.J. Meijers-Heijboer, PhD - Clinical genetics - R.J.A. van Moorselaar, MD, PhD - Urology - Prof. C.J.J. Mulder, MD, PhD Gastro-enterology and hepatology - Prof. P.E. Postmus, MD, PhD - Pulmonology - Prof. P.J. Ringens, MD, PhD Ophthalmonoly 12

14 Chapter 2: Organization of CCA/V-ICI - Prof. J.J. Roord, MD, PhD - Paediatrics - B.J. van Royen (a.i.), MD, PhD - Orthopaedics - Prof. B.J. Slotman, MD, PhD - Radiotherapy - Prof. Th.M. Starink, MD, PhD - Dermatology - Prof. C.M.J.E. Vandenbroucke-Grauls, PhD - Medical Microbiology and Infection control - Prof. W.P. Vandertop, MD, PhD - Neurosurgery - Prof. H. Verheul, MD, PhD - Medical Oncology - Prof. I. van der Waal, MD, PhD - Oral and Maxillofacial Surgery and Pathology Internal Advisory Board: The members of the internal advisory board consist of 5 to 10 heads of departments involved in cancer and immunology within the VUMC. The chairman is member of the MB. The board meets 4 times a year. Internal Advisory Board members: - Prof. C.R. Leemans, MD, PhD (Chair) - Prof. M.A. Blankenstein, PhD - Prof. B.A.C. Dijkmans, MD, PhD - Prof. C.D. Dijkstra, MD. PhD - Prof. J.J. Heimans, MD, PhD - Prof. C.J.L.M. Meijer, MD, PhD - Prof. H. Meijers, MD, PhD - Prof. C.J.J. Mulder, MD, PhD - Prof. P.E. Postmus, MD, PhD - Prof. B.J. Slotman, MD, PhD - Prof. H.M.W. Verheul, MD, PhD External Advisory Board: The members of the external advisory board consist of two VUMC staff members outside CCA/V-ICI, two external experts in Oncology, one external expert in Immunology and three delegates proposed by the main CCA sponsors. The members of the Advisory Board are appointed by the VUMC Board of Directors. The Board of Directors selects the members upon recommendation of the Management Board (MB) of CCA/V-ICI. The advisory board advises CCA/V-ICI about its strategic policy. The advisory board meets at least every 6 months. External Advisory Board members: - J.W.M. Brenninkmeijer (Chairman Stichting Translationele Research (CCA) - Prof. H. Brug, PhD (Director Institute for Research in Extramural Medicine (EMGO, VUmc)) - J.B.A.G. Haanen, MD, PhD (Medical Oncology, NKI) - Prof. V.W.M van Hinsbergh, PhD (Director Institute for Cardiovascular Research (IcaRVU, VUMC)) - Ir. G.J. Kleisterlee (Chairman Stichting CCA (CCA)) - Prof. Ph. Lambin, PhD (GROW research institute, University Maastricht) - Prof. R.A.W. van Lier, PhD (Experimental Immunology AMC) - K. Storm (Member Stichting Translationele Research and Stichting CCA (CCA)) Scientific Research Committee (CWO) The CWO is divided into a section that advises merely animal related protocols and a section that advises patient related protocols and other project proposals. The CWO advises about the research policy and about the feasibility of new research projects upon request of the MB. The CWO advises the MB specifically about the quality and the feasibility of all research proposals that need permission of the ethical committees for patient related or animal related research before they can be realized. Research proposals made on behalf of (inter)nationally recognized joint ventures (EORTC, HOVON, SIOP, SKION) and multi-center studies in which the VUMC is not the main judging committee, are judged only marginally on local feasibility. 13

15 Chapter 2: Organization of CCA?V-ICI The CWO also advises on other research proposals for which judgment by the CWO is desired. The CWO gives asked and unasked advice to the MB about the quality of research within CCA/V-ICI. The CWO section for patient related protocols meets twice a month, the CWO section for animal related protocols meets once a month. The VUMC Management Regulations stipulate that the CCA/V-ICI CWO section for patients related protocols is composed of 5 to 9 members. In view of the institute s size and in order to have sufficient expertise in the different research fields, the CWO has been extended to a maximum of 15 members. Scientific Research Committee (CWO) members - Section for patient related protocols: - A.A. van der Loosdrecht, MD, PhD (chair) - A.A. van Bodegraven, MD, PhD - B.J.M. Braakhuis, PhD - A.J.M. van den Eertwegh, MD, PhD - M. van Egmond, PhD - T. Geijtenbeek, PhD - N.H. Hendrikse, PhD - G.K. Kuipers, PhD (secretary) - F.B.J.M. Thunnissen, MD, PhD - A.E. Voskuyl, MD, PhD - Q. Waisfisz, PhD Scientific Research Committee (CWO) members - Section for animal related protocols: - Prof. R. Scheper, PhD (chair) - B.J. Appelmelk, PhD - V. van Beusechem, PhD - Prof. G. Kraal, PhD - G.K. Kuipers, PhD (secretary) Translational Management & Care Workgroup This workgroup covers the clinical implementation of research activities within CCA/V-ICI. Research within programs 1-4 have their focus on laboratory research and/or take place mainly within one department. Large-scale research projects, involving more than one department will be covered by this workgroup. This workgroup aims to improve the communication between clinical care and fundamental research and to facilitate translational research. Workgroup leader: - Prof. W.R. Gerritsen, MD, PhD (Medical Oncology) Committee for Education & Training This committee supervises and advices about all training and education activities within CCA/V-ICI. The graduate training is organized within the Oncology Graduate School Amsterdam (OOA) and the Leiden Amsterdam Institute for Immunology (ALIFI). More in detail, by means of subgroups, this committee organizes and advises about training in the framework of the: - oncology profile - immunology profile - masters education in oncology - masters education in immunology - graduate students education - postgraduate education - SMBWO (Foundation for the Training of Biomedical Scientists) - NVVI (Dutch Society for Immunology) - all other types of education within CCA/V-ICI. Each of these subgroups is composed of the main teachers within the education involved. The committee gives asked and unasked advice about the quality and quality maintenance of education within CCA/V-ICI. The committee meets at least six times a year. 14

16 Chapter 2: Organization of CCA/V-ICI Members of the Committee for Education & Training: - Prof. C.R Leemans (chair), MD, PhD - Prof. R.H.J. Beelen, PhD - Prof. dr. G.A. Meijer, MD, PhD - R.A. Puras, PhD - E.M. Ruhé-Hoogervorst (secretary), PhD Subgroups: Oncology profile committee members: - B.J.M. Braakhuis, MD, PhD - Prof. E. Boven, MD, PhD - A.A. van de Loosdrecht, MD, PhD - Prof. G.A. Meijer, MD, PhD - E.M. Ruhé-Hoogervorst, PhD (profile coordinator ) Immunology profile committee members: - B.J. Appelmelk, PhD - M. van Agtmael, PhD - B.M.E. von Blomberg, PhD - I.E.M. Bultink, PhD - I.M.U van Hoogstraten, PhD - G.K. Kuipers, PhD (profile coordinator) - M.W.J. Schreurs, PhD Master Oncology: - Prof. G.A. Meijer, MD, PhD, director - R.A. Puras, PhD, coordinator Education committee: - Prof. P.J.F. Snijders PhD, chairman - Prof. R.H.A. Beelen, PhD, advisor - Prof. G.J. Peters, PhD, advisor - Prof. R.J. Scheper, PhD, advisor - N. van den Berg, student master Oncology, member - Muggen, student master Oncology, member - Verly, student master Oncology, member - N. Vlieland, student master Oncology, member Examination committee: - Prof. G.J. Peters, PhD, chairman - Prof. R.H.L. Beelen, PhD, vice-chairman - Prof. R.J. Scheper, MD, PhD, member - R.A. Puras, PhD, secretary Coordinator of the Master Immunology - Prof. Y. van Kooyk, PhD Board of examiners Biomedical Science FALW (including differentiation master immunology) - Prof. R.H.J. Beelen, PhD, chairman - B.M. Bakker, PhD - P. de Boer, PhD, secretary - L van den Grint, PhD - C. Zonneveld, PhD, vice-chairman 15

17 Chapter 2: Organization of CCA?V-ICI Directorate OOA (Oncology Graduate School Amsterdam) - Prof. G.A. Meijer, MD, PhD, chairman (VUmc) - Prof. J.P. Medema, PhD (AMC) - E.M. Ruhé-Hoogervorst, PhD, secretary (VUmc) - Prof. T. Sixma, PhD (NKI) ALIFI PhD committee (Amsterdam Leiden Institute For Immunology) - Prof. R.A.W. van Lier, PhD (AMC) - Prof. R.E. Mebius, PhD (VUmc-CCA/V-ICI) - Prof. H. Schuitemaker, PhD (Sanquin) 16

18 Chapter 3: Research programs & running projects 3. Research programs & running projects The research in the four CCA/V-ICI programs: 1. Oncogenesis, 2. Immunopathogenesis, 3. Disease profiling and 4. Therapy is described in the next paragraphs. For every CCA/V-ICI research program a summary is given of the current research lines and perspectives for the future are presented. In addition an overview of the ongoing projects is displayed Program 1: Oncogenesis Program leaders: - Prof. R.H. Brakenhoff, PhD (Otolaryngology/Head-Neck Surgery) - Prof. H. Joenje, PhD (Clinical Genetics) - Prof. P.J.F. Snijders, PhD (Pathology) Program 1 covers both basic and translational research and is divided into three sub-themes: 1. Viral oncogenesis 2. Cancer genomics 3. Genetic predisposition A major common objective of the research brought together in this program is to identify and characterize viral and non-viral cancer genes as well as genes responsible for inherited cancer predisposition. Their roles in oncogenic pathways are evaluated in models and clinical material. In addition, molecular markers are sought that may be utilized for a) screening for cancer and precancerous lesions, b) risk assessment of precancerous lesions, and c) cancer prevention. To this end an integrated bench to bedside approach is followed encompassing: 1) marker identification and clinical validation, 2) test development, validation and up-scaling by robotics, 3) risk group identification, 4) cost-effectiveness modelling, and 5) public acceptance studies. Screening studies are running for oral precancer, colorectal cancer and cervical cancer, in various risk groups, and often in the context of population-based screening trials. 1. Viral oncogenesis This subtheme focuses on the role of human papillomaviruses (HPVs) and Epstein Barr virus (EBV) in the development of human cancers, such as anogenital cancers, head and neck cancers, and lymphomas. Virus-induced oncogenic progression is investigated using both in vitro models and clinically well-defined patient material, and the genes involved in this process are identified and characterized. Viral and host markers are already being tested in screening and clinical trials for their capability to assess the risk of premalignant disease with an increased sensitivity and specificity compared to currently existing methods, and newly identified markers will be investigated likewise. 2. Cancer genomics Aimed at testing progression models for several human cancers, such as head and neck, lung, gastrointestinal, cervical and ovarian cancers, this subtheme uses well-characterized cohorts of patients and state-of-the art high-throughput methods for genetic, epigenetic, transcriptome and proteome analyses. Candidate cancer genes are identified, placed in their respective cancer pathways, and tested for their oncogenic capacity with the aid of in vitro models. Promising progression markers are evaluated in clinical studies. 3. Genetic predisposition In this subtheme understanding the molecular mechanisms of genome destabilization, as related to the occurrence of cancer, both familial and sporadic is studied. Attention is currently focusing on Fanconi anemia (FA), for which the pathway is being unravelled (13 FA genes known to date) and mouse models are being developed. It is recognized that a subset of sporadic cancers may possess a cellular FA phenotype, which might be exploited through targeted therapeutic intervention. The possibility to sensitize (resistant) tumor cells by inhibition of the FA/BRCA pathway will also be explored. Recently the genetic predisposition to breast/ovarian and colorectal cancer has come into focus and will be developed during the years to come. A strong aspect of the research brought together in this program is that patient-oriented research is complemented by unique model systems allowing to dissect the carcinogenic process in the laboratory. These model systems include: HPV-transformed cultured keratinocytes mimicking cervical carcinogenesis (Pathology), conditionally immortalized oral keratinocytes allowing 17

19 Chapter 3: Research programs & running projects unraveling of the carcinogenic cascade mimicking head and neck carcinogenesis (ORL/HNS), and transgenic animals to study the role of genomic instability in the origin of cancer (Clinical Genetics). Research highlights Program 1 within period Establishment that implementation of HPV testing in regular cervical screening leads to earlier detection of cervical (pre)cancerous lesions, permitting extension of the screening interval. 2. Demonstration that offering self-sampling of cervico-vaginal specimens for HPV testing to nonattendees of regular cervical screening is an effective instrument to increase the coverage of the screening program. 3. Collection of evidence that high-grade cervical premalignant lesions can be subdivided into potentially early and advanced lesions on the basis of their chromosomal profiles and that HPV positive women with clinically relevant cervical lesions can be recognised by hypermethylation of certain tumor suppressor genes. 4. Development of a novel test algorithm for archival formalin fixed paraffin-embedded specimens to assess HPV involvement and establishment of the role of HPV in penile and head and neck cancer, the latter both in sporadic patient groups as in genetically predisposed Fanconi anemia patients. 5. Development of a non-invasive high-througput molecular screening test for oral precancer. 6. Classification of head and neck cancers into in least three prognostically relevant groups: those with transcriptionally active HPV, those with many genetic changes, and those without apparent changes and a normal DNA index. 7. Generation of a unique in vitro model for head and neck cancer using conditionally immortalized oral keratinocytes that will pay off the coming years. 8. Identification of five novel Fanconi anemia genes: FANCB (responsible for an X-linked form of FA), BRIP1/FANCJ (encoding a BRCA1-interacting helicase), FANCM/Hef (encoding a DNA gyrase), PALB2/FANCN (a stabilizer of BRCA2), and FANCI (encoding a binding partner of FANCD2). 9. Identification of ESCO2 as the gene defective in Roberts syndrome, a neighboring syndrome characterized by a specific type of chromosomal instability. The latter two discoveries have yielded valuable pieces to the puzzle of the FA/BRCA pathway of genomic maintenance. 10. Identification of biomarkers for stool based and serum based colorectal cancer screening The activities of program 1 can further be inferred from the extra impuls by a large Center for Translational Molecular Medicine grant with the acronym DECODE to the research line on early detection of colorectal cancer, coordinated by VUmc (prof GA Meijer). A main focus of this 18.5 million euro program will be large scale validation of molecular markers for early detection of colorectal cancer. In addition, within this program large, unique biobanks have been established. These include 200,000 cervical scrape samples from regular screening and triage cohorts, 15,000 brush samples of the oral cavity of various controls groups, Fanconi anemia patients, leukoplakia patients and treated oral cancer patients. We also have collected clinical information as well as tumor biopsies, mucosa biopsies, serum and plasma of over 350 head and neck and 200 lung cancer patients. In addition, 1,000 AFB-guided bronchial biopties of patients at risk of lung cancer, 600 sputum samples of lung cancer and COPD patients as well as 750 faeces samples of colorectal cancer cases and controls have been collected and stored. The total number of genetic subtypes in Fanconi anemia has now grown to 13. However, a unique collection of cell lines and materials from Fanconi anemia families has been accumulated containing a sizable number of unclassifiable cell lines that still wait for their gene defects to be identified. This includes patients with overlapping syndromes such as Seckel syndrome. Perspectives Within the next five years several research aims are defined. These include the establishment of a novel, cost-effective algorithm for primary HPV testing in cervical screening with additional biomarkers added for optimal triage of HPV positive women. We will also have developed (epi)genetic screening assays for colorectal and oral cancer and precancer detection, and gained insight in the cost effectiveness of population-based screening programs in the various risk groups. In addition, we expect that the function of several existing candidate-cancer genes in head and neck, gastrointestinal, lung and cervical cancer will have been elucidated and their impact on human cancer will have been evaluated. We further expect to have detailed progression models 18

20 Chapter 3: Research programs & running projects worked out for head and neck cancer, cervical cancer as well as gastrointestinal cancers, and to have identified novel candidate-cancer genes that play a role in the development of these tumors using a combined approach of functional genetic screens, validation of putative targets by genetic analysis of tumor DNA and testing in models. Novel genes involved in the FA pathway and other chromosome fragility syndromes will have been mapped and/or identified. Mouse models for genome destabilization syndromes will have been generated and the role of FA genes in sporadic human cancers ascertained. Finally, we will have established whether loss of the FA pathway makes cells hypersensitive to inhibition of other biochemical pathways in so called synthetic lethality screens. This information may be applicable to develop new non-genotoxic therapies for sporadic cancers with the FA phenotype. In addition, targeted interference with the FA/BRCA pathway will be explored as a means to sensitize (resistant) tumor cells for chemotherapy. Together, it will be clear that the knowledge of the molecular alterations leading to cancer, as to be gained from this CCA/V-ICI program, will be of vital importance for the development of new measures to successfully prevent and/or treat cancer in the human population. Summary of the research aims for the coming 5 years: 1. Elucidation of specific genomic stabilisation mechanisms and the role of deficiencies in these mechanisms in the occurrence of cancer, both familial and sporadic. Interference with recognized targets will be explored as a means to sensitize tumor cells. This approach includes in vitro model systems as well as animal models. 2. Determination of the role of specific cancer genes in the origin of sporadic tumors. 3. Establishing the exact role of oncogenic viruses in the origin of cancer, in particular HPV and EBV. This includes the identification of viral cancer genes and additional genetic and epigenetic alterations essential for the tumors they induce. The roles of these genetic alterations in oncogenesis will be assessed, both in in vitro models and in the cancer patient. 4. Unraveling the carcinogenic process in squamous cell carcinoma of the upper aerodigestive tract and colorectal cancer, both in in vitro models, and in the cancer patient. This includes the recognition of the cancer genes and mirnas that are most relevant in these tumors, and can be exploited for development of treatment strategies. 5. Detection of new markers to monitor progressive precursor lesions of the cervix, head and neck, colon, lung and ovarium that may develop into carcinoma. 6. Development and improvement of high-throughput molecular diagnostic methods for secondary prevention of cervical (i.e. scrapings), head and neck (i.e. scrapings), colorectal (i.e. faeces), and lung (i.e. sputum) cancer. Collaboration This program is build around the three major departments that participate: Pathology, Otolaryngology/Head-Neck Surgery, and Clinical Genetics. The collaboration not only involves common research interests, but also extends to the organization of the annual master course Oncogenesis. The program leaders meet at least monthly, to make optimal use of opportunities for collaboration, and this has led to a number of important papers. The recent development of an institution for early diagnosis and prevention of cancer (Cancer Center Amsterdam, in collaboration with V-ICI) has added new perspectives on a fruitful collaboration within and amongst the various programs. Especially the establishment of a Familial Cancer Clinic with a separate Laboratory for Clinical Oncogenetics, will stimulate further collaboration within the program. Collaboration has been established with many outstanding groups, including those of the Netherlands Cancer Institute (Prof. R. Bernards, Prof. D. Peeper, Dr. R. Agami, Prof. S. Horenblas, Prof. A. Berns and Prof. H. Te Riele) and the Hubrecht laboratory is expected to pay off in the years to come. Both Profs. Peeper and Te Riele have been appointed to VUmc, and are active participants within CCA/V-ICI. There are also intensive contacts with HPV, EBV and Fanconi anemia support groups all over the worlds. Means Modern technology such as proteomics technology, microarray platforms and functional genetic screens are needed to identify new biomarkers and candidate-cancer genes that may be exploited as reliable risk-predictors for the progression of premalignant lesions, especially in cervix, colon, the head & neck region, and the lung. In addition, biostatistical support is warranted, as well as investment in high-throughput robotics. Mouse models are accessible through Prof Te Riele. 19

21 Chapter 3: Research programs & running projects Ongoing projects program 1 Cervical cancer and HPV: towards improved modalities for screening, diagnosis, and methods of cure 1. Development and clinical validation of a methylation marker set for the triage of hrhpv positive women S. Snellenberg, R.D.M. Steenbergen, D.A.M. Heideman, C.J.L.M. Meijer, P.J.F. Snijders Dept. of Pathology, VU University Medical Center Amsterdam 2. DySIS colposcopic imaging study to assess and map the acetowhitening effects of the cervix J.A. Louwers1, M. Kocken1, A. Zaal1, P.J.F. Snijders1, M. van Baal1, W.A. ter Harmsel2, C.J.L.M. Meijer1, R.H.M. Verheijen3 1) VU University Medical Center, Amsterdam, 2) Reinier de Graaf groep, Delft/Voorburg, 3) University Medical Center Utrecht, Utrecht Forth Photonics, Athens, Greece 3. HPV testing and the long term risk of cervical premalignant disease M. Kocken1, J.A. Louwers1, A. Zaal1, J. Berkhof1 P.J.F. Snijders1, R.H.M. Verheijen2, W.A. ter Harmsel3,Th.J.M Helmerhorst4,C.J.L.M. Meijer1 1) VU University Medical Center, Amsterdam, 2) University Medical Center Utrecht, Utrecht, 3) Reinier de Graaf groep, Delft/Voorburg, 4) Erasmus University Medical Center, Rotterdam HumaVac 4. HPV-015 prophylactic vaccination study J.A. Louwers1, M. Kocken1, A. Zaal, W.A. ter Harmsel2, Th.J.M. Helmerhorst3, C.J.L.M. Meijer1, Wim Quint4, P.J.F. Snijders1, R.H.M. Verheijen5 1) VU University Medical Center, Amsterdam, 2) Reinier de Graaf groep, Delft/Voorburg, 3) ErasmusMC University Medical Center, Rotterdam, 4) DDL Diagnostic Laboratory, Voorburg, 5) Utrecht University Medical Center, Utrecht GlaxoSmithKline Biologicals, Rixensart, Belgium 5. Human papillomavirus infection and cervical cancer: epidemiology and screening D. Rijkaard, D.A.M. Heideman, F.J. van Kemenade, B. Hesselink, L. Rozendaal, H. Berkhof, PJF Snijders, CJLM Meijer Dept. of Pathology, VU University Medical Center, Amsterdam ZON-MW and ; RIVM / Human papillomavirus variant analysis D.A.M. Heideman, PJF Snijders, CJLM Meijer Dept. of Pathology, VU University Medical Center Amsterdam 7. Identification and clinical validation of methylation markers for cervical adenocarcinomas and their precursor lesions W. van der Meide, P.J.F. Snijders, D.A.M. Heideman, C.J.L.M. Meijer, R.D.M. Steenbergen Dept. of Pathology, VU University Medical Center Amsterdam KWF 8. Identification on genetic variation in genes involved in the clearance vs persistence of hrhpv infections S. Ouburg1, C.J.L.M. Meijer1, P.J.F. Snijders1, A.S. Peña1, B. Ylstra, S.A. Morré1 Laboratory of Immunogenetics and Molecular Pathology and Micro-Array facility: Dept Pathology 9. Improvement of cervical screening by offering self-sampling for hrhpv testing to women that do not participate in the regular screening programme M. Gok, D.A.M. Heideman, F. van Kemenade, P.J.F. Snijders, C.J.L.M. Meijer Dept. of Pathology, VU University Medical Center Amsterdam IKA, GGD, SO (PROHTECT) Cervical cancer and HPV: towards improved modalities for screening, diagnosis, and methods of cure 10. Stratifying high-risk HPV positive women for risk of CIN 3 and cervical carcinoma by HPV transcript analysis M. Dijkstra, D.A.M. Heideman, R.H.M. Verheijen, C.J.L.M. Meijer, P.J.F. Snijders Dept. of Pathology, VU University Medical Center, Amsterdam KWF VU Characterization of DNA stability genes and proteins 11. Characterization of DNA stability genes and their role in cancer predisposition S. Agarwal, N. Ameziane, S.T. Bakker, P. vd Lelij, M. Adank, M. Massink, M. Corbin, C. Stoepker, B. Mol, M.A. Rooimans, A.B. Oostra, J. Steltenpool, S. van Mil, Y. Waterham, G. Pals, F. Arwert, E.M. Leter, F.H. Menko, J.C. Dorman, Q. Waisfisz, e.a. Dept. of Clinical Genetics, VU University Medical Center Dutch Cancer Society VU , NKI ; FA Research Fund; NWO; CCA/V-ICI 12. Proteins interacting with FANCI and PALB2 A. Haitjema, J.C. Dorsman, H. Joenje Dept. of Clinical Genetics, VU University Medical Center, Amsterdam FARF 13. Regulation of replication-coupled DNA maintenance S. Agarwal, J.P. de Winter Dept. of Clinical Genetics, VU University Medical Center Amsterdam NWO/A.L.W. 2007/06307/ALW 14. Significance of the Fanconi anemia caretaker pathway in development and treatment of cancer S. Bakker, H. Joenje, H.P.J. te Riele Dept. of Clinical Genetics, VU University Medical Center, Amsterdam KWF The Fanconi anemial/brca pathway in oral squamous cell carcinomas C. Stoepker, J.P. de Winter, H. Joenje Dept. of Clinical Genetics, VU University Medical Center, Amsterdam 20

22 Chapter 3: Research programs & running projects 16. Role of sister chromatid cohesion in the maintenance of genetic stability P. van der Lelij, H. Joenje, J.P. de Winter Dept. of Clinical Genetics and Human Genetics, VU University Medical Center, Amsterdam CCA/V-ICI PV05/05 Prom Detection and treatment of oral preneoplasia 17. Development of virotherapy using retargeted adenoviruses to eradicate preneoplastic lesions of the oral cavity and oropharynx H.J.T. van Zeeburg1, V.W. van Beusechem2, B.J.M. Braakhuis1, R.H. Brakenhoff1 Section Tumor Biology, Dept. of Otolaryngology/Head-Neck Surgery1, Division Gene Therapy Dept. of Medical Oncology2, Vu University Medical Center, Amsterdam KWF Diagnosis and therapy of genetically altered mucosal lesions in the oral cavity and oropharynx J.F. Bremmer2, A. Brink1,2, J.A.M. Belien3, E. Bloemena3, B.J.M. Braakhuis1, C.R. Leemans1, I. van der Waal2, R.H. Brakenhoff1 Depts of 1Otolaryngology/Head-Neck Surgery, 2Oral and Maxillofacial Surgery and 3Pathology, VU University Medical Center ACTA 19. Population-based screening for precursor lesions in the oral cavity R.H. Brakenhoff, C.R. Leemans Dept. Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam CCA 20. Prognostic validation of a non-invasive screening method for early diagnosis of oral precursor lesions in Fanconi Anemia patients T. Wu, R.H. Brakenhoff Dept. of Otolaryngology, Head and Neck Surgery, VU University Center Amsterdam Fanconi-Anämie Hilfe Head and neck cancer predisposition 21. High sensitivity to DNA damage in the aetiology of head and neck squamous cell carcinoma in young adults and individuals not exposed to tobacco smoke and excessive alcohol (SenseDNA) B.J.M. Braakhuis1,, H. Joenje3,, R.H. Brakenhoff1, P. Graveland1,G. Flach G1 1Section Tumor Biol, Dept. of Otolaryngology/Head-Neck Surg, 2Dept. of Pediatric Oncol/Hematol, 3Dept of Clin Gen, VU University Medical Center, Amster dam, and 4Dept. Biomolecular Mass Spectrometry, University Utrecht internal 22. Mutagen sensitivity: clinical relevance and underlying mechanisms B.J.M. Braakhuis1, J. Cloos2, M. Slijper3, R.H. Brakenhoff1 1Section Tumor Biol, Dept. of Otolaryngology/Head-Neck Surg, 2Dept. of Pediatric Oncol/Hematol, 3Dept. Biomolecular Mass Spectrometry, University Utrecht. internal Head and neck carcinogenesis and cancer genes 23. Functional characterization of stem cells and signal transduction pathways in head and neck squamous cell carcinoma S.R. de Kemp, B.J.M. Braakhuis, C.R. Leemans, R.H. Brakenhoff Section Tumor Biology, Dept. of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amster dam CCA/V-ICI 24. Identification of oncogenic micrornas and classical cancer genes involved in head and neck squamous cell carcinoma by a functional genomics approach M. van der Plas, B.J.M. Braakhuis, S.R. de Kemp, S. Smeets, C.R. Leemans, R.H. Brakenhoff Section Tumor Biology, Dept. of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amster dam CCA/V-ICI HPV-mediated carcinogenesis 25. Defining the essential molecular pathways involved in cervical carcinogenesis F.E. Henken, P.J.F. Snijders, D.A.M. Heideman, C.J.L.M. Meijer, R.D.M. Steenbergen Dept. of Pathology, VU University Medical Center, Amsterdam CCA/V-ICI 26. Genetic profiling of CIN 3 lesions diagnosed in the subsequent screening round following screening by HPV testing and cytology M. Bierkens, R.D.M. Steenbergen, D.A.M. Heideman, C.J.L.M. Meijer, P.J.F. Snijders Dept. of Pathology, VU University Medical Center, Amsterdam CCA/V-ICI 27. Profiling of aberrant microrna methylation events that are functionally relevant during cervical carcinogenesis S.W. Wilting, R.D.M. Steenbergen, D.A.M. Heideman, P.J.F. Snijders, C.J.L.M. Meijer Dept. of Pathology, VU University Medical Center, Amsterdam CCA/V-ICI 28. The role of human papilloma virus in non-cervical cancer D.A.M. Heideman, M. Bleeker, C.J.L.M. Meijer, R.D.M. Steenbergen, P.J.F. Snijders Dept. of Pathology, VU University Medical Center, Amsterdam 29. TSLC1 silencing, a marker for risk assessment of cervical cancer R.M. Overmeer, P.J.F. Snijders, D.A.M. Heideman, C.J.L.M. Meijer, R.D.M. Steenbergen Dept. of Pathology, VU University Medical Center, Amsterdam KWF Immunopathogenesis of EBV-associated cancers 30. Immune responses to EBV tumour-associated proteins in nasopharyngeal carcinoma D. Paramita, J.M. Middeldorp Dept. of Pathology, VU University Medical Center, Amsterdam EU Asia-Link ASI B7-301/98/